|
1
|
Niazi V, Parseh B, Ghafouri-Fard S. The role of genetic/epigenetic factors and microenvironment in hematopoietic stem cell ageing. Biogerontology 2025; 26:76. [PMID: 40119993 DOI: 10.1007/s10522-025-10218-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 03/09/2025] [Indexed: 03/25/2025]
Abstract
Hematopoietic stem cells (HSCs) ageing is a phenomenon described by reduction in self-renewal capacity, compromised homing, a bias towards myeloid differentiation, and defective reconstitution function. The molecular mechanisms of HSCs ageing have been investigated by several groups. In a broad classification, the underlying causes can be grouped into the intrinsic factors and those related to the microenvironment. Determination of the exact mechanism of HSCs ageing and detailed molecular events during its initiation and progression will help in the establishment of novel therapies for the treatment or prevention of ageing-related hematopoietic disorders. This review offers an overview of genetic and epigenetic causes of HSCs ageing. The findings of these investigations paved the way for design of novel strategies for rejuvenation of HSCs.
Collapse
Affiliation(s)
- Vahid Niazi
- Stem Cell Research Center, Golestan University of Medical Science, Gorgan, Iran
- School of Advanced Technologies in Medicine, Golestan University of Medical Science, Gorgan, Iran
| | - Benyamin Parseh
- Stem Cell Research Center, Golestan University of Medical Science, Gorgan, Iran
- School of Advanced Technologies in Medicine, Golestan University of Medical Science, Gorgan, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
2
|
Li X, Wang J, Hu L, Cheng T. How age affects human hematopoietic stem and progenitor cells and the strategies to mitigate aging. Exp Hematol 2025; 143:104711. [PMID: 39788412 DOI: 10.1016/j.exphem.2025.104711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 12/29/2024] [Accepted: 12/30/2024] [Indexed: 01/12/2025]
Abstract
Hematopoietic stem cells (HSCs) are central to blood formation and play a pivotal role in hematopoietic and systemic aging. With aging, HSCs undergo significant functional changes, such as an increased stem cell pool, declined homing and reconstitution capacity, and skewed differentiation toward myeloid and megakaryocyte/platelet progenitors. These phenotypic alterations are likely due to the expansion of certain clones, known as clonal hematopoiesis (CH), which leads to disrupted hematopoietic homeostasis, including anemia, impaired immunity, higher risks of hematological malignancies, and even associations with cardiovascular disease, highlighting the broader impact of HSC aging on overall health. HSC aging is driven by a range of mechanisms involving both intrinsic and extrinsic factors, such as DNA damage accumulation, epigenetic remodeling, inflammaging and metabolic regulation. In this review, we summarize the updated understanding of age-related changes in hematopoietic stem and progenitor cells (HSPCs) and the mechanisms underlying the aging process in mammalian models, especially in human study. Additionally, we provide insights into potential therapeutic strategies to counteract aging process and enhance HSC regenerative capacity, which will support therapeutic interventions and promote healthy aging.
Collapse
Affiliation(s)
- Xueling Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin, China
| | - Jianwei Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin, China
| | - Linping Hu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin, China.
| | - Tao Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin, China.
| |
Collapse
|
|
3
|
Fang S, Jiang M, Jiao J, Zhao H, Liu D, Gao D, Wang T, Yang Z, Yuan H. Unraveling the ROS-Inflammation-Immune Balance: A New Perspective on Aging and Disease. Aging Dis 2025:AD.2024.1253. [PMID: 39812539 DOI: 10.14336/ad.2024.1253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 01/03/2025] [Indexed: 01/16/2025] Open
Abstract
Increased entropy is a common cause of disease and aging. Lifespan entropy is the overall increase in disorder caused by a person over their lifetime. Aging leads to the excessive production of reactive oxygen species (ROS), which damage the antioxidant system and disrupt redox balance. Organ aging causes chronic inflammation, disrupting the balance of proinflammatory and anti-inflammatory factors. Inflammaging, which is a chronic low-grade inflammatory state, is activated by oxidative stress and can lead to immune system senescence. During this process, entropy increases significantly as the body transitions from a state of low order to high disorder. However, the connection among inflammation, aging, and immune system activity is still not fully understood. This review introduces the idea of the ROS-inflammation-immune balance for the first time and suggests that this balance may be connected to aging and the development of age-related diseases. We also explored how the balance of these three factors controls and affects age-related diseases. Moreover, imbalance in the relationship described above disrupts the regular structures of cells and alters their functions, leading to cellular damage and the emergence of a disorganized state marked by increased entropy. Maintaining a low entropy state is crucial for preventing and reversing aging processes. Consequently, we examined the current preclinical evidence for antiaging medications that target this balance. Ultimately, comprehending the intricate relationships between these three factors and the risk of age-related diseases in organisms will aid in the development of clinical interventions that promote long-term health.
Collapse
Affiliation(s)
- Sihang Fang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Mingjun Jiang
- Respiratory Department, Beijing Children's Hospital, Capital Medical University, China National Clinical Research Center of Respiratory Diseases, National Center for Children's Health, Beijing, China
| | - Juan Jiao
- Department of Clinical Laboratory, the Seventh Medical Center of PLA General Hospital, Beijing, China
| | - Hongye Zhao
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Dizhi Liu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Danni Gao
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Tenger Wang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Ze Yang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Huiping Yuan
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| |
Collapse
|
|
4
|
Kim MS, Kim TH. Anti-Aging Tests for Middle Aged Women. J Menopausal Med 2024; 30:164-169. [PMID: 39829193 PMCID: PMC11745732 DOI: 10.6118/jmm.24012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 09/06/2024] [Accepted: 10/19/2024] [Indexed: 01/22/2025] Open
Abstract
The interest in aging and anti-aging research has increased significantly in recent years, leading to rapid expansion in the anti-aging market. Aging is associated with gradual physiological changes and an elevated risk of age-related ailments, and is divided into three categories: usual aging, successful aging, and pathological aging. Each category is associated with distinct implications for health and well-being. Middle-aged women who experience accelerated physiological changes that are intensified by hormonal changes during menopause are particularly vulnerable to chronic diseases. The importance of anti-aging tests is increasing since they enable early identification and intervention. Telomere length, oxidative stress markers, DNA repair markers, RNA profiles, inflammatory markers, hormone levels, and epigenetic changes are some molecular parameters studied to test for aging. In addition, a thorough review of middle-aged women's anti-aging profiles also includes monitoring the vitamin D levels and assessing the effects of endocrine-disrupting substances on ovarian aging. The application of personalized medicine paradigms, utilizing various diagnostic methods, will enable accurate risk prediction and the implementation of focused therapies, ultimately promoting the extension of health span and the improvement of quality of life in middle-aged women.
Collapse
Affiliation(s)
- Min-Sun Kim
- Department of Laboratory Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Tae-Hee Kim
- Department of Obstetrics and Gynecology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea.
| |
Collapse
|
|
5
|
Kushinsky S, Puccetti MV, Adams CM, Shkundina I, James N, Mahon BM, Michener P, Eischen CM. DNA fork remodeling proteins, Zranb3 and Smarcal1, are uniquely essential for aging hematopoiesis. Aging Cell 2024; 23:e14281. [PMID: 39044358 PMCID: PMC11561652 DOI: 10.1111/acel.14281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/25/2024] [Accepted: 07/01/2024] [Indexed: 07/25/2024] Open
Abstract
Over a lifetime, hematopoietic stem and progenitor cells (HSPCs) are forced to repeatedly proliferate to maintain hematopoiesis, increasing their susceptibility to DNA damaging replication stress. However, the proteins that mitigate this stress, protect HSPC replication, and prevent aging-driven dysregulation are unknown. We report two evolutionarily conserved, ubiquitously expressed chromatin remodeling enzymes with similar DNA replication fork reversal biochemical functions, Zranb3 and Smarcal1, have surprisingly specialized roles in distinct HSPC populations. While both proteins actively mitigate replication stress and prevent DNA damage and breaks during lifelong hematopoiesis, the loss of either resulted in distinct biochemical and biological consequences. Notably, defective long-term HSC function, revealed with bone marrow transplantation, caused hematopoiesis abnormalities in young mice lacking Zranb3. Aging significantly worsened these hematopoiesis defects in Zranb3-deficient mice, including accelerating the onset of myeloid-biased hematopoietic dysregulation to early in life. Such Zranb3-deficient HSPC abnormalities with age were driven by accumulated DNA damage and replication stress. Conversely, Smarcal1 loss primarily negatively affected progenitor cell functions that were exacerbated with aging, resulting in a lymphoid bias. Simultaneous loss of both Zranb3 and Smarcal1 compounded HSPC defects. Additionally, HSPC DNA replication fork dynamics had unanticipated HSPC type and age plasticity that depended on the stress and Zranb3 and/or Smarcal1. Our data reveal both Zranb3 and Smarcal1 have essential HSPC cell intrinsic functions in lifelong hematopoiesis that protect HSPCs from replication stress and DNA damage in unexpected, unique ways.
Collapse
Affiliation(s)
- Saul Kushinsky
- Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaPennsylvaniaUSA
| | - Matthew V. Puccetti
- Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaPennsylvaniaUSA
- Department of NeurologyBrigham and Women's Hospital, Harvard Medical SchoolBostonMassachusettsUSA
| | - Clare M. Adams
- Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaPennsylvaniaUSA
| | - Irina Shkundina
- Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaPennsylvaniaUSA
| | - Nikkole James
- Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaPennsylvaniaUSA
| | - Brittany M. Mahon
- Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaPennsylvaniaUSA
| | - Peter Michener
- Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaPennsylvaniaUSA
| | - Christine M. Eischen
- Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaPennsylvaniaUSA
| |
Collapse
|
|
6
|
Ajoolabady A, Pratico D, Tang D, Zhou S, Franceschi C, Ren J. Immunosenescence and inflammaging: Mechanisms and role in diseases. Ageing Res Rev 2024; 101:102540. [PMID: 39395575 DOI: 10.1016/j.arr.2024.102540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 10/02/2024] [Accepted: 10/03/2024] [Indexed: 10/14/2024]
Abstract
Age-related changes initiate a cascade of cellular and molecular alterations that lead to immune system dysfunction or abnormal activation, predisposing individuals to age-related diseases. This phenomenon, commonly referred to as immunosenescence, highlighting aging-associated progressive decline of the immune system. Moreover, mounting evidence suggests that immunosenescence contributes to a related pathological phenomenon known as inflammaging. Inflammaging refers to chronic, low-grade, and systemic inflammation associated with aging, occurring despite the absence of overt stimuli. In the body, inflammation is typically activated in response to overt stimuli such as bacterial/microbial invasion or a pathological state, however, inflammaging occurrence and its underpinning mechanisms seem to be independent and in the absence of such stimuli. Despite recent advancements in molecular characterization and the scrutiny of disease relevance, these two interconnected concepts have remained largely unexplored and unrecognized. In this comprehensive review, we aim to shed light on the mechanistic and cellular aspects of immunosenescence and inflammaging, as well as their pivotal roles in the pathogenesis of aging-related diseases, including cancer, infections, dementia, and neurodegenerative disorders.
Collapse
Affiliation(s)
- Amir Ajoolabady
- Department of Biomedical Engineering, University of Alabama at Birmingham, AL 35294, USA
| | - Domenico Pratico
- Alzheimer's Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Shuqin Zhou
- Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai 200072, China
| | - Claudio Franceschi
- IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy; Department of Applied Mathematics and Laboratory of Systems Biology of Aging, Lobachevsky University, Nizhny Novgorod, Russia.
| | - Jun Ren
- Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
| |
Collapse
|
|
7
|
Watanuki S, Kobayashi H, Sugiura Y, Yamamoto M, Karigane D, Shiroshita K, Sorimachi Y, Morikawa T, Fujita S, Shide K, Haraguchi M, Tamaki S, Mikawa T, Kondoh H, Nakano H, Sumiyama K, Nagamatsu G, Goda N, Okamoto S, Nakamura-Ishizu A, Shimoda K, Suematsu M, Suda T, Takubo K. SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production. Cell Stem Cell 2024; 31:1145-1161.e15. [PMID: 38772377 DOI: 10.1016/j.stem.2024.04.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 02/20/2024] [Accepted: 04/30/2024] [Indexed: 05/23/2024]
Abstract
Aging generally predisposes stem cells to functional decline, impairing tissue homeostasis. Here, we report that hematopoietic stem cells (HSCs) acquire metabolic resilience that promotes cell survival. High-resolution real-time ATP analysis with glucose tracing and metabolic flux analysis revealed that old HSCs reprogram their metabolism to activate the pentose phosphate pathway (PPP), becoming more resistant to oxidative stress and less dependent on glycolytic ATP production at steady state. As a result, old HSCs can survive without glycolysis, adapting to the physiological cytokine environment in bone marrow. Mechanistically, old HSCs enhance mitochondrial complex II metabolism during stress to promote ATP production. Furthermore, increased succinate dehydrogenase assembly factor 1 (SDHAF1) in old HSCs, induced by physiological low-concentration thrombopoietin (TPO) exposure, enables rapid mitochondrial ATP production upon metabolic stress, thereby improving survival. This study provides insight into the acquisition of resilience through metabolic reprogramming in old HSCs and its molecular basis to ameliorate age-related hematopoietic abnormalities.
