1
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Ji Z, Zhang Y, Hu G, Hong S, Su Z, Zhang Q, Wang L, Wang T, Yu S, Bu Q, Yuan F, Zhu X, Jia G. Hexavalent chromium and cellular senescence: A comprehensive analysis from chromate-exposed occupational population and chromate-inhaled mouse model. JOURNAL OF HAZARDOUS MATERIALS 2025; 493:138387. [PMID: 40286659 DOI: 10.1016/j.jhazmat.2025.138387] [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: 02/16/2025] [Revised: 04/15/2025] [Accepted: 04/22/2025] [Indexed: 04/29/2025]
Abstract
Cellular senescence may predominantly drive the progression of early subclinical injury under conditions of low-dose, long-term occupational exposure. However, previous research has largely overlooked the cellular senescence induced by hexavalent chromium [Cr(VI)]. To bridge the gap, 304 workers from a chromate facility were enrolled, and a mouse model was used to confirm the effects of Cr(VI) on cellular senescence. A 2.7-fold increase in blood Cr was related to the changes of p53 [23.19 (13.06, 34.23)%], serum α-Klotho [11.45 (6.13, 17.04)%], adipsin [-14.11(-22.16, -5.24)%], leptin [-4.32(-6.99, -1.58)%] and resistin [-3.29(-5.54, -0.98)%]. There were significant correlations of blood Cr with DNA methylation of ELOVL2 and hTERT genes. Furthermore, methylation at hTERT Pos1, Pos2, Pos6, and Pos8 significantly mediated the relationship between blood Cr and p53. In the mouse model, we observed significantly higher mRNA expression levels of key genes in the p53/p21 and Rb/p16 pathways and senescence-associated β-galactosidase positive cell ratio in the exposed group. In conclusion, we found that p53 in human peripheral blood cells serves as a Cr(VI)-induced senescence biomarker, with α-Klotho upregulation and adipokines (adipsin, leptin, and resistin) downregulation indicating compensatory responses, as well as hTERT methylation partially mediating Cr(VI)-senescence association.
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Affiliation(s)
- Zhiqiang Ji
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100191, PR China
| | - Yali Zhang
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100191, PR China
| | - Guiping Hu
- School of Engineering Medicine and Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Beijing 100191, PR China
| | - Shiyi Hong
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100191, PR China
| | - Zekang Su
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100191, PR China
| | - Qiaojian Zhang
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100191, PR China
| | - Li Wang
- Department of Toxicology, School of Public Health, Baotou Medical College, Baotou, Inner Mongolia 014040, PR China
| | - Tiancheng Wang
- Department of Clinical Laboratory, Third Hospital of Peking University, Beijing 100191, PR China
| | - Shanfa Yu
- Henan Institute for Occupational Medicine, Zhengzhou, Henan 450052, PR China
| | - Qian Bu
- The Disease Control and Prevention Center of Tongnan District, Chongqing 402660, PR China
| | - Fang Yuan
- Department of Occupational Health and Radiological Health, Chongqing Center for Disease Control and Prevention, Chongqing 400042, PR China
| | - Xiaojun Zhu
- National Center for Occupational Safety and Health, Beijing 102308, PR China
| | - Guang Jia
- Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, School of Public Health, Peking University, Beijing 100191, PR China.