Collapse
Affiliation(s)
- Shintaro Watanuki
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hiroshi Kobayashi
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Department of Cell Fate Biology and Stem Cell Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
| | - Yuki Sugiura
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
| | - Masamichi Yamamoto
- Department of Research Promotion and Management, National Cerebral and Cardiovascular Center, Osaka 564-8565, Japan
| | - Daiki Karigane
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Kohei Shiroshita
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yuriko Sorimachi
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo 162-8480, Japan
| | - Takayuki Morikawa
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Shinya Fujita
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Kotaro Shide
- Division of Hematology, Diabetes, and Endocrinology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan
| | - Miho Haraguchi
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Shinpei Tamaki
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Takumi Mikawa
- Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Hiroshi Kondoh
- Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Hiroyasu Nakano
- Department of Biochemistry, Toho University School of Medicine, Tokyo 143-8540, Japan
| | - Kenta Sumiyama
- Laboratory of Animal Genetics and Breeding, Department of Animal Sciences, Graduate School of Bioagricultural Sciences, Nagoya University, Aichi 464-8601, Japan; RIKEN Center for Biosystems Dynamics Research, Laboratory for Mouse Genetic Engineering, Osaka 565-0871, Japan
| | - Go Nagamatsu
- Center for Advanced Assisted Reproductive Technologies, University of Yamanashi, Kofu 400-8501, Japan
| | - Nobuhito Goda
- Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo 162-8480, Japan
| | - Shinichiro Okamoto
- Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Ayako Nakamura-Ishizu
- Department of Microscopic and Developmental Anatomy, Tokyo Women's Medical University, Tokyo 162-8666, Japan
| | - Kazuya Shimoda
- Division of Hematology, Diabetes, and Endocrinology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan
| | - Makoto Suematsu
- Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Live Imaging Center, Central Institute for Experimental Medicine and Life Science, Kawasaki 210-0821, Japan
| | - Toshio Suda
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; International Research Center for Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
| | - Keiyo Takubo
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Department of Cell Fate Biology and Stem Cell Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
| |
Collapse
|
|
8
|
Tolstykh EI, Vozilova AV, Akleyev AV, Zalyapin VI. Model of age-dependent dynamics and biokinetics of T-cells as natural biodosimeters. RADIATION AND ENVIRONMENTAL BIOPHYSICS 2024; 63:405-421. [PMID: 38829435 DOI: 10.1007/s00411-024-01072-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 04/25/2024] [Indexed: 06/05/2024]
Abstract
Circulating T-lymphocytes are used as "natural biodosimeters" for estimating radiation doses, since the frequency of chromosomal aberrations induced in them is proportional to the accumulated dose. Moreover, stable chromosomal aberrations (translocations) are detected years and decades after exposure. Internal incorporation of radionuclides often leads to non-uniform exposure, which resulted in difficulties in the application of retrospective biodosimetry using T-lymphocytes. Some properties of T-lymphocytes complicate retrospective biodosimetry in this case: (1) the thymic production of T-cells depends significantly on age, the maximum is observed in early childhood; (2) the "lymphocyte-dosimeter" accumulates changes (translocations) while circulating through the body. The objective of this paper is to describe the technical characteristics of the model of age dynamics and T-cell biokinetics and approaches to assessing the dose to circulating lymphocytes under various exposure scenarios. The model allows to quantify the fractions of T-lymphocytes that were formed before and after exposure. The model takes into account the time fractions that circulating lymphocytes spend in various lymphoid organs. Age-related thymic involution was also considered. The model predicts that after internal exposure to 90Sr, the doses to T-lymphocytes can differ significantly from the doses to the bone marrow and other tissues. For uniform external γ-exposure, and for internal exposure due to non-bone -seeking radionuclides (for example, 144Ce), predicted doses to T-lymphocytes are very close to bone marrow doses. The model allows to quantify the correction factors for FISH-based doses to obtain doses to organs and tissues.
Collapse
Affiliation(s)
- Evgenia I Tolstykh
- Urals Research Center for Radiation Medicine, 68-A, Vorovsky Street, Chelyabinsk, 454076, Russia.
| | - Alexandra V Vozilova
- Urals Research Center for Radiation Medicine, 68-A, Vorovsky Street, Chelyabinsk, 454076, Russia
| | - Alexander V Akleyev
- Urals Research Center for Radiation Medicine, 68-A, Vorovsky Street, Chelyabinsk, 454076, Russia
- Department of Radiation Biology, Chelyabinsk State University, Chelyabinsk, Russia
| | - Vladimir I Zalyapin
- Mathematical Analysis Department, South Ural State University, Chelyabinsk, Russia
| |
Collapse
|
|
9
|
Abbasizadeh N, Burns CS, Verrinder R, Ghazali F, Seyedhassantehrani N, Spencer JA. Age and dose dependent changes to the bone and bone marrow microenvironment after cytotoxic conditioning with busulfan. Front Cell Dev Biol 2024; 12:1441381. [PMID: 39139448 PMCID: PMC11319712 DOI: 10.3389/fcell.2024.1441381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 07/09/2024] [Indexed: 08/15/2024] Open
Abstract
Preparative regimens before Hematopoietic Cell Transplantation (HCT) damage the bone marrow (BM) microenvironment, potentially leading to secondary morbidity and even mortality. The precise effects of cytotoxic preconditioning on bone and BM remodeling, regeneration, and subsequent hematopoietic recovery over time remain unclear. Moreover, the influence of recipient age and cytotoxic dose have not been fully described. In this study, we longitudinally investigated bone and BM remodeling after busulfan treatment with low intensity (LI) and high intensity (HI) regimens as a function of animal age. As expected, higher donor chimerism was observed in young mice in both LI and HI regimens compared to adult mice. Noticeably in adult mice, significant engraftment was only observed in the HI group. The integrity of the blood-bone marrow barrier in calvarial BM blood vessels was lost after busulfan treatment in the young mice and remained altered even 6 weeks after HCT. In adult mice, the severity of vascular leakage appeared to be dose-dependent, being more pronounced in HI compared to LI recipients. Interestingly, no noticeable change in blood flow velocity was observed following busulfan treatment. Ex vivo imaging of the long bones revealed a reduction in the frequency and an increase in the diameter and density of the blood vessels shortly after treatment, a phenomenon that largely recovered in young mice but persisted in older mice after 6 weeks. Furthermore, analysis of bone remodeling indicated a significant alteration in bone turnover at 6 weeks compared to earlier timepoints in both young and adult mice. Overall, our results reveal new aspects of bone and BM remodeling, as well as hematopoietic recovery, which is dependent on the cytotoxic dose and recipient age.
Collapse
Affiliation(s)
- Nastaran Abbasizadeh
- Department of Bioengineering, University of California, Merced, Merced, CA, United States
- Center for Cellular and Biomolecular Machines, University of California, Merced, Merced, CA, United States
| | - Christian S. Burns
- Department of Bioengineering, University of California, Merced, Merced, CA, United States
- Center for Cellular and Biomolecular Machines, University of California, Merced, Merced, CA, United States
| | - Ruth Verrinder
- Department of Bioengineering, University of California, Merced, Merced, CA, United States
- Center for Cellular and Biomolecular Machines, University of California, Merced, Merced, CA, United States
| | - Farhad Ghazali
- Department of Bioengineering, University of California, Merced, Merced, CA, United States
| | - Negar Seyedhassantehrani
- Department of Bioengineering, University of California, Merced, Merced, CA, United States
- Center for Cellular and Biomolecular Machines, University of California, Merced, Merced, CA, United States
| | - Joel A. Spencer
- Department of Bioengineering, University of California, Merced, Merced, CA, United States
- Center for Cellular and Biomolecular Machines, University of California, Merced, Merced, CA, United States
- Health Sciences Research Institute, University of California, Merced, Merced, CA, United States
| |
Collapse
|
|
10
|
Manohar S, Neurohr GE. Too big not to fail: emerging evidence for size-induced senescence. FEBS J 2024; 291:2291-2305. [PMID: 37986656 DOI: 10.1111/febs.16983] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 10/02/2023] [Accepted: 10/17/2023] [Indexed: 11/22/2023]
Abstract
Cellular senescence refers to a permanent and stable state of cell cycle exit. This process plays an important role in many cellular functions, including tumor suppression. It was first noted that senescence is associated with increased cell size in the early 1960s; however, how this contributes to permanent cell cycle exit was poorly understood until recently. In this review, we discuss new findings that identify increased cell size as not only a consequence but also a cause of permanent cell cycle exit. We highlight recent insights into how increased cell size alters normal cellular physiology and creates homeostatic imbalances that contribute to senescence induction. Finally, we focus on the potential clinical implications of these findings in the context of cell cycle arrest-causing cancer therapeutics and speculate on how tumor cell size changes may impact outcomes in patients treated with these drugs.
Collapse
Affiliation(s)
- Sandhya Manohar
- Department of Biology, Institute for Biochemistry, ETH Zürich, Switzerland
| | - Gabriel E Neurohr
- Department of Biology, Institute for Biochemistry, ETH Zürich, Switzerland
| |
Collapse
|
|
11
|
Park JC, Kim YJ, Hwang GH, Kang CY, Bae S, Cha HJ. Enhancing genome editing in hPSCs through dual inhibition of DNA damage response and repair pathways. Nat Commun 2024; 15:4002. [PMID: 38734692 PMCID: PMC11088699 DOI: 10.1038/s41467-024-48111-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 04/22/2024] [Indexed: 05/13/2024] Open
Abstract
Precise genome editing is crucial for establishing isogenic human disease models and ex vivo stem cell therapy from the patient-derived hPSCs. Unlike Cas9-mediated knock-in, cytosine base editor and prime editor achieve the desirable gene correction without inducing DNA double strand breaks. However, hPSCs possess highly active DNA repair pathways and are particularly susceptible to p53-dependent cell death. These unique characteristics impede the efficiency of gene editing in hPSCs. Here, we demonstrate that dual inhibition of p53-mediated cell death and distinct activation of the DNA damage repair system upon DNA damage by cytosine base editor or prime editor additively enhanced editing efficiency in hPSCs. The BE4stem system comprised of p53DD, a dominant negative p53, and three UNG inhibitor, engineered to specifically diminish base excision repair, improves cytosine base editor efficiency in hPSCs. Addition of dominant negative MLH1 to inhibit mismatch repair activity and p53DD in the conventional prime editor system also significantly enhances prime editor efficiency in hPSCs. Thus, combined inhibition of the distinct cellular cascades engaged in hPSCs upon gene editing could significantly enhance precise genome editing in these cells.
Collapse
Affiliation(s)
- Ju-Chan Park
- College of Pharmacy, Seoul National University, Seoul, Republic of Korea
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Yun-Jeong Kim
- College of Pharmacy, Seoul National University, Seoul, Republic of Korea
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Gue-Ho Hwang
- Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Chan Young Kang
- Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sangsu Bae
- Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyuk-Jin Cha
- College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
| |
Collapse
|
|
12
|
Smith JT, Noren Hooten N, Mode NA, Zonderman AB, Ezike N, Kaushal S, Evans MK. Frailty, sex, and poverty are associated with DNA damage and repair in frail, middle-aged urban adults. DNA Repair (Amst) 2023; 129:103530. [PMID: 37437502 PMCID: PMC10807508 DOI: 10.1016/j.dnarep.2023.103530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 04/17/2023] [Accepted: 06/27/2023] [Indexed: 07/14/2023]
Abstract
Frailty is an age-related syndrome characterized by reduced recovery from stressors and increased risks of morbidity and mortality. Although frailty is usually studied in those over 65 years, our previous work showed that frailty is both present and a risk factor for premature mortality in midlife. We identified altered gene expression patterns and biological pathways associated with inflammation in frailty. Evidence suggests DNA oxidation damage related to inflammation accumulates with age, and that DNA repair capacity (DRC) declines with age and age-related conditions. We hypothesized that inter-individual differences in DNA oxidation damage and DRC are associated with frailty status and poverty level. Using the CometChip assay, we assessed baseline single-strand breaks and hydrogen peroxide (H2O2)-induced DNA oxidation damage and DRC in non-frail and frail middle-aged African American and White individuals with household incomes above and below poverty. Analysis of baseline single-strand breaks showed no associations with frailty, poverty, race, or sex. However, we identified an interaction between frailty and poverty in H2O2-induced DNA oxidation damage. We also identified interactions between sex and frailty as well as sex and poverty status with DRC. The social determinant of health, poverty, associates with DRC in men. Baseline DNA damage, H2O2-induced DNA damage as well as DRC were associated with serum cytokine levels. IL-10 levels were inversely associated with baseline DNA damage as well as H2O2-induced DNA damage, DRC was altered by IL-4 levels and sex, and by TNF-α levels in the context of sex and poverty status. This is the first evidence that DRC may be influenced by poverty status at midlife. Our data show that social determinants of health should be considered in examining biological pathways through which disparate age-related health outcomes become manifest.
Collapse
Affiliation(s)
- Jessica T Smith
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States
| | - Nicole Noren Hooten
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States
| | - Nicolle A Mode
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States
| | - Alan B Zonderman
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States
| | - Ngozi Ezike
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States
| | - Simran Kaushal
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States
| | - Michele K Evans
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States.
| |
Collapse
|
|
13
|
Wang M, Brandt LTL, Wang X, Russell H, Mitchell E, Kamimae-Lanning AN, Brown JM, Dingler FA, Garaycoechea JI, Isobe T, Kinston SJ, Gu M, Vassiliou GS, Wilson NK, Göttgens B, Patel KJ. Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner. Mol Cell 2023; 83:2417-2433.e7. [PMID: 37348497 PMCID: PMC7614878 DOI: 10.1016/j.molcel.2023.05.035] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 04/18/2023] [Accepted: 05/25/2023] [Indexed: 06/24/2023]
Abstract
Aged hematopoietic stem cells (HSCs) display diminished self-renewal and a myeloid differentiation bias. However, the drivers and mechanisms that underpin this fundamental switch are not understood. HSCs produce genotoxic formaldehyde that requires protection by the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. We find that the HSCs in young Aldh2-/-Fancd2-/- mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition, and myeloid-biased differentiation quantified by single HSC transplantation. In addition, the p53 response is vigorously activated in Aldh2-/-Fancd2-/- HSCs, while p53 deletion rescued this aged HSC phenotype. To further define the origins of the myeloid differentiation bias, we use a GFP genetic reporter to find a striking enrichment of Vwf+ myeloid and megakaryocyte-lineage-biased HSCs. These results indicate that metabolism-derived formaldehyde-DNA damage stimulates the p53 response in HSCs to drive accelerated aging.
Collapse
Affiliation(s)
- Meng Wang
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK.
| | - Laura T L Brandt
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK
| | - Xiaonan Wang
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK; School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Holly Russell
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Emily Mitchell
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK; Wellcome Sanger Institute, Hinxton, UK
| | - Ashley N Kamimae-Lanning
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Jill M Brown
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Felix A Dingler
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Juan I Garaycoechea
- Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center, Utrecht, the Netherlands
| | - Tomoya Isobe
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Sarah J Kinston
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Muxin Gu
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - George S Vassiliou
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Nicola K Wilson
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Berthold Göttgens
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Ketan J Patel
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
| |
Collapse
|
|
14
|
Abstract
The process of aging manifests from a highly interconnected network of biological cascades resulting in the degradation and breakdown of every living organism over time. This natural development increases risk for numerous diseases and can be debilitating. Academic and industrial investigators have long sought to impede, or potentially reverse, aging in the hopes of alleviating clinical burden, restoring functionality, and promoting longevity. Despite widespread investigation, identifying impactful therapeutics has been hindered by narrow experimental validation and the lack of rigorous study design. In this review, we explore the current understanding of the biological mechanisms of aging and how this understanding both informs and limits interpreting data from experimental models based on these mechanisms. We also discuss select therapeutic strategies that have yielded promising data in these model systems with potential clinical translation. Lastly, we propose a unifying approach needed to rigorously vet current and future therapeutics and guide evaluation toward efficacious therapies.
Collapse
Affiliation(s)
- Robert S Rosen
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA;
| | - Martin L Yarmush
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA;
| |
Collapse
|
|
15
|
Yang F, Nourse C, Helgason GV, Kirschner K. Unraveling Heterogeneity in the Aging Hematopoietic Stem Cell Compartment: An Insight From Single-cell Approaches. Hemasphere 2023; 7:e895. [PMID: 37304939 PMCID: PMC10256339 DOI: 10.1097/hs9.0000000000000895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 04/18/2023] [Indexed: 06/13/2023] Open
Abstract
Specific cell types and, therefore, organs respond differently during aging. This is also true for the hematopoietic system, where it has been demonstrated that hematopoietic stem cells alter a variety of features, such as their metabolism, and accumulate DNA damage, which can lead to clonal outgrowth over time. In addition, profound changes in the bone marrow microenvironment upon aging lead to senescence in certain cell types such as mesenchymal stem cells and result in increased inflammation. This heterogeneity makes it difficult to pinpoint the molecular drivers of organismal aging gained from bulk approaches, such as RNA sequencing. A better understanding of the heterogeneity underlying the aging process in the hematopoietic compartment is, therefore, needed. With the advances of single-cell technologies in recent years, it is now possible to address fundamental questions of aging. In this review, we discuss how single-cell approaches can and indeed are already being used to understand changes observed during aging in the hematopoietic compartment. We will touch on established and novel methods for flow cytometric detection, single-cell culture approaches, and single-cell omics.
Collapse
Affiliation(s)
- Fei Yang
- School of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
| | - Craig Nourse
- School of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
| | - G. Vignir Helgason
- School of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom
| | - Kristina Kirschner
- School of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
| |
Collapse
|
|
16
|
Ferrari S, Valeri E, Conti A, Scala S, Aprile A, Di Micco R, Kajaste-Rudnitski A, Montini E, Ferrari G, Aiuti A, Naldini L. Genetic engineering meets hematopoietic stem cell biology for next-generation gene therapy. Cell Stem Cell 2023; 30:549-570. [PMID: 37146580 DOI: 10.1016/j.stem.2023.04.014] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/31/2023] [Accepted: 04/12/2023] [Indexed: 05/07/2023]
Abstract
The growing clinical success of hematopoietic stem/progenitor cell (HSPC) gene therapy (GT) relies on the development of viral vectors as portable "Trojan horses" for safe and efficient gene transfer. The recent advent of novel technologies enabling site-specific gene editing is broadening the scope and means of GT, paving the way to more precise genetic engineering and expanding the spectrum of diseases amenable to HSPC-GT. Here, we provide an overview of state-of-the-art and prospective developments of the HSPC-GT field, highlighting how advances in biological characterization and manipulation of HSPCs will enable the design of the next generation of these transforming therapeutics.
Collapse
Affiliation(s)
- Samuele Ferrari
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Erika Valeri
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Anastasia Conti
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Serena Scala
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Annamaria Aprile
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Raffaella Di Micco
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Anna Kajaste-Rudnitski
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Eugenio Montini
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Giuliana Ferrari
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy; Vita-Salute San Raffaele University, Milan 20132, Italy
| | - Alessandro Aiuti
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy; Vita-Salute San Raffaele University, Milan 20132, Italy
| | - Luigi Naldini
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy; Vita-Salute San Raffaele University, Milan 20132, Italy.
| |
Collapse
|
|
17
|
Bao H, Cao J, Chen M, Chen M, Chen W, Chen X, Chen Y, Chen Y, Chen Y, Chen Z, Chhetri JK, Ding Y, Feng J, Guo J, Guo M, He C, Jia Y, Jiang H, Jing Y, Li D, Li J, Li J, Liang Q, Liang R, Liu F, Liu X, Liu Z, Luo OJ, Lv J, Ma J, Mao K, Nie J, Qiao X, Sun X, Tang X, Wang J, Wang Q, Wang S, Wang X, Wang Y, Wang Y, Wu R, Xia K, Xiao FH, Xu L, Xu Y, Yan H, Yang L, Yang R, Yang Y, Ying Y, Zhang L, Zhang W, Zhang W, Zhang X, Zhang Z, Zhou M, Zhou R, Zhu Q, Zhu Z, Cao F, Cao Z, Chan P, Chen C, Chen G, Chen HZ, Chen J, Ci W, Ding BS, Ding Q, Gao F, Han JDJ, Huang K, Ju Z, Kong QP, Li J, Li J, Li X, Liu B, Liu F, Liu L, Liu Q, Liu Q, Liu X, Liu Y, Luo X, Ma S, Ma X, Mao Z, Nie J, Peng Y, Qu J, Ren J, Ren R, Song M, Songyang Z, Sun YE, Sun Y, Tian M, Wang S, et alBao H, Cao J, Chen M, Chen M, Chen W, Chen X, Chen Y, Chen Y, Chen Y, Chen Z, Chhetri JK, Ding Y, Feng J, Guo J, Guo M, He C, Jia Y, Jiang H, Jing Y, Li D, Li J, Li J, Liang Q, Liang R, Liu F, Liu X, Liu Z, Luo OJ, Lv J, Ma J, Mao K, Nie J, Qiao X, Sun X, Tang X, Wang J, Wang Q, Wang S, Wang X, Wang Y, Wang Y, Wu R, Xia K, Xiao FH, Xu L, Xu Y, Yan H, Yang L, Yang R, Yang Y, Ying Y, Zhang L, Zhang W, Zhang W, Zhang X, Zhang Z, Zhou M, Zhou R, Zhu Q, Zhu Z, Cao F, Cao Z, Chan P, Chen C, Chen G, Chen HZ, Chen J, Ci W, Ding BS, Ding Q, Gao F, Han JDJ, Huang K, Ju Z, Kong QP, Li J, Li J, Li X, Liu B, Liu F, Liu L, Liu Q, Liu Q, Liu X, Liu Y, Luo X, Ma S, Ma X, Mao Z, Nie J, Peng Y, Qu J, Ren J, Ren R, Song M, Songyang Z, Sun YE, Sun Y, Tian M, Wang S, Wang S, Wang X, Wang X, Wang YJ, Wang Y, Wong CCL, Xiang AP, Xiao Y, Xie Z, Xu D, Ye J, Yue R, Zhang C, Zhang H, Zhang L, Zhang W, Zhang Y, Zhang YW, Zhang Z, Zhao T, Zhao Y, Zhu D, Zou W, Pei G, Liu GH. Biomarkers of aging. SCIENCE CHINA. LIFE SCIENCES 2023; 66:893-1066. [PMID: 37076725 PMCID: PMC10115486 DOI: 10.1007/s11427-023-2305-0] [Show More Authors] [Citation(s) in RCA: 167] [Impact Index Per Article: 83.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 02/27/2023] [Indexed: 04/21/2023]
Abstract
Aging biomarkers are a combination of biological parameters to (i) assess age-related changes, (ii) track the physiological aging process, and (iii) predict the transition into a pathological status. Although a broad spectrum of aging biomarkers has been developed, their potential uses and limitations remain poorly characterized. An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research: How old are we? Why do we get old? And how can we age slower? This review aims to address this need. Here, we summarize our current knowledge of biomarkers developed for cellular, organ, and organismal levels of aging, comprising six pillars: physiological characteristics, medical imaging, histological features, cellular alterations, molecular changes, and secretory factors. To fulfill all these requisites, we propose that aging biomarkers should qualify for being specific, systemic, and clinically relevant.
Collapse
Affiliation(s)
- Hainan Bao
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
| | - Jiani Cao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Mengting Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Min Chen
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Clinical Research Center of Metabolic and Cardiovascular Disease, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Wei Chen
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Xiao Chen
- Department of Nuclear Medicine, Daping Hospital, Third Military Medical University, Chongqing, 400042, China
| | - Yanhao Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yu Chen
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Yutian Chen
- The Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Zhiyang Chen
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Ageing and Regenerative Medicine, Jinan University, Guangzhou, 510632, China
| | - Jagadish K Chhetri
- National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Yingjie Ding
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Junlin Feng
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jun Guo
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China
| | - Mengmeng Guo
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Chuting He
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Yujuan Jia
- Department of Neurology, First Affiliated Hospital, Shanxi Medical University, Taiyuan, 030001, China
| | - Haiping Jiang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Ying Jing
- Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
| | - Dingfeng Li
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China
| | - Jiaming Li
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jingyi Li
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Qinhao Liang
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430072, China
| | - Rui Liang
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, 300384, China
| | - Feng Liu
- MOE Key Laboratory of Gene Function and Regulation, Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Institute of Healthy Aging Research, Sun Yat-sen University, Guangzhou, 510275, China
| | - Xiaoqian Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Zuojun Liu
- School of Life Sciences, Hainan University, Haikou, 570228, China
| | - Oscar Junhong Luo
- Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Jianwei Lv
- School of Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Jingyi Ma
- The State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Kehang Mao
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, 100871, China
| | - Jiawei Nie
- Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine (Shanghai), International Center for Aging and Cancer, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xinhua Qiao
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xinpei Sun
- Peking University International Cancer Institute, Health Science Center, Peking University, Beijing, 100101, China
| | - Xiaoqiang Tang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
| | - Jianfang Wang
- Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Qiaoran Wang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Siyuan Wang
- Clinical Research Institute, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Xuan Wang
- Hepatobiliary and Pancreatic Center, Medical Research Center, Beijing Tsinghua Changgung Hospital, Beijing, 102218, China
| | - Yaning Wang
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yuhan Wang
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Rimo Wu
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510005, China
| | - Kai Xia
- Center for Stem Cell Biologyand Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China
- National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Fu-Hui Xiao
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China
- State Key Laboratory of Genetic Resources and Evolution, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Lingyan Xu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yingying Xu
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
| | - Haoteng Yan
- Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China
| | - Liang Yang
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, 510530, China
| | - Ruici Yang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuanxin Yang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China
| | - Yilin Ying
- Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine/Ruijin Hospital, Shanghai, 200025, China
| | - Le Zhang
- Gerontology Center of Hubei Province, Wuhan, 430000, China
- Institute of Gerontology, Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Weiwei Zhang
- Department of Cardiology, The Second Medical Centre, Chinese PLA General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing, 100853, China
| | - Wenwan Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xing Zhang
- Key Laboratory of Ministry of Education, School of Aerospace Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Zhuo Zhang
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
- Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Min Zhou
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, China
| | - Rui Zhou
- Department of Nuclear Medicine and PET Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Qingchen Zhu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Zhengmao Zhu
- Department of Genetics and Cell Biology, College of Life Science, Nankai University, Tianjin, 300071, China
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Feng Cao
- Department of Cardiology, The Second Medical Centre, Chinese PLA General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing, 100853, China.
| | - Zhongwei Cao
- State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
| | - Piu Chan
- National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
| | - Chang Chen
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Guobing Chen
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, 510632, China.
- Guangdong-Hong Kong-Macau Great Bay Area Geroscience Joint Laboratory, Guangzhou, 510000, China.
| | - Hou-Zao Chen
- Department of Biochemistryand Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
| | - Jun Chen
- Peking University Research Center on Aging, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Department of Integration of Chinese and Western Medicine, School of Basic Medical Science, Peking University, Beijing, 100191, China.
| | - Weimin Ci
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
| | - Bi-Sen Ding
- State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
| | - Qiurong Ding
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Feng Gao
- Key Laboratory of Ministry of Education, School of Aerospace Medicine, Fourth Military Medical University, Xi'an, 710032, China.
| | - Jing-Dong J Han
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, 100871, China.
| | - Kai Huang
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Clinical Research Center of Metabolic and Cardiovascular Disease, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Ageing and Regenerative Medicine, Jinan University, Guangzhou, 510632, China.
| | - Qing-Peng Kong
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China.
- State Key Laboratory of Genetic Resources and Evolution, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
| | - Ji Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jian Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China.
| | - Xin Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Baohua Liu
- School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, 518060, China.
| | - Feng Liu
- Metabolic Syndrome Research Center, The Second Xiangya Hospital, Central South Unversity, Changsha, 410011, China.
| | - Lin Liu
- Department of Genetics and Cell Biology, College of Life Science, Nankai University, Tianjin, 300071, China.
- Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
- Institute of Translational Medicine, Tianjin Union Medical Center, Nankai University, Tianjin, 300000, China.
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300350, China.
| | - Qiang Liu
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China.
| | - Qiang Liu
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
- Tianjin Institute of Immunology, Tianjin Medical University, Tianjin, 300070, China.
| | - Xingguo Liu
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, 510530, China.
| | - Yong Liu
- College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430072, China.
| | - Xianghang Luo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, China.
| | - Shuai Ma
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Xinran Ma
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
| | - Zhiyong Mao
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
| | - Jing Nie
- The State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Yaojin Peng
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Jie Ren
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Ruibao Ren
- Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine (Shanghai), International Center for Aging and Cancer, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- International Center for Aging and Cancer, Hainan Medical University, Haikou, 571199, China.
| | - Moshi Song
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Zhou Songyang
- MOE Key Laboratory of Gene Function and Regulation, Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Institute of Healthy Aging Research, Sun Yat-sen University, Guangzhou, 510275, China.
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
| | - Yi Eve Sun
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
| | - Yu Sun
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
- Department of Medicine and VAPSHCS, University of Washington, Seattle, WA, 98195, USA.
| | - Mei Tian
- Human Phenome Institute, Fudan University, Shanghai, 201203, China.
| | - Shusen Wang
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, 300384, China.
| | - Si Wang
- Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
| | - Xia Wang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
| | - Xiaoning Wang
- Institute of Geriatrics, The second Medical Center, Beijing Key Laboratory of Aging and Geriatrics, National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Yan-Jiang Wang
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, 400042, China.
| | - Yunfang Wang
- Hepatobiliary and Pancreatic Center, Medical Research Center, Beijing Tsinghua Changgung Hospital, Beijing, 102218, China.
| | - Catherine C L Wong
- Clinical Research Institute, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China.
| | - Andy Peng Xiang
- Center for Stem Cell Biologyand Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China.