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2
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Chandra A, Law SF, Pignolo RJ. Changing landscape of hematopoietic and mesenchymal cells and their interactions during aging and in age-related skeletal pathologies. Mech Ageing Dev 2025; 225:112059. [PMID: 40220914 PMCID: PMC12103995 DOI: 10.1016/j.mad.2025.112059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 03/26/2025] [Accepted: 04/09/2025] [Indexed: 04/14/2025]
Abstract
Aging profoundly impacts mesenchymal and hematopoietic lineage cells, including their progenitors-the skeletal stem cells (SSCs) and hematopoietic stem cells (HSCs), respectively. SSCs are crucial for skeletal development, homeostasis, and regeneration, maintaining bone integrity by differentiating into osteoblasts, adipocytes, and other lineages that contribute to the bone marrow (BM) microenvironment. Meanwhile, HSCs sustain hematopoiesis and immune function. With aging, SSCs and HSCs undergo significant functional decline, partly driven by cellular senescence-a hallmark of aging characterized by irreversible growth arrest, secretion of pro-inflammatory factors (senescence associated secretory phenotype, SASP), and impaired regenerative potential. In SSCs, senescence skews lineage commitment toward adipogenesis at the expense of osteogenesis, contributing to increased bone marrow adiposity , reduced bone quality, and osteoporosis. Similarly, aged HSCs exhibit diminished self-renewal, biased differentiation, and heightened inflammation, compromising hematopoietic output and immune function. In this review, we examine the age-related cellular and molecular changes in SSCs and HSCs, their lineage decisions in the aging microenvironment, and the interplay between skeletal and hematopoietic compartments. We also discuss the role of senescence-driven alterations in BM homeostasis and how targeting cellular aging mechanisms may offer therapeutic strategies for mitigating age-related skeletal and hematopoietic decline.
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Affiliation(s)
- Abhishek Chandra
- Department of Physiology and Biomedical Engineering, USA; Department of Medicine, Divisions of Hospital Internal Medicine and Section on Geriatric Medicine and Gerontology, USA; Robert and Arlene Kogod Aging Center, Mayo Clinic, Rochester, MN, USA.
| | - Susan F Law
- Robert and Arlene Kogod Aging Center, Mayo Clinic, Rochester, MN, USA
| | - Robert J Pignolo
- Department of Physiology and Biomedical Engineering, USA; Department of Medicine, Divisions of Hospital Internal Medicine and Section on Geriatric Medicine and Gerontology, USA; Robert and Arlene Kogod Aging Center, Mayo Clinic, Rochester, MN, USA
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3
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Picos A, Seoane N, Campos-Toimil M, Viña D. Vascular senescence and aging: mechanisms, clinical implications, and therapeutic prospects. Biogerontology 2025; 26:118. [PMID: 40418230 PMCID: PMC12106568 DOI: 10.1007/s10522-025-10256-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Accepted: 05/11/2025] [Indexed: 05/27/2025]
Abstract
The aging vasculature is characterized by endothelial dysfunction, arterial stiffness, and increased susceptibility to vascular pathologies. Central to these changes is the process of cellular senescence, where endothelial and vascular smooth muscle cells lose their replicative and functional capacity and adopt a pro-inflammatory secretory phenotype. This review provides an overview of the key mechanisms underlying vascular senescence, including the p53/p21 and p16/Rb pathways, the senescence-associated secretory phenotype (SASP), and oxidative stress, examines its contribution to cardiovascular diseases in older adults, and highlights emerging therapeutic strategies aimed at delaying or reversing these age-related vascular changes. In vascular cells, DNA damage, oxidative stress, and chronic inflammation associated with aging converge to amplify senescence. Clinically, vascular senescence is linked with hypertension, atherosclerosis, and increased overall cardiovascular risk. Several interventions, ranging from senolytics to lifestyle factors, show promise in mitigating these changes; however, long-term studies are needed. Given that vascular senescence is a pivotal driver of cardiovascular pathology in aging, targeting senescent cells or their secretory phenotype may potentially offer new avenues for preventing or attenuating age-related vascular diseases. This review presents an updated and integrative overview of vascular senescence, connecting fundamental cellular mechanisms with their clinical manifestations and highlighting the most promising therapeutic interventions.
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Affiliation(s)
- Aitor Picos
- Physiology and Pharmacology of Chronic Diseases (FIFAEC), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
- Translational Research in Neurological Diseases (ITEN), Health Research Institute of Santiago de Compostela (IDIS), USC University Hospital Complex (CHUS), SERGAS, Santiago de Compostela, Spain.
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
| | - Nuria Seoane
- Physiology and Pharmacology of Chronic Diseases (FIFAEC), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782, Santiago de Compostela, Spain
- Translational Research in Neurological Diseases (ITEN), Health Research Institute of Santiago de Compostela (IDIS), USC University Hospital Complex (CHUS), SERGAS, Santiago de Compostela, Spain
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain
| | - Manuel Campos-Toimil
- Physiology and Pharmacology of Chronic Diseases (FIFAEC), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
- Translational Research in Neurological Diseases (ITEN), Health Research Institute of Santiago de Compostela (IDIS), USC University Hospital Complex (CHUS), SERGAS, Santiago de Compostela, Spain.