- National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
| | - Yichuan Xiao
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Zhengwei Xie
- Peking University International Cancer Institute, Health Science Center, Peking University, Beijing, 100101, China.
- Beijing & Qingdao Langu Pharmaceutical R&D Platform, Beijing Gigaceuticals Tech. Co. Ltd., Beijing, 100101, China.
| | - Daichao Xu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
| | - Jing Ye
- Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine/Ruijin Hospital, Shanghai, 200025, China.
| | - Rui Yue
- Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
| | - Cuntai Zhang
- Gerontology Center of Hubei Province, Wuhan, 430000, China.
- Institute of Gerontology, Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Hongbo Zhang
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
| | - Liang Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Weiqi Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Yong Zhang
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510005, China.
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
| | - Yun-Wu Zhang
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361102, China.
| | - Zhuohua Zhang
- Key Laboratory of Molecular Precision Medicine of Hunan Province and Center for Medical Genetics, Institute of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, 410078, China.
- Department of Neurosciences, Hengyang Medical School, University of South China, Hengyang, 421001, China.
| | - Tongbiao Zhao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Yuzheng Zhao
- Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
- Research Unit of New Techniques for Live-cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing, 100730, China.
| | - Dahai Zhu
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510005, China.
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
| | - Weiguo Zou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Gang Pei
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Biomedicine, The Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai, 200070, China.
| | - Guang-Hui Liu
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
| |
Collapse
|
|
18
|
Antherieu G, Heiblig M, Freyer G, Ghesquieres H, Falandry C. Impact of Age on Poly(ADP-Ribose) Polymerase Inhibitor (PARPi)-Induced Lymphopenia: A Scoping Review of the Literature and Internal Analysis of a Retrospective Database. Drugs Aging 2023; 40:397-405. [PMID: 37081248 PMCID: PMC10118227 DOI: 10.1007/s40266-023-01023-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2023] [Indexed: 04/22/2023]
Abstract
BACKGROUND Poly(ADP-ribose) polymerase inhibitors (PARPi) are increasingly used in oncology; their hematological toxicities affect classically red, platelet and neutrophil lineages, but some opportunistic infections have been reported concomitantly to deep lymphopenias. OBJECTIVE This study was designed to provide an external and internal analysis of the crossed impacts of PARPi and age on lymphopenia risk. PATIENTS AND METHODS A scoping review was performed on the PubMed and Embase databases to assess the reporting of lymphocyte rates in original studies on PARPi treatment for adult patients up to 1 April 2022. A retrospective cohort was extracted from the medical charts of all patients treated for gynecological cancer at our institution from 2015 to 2022 in accordance with ethical regulations. RESULTS The scoping review research strategy retrieved 5840 abstracts; 225 studies were selected for full-text analysis. Lymphopenia was reported in 41.8% of the studies; frequency of all-grade and grade ≥ 3 lymphopenia reached 20.5% and 8.9%, respectively. Grade ≥ 3 lymphopenia was significantly higher in studies including older patients (median age ≥ 60 years vs. < 60 years), at 7.5% vs. 10.3% (p < 0.0001). PARIB-OLD-HCL included 46 patients, 19 of whom were aged < 70 years (median 44 years) and 27 of whom were aged ≥ 70 years (median 79 years); the frequency of all-grade and grade ≥ 3 lymphopenia reached 67% (< 70 years: 63%; ≥ 70 years: 70%) and 13% (< 70 years: 5%; ≥ 70 years: 19%), respectively. CONCLUSION Lymphopenia events were much more frequent in real-life than in previously reported studies, particularly in older patients. Future work is needed to improve patient follow-up and discuss prophylactic strategies.
Collapse
Affiliation(s)
- Gabriel Antherieu
- Department of Hematology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France
| | - Maël Heiblig
- Department of Hematology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France
| | - Gilles Freyer
- Department of Medical Oncology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France
| | - Hervé Ghesquieres
- Department of Hematology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France
| | - Claire Falandry
- Geriatric Department of Geriatric Oncology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.
| |
Collapse
|
|
19
|
Ortiz GGR, Mohammadi Y, Nazari A, Ataeinaeini M, Kazemi P, Yasamineh S, Al-Naqeeb BZT, Zaidan HK, Gholizadeh O. A state-of-the-art review on the MicroRNAs roles in hematopoietic stem cell aging and longevity. Cell Commun Signal 2023; 21:85. [PMID: 37095512 PMCID: PMC10123996 DOI: 10.1186/s12964-023-01117-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 03/25/2023] [Indexed: 04/26/2023] Open
Abstract
Aging is a biological process determined through time-related cellular and functional impairments, leading to a decreased standard of living for the organism. Recently, there has been an unprecedented advance in the aging investigation, especially the detection that the rate of senescence is at least somewhat regulated via evolutionarily preserved genetic pathways and biological processes. Hematopoietic stem cells (HSCs) maintain blood generation over the whole lifetime of an organism. The senescence process influences many of the natural features of HSC, leading to a decline in their capabilities, independently of their microenvironment. New studies show that HSCs are sensitive to age-dependent stress and gradually lose their self-renewal and regeneration potential with senescence. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally inhibit translation or stimulate target mRNA cleavage of target transcripts via the sequence-particular connection. MiRNAs control various biological pathways and processes, such as senescence. Several miRNAs are differentially expressed in senescence, producing concern about their use as moderators of the senescence process. MiRNAs play an important role in the control of HSCs and can also modulate processes associated with tissue senescence in specific cell types. In this review, we display the contribution of age-dependent alterations, including DNA damage, epigenetic landscape, metabolism, and extrinsic factors, which affect HSCs function during aging. In addition, we investigate the particular miRNAs regulating HSCs senescence and age-associated diseases. Video Abstract.
Collapse
Affiliation(s)
- Geovanny Genaro Reivan Ortiz
- Laboratory of Basic Psychology, Behavioral Analysis and Programmatic Development (PAD-LAB), Catholic University of Cuenca, Cuenca, Ecuador
| | - Yasaman Mohammadi
- Faculty of Dentistry, Islamic Azad University, Shiraz Branch, Shiraz, Iran
| | - Ahmad Nazari
- Tehran University of Medical Sciences, Tehran, Iran
| | | | - Parisa Kazemi
- Faculty of Dentistry, Ilam University of Medical Sciences, Ilam, Iran
| | - Saman Yasamineh
- Stem Cell Research Center at, Tabriz University of Medical Sciences, Tabriz, Iran.
| | | | - Haider Kamil Zaidan
- Department of Medical Laboratories Techniques, Al-Mustaqbal University College, Hillah, Babylon, Iraq
| | - Omid Gholizadeh
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
20
|
Abstract
Changes in bone architecture and metabolism with aging increase the likelihood of osteoporosis and fracture. Age-onset osteoporosis is multifactorial, with contributory extrinsic and intrinsic factors including certain medical problems, specific prescription drugs, estrogen loss, secondary hyperparathyroidism, microenvironmental and cellular alterations in bone tissue, and mechanical unloading or immobilization. At the histological level, there are changes in trabecular and cortical bone as well as marrow cellularity, lineage switching of mesenchymal stem cells to an adipogenic fate, inadequate transduction of signals during skeletal loading, and predisposition toward senescent cell accumulation with production of a senescence-associated secretory phenotype. Cumulatively, these changes result in bone remodeling abnormalities that over time cause net bone loss typically seen in older adults. Age-related osteoporosis is a geriatric syndrome due to the multiple etiologies that converge upon the skeleton to produce the ultimate phenotypic changes that manifest as bone fragility. Bone tissue is dynamic but with tendencies toward poor osteoblastic bone formation and relative osteoclastic bone resorption with aging. Interactions with other aging physiologic systems, such as muscle, may also confer detrimental effects on the aging skeleton. Conversely, individuals who maintain their BMD experience a lower risk of fractures, disability, and mortality, suggesting that this phenotype may be a marker of successful aging. © 2023 American Physiological Society. Compr Physiol 13:4355-4386, 2023.
Collapse
Affiliation(s)
- Robert J Pignolo
- Department of Medicine, Divisions of Geriatric Medicine and Gerontology, Endocrinology, and Hospital Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.,The Department of Physiology and Biomedical Engineering, and the Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA
| |
Collapse
|
|
21
|
Cai Y, Song W, Li J, Jing Y, Liang C, Zhang L, Zhang X, Zhang W, Liu B, An Y, Li J, Tang B, Pei S, Wu X, Liu Y, Zhuang CL, Ying Y, Dou X, Chen Y, Xiao FH, Li D, Yang R, Zhao Y, Wang Y, Wang L, Li Y, Ma S, Wang S, Song X, Ren J, Zhang L, Wang J, Zhang W, Xie Z, Qu J, Wang J, Xiao Y, Tian Y, Wang G, Hu P, Ye J, Sun Y, Mao Z, Kong QP, Liu Q, Zou W, Tian XL, Xiao ZX, Liu Y, Liu JP, Song M, Han JDJ, Liu GH. The landscape of aging. SCIENCE CHINA. LIFE SCIENCES 2022; 65:2354-2454. [PMID: 36066811 PMCID: PMC9446657 DOI: 10.1007/s11427-022-2161-3] [Citation(s) in RCA: 193] [Impact Index Per Article: 64.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 07/05/2022] [Indexed: 02/07/2023]
Abstract
Aging is characterized by a progressive deterioration of physiological integrity, leading to impaired functional ability and ultimately increased susceptibility to death. It is a major risk factor for chronic human diseases, including cardiovascular disease, diabetes, neurological degeneration, and cancer. Therefore, the growing emphasis on "healthy aging" raises a series of important questions in life and social sciences. In recent years, there has been unprecedented progress in aging research, particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes. In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases, we review the descriptive, conceptual, and interventive aspects of the landscape of aging composed of a number of layers at the cellular, tissue, organ, organ system, and organismal levels.
Collapse
Affiliation(s)
- Yusheng Cai
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Wei Song
- Frontier Science Center for Immunology and Metabolism, Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Jiaming Li
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ying Jing
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Chuqian Liang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Liyuan Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
| | - Xia Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Wenhui Zhang
- University of Chinese Academy of Sciences, Beijing, 100049, China
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Beibei Liu
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
| | - Yongpan An
- Peking University International Cancer Institute, Peking University Health Science Center, Peking University, Beijing, 100191, China
| | - Jingyi Li
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Baixue Tang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China
| | - Siyu Pei
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xueying Wu
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yuxuan Liu
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, 100084, China
| | - Cheng-Le Zhuang
- Colorectal Cancer Center/Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, 200072, China
| | - Yilin Ying
- Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- International Laboratory in Hematology and Cancer, Shanghai Jiaotong University School of Medicine/Ruijin Hospital, Shanghai, 200025, China
| | - Xuefeng Dou
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yu Chen
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Fu-Hui Xiao
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China
| | - Dingfeng Li
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
| | - Ruici Yang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Ya Zhao
- Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, 330031, China
| | - Yang Wang
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Lihui Wang
- Institute of Ageing Research, Hangzhou Normal University, School of Basic Medical Sciences, Hangzhou, 311121, China
| | - Yujing Li
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Shuai Ma
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
- The Fifth People's Hospital of Chongqing, Chongqing, 400062, China.
| | - Xiaoyuan Song
- MOE Key Laboratory of Cellular Dynamics, Hefei National Research Center for Physical Sciences at the Microscale, CAS Key Laboratory of Brain Function and Disease, Neurodegenerative Disorder Research Center, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
| | - Jie Ren
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Liang Zhang
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Jun Wang
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Weiqi Zhang
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
| | - Zhengwei Xie
- Peking University International Cancer Institute, Peking University Health Science Center, Peking University, Beijing, 100191, China.
| | - Jing Qu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Jianwei Wang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
| | - Yichuan Xiao
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Ye Tian
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Gelin Wang
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, 100084, China.
| | - Ping Hu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Colorectal Cancer Center/Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, 200072, China.
- Guangzhou Laboratory, Guangzhou International Bio Island, Guangzhou, 510005, China.
| | - Jing Ye
- Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
- International Laboratory in Hematology and Cancer, Shanghai Jiaotong University School of Medicine/Ruijin Hospital, Shanghai, 200025, China.
| | - Yu Sun
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
- Department of Medicine and VAPSHCS, University of Washington, Seattle, 98195, USA.
| | - Zhiyong Mao
- Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
| | - Qing-Peng Kong
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China.
| | - Qiang Liu
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China.
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
| | - Weiguo Zou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Xiao-Li Tian
- Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, 330031, China.
| | - Zhi-Xiong Xiao
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, China.
| | - Yong Liu
- Frontier Science Center for Immunology and Metabolism, Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan, 430071, China.
| | - Jun-Ping Liu
- Institute of Ageing Research, Hangzhou Normal University, School of Basic Medical Sciences, Hangzhou, 311121, China.
- Department of Immunology and Pathology, Monash University Faculty of Medicine, Prahran, Victoria, 3181, Australia.
- Hudson Institute of Medical Research, and Monash University Department of Molecular and Translational Science, Clayton, Victoria, 3168, Australia.
| | - Moshi Song
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Jing-Dong J Han
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology, Peking University, Beijing, 100871, China.
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
| |
Collapse
|
|
22
|
Singh B, Kumar Rai A. Loss of immune regulation in aged T-cells: A metabolic review to show lack of ability to control responses within the self. Hum Immunol 2022; 83:808-817. [DOI: 10.1016/j.humimm.2022.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 09/19/2022] [Accepted: 10/04/2022] [Indexed: 11/04/2022]
|
|
23
|
Stover PJ, Field MS, Brawley HN, Angelin B, Iversen PO, Frühbeck G. Nutrition and stem cell integrity in aging. J Intern Med 2022; 292:587-603. [PMID: 35633146 DOI: 10.1111/joim.13507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Adult stem cells (SCs) represent the regenerative capacity of organisms throughout their lifespan. The maintenance of robust SC populations capable of renewing organs and physiological systems is one hallmark of healthy aging. The local environment of SCs, referred to as the niche, includes the nutritional milieu, which is essential to maintain the quantity and quality of SCs available for renewal and regeneration. There is increased recognition that SCs have unique metabolism and conditional nutrient needs compared to fully differentiated cells. However, the contribution of SC nutrition to overall human nutritional requirements is an understudied and underappreciated area of investigation. Nutrient needs vary across the lifespan and are modified by many factors including individual health, disease, physiological states including pregnancy, age, sex, and during recovery from injury. Although current nutrition guidance is generally derived for apparently healthy populations and to prevent nutritional deficiency diseases, there are increased efforts to establish nutrient-based and food-based recommendations based on reducing chronic disease. Understanding the dynamics of SC nutritional needs throughout the life span, including the role of nutrition in extending biological age by blunting biological systems decay, is fundamental to establishing food and nutrient guidance for chronic disease reduction and health maintenance. This review summarizes a 3-day symposium of the Marabou Foundation (www.marabousymposium.org) held to examine the metabolic properties and unique nutritional needs of adult SCs and their role in healthy aging and age-related chronic disease.