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
| | - Dolores Viña
- Physiology and Pharmacology of Chronic Diseases (FIFAEC), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782, Santiago de Compostela, Spain
- Translational Research in Neurological Diseases (ITEN), Health Research Institute of Santiago de Compostela (IDIS), USC University Hospital Complex (CHUS), SERGAS, Santiago de Compostela, Spain
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain
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Tavares-Marcos C, Correia M, de Jesus BB. Telomeres as hallmarks of iPSC aging: a review on telomere dynamics during stemness and cellular reprogramming. Ageing Res Rev 2025:102773. [PMID: 40414363 DOI: 10.1016/j.arr.2025.102773] [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: 04/03/2025] [Revised: 05/03/2025] [Accepted: 05/14/2025] [Indexed: 05/27/2025]
Abstract
Telomeres, the protective ends of chromosome, are key to tissue repair and regeneration. Telomere shortening is linked to aging and age-related disorders, while excessive telomerase activity may support tissue regeneration or transformation. Some of the functions of telomeres and telomerase may be mediated by its important role in the process of stemness. Active telomerase, and subsequent telomerase-dependent telomere extension, supports stem-cells self-renewal and pluripotency - essential for tissue healing. During cellular reprogramming, differentiated cells are converted into induced pluripotent stem cells (iPSCs), which resemble embryonic stem cells. During iPSC derivation, telomere length is reset, enhancing iPSCs' regenerative potential. During this process, incomplete telomerase activation and telomere extension can lead to genomic instability and/or haltered cell functionality. Understanding the intricate relation of telomeres, telomerase and stemness may be critical when designing novel cell-based therapies targeting degenerative diseases or to unlock strategies to delay aging. Here, we explore the recent bibliography linking these areas, raising awareness of their important when designing novel breakthroughs in health and longevity.
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Affiliation(s)
- Carlota Tavares-Marcos
- Department of Medical Sciences and Institute of Biomedicine - iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Magda Correia
- Department of Medical Sciences and Institute of Biomedicine - iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Bruno Bernardes de Jesus
- Department of Medical Sciences and Institute of Biomedicine - iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal.
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5
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Wu C, Chen D, Stout MB, Wu M, Wang S. Hallmarks of ovarian aging. Trends Endocrinol Metab 2025; 36:418-439. [PMID: 40000274 DOI: 10.1016/j.tem.2025.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 02/27/2025]
Abstract
Ovarian aging is considered to be the pacemaker of female aging, and is linked to various comorbidities such as osteoporosis, cardiovascular diseases, and cognitive decline. Many efforts have been made to determine the mechanisms underlying ovarian aging, but their potential to act as hallmarks to predict and intervene in this process currently remains unclear. In this review we propose nine hallmarks as common features of ovarian aging: genomic instability, telomere attrition, epigenetic alterations, impaired autophagy, cellular senescence, deregulated nutrient-sensing, mitochondrial dysfunction, oxidative stress, and chronic inflammation. Understanding the interaction between these hallmarks poses a significant challenge but may also pave the way to the identification of pharmaceutical targets that can attenuate ovarian aging.
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Affiliation(s)
- Chuqing Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, 430030 Wuhan, Hubei, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, 430030 Wuhan, Hubei, China
| | - Dan Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, 430030 Wuhan, Hubei, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, 430030 Wuhan, Hubei, China
| | - Michael B Stout
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK, USA
| | - Meng Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, 430030 Wuhan, Hubei, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, 430030 Wuhan, Hubei, China.
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, 430030 Wuhan, Hubei, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, 430030 Wuhan, Hubei, China.
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6
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Hanley SM, Schutte NS, Bellamy J, Denham J. Shorter Telomeres and Faster Telomere Attrition in Individuals With Five Syndromic Forms of Intellectual Disability: A Systematic Review and Meta-Analysis. JOURNAL OF INTELLECTUAL DISABILITY RESEARCH : JIDR 2025. [PMID: 40274277 DOI: 10.1111/jir.13244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 04/08/2025] [Accepted: 04/09/2025] [Indexed: 04/26/2025]
Abstract
BACKGROUND People with intellectual disability suffer complex challenges due to adaptive functioning limitations, high rates of chronic diseases and shortened lifespans compared with the general population. Telomere shortening is a hallmark of ageing, and short telomeres are linked to neurological disorders. The main objective of this systematic review and meta-analysis was to identify any differences in telomere length and the rate of telomere attrition in leukocytes and fibroblasts from people with intellectual disability and controls. METHODS PubMed, Scopus and ScienceDirect were searched. Articles that compared telomere length in individuals with intellectual disability to apparently healthy age-matched controls were included. Risk of bias was assessed using the AXIS tool and data were analysed using CMA. RESULTS Fifteen studies comprised of 17 comparisons provided data and were included in meta-analyses. Compared with healthy controls (N = 481), people with intellectual disability (N = 366) from a known genetic syndrome (Cri du chat, Down, Hoyeraal-Hreidarsson, Williams or Nicolaides-Baraitser) possessed shorter leukocyte telomeres (SMD: -0.853 [95% CI: -1.622 to -0.084], p = 0.03). Similarly, relative to controls (N = 16), people with syndromic intellectual disability (N = 21) possessed shorter fibroblast telomeres (-1.389 [-2.179 to -0.599], p = 0.001). Furthermore, people with syndromic forms of intellectual disability also demonstrated a faster rate (2.09-fold) of telomere shortening. CONCLUSIONS Consistent with epidemiological findings on mortality and morbidity risk, people with syndromic intellectual disability appear to undergo a faster rate of biological ageing compared to the general population. These findings emphasise the need for healthy ageing lifestyle (i.e., exercise and stress management) and therapeutic interventions for people with syndromic intellectual disability.
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Affiliation(s)
- Sarah M Hanley
- School of Psychology, University of New England, Armidale, New South Wales, Australia
| | - Nicola S Schutte
- School of Psychology, University of New England, Armidale, New South Wales, Australia
| | - Jessica Bellamy
- School of Medical, Indigenous and Health Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia
- Department of Developmental Disability Neuropsychiatry (3DN), School of Clinical Medicine, UNSW Sydney, Sydney, New South Wales, Australia
| | - Joshua Denham
- School of Health and Medical Sciences, University of Southern Queensland, Toowoomba, Queensland, Australia
- Centre for Health Research, Toowoomba, Queensland, Australia
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Park TI, Yang AH, Kanth BK, Pack SP. Aptamers as Diagnostic and Therapeutic Agents for Aging and Age-Related Diseases. BIOSENSORS 2025; 15:232. [PMID: 40277546 PMCID: PMC12024714 DOI: 10.3390/bios15040232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 04/01/2025] [Accepted: 04/02/2025] [Indexed: 04/26/2025]
Abstract
In the 21st century, the demographic shift toward an aging population has posed a significant challenge, particularly with respect to age-related diseases, which constitute a major threat to human health. Accordingly, the detection, prevention, and treatment of aging and age-related diseases have become critical issues, and the introduction of novel molecular recognition elements, called aptamers, has been considered. Aptamers, a class of oligonucleotides, can bind to target molecules with high specificity. In addition, aptamers exhibit superior stability, biocompatibility, and applicability, rendering them promising tools for the diagnosis and treatment of human diseases. In this paper, we present a comprehensive overview of aptamers, systematic evolution of ligands by exponential enrichment (SELEX), biomarkers associated with aging, as well as aptamer-based diagnostic and therapeutic platforms. Finally, the limitations associated with predicting and preventing age-related conditions are discussed, along with potential solutions based on advanced technologies and theoretical approaches.
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Affiliation(s)
- Tae-In Park
- Department of Biotechnology and Bioinformatics, Korea University, Sejong 30019, Republic of Korea; (T.-I.P.); (A.H.Y.)
| | - Ah Hyun Yang
- Department of Biotechnology and Bioinformatics, Korea University, Sejong 30019, Republic of Korea; (T.-I.P.); (A.H.Y.)
| | - Bashistha Kumar Kanth