Collapse
Affiliation(s)
- P J Stover
- Texas A&M AgriLife Institute for Advancing Health through Agriculture, Texas A&M University, College Station, Texas, USA
| | - M S Field
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA
| | - H N Brawley
- Texas A&M AgriLife Institute for Advancing Health through Agriculture, Texas A&M University, College Station, Texas, USA
| | - B Angelin
- Cardiometabolic Unit, Clinical Department of Endocrinology, and Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Stockholm, Sweden
| | - P O Iversen
- Department of Nutrition, University of Oslo, Oslo, Norway
| | - G Frühbeck
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, CIBEROBN, IdiSNA, Pamplona, Navarra, Spain
| |
Collapse
|
|
24
|
Hohman LS, Osborne LC. A gut-centric view of aging: Do intestinal epithelial cells contribute to age-associated microbiota changes, inflammaging, and immunosenescence? Aging Cell 2022; 21:e13700. [PMID: 36000805 PMCID: PMC9470900 DOI: 10.1111/acel.13700] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 07/07/2022] [Accepted: 08/03/2022] [Indexed: 01/25/2023] Open
Abstract
Intestinal epithelial cells (IECs) serve as both a physical and an antimicrobial barrier against the microbiota, as well as a conduit for signaling between the microbiota and systemic host immunity. As individuals age, the balance between these systems undergoes a myriad of changes due to age-associated changes to the microbiota, IECs themselves, immunosenescence, and inflammaging. In this review, we discuss emerging data related to age-associated loss of intestinal barrier integrity and posit that IEC dysfunction may play a central role in propagating age-associated alterations in microbiota composition and immune homeostasis.
Collapse
Affiliation(s)
- Leah S. Hohman
- Department of Microbiology & Immunology, Life Sciences InstituteUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Lisa C. Osborne
- Department of Microbiology & Immunology, Life Sciences InstituteUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| |
Collapse
|
|
25
|
Orschell CM, Wu T, Patterson AM. Impact of Age, Sex, and Genetic Diversity in Murine Models of the Hematopoietic Acute Radiation Syndrome (H-ARS) and the Delayed Effects of Acute Radiation Exposure (DEARE). CURRENT STEM CELL REPORTS 2022; 8:139-149. [PMID: 36798890 PMCID: PMC9928166 DOI: 10.1007/s40778-022-00214-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2022] [Indexed: 10/17/2022]
Abstract
Purpose of review Malicious or accidental radiation exposure increases risk for the hematopoietic acute radiation syndrome (H-ARS) and the delayed effects of acute radiation exposure (DEARE). Radiation medical countermeasure (MCM) development relies on robust animal models reflective of all age groups and both sexes. This review details critical considerations in murine H-ARS and DEARE model development including divergent radiation responses dependent on age, sex, and genetic diversity. Recent findings Radioresistance increases with murine age from pediatrics through geriatrics. Between sexes, radioresistance is higher in male weanlings, pubescent females, and aged males, corresponding with accelerated myelopoiesis. Jackson diversity outbred (JDO) mice resemble non-human primates in radiation response for modeling human diversity. Weanlings and JDO models exhibit less DEARE than other models. Summary Highly characterized age-, sex- and diversity-conscious murine models of H-ARS and DEARE provide powerful and essential tools in MCM development for all radiation victims.
Collapse
Affiliation(s)
| | - Tong Wu
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Andrea M. Patterson
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| |
Collapse
|
|
26
|
González-Bermúdez L, Genescà A, Terradas M, Martín M. Role of H4K16 acetylation in 53BP1 recruitment to double-strand break sites in in vitro aged cells. Biogerontology 2022; 23:499-514. [PMID: 35851632 PMCID: PMC9388460 DOI: 10.1007/s10522-022-09979-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 06/29/2022] [Indexed: 12/20/2022]
Abstract
AbstractIncreased frequency of DNA double strand breaks (DSBs) with aging suggests an age-associated decline in DSB repair efficiency, which is also influenced by the epigenetic landscape. H4 acetylation at lysine 16 (H4K16Ac) has been related to DSB repair since deacetylation of this mark is required for efficient 53BP1 recruitment to DSBs. Although age-associated changes in H4K16Ac levels have been studied, their contribution to age-related DSB accumulation remains unknown. In vitro aged Human Dermal Fibroblasts (HDFs) display lower levels of H4K16A that correlate with reduced recruitment of 53BP1 to basal DSBs. Following DNA damage induction, early passage (EP) cells suffered from a transient H4K16 deacetylation that allowed proper 53BP1 recruitment to DSBs. In contrast, to reach this specific and optimum level, aged cells responded by increasing their overall lower H4K16Ac levels. Induced hyperacetylation of late passage (LP) cells using trichostatin A increased H4K16Ac levels but did not ameliorate 53BP1 recruitment. Instead, deacetylation induced by MOF silencing reduced H4K16Ac levels and compromised 53BP1 recruitment in both EP and LP cells. Age-associated decrease of H4K16Ac levels contributes to the repair defect displayed by in vitro aged cells. H4K16Ac responds to DNA damage in order to reach a specific, optimum level that allows proper 53BP1 recruitment. This response may be compromised with age, as LP cells depart from lower H4K16Ac levels. Variations in H4K16Ac following the activation of the DNA damage response and aging point at this histone mark as a key mediator between DNA repair and age-associated chromatin alterations.
Collapse
Affiliation(s)
- Lourdes González-Bermúdez
- Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Anna Genescà
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain
| | - Mariona Terradas
- Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain
| | - Marta Martín
- Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, Spain
| |
Collapse
|
|
27
|
Vougioukalaki M, Demmers J, Vermeij WP, Baar M, Bruens S, Magaraki A, Kuijk E, Jager M, Merzouk S, Brandt RM, Kouwenberg J, van Boxtel R, Cuppen E, Pothof J, Hoeijmakers JHJ. Different responses to DNA damage determine ageing differences between organs. Aging Cell 2022; 21:e13562. [PMID: 35246937 PMCID: PMC9009128 DOI: 10.1111/acel.13562] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 12/17/2021] [Accepted: 01/05/2022] [Indexed: 12/13/2022] Open
Abstract
Organs age differently, causing wide heterogeneity in multimorbidity, but underlying mechanisms are largely elusive. To investigate the basis of organ-specific ageing, we utilized progeroid repair-deficient Ercc1Δ /- mouse mutants and systematically compared at the tissue, stem cell and organoid level two organs representing ageing extremes. Ercc1Δ /- intestine shows hardly any accelerated ageing. Nevertheless, we found apoptosis and reduced numbers of intestinal stem cells (ISCs), but cell loss appears compensated by over-proliferation. ISCs retain their organoid-forming capacity, but organoids perform poorly in culture, compared with WT. Conversely, liver ages dramatically, even causing early death in Ercc1-KO mice. Apoptosis, p21, polyploidization and proliferation of various (stem) cells were prominently elevated in Ercc1Δ /- liver and stem cell populations were either largely unaffected (Sox9+), or expanding (Lgr5+), but were functionally exhausted in organoid formation and development in vitro. Paradoxically, while intestine displays less ageing, repair in WT ISCs appears inferior to liver as shown by enhanced sensitivity to various DNA-damaging agents, and lower lesion removal. Our findings reveal organ-specific anti-ageing strategies. Intestine, with short lifespan limiting time for damage accumulation and repair, favours apoptosis of damaged cells relying on ISC plasticity. Liver with low renewal rates depends more on repair pathways specifically protecting the transcribed compartment of the genome to promote sustained functionality and cell preservation. As shown before, the hematopoietic system with intermediate self-renewal mainly invokes replication-linked mechanisms, apoptosis and senescence. Hence, organs employ different genome maintenance strategies, explaining heterogeneity in organ ageing and the segmental nature of DNA-repair-deficient progerias.
Collapse
Affiliation(s)
- Maria Vougioukalaki
- Department Molecular Genetics Erasmus University Medical Center Rotterdam Rotterdam The Netherlands
| | - Joris Demmers
- Department Molecular Genetics Erasmus University Medical Center Rotterdam Rotterdam The Netherlands
| | - Wilbert P. Vermeij
- Princess Máxima Center for Pediatric Oncology Oncode Institute Utrecht The Netherlands
| | - Marjolein Baar
- Center for Molecular Medicine University Medical Center Utrecht Utrecht The Netherlands
| | - Serena Bruens
- Department Molecular Genetics Erasmus University Medical Center Rotterdam Rotterdam The Netherlands
| | - Aristea Magaraki
- Department of Developmental Biology Oncode Institute Rotterdam The Netherlands
| | - Ewart Kuijk
- Division Biomedical Genetics Center for Molecular Medicine and Cancer Genomics Netherlands University Medical Center Utrecht Utrecht University Utrecht The Netherlands
| | - Myrthe Jager
- Department of Genetics Center for Molecular Medicine University Medical Center Utrecht Utrecht University Utrecht The Netherlands
| | - Sarra Merzouk
- Department of Developmental Biology Oncode Institute Rotterdam The Netherlands
| | - Renata M.C. Brandt
- Department Molecular Genetics Erasmus University Medical Center Rotterdam Rotterdam The Netherlands
| | - Janneke Kouwenberg
- Department Molecular Genetics Erasmus University Medical Center Rotterdam Rotterdam The Netherlands
| | - Ruben van Boxtel
- Princess Máxima Center for Pediatric Oncology Oncode Institute Utrecht The Netherlands
| | - Edwin Cuppen
- Division Biomedical Genetics Center for Molecular Medicine and Cancer Genomics Netherlands University Medical Center Utrecht Utrecht University Utrecht The Netherlands
- Hartwig Medical Foundation Amsterdam Netherlands
| | - Joris Pothof
- Department Molecular Genetics Erasmus University Medical Center Rotterdam Rotterdam The Netherlands
| | - Jan H. J. Hoeijmakers
- Department Molecular Genetics Erasmus University Medical Center Rotterdam Rotterdam The Netherlands
- Princess Máxima Center for Pediatric Oncology Oncode Institute Utrecht The Netherlands
- Institute for Genome Stability in Ageing and Disease Cologne Excellence Cluster for Cellular Stress Responses in Aging‐Associated Diseases (CECAD) University Hospital of Cologne Cologne Germany
| |
Collapse
|
|
28
|
Jacob J, Aggarwal A, Aggarwal A, Bhattacharyya S, Kumar V, Sharma V, Sahni D. Senescent chondrogenic progenitor cells derived from articular cartilage of knee osteoarthritis patients contributes to senescence-associated secretory phenotype via release of IL-6 and IL-8. Acta Histochem 2022; 124:151867. [PMID: 35192993 DOI: 10.1016/j.acthis.2022.151867] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/09/2022] [Accepted: 02/11/2022] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Despite the presence of chondrogenic progenitor cells (CPCs) in knee osteoarthritis patients they are unable to repair the damaged cartilage. This study aimed to evaluate the oxidative stress, cellular senescence, and senescence-associated secretory phenotype (SASP) in the CPCs derived from osteoarthritic cartilage and compare with the CPCs of healthy articular cartilage. METHODS Isolated CPCs were characterized based on phenotypic expression of stem cell markers, clonogenicity, and tri-lineage differentiation assay. Production of ROS was measured using DCFDA assay. Cellular senescence in CPCs was assessed by senescence-associated beta-galactosidase assay and expression of senescence markers at the gene level using real-time PCR. Morphological features associated with senescent OA-CPCs were studied using scanning electron microscopy. To study SASP, the production of inflammatory cytokines was assessed in the culture supernatant using a flow-cytometer based cytometric bead array. RESULTS OA-CPCs exhibited elevated ROS levels along with a relatively high percentage of senescent cells compared to non-OA CPCs, and a positive correlation exists between ROS production and senescence. The morphological assessment of senescent CPCs revealed increased cell size and multiple nuclei in senescent OA-CPCs. These results were further validated by elevated expression of senescence genes p16, p21, and p53. Additionally, culture supernatant of senescent OA-CPCs expressed IL-6 and IL-8 cytokines indicative of SASP. CONCLUSIONS Despite exhibiting similar expression of stem cell markers and clonogenicity, CPCs undergo oxidative stress in diseased knee joint leading to increased production of intracellular ROS in chondrogenic progenitor cells that support cellular senescence. Further, senescence in OA-CPCs is mediated via the release of pro-inflammatory cytokines, IL-6 and IL-8.
Collapse
Affiliation(s)
- Justin Jacob
- Department of Anatomy, Research Block B, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
| | - Anjali Aggarwal
- Department of Anatomy, Research Block B, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
| | - Aditya Aggarwal
- Department of Orthopedics, Nehru Hospital, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
| | - Shalmoli Bhattacharyya
- Department of Biophysics, Research Block B, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
| | - Vishal Kumar
- Department of Orthopedics, Nehru Hospital, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
| | - Vinit Sharma
- Department of Anatomy, Research Block B, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
| | - Daisy Sahni
- Department of Anatomy, Research Block B, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
| |
Collapse
|
|
29
|
Montazersaheb S, Ehsani A, Fathi E, Farahzadi R. Cellular and Molecular Mechanisms Involved in Hematopoietic Stem Cell Aging as a Clinical Prospect. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2713483. [PMID: 35401928 PMCID: PMC8993567 DOI: 10.1155/2022/2713483] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 02/28/2022] [Accepted: 03/22/2022] [Indexed: 11/17/2022]
Abstract
There is a hot topic in stem cell research to investigate the process of hematopoietic stem cell (HSC) aging characterized by decreased self-renewal ability, myeloid-biased differentiation, impaired homing, and other abnormalities related to hematopoietic repair function. It is of crucial importance that HSCs preserve self-renewal and differentiation ability to maintain hematopoiesis under homeostatic states over time. Although HSC numbers increase with age in both mice and humans, this cannot compensate for functional defects of aged HSCs. The underlying mechanisms regarding HSC aging have been studied from various perspectives, but the exact molecular events remain unclear. Several cell-intrinsic and cell-extrinsic factors contribute to HSC aging including DNA damage responses, reactive oxygen species (ROS), altered epigenetic profiling, polarity, metabolic alterations, impaired autophagy, Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, nuclear factor- (NF-) κB pathway, mTOR pathway, transforming growth factor-beta (TGF-β) pathway, and wingless-related integration site (Wnt) pathway. To determine how deficient HSCs develop during aging, we provide an overview of different hallmarks, age-related signaling pathways, and epigenetic modifications in young and aged HSCs. Knowing how such changes occur and progress will help researchers to develop medications and promote the quality of life for the elderly and possibly alleviate age-associated hematopoietic disorders. The present review is aimed at discussing the latest advancements of HSC aging and the role of HSC-intrinsic factors and related events of a bone marrow niche during HSC aging.
Collapse
Affiliation(s)
- Soheila Montazersaheb
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Ehsani
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ezzatollah Fathi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Raheleh Farahzadi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
30
|
Casciati A, Tanori M, Gianlorenzi I, Rampazzo E, Persano L, Viola G, Cani A, Bresolin S, Marino C, Mancuso M, Merla C. Effects of Ultra-Short Pulsed Electric Field Exposure on Glioblastoma Cells. Int J Mol Sci 2022; 23:ijms23063001. [PMID: 35328420 PMCID: PMC8950115 DOI: 10.3390/ijms23063001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/02/2022] [Accepted: 03/08/2022] [Indexed: 12/12/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common brain cancer in adults. GBM starts from a small fraction of poorly differentiated and aggressive cancer stem cells (CSCs) responsible for aberrant proliferation and invasion. Due to extreme tumor heterogeneity, actual therapies provide poor positive outcomes, and cancers usually recur. Therefore, alternative approaches, possibly targeting CSCs, are necessary against GBM. Among emerging therapies, high intensity ultra-short pulsed electric fields (PEFs) are considered extremely promising and our previous results demonstrated the ability of a specific electric pulse protocol to selectively affect medulloblastoma CSCs preserving normal cells. Here, we tested the same exposure protocol to investigate the response of U87 GBM cells and U87-derived neurospheres. By analyzing different in vitro biological endpoints and taking advantage of transcriptomic and bioinformatics analyses, we found that, independent of CSC content, PEF exposure affected cell proliferation and differentially regulated hypoxia, inflammation and P53/cell cycle checkpoints. PEF exposure also significantly reduced the ability to form new neurospheres and inhibited the invasion potential. Importantly, exclusively in U87 neurospheres, PEF exposure changed the expression of stem-ness/differentiation genes. Our results confirm this physical stimulus as a promising treatment to destabilize GBM, opening up the possibility of developing effective PEF-mediated therapies.
Collapse
Affiliation(s)
- Arianna Casciati
- Italian National Agency for Energy New Technologies and Sustainable Economic Development (ENEA), Division of Health Protection Technologies, Via Anguillarese 301, 00123 Rome, Italy; (A.C.); (M.T.); (C.M.)
| | - Mirella Tanori
- Italian National Agency for Energy New Technologies and Sustainable Economic Development (ENEA), Division of Health Protection Technologies, Via Anguillarese 301, 00123 Rome, Italy; (A.C.); (M.T.); (C.M.)
| | - Isabella Gianlorenzi
- Department of Ecological and Biological Sciences, University of Tuscia, Largo dell’Università, snc, 01100 Viterbo, Italy;
| | - Elena Rampazzo
- Department of Women’s and Children’s Health (SDB), University of Padova, via Giustiniani 3, 35128 Padova, Italy; (E.R.); (L.P.); (G.V.); (A.C.); (S.B.)
- Division of Pediatric Hematology, Oncology and Hematopoietic Cell & Gene Therapy, Pediatric Research Institute (IRP), Corso Stati Uniti 4, 35127 Padova, Italy
| | - Luca Persano
- Department of Women’s and Children’s Health (SDB), University of Padova, via Giustiniani 3, 35128 Padova, Italy; (E.R.); (L.P.); (G.V.); (A.C.); (S.B.)
- Division of Pediatric Hematology, Oncology and Hematopoietic Cell & Gene Therapy, Pediatric Research Institute (IRP), Corso Stati Uniti 4, 35127 Padova, Italy
| | - Giampietro Viola
- Department of Women’s and Children’s Health (SDB), University of Padova, via Giustiniani 3, 35128 Padova, Italy; (E.R.); (L.P.); (G.V.); (A.C.); (S.B.)
- Division of Pediatric Hematology, Oncology and Hematopoietic Cell & Gene Therapy, Pediatric Research Institute (IRP), Corso Stati Uniti 4, 35127 Padova, Italy
| | - Alice Cani
- Department of Women’s and Children’s Health (SDB), University of Padova, via Giustiniani 3, 35128 Padova, Italy; (E.R.); (L.P.); (G.V.); (A.C.); (S.B.)
- Division of Pediatric Hematology, Oncology and Hematopoietic Cell & Gene Therapy, Pediatric Research Institute (IRP), Corso Stati Uniti 4, 35127 Padova, Italy
| | - Silvia Bresolin
- Department of Women’s and Children’s Health (SDB), University of Padova, via Giustiniani 3, 35128 Padova, Italy; (E.R.); (L.P.); (G.V.); (A.C.); (S.B.)
- Division of Pediatric Hematology, Oncology and Hematopoietic Cell & Gene Therapy, Pediatric Research Institute (IRP), Corso Stati Uniti 4, 35127 Padova, Italy
| | - Carmela Marino
- Italian National Agency for Energy New Technologies and Sustainable Economic Development (ENEA), Division of Health Protection Technologies, Via Anguillarese 301, 00123 Rome, Italy; (A.C.); (M.T.); (C.M.)
| | - Mariateresa Mancuso
- Italian National Agency for Energy New Technologies and Sustainable Economic Development (ENEA), Division of Health Protection Technologies, Via Anguillarese 301, 00123 Rome, Italy; (A.C.); (M.T.); (C.M.)
- Correspondence: (M.M.); (C.M.)
| | - Caterina Merla
- Italian National Agency for Energy New Technologies and Sustainable Economic Development (ENEA), Division of Health Protection Technologies, Via Anguillarese 301, 00123 Rome, Italy; (A.C.); (M.T.); (C.M.)
- Correspondence: (M.M.); (C.M.)
| |
Collapse
|
|
31
|
Noren Hooten N, Pacheco NL, Smith JT, Evans MK. The accelerated aging phenotype: The role of race and social determinants of health on aging. Ageing Res Rev 2022; 73:101536. [PMID: 34883202 PMCID: PMC10862389 DOI: 10.1016/j.arr.2021.101536] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 11/12/2021] [Accepted: 12/03/2021] [Indexed: 02/06/2023]
Abstract
The pursuit to discover the fundamental biology and mechanisms of aging within the context of the physical and social environment is critical to designing interventions to prevent and treat its complex phenotypes. Aging research is critically linked to understanding health disparities because these inequities shape minority aging, which may proceed on a different trajectory than the overall population. Health disparities are characteristically seen in commonly occurring age-associated diseases such as cardiovascular and cerebrovascular disease as well as diabetes mellitus and cancer. The early appearance and increased severity of age-associated disease among African American and low socioeconomic status (SES) individuals suggests that the factors contributing to the emergence of health disparities may also induce a phenotype of 'premature aging' or 'accelerated aging' or 'weathering'. In marginalized and low SES populations with high rates of early onset age-associated disease the interaction of biologic, psychosocial, socioeconomic and environmental factors may result in a phenotype of accelerated aging biologically similar to premature aging syndromes with increased susceptibility to oxidative stress, premature accumulation of oxidative DNA damage, defects in DNA repair and higher levels of biomarkers of oxidative stress and inflammation. Health disparities, therefore, may be the end product of this complex interaction in populations at high risk. This review will examine the factors that drive both health disparities and the accelerated aging phenotype that ultimately contributes to premature mortality.
Collapse
Affiliation(s)
- Nicole Noren Hooten
- Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA
| | - Natasha L Pacheco
- Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA
| | - Jessica T Smith
- Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA
| | - Michele K Evans
- Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
| |
Collapse
|
|
32
|
Immune Memory in Aging: a Wide Perspective Covering Microbiota, Brain, Metabolism, and Epigenetics. Clin Rev Allergy Immunol 2021; 63:499-529. [PMID: 34910283 PMCID: PMC8671603 DOI: 10.1007/s12016-021-08905-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/24/2021] [Indexed: 11/06/2022]
Abstract
Non-specific innate and antigen-specific adaptive immunological memories are vital evolutionary adaptations that confer long-lasting protection against a wide range of pathogens. Adaptive memory is established by memory T and B lymphocytes following the recognition of an antigen. On the other hand, innate immune memory, also called trained immunity, is imprinted in innate cells such as macrophages and natural killer cells through epigenetic and metabolic reprogramming. However, these mechanisms of memory generation and maintenance are compromised as organisms age. Almost all immune cell types, both mature cells and their progenitors, go through age-related changes concerning numbers and functions. The aging immune system renders the elderly highly susceptible to infections and incapable of mounting a proper immune response upon vaccinations. Besides the increased infectious burden, older individuals also have heightened risks of metabolic and neurodegenerative diseases, which have an immunological component. This review discusses how immune function, particularly the establishment and maintenance of innate and adaptive immunological memory, regulates and is regulated by epigenetics, metabolic processes, gut microbiota, and the central nervous system throughout life, with a focus on old age. We explain in-depth how epigenetics and cellular metabolism impact immune cell function and contribute or resist the aging process. Microbiota is intimately linked with the immune system of the human host, and therefore, plays an important role in immunological memory during both homeostasis and aging. The brain, which is not an immune-isolated organ despite former opinion, interacts with the peripheral immune cells, and the aging of both systems influences the health of each other. With all these in mind, we aimed to present a comprehensive view of the aging immune system and its consequences, especially in terms of immunological memory. The review also details the mechanisms of promising anti-aging interventions and highlights a few, namely, caloric restriction, physical exercise, metformin, and resveratrol, that impact multiple facets of the aging process, including the regulation of innate and adaptive immune memory. We propose that understanding aging as a complex phenomenon, with the immune system at the center role interacting with all the other tissues and systems, would allow for more effective anti-aging strategies.
Collapse
|
|
33
|
DNA damage response of haematopoietic stem and progenitor cells to high-LET neutron irradiation. Sci Rep 2021; 11:20854. [PMID: 34675263 PMCID: PMC8531011 DOI: 10.1038/s41598-021-00229-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 10/05/2021] [Indexed: 11/23/2022] Open
Abstract
The radiosensitivity of haematopoietic stem and progenitor cells (HSPCs) to neutron radiation remains largely underexplored, notwithstanding their potential role as target cells for radiation-induced leukemogenesis. New insights are required for radiation protection purposes, particularly for aviation, space missions, nuclear accidents and even particle therapy. In this study, HSPCs (CD34+CD38+ cells) were isolated from umbilical cord blood and irradiated with 60Co γ-rays (photons) and high energy p(66)/Be(40) neutrons. At 2 h post-irradiation, a significantly higher number of 1.28 ± 0.12 γ-H2AX foci/cell was observed after 0.5 Gy neutrons compared to 0.84 ± 0.14 foci/cell for photons, but this decreased to similar levels for both radiation qualities after 18 h. However, a significant difference in late apoptosis was observed with Annexin-V+/PI+ assay between photon and neutron irradiation at 18 h, 43.17 ± 6.10% versus 55.55 ± 4.87%, respectively. A significant increase in MN frequency was observed after both 0.5 and 1 Gy neutron irradiation compared to photons illustrating higher levels of neutron-induced cytogenetic damage, while there was no difference in the nuclear division index between both radiation qualities. The results point towards a higher induction of DNA damage after neutron irradiation in HSPCs followed by error-prone DNA repair, which contributes to genomic instability and a higher risk of leukemogenesis.
Collapse
|
|
34
|
Samoilova EM, Belopasov VV, Ekusheva EV, Zhang C, Troitskiy AV, Baklaushev VP. Epigenetic Clock and Circadian Rhythms in Stem Cell Aging and Rejuvenation. J Pers Med 2021; 11:1050. [PMID: 34834402 PMCID: PMC8620936 DOI: 10.3390/jpm11111050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/12/2021] [Accepted: 10/14/2021] [Indexed: 12/12/2022] Open
Abstract
This review summarizes the current understanding of the interaction between circadian rhythms of gene expression and epigenetic clocks characterized by the specific profile of DNA methylation in CpG-islands which mirror the senescence of all somatic cells and stem cells in particular. Basic mechanisms of regulation for circadian genes CLOCK-BMAL1 as well as downstream clock-controlled genes (ССG) are also discussed here. It has been shown that circadian rhythms operate by the finely tuned regulation of transcription and rely on various epigenetic mechanisms including the activation of enhancers/suppressors, acetylation/deacetylation of histones and other proteins as well as DNA methylation. Overall, up to 20% of all genes expressed by the cell are subject to expression oscillations associated with circadian rhythms. Additionally included in the review is a brief list of genes involved in the regulation of circadian rhythms, along with genes important for cell aging, and oncogenesis. Eliminating some of them (for example, Sirt1) accelerates the aging process, while the overexpression of Sirt1, on the contrary, protects against age-related changes. Circadian regulators control a number of genes that activate the cell cycle (Wee1, c-Myc, p20, p21, and Cyclin D1) and regulate histone modification and DNA methylation. Approaches for determining the epigenetic age from methylation profiles across CpG islands in individual cells are described. DNA methylation, which characterizes the function of the epigenetic clock, appears to link together such key biological processes as regeneration and functioning of stem cells, aging and malignant transformation. Finally, the main features of adult stem cell aging in stem cell niches and current possibilities for modulating the epigenetic clock and stem cells rejuvenation as part of antiaging therapy are discussed.
Collapse
Affiliation(s)
- Ekaterina M. Samoilova
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, 115682 Moscow, Russia; (A.V.T.); (V.P.B.)
| | | | - Evgenia V. Ekusheva
- Academy of Postgraduate Education of the Federal Scientific and Clinical Center for Specialized Types of Medical Care and Medical Technologies, FMBA of Russia, 125371 Moscow, Russia;
| | - Chao Zhang
- Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China;
| | - Alexander V. Troitskiy
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, 115682 Moscow, Russia; (A.V.T.); (V.P.B.)
| | - Vladimir P. Baklaushev
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, 115682 Moscow, Russia; (A.V.T.); (V.P.B.)
| |
Collapse
|
|
35
|
PER2: a potential molecular marker for hematological malignancies. Mol Biol Rep 2021; 48:7587-7595. [PMID: 34642831 DOI: 10.1007/s11033-021-06751-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 09/16/2021] [Indexed: 11/27/2022]
Abstract
Circadian rhythm is a periodic change of organism according to the law of external environment, which is manifested in metabolism, cell proliferation, physiology and behavior. In recent years, the role of circadian genes in the occurrence and progression of hematological malignancies have been continuously demonstrated. PER2 is the core component of the circadian rhythm playing an important role in regulating the circadian rhythm of the biological clock. This review summarizes the research progress of PER2 in hematological malignancies, especially leukemia, in order to better understand its role in hematological malignancies, and provide new ideas for clinical diagnosis and treatment.
Collapse
|
|
36
|
Yang Y, Kong R, Goh FG, Somers WG, Hime GR, Li Z, Cai Y. dRTEL1 is essential for the maintenance of Drosophila male germline stem cells. PLoS Genet 2021; 17:e1009834. [PMID: 34644293 PMCID: PMC8513875 DOI: 10.1371/journal.pgen.1009834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 09/23/2021] [Indexed: 11/19/2022] Open
Abstract
Stem cells have the potential to maintain undifferentiated state and differentiate into specialized cell types. Despite numerous progress has been achieved in understanding stem cell self-renewal and differentiation, many fundamental questions remain unanswered. In this study, we identify dRTEL1, the Drosophila homolog of Regulator of Telomere Elongation Helicase 1, as a novel regulator of male germline stem cells (GSCs). Our genome-wide transcriptome analysis and ChIP-Seq results suggest that dRTEL1 affects a set of candidate genes required for GSC maintenance, likely independent of its role in DNA repair. Furthermore, dRTEL1 prevents DNA damage-induced checkpoint activation in GSCs. Finally, dRTEL1 functions to sustain Stat92E protein levels, the key player in GSC maintenance. Together, our findings reveal an intrinsic role of the DNA helicase dRTEL1 in maintaining male GSC and provide insight into the function of dRTEL1.
Collapse
Affiliation(s)
- Ying Yang
- Temasek Life Sciences Laboratory, National University of Singapore, Singapore, Singapore
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
- Department of Pathology, Peking University Health Science Center, Beijing, China
| | - Ruiyan Kong
- College of Life Sciences, Capital Normal University, Beijing, China
| | - Feng Guang Goh
- Temasek Life Sciences Laboratory, National University of Singapore, Singapore, Singapore
| | - W. Gregory Somers
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Australia
| | - Gary R. Hime
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Australia
| | - Zhouhua Li
- College of Life Sciences, Capital Normal University, Beijing, China
| | - Yu Cai
- Temasek Life Sciences Laboratory, National University of Singapore, Singapore, Singapore
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| |
Collapse
|
|
37
|
Rall-Scharpf M, Friedl TWP, Biechonski S, Denkinger M, Milyavsky M, Wiesmüller L. Sex-specific differences in DNA double-strand break repair of cycling human lymphocytes during aging. Aging (Albany NY) 2021; 13:21066-21089. [PMID: 34506302 PMCID: PMC8457596 DOI: 10.18632/aging.203519] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 08/10/2021] [Indexed: 12/15/2022]
Abstract
The gender gap in life expectancy and cancer incidence suggests differences in the aging process between the sexes. Genomic instability has been recognized as a key factor in aging, but little is known about sex-specific differences. Therefore, we analyzed DNA double-strand break (DSB) repair in cycling human peripheral blood lymphocytes (PBL) from male and female donors of different age. Reporter-based DSB repair analyses revealed differential regulation of pathway usage in PBL from male and female donors with age: Non-homologous end joining (NHEJ) was inversely regulated in men and women; the activity of pathways requiring end processing and strand annealing steps such as microhomology-mediated end joining (MMEJ) declined with age in women but not in men. Screening candidate proteins identified the NHEJ protein KU70 as well as the end resection regulatory factors ATM and BLM showing reduced expression during aging in women. Consistently, the regulatory factor BLM contributed to the MMEJ proficiency in young but not in old women as demonstrated by knockdown analysis. In conclusion, we show that DSB repair is subject to changes upon aging and age-related changes in DSB repair are distinct in men and women.
Collapse
Affiliation(s)
| | - Thomas W P Friedl
- Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany
| | - Shahar Biechonski
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel
| | - Michael Denkinger
- Institute for Geriatric Research Unit, Agaplesion Bethesda Hospital, Ulm University, Ulm, Germany
| | - Michael Milyavsky
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel
| | - Lisa Wiesmüller
- Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany
| |
Collapse
|
|
38
|
Borgoni S, Kudryashova KS, Burka K, de Magalhães JP. Targeting immune dysfunction in aging. Ageing Res Rev 2021; 70:101410. [PMID: 34280555 DOI: 10.1016/j.arr.2021.101410] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/28/2021] [Accepted: 07/14/2021] [Indexed: 12/23/2022]
Abstract
Human aging is a multifactorial phenomenon that affects numerous organ systems and cellular processes, with the immune system being one of the most dysregulated. Immunosenescence, the gradual deterioration of the immune system, and inflammaging, a chronic inflammatory state that persists in the elderly, are among the plethora of immune changes that occur during aging. Almost all populations of immune cells change with age in terms of numbers and/or activity. These alterations are in general highly detrimental, resulting in an increased susceptibility to infections, reduced healing abilities, and altered homeostasis that promote the emergence of age-associated diseases such as cancer, diabetes, and other diseases associated with inflammation. Thanks to recent developments, several strategies have been proposed to target central immunological processes or specific immune subpopulations affected by aging. These therapeutic approaches could soon be applied in the clinic to slow down or even reverse specific age-induced immune changes in order to rejuvenate the immune system and prevent or reduce the impact of various diseases. Due to its systemic nature and interconnection with all the other systems in the body, the immune system is an attractive target for aging intervention because relatively targeted modifications to a small set of cells have the potential to improve the health of multiple organ systems. Therefore, anti-aging immune targeting therapies could represent a potent approach for improving healthspan. Here, we review aging changes in the major components of the immune system, we summarize the current immune-targeting therapeutic approaches in the context of aging and discuss the future directions in the field of immune rejuvenation.
Collapse
|
|
39
|
Opportunities and Challenges in Stem Cell Aging. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1341:143-175. [PMID: 33748933 DOI: 10.1007/5584_2021_624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Studying aging, as a physiological process that can cause various pathological phenotypes, has attracted lots of attention due to its increasing burden and prevalence. Therefore, understanding its mechanism to find novel therapeutic alternatives for age-related disorders such as neurodegenerative and cardiovascular diseases is essential. Stem cell senescence plays an important role in aging. In the context of the underlying pathways, mitochondrial dysfunction, epigenetic and genetic alterations, and other mechanisms have been studied and as a consequence, several rejuvenation strategies targeting these mechanisms like pharmaceutical interventions, genetic modification, and cellular reprogramming have been proposed. On the other hand, since stem cells have great potential for disease modeling, they have been useful for representing aging and its associated disorders. Accordingly, the main mechanisms of senescence in stem cells and promising ways of rejuvenation, along with some examples of stem cell models for aging are introduced and discussed. This review aims to prepare a comprehensive summary of the findings by focusing on the most recent ones to shine a light on this area of research.
Collapse
|
|
40
|
Chen YK, Tan YY, Yao M, Lin HC, Tsai MH, Li YY, Hsu YJ, Huang TT, Chang CW, Cheng CM, Chuang CY. Bisphenol A-induced DNA damages promote to lymphoma progression in human lymphoblastoid cells through aberrant CTNNB1 signaling pathway. iScience 2021; 24:102888. [PMID: 34401669 PMCID: PMC8350018 DOI: 10.1016/j.isci.2021.102888] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 05/24/2021] [Accepted: 07/19/2021] [Indexed: 01/10/2023] Open
Abstract
Lymphoma is a group of blood cancers that develop from the immune system, and one of the main risk factors is associated with exposure to environmental chemicals. Bisphenol A (BPA) is a common chemical used in the manufacture of materials in polycarbonate and epoxy plastic products and can interfere with the immune system. BPA is considered to possibly induce lymphoma development by affecting the immune system, but its potential mechanisms have not been well established. This study performed a gene-network analysis of microarray data sets in human lymphoma tissues as well as in human cells with BPA exposure to explore module genes and construct the potential pathway for lymphomagenesis in response to BPA. This study provided evidence that BPA exposure resulted in disrupted cell cycle and DNA damage by activating CTNNB1, the initiator of the aberrant constructed CTNNB1-NFKB1-AR-IGF1-TWIST1 pathway, which may potentially lead to lymphomagenesis.
Collapse
Affiliation(s)
- Yin-Kai Chen
- Department of Hematology, National Taiwan University Cancer Center, Taipei, 106, Taiwan
| | - Yan-Yan Tan
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, 101, section 2, Kuang-Fu Road, Hsinchu, 30013, Taiwan
| | - Min Yao
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan
| | - Ho-Chen Lin
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, 101, section 2, Kuang-Fu Road, Hsinchu, 30013, Taiwan
| | - Mon-Hsun Tsai
- Institute of Biotechnology, National Taiwan University, Taipei, 106, Taiwan
| | - Yu-Yun Li
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, 101, section 2, Kuang-Fu Road, Hsinchu, 30013, Taiwan
| | - Yih-Jen Hsu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan
| | - Tsung-Tao Huang
- Biomedical Platform and Incubation Service Division, Taiwan Instrument Research Institute, National Applied Research Laboratories, Hsinchu, 302, Taiwan
| | - Chia-Wei Chang
- Biomedical Platform and Incubation Service Division, Taiwan Instrument Research Institute, National Applied Research Laboratories, Hsinchu, 302, Taiwan
| | - Chih-Ming Cheng
- Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, 310, Taiwan
- Mike & Clement TECH Co., Ltd., Changhua Country, Taiwan
| | - Chun-Yu Chuang
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, 101, section 2, Kuang-Fu Road, Hsinchu, 30013, Taiwan
| |
Collapse
|
|
41
|
Barabino SML, Citterio E, Ronchi AE. Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cancers (Basel) 2021; 13:cancers13153753. [PMID: 34359655 PMCID: PMC8345071 DOI: 10.3390/cancers13153753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/21/2021] [Accepted: 07/23/2021] [Indexed: 12/19/2022] Open
Abstract
Simple Summary The advent of DNA massive sequencing technologies has allowed for the first time an extensive look into the heterogeneous spectrum of genes and mutations underpinning myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). In this review, we wish to explore the most recent advances and the rationale for the potential therapeutic interest of three main actors in myelo-leukemic transformation: transcription factors that govern myeloid differentiation; RNA splicing factors, which ensure proper mRNA maturation and whose mutations increase R-loops formation; and deubiquitinating enzymes, which contribute to genome stability in hematopoietic stem cells (HSCs). Abstract Myeloid neoplasms encompass a very heterogeneous family of diseases characterized by the failure of the molecular mechanisms that ensure a balanced equilibrium between hematopoietic stem cells (HSCs) self-renewal and the proper production of differentiated cells. The origin of the driver mutations leading to preleukemia can be traced back to HSC/progenitor cells. Many properties typical to normal HSCs are exploited by leukemic stem cells (LSCs) to their advantage, leading to the emergence of a clonal population that can eventually progress to leukemia with variable latency and evolution. In fact, different subclones might in turn develop from the original malignant clone through accumulation of additional mutations, increasing their competitive fitness. This process ultimately leads to a complex cancer architecture where a mosaic of cellular clones—each carrying a unique set of mutations—coexists. The repertoire of genes whose mutations contribute to the progression toward leukemogenesis is broad. It encompasses genes involved in different cellular processes, including transcriptional regulation, epigenetics (DNA and histones modifications), DNA damage signaling and repair, chromosome segregation and replication (cohesin complex), RNA splicing, and signal transduction. Among these many players, transcription factors, RNA splicing proteins, and deubiquitinating enzymes are emerging as potential targets for therapeutic intervention.
Collapse
|
|
42
|
TFEB protein expression is reduced in aged brains and its overexpression mitigates senescence-associated biomarkers and memory deficits in mice. Neurobiol Aging 2021; 106:26-36. [PMID: 34229273 DOI: 10.1016/j.neurobiolaging.2021.06.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 05/18/2021] [Accepted: 06/03/2021] [Indexed: 12/16/2022]
Abstract
Identification of molecules and molecular pathways that can ameliorate aging-associated decline in cognitive function is crucial. Here we report that the protein levels of transcription factor EB (TFEB) were markedly reduced in both the cytosolic and nuclear fractions of the frontal cortex and hippocampus at 18-months of age relative to 6 months in the normal male wild-type mice. In the transgenic mice with ectopic expression of flag-TFEB in neurons, we observed that the levels of actin-normalized PGC1α and mtTFA were significantly increased in both the cortex and the hippocampus. Additionally, we confirmed increased mitochondria numbers in the flag-TFEB mice by transmission electron microscopy. Most importantly, TFEB expression in the 18-month-old transgenic mice mitigated markers of senescence including P16INK4a, γ-H2AX, and lamin B1, and improved memory skills implying that TFEB may exert an anti-aging effect by modulating neuronal senescence. Taken together these data strongly support that TFEB can be a useful therapeutic target for brain senescent cells to help overcome the age-related issues in cognition and possibly, achieve healthy aging.
Collapse
|
|
43
|
Durdik M, Kosik P, Jakl L, Kozackova M, Markova E, Vigasova K, Beresova K, Jakubikova J, Horvathova E, Zastko L, Fekete M, Zavacka I, Pobijakova M, Belyaev I. Imaging flow cytometry and fluorescence microscopy in assessing radiation response in lymphocytes from umbilical cord blood and cancer patients. Cytometry A 2021; 99:1198-1208. [PMID: 34089242 DOI: 10.1002/cyto.a.24468] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 05/31/2021] [Accepted: 06/01/2021] [Indexed: 12/28/2022]
Abstract
DNA double strand breaks (DSB) induced by ionizing radiation (IR) are usually measured using γH2AX/53BP1 DNA repair foci, that is considered to be the most sensitive assay for DSB analysis. While fluorescence microscopy (FM) is the gold standard for this analysis, imaging flow cytometry (IFC) may offer number of advantages such as lack of the fluorescence background, higher number of cells analyzed, and higher sensitivity in detection of DNA damage induced by IR at low doses. Along with appearance of γH2AX foci, the variable fraction of the cells exhibits homogeneously stained γH2AX signal resulting in so-called γH2AX pan-staining, which is believed to appear at early stages of apoptosis. Here, we investigated incidence of γH2AX pan-staining at different time points after irradiation with γ-rays using IFC and compared the obtained data with the data from FM. Appearance of γH2AX pan-staining during the apoptotic process was further analyzed by fluorescence-activated cell sorting (FACS) of cells at different stages of apoptosis and subsequent immunofluorescence analysis. Our results show that IFC was able to reveal dose dependence of pan-staining, while FM failed to detect all pan-staining cells. Moreover, we found that γH2AX pan-staining could be induced by therapeutic, but not low doses of γ-rays and correlate well with percentage of apoptotic cells was analyzed using flow cytometric Annexin-V/7-AAD assay. Further investigations showed that γH2AX pan-staining is formed in the early phases of apoptosis and remains until later stages of apoptotic process. Apoptotic DNA fragmentation as detected with comet assay using FM correlated with the percentage of live and late apoptotic/necrotic cells as analyzed by flow cytometry. Lastly, we successfully tested IFC for detection of γH2AX pan-staining and γH2AX/53BP1 DNA repair foci in lymphocyte of breast cancer patients after radiotherapy, which may be useful for assessing individual radiosensitivity in a clinically relevant cohort of patients.
Collapse
Affiliation(s)
- Matus Durdik
- Department of Radiobiology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Pavol Kosik
- Department of Radiobiology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Lukas Jakl
- Department of Radiobiology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Maria Kozackova
- Department of Radiobiology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Eva Markova
- Department of Radiobiology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Katarina Vigasova
- Department of Radiobiology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Katarina Beresova
- Department of Radiobiology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Jana Jakubikova
- Department of Tumor Immunology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Eva Horvathova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Lucian Zastko
- Department of Radiobiology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Marta Fekete
- Department of Radiation Oncology, National Cancer Institute, Bratislava, Slovakia
| | - Ingrid Zavacka
- Department of Radiation Oncology, National Cancer Institute, Bratislava, Slovakia
| | - Margita Pobijakova
- Department of Radiation Oncology, National Cancer Institute, Bratislava, Slovakia
| | - Igor Belyaev
- Department of Radiobiology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Bratislava, Slovakia
| |
Collapse
|
|
44
|
Evaluation of Calyculin A Effect on γH2AX/53BP1 Focus Formation and Apoptosis in Human Umbilical Cord Blood Lymphocytes. Int J Mol Sci 2021; 22:ijms22115470. [PMID: 34067339 PMCID: PMC8196852 DOI: 10.3390/ijms22115470] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/18/2021] [Accepted: 05/20/2021] [Indexed: 12/13/2022] Open
Abstract
Dephosphorylation inhibitor calyculin A (cal A) has been reported to inhibit the disappearance of radiation-induced γH2AX DNA repair foci in human lymphocytes. However, other studies reported no change in the kinetics of γH2AX focus induction and loss in irradiated cells. While apoptosis might interplay with the kinetics of focus formation, it was not followed in irradiated cells along with DNA repair foci. Thus, to validate plausible explanations for significant variability in outputs of these studies, we evaluated the effect of cal A (1 and 10 nM) on γH2AX/53BP1 DNA repair foci and apoptosis in irradiated (1, 5, 10, and 100 cGy) human umbilical cord blood lymphocytes (UCBL) using automated fluorescence microscopy and annexin V-FITC/propidium iodide assay/γH2AX pan-staining, respectively. No effect of cal A on γH2AX and colocalized γH2AX/53BP1 foci induced by low doses (≤10 cGy) of γ-rays was observed. Moreover, 10 nM cal A treatment decreased the number of all types of DNA repair foci induced by 100 cGy irradiation. 10 nM cal A treatment induced apoptosis already at 2 h of treatment, independently from the delivered dose. Apoptosis was also detected in UCBL treated with lower cal A concentration, 1 nM, at longer cell incubation, 20 and 44 h. Our data suggest that apoptosis triggered by cal A in UCBL may underlie the failure of cal A to maintain radiation-induced γH2AX foci. All DSB molecular markers used in this study responded linearly to low-dose irradiation. Therefore, their combination may represent a strong biodosimetry tool for estimation of radiation response to low doses. Assessment of colocalized γH2AX/53BP1 improved the threshold of low dose detection.
Collapse
|
|
45
|
Rübe CE, Bäumert C, Schuler N, Isermann A, Schmal Z, Glanemann M, Mann C, Scherthan H. Human skin aging is associated with increased expression of the histone variant H2A.J in the epidermis. NPJ Aging Mech Dis 2021; 7:7. [PMID: 33795696 PMCID: PMC8016850 DOI: 10.1038/s41514-021-00060-z] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 01/26/2021] [Indexed: 01/08/2023] Open
Abstract
Cellular senescence is an irreversible growth arrest that occurs as a result of damaging stimuli, including DNA damage and/or telomere shortening. Here, we investigate histone variant H2A.J as a new biomarker to detect senescent cells during human skin aging. Skin biopsies from healthy volunteers of different ages (18–90 years) were analyzed for H2A.J expression and other parameters involved in triggering and/or maintaining cellular senescence. In the epidermis, the proportions of H2A.J-expressing keratinocytes increased from ≈20% in young to ≈60% in aged skin. Inverse correlations between Ki67- and H2A.J staining in germinative layers may reflect that H2A.J-expressing cells having lost their capacity to divide. As cellular senescence is triggered by DNA-damage signals, persistent 53BP1-foci, telomere lengths, and telomere-associated damage foci were analyzed in epidermal keratinocytes. Only slight age-related telomere attrition and few persistent nuclear 53BP1-foci, occasionally colocalizing with telomeres, suggest that unprotected telomeres are not a significant cause of senescence during skin aging. Quantification of integrin-α6+ basal cells suggests that the number and function of stem/progenitor cells decreased during aging and their altered proliferation capacities resulted in diminished tissue renewal with epidermal thinning. Collectively, our findings suggest that H2A.J is a sensitive marker of epidermal aging in human skin.
Collapse
Affiliation(s)
- Claudia E Rübe
- Saarland University Hospital, Department of Radiation Oncology, Homburg/Saar, Germany.
| | - Caroline Bäumert
- Saarland University Hospital, Department of Radiation Oncology, Homburg/Saar, Germany
| | - Nadine Schuler
- Saarland University Hospital, Department of Radiation Oncology, Homburg/Saar, Germany
| | - Anna Isermann
- Saarland University Hospital, Department of Radiation Oncology, Homburg/Saar, Germany
| | - Zoé Schmal
- Saarland University Hospital, Department of Radiation Oncology, Homburg/Saar, Germany
| | - Matthias Glanemann
- Saarland University Hospital, Department of Visceral Surgery, Homburg/Saar, Germany
| | - Carl Mann
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette Cedex, France
| | - Harry Scherthan
- Bundeswehr Inst. of Radiobiology affiliated to the Univ. of Ulm, München, Germany
| |
Collapse
|
|
46
|
Chen Y, Sun J, Ju Z, Wang ZQ, Li T. Nbs1-mediated DNA damage repair pathway regulates haematopoietic stem cell development and embryonic haematopoiesis. Cell Prolif 2021; 54:e12972. [PMID: 33586242 PMCID: PMC7941224 DOI: 10.1111/cpr.12972] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/27/2020] [Accepted: 12/07/2020] [Indexed: 12/16/2022] Open
Abstract
Objectives DNA damages pose threats to haematopoietic stem cells (HSC) maintenance and haematopoietic system homeostasis. Quiescent HSCs in adult mouse bone marrow are resistant to DNA damage, while human umbilical cord blood‐derived proliferative HSCs are prone to cell death upon ionizing radiation. Murine embryonic HSCs proliferate in foetal livers and divide symmetrically to generate HSC pool. How murine embryonic HSCs respond to DNA damages is not well‐defined. Materials and methods Mice models with DNA repair molecule Nbs1 or Nbs1/p53 specifically deleted in embryonic HSCs were generated. FACS analysis, in vitro and in vivo HSC differentiation assays, qPCR, immunofluorescence and Western blotting were used to delineate roles of Nbs1‐p53 signaling in HSCs and haematopoietic progenitors. Results Nbs1 deficiency results in persistent DNA breaks in embryonic HSCs, compromises embryonic HSC development and finally results in mouse perinatal lethality. The persistent DNA breaks in Nbs1 deficient embryonic HSCs render cell cycle arrest, while driving a higher rate of cell death in haematopoietic progenitors. Although Nbs1 deficiency promotes Atm‐Chk2‐p53 axis activation in HSCs and their progenies, ablation of p53 in Nbs1 deficient HSCs accelerates embryonic lethality. Conclusions Our study discloses that DNA double‐strand repair molecule Nbs1 is essential in embryonic HSC development and haematopoiesis. Persistent DNA damages result in distinct cell fate in HSCs and haematopoietic progenitors. Nbs1 null HSCs tend to be maintained through cell cycle arrest, while Nbs1 null haematopoietic progenitors commit cell death. The discrepancies are mediated possibly by different magnitude of p53 signaling.
Collapse
Affiliation(s)
- Yu Chen
- Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Jie Sun
- Jiangsu Hansoh Pharmaceutical Group Co., Ltd., Lianyungang, China
| | - Zhenyu Ju
- Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Zhao-Qi Wang
- Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.,Faculty of Biology and Pharmacy, Friedrich-Schiller University of Jena, Jena, Germany
| | - Tangliang Li
- Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China.,State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China.,NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, China
| |
Collapse
|
|
47
|
Abstract
PURPOSE OF REVIEW Hematopoietic stem cells (HSCs) are defined by their ability to self-renew and differentiate to replenish all blood lineages throughout adult life. Under homeostasis, the majority of HSCs are quiescent, and few stem cells are cycling to sustain hematopoiesis. However, HSCs can be induced to proliferate and differentiate in response to stress signals produced during infection, inflammation, chemotherapy, radiation, bone marrow transplantation, and aging. Recent evidence suggests that acute and chronic stress impact the number and function of HSCs including their ability to repopulate and produce mature cells. This review will focus on how chronic stress affects HSC biology and methods to mitigate HSC loss during chronic hematopoietic stress. RECENT FINDINGS Quiescent HSCs exit dormancy, divide, and differentiate to maintain steady-state hematopoiesis. Under conditions of acute stress including infection or blood loss some HSCs are pushed into division by cytokines and proinflammatory stimuli to differentiate and provide needed myeloid and erythroid cells to protect and reconstitute the host; after which, hematopoiesis returns to steady-state with minimal loss of HSC function. However, under conditions of chronic stress including serial bone marrow transplantation (BMT), chronic inflammation, and genotoxic stress (chemotherapy) and aging, HSCs are continuously induced to proliferate and undergo accelerated exhaustion. Recent evidence demonstrates that ablation of inhibitor of DNA binding 1 (Id1) gene can protect HSCs from exhaustion during chronic proliferative stress by promoting HSC quiescence. SUMMARY Increasing our understanding of the molecular processes that protect HSCs from chronic proliferative stress could lead to therapeutic opportunities to prevent accelerated HSC exhaustion during physiological stress, genotoxic stress, BMT, and aging.
Collapse
|
|
48
|
Grajeda Y, Arias N, Barrios A, Pervin S, Singh R. Aging-induced stem cell dysfunction: Molecular mechanisms and potential therapeutic avenues. STEM CELLS AND AGING 2021:203-222. [DOI: 10.1016/b978-0-12-820071-1.00005-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
49
|
García‐Lepe UO, Cruz‐Ramírez A, Bermúdez‐Cruz RM. DNA repair during regeneration in
Ambystoma mexicanum. Dev Dyn 2020; 250:788-799. [DOI: 10.1002/dvdy.276] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 11/19/2020] [Accepted: 12/03/2020] [Indexed: 12/22/2022] Open
Affiliation(s)
- Ulises Omar García‐Lepe
- Genetics and Molecular Biology Department Centro de Investigacion y Estudios Avanzados del IPN Mexico city Mexico
| | - Alfredo Cruz‐Ramírez
- Molecular and Developmental Complexity Group Unidad de Genómica Avanzada (LANGEBIO), Centro de Investigación y de Estudios Avanzados del IPN Guanajuato Mexico
| | - Rosa María Bermúdez‐Cruz
- Genetics and Molecular Biology Department Centro de Investigacion y Estudios Avanzados del IPN Mexico city Mexico
| |
Collapse
|
|
50
|
Propagation and Maintenance of Cancer Stem Cells: A Major Influence of the Long Non-Coding RNA H19. Cells 2020; 9:cells9122613. [PMID: 33291403 PMCID: PMC7762009 DOI: 10.3390/cells9122613] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/02/2020] [Accepted: 12/03/2020] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) represent a rare population of tumor cells that exhibit stem cell properties with the abilities of self-renewal and differentiation. These cells are now widely accepted to be responsible for tumor initiation, development, resistance to conventional therapies, and recurrence. Thus, a better understanding of the molecular mechanisms involved in the control of CSCs is essential to improve patient management in terms of diagnostics and therapies. CSCs are regulated by signals of the tumor microenvironment as well as intrinsic genetic and epigenetic modulators. H19, the first identified lncRNA is involved in the development and progression of many different cancer types. Recently, H19 has been demonstrated to be implicated in the regulation of CSCs in different types of cancers. The aim of this review is to provide an overview of the role and mechanisms of action of H19 in the regulation of CSCs. We summarize how H19 may regulate CSC division and cancer cell reprogramming, thus affecting metastasis and drug resistance. We also discuss the potential clinical implications of H19.
Collapse
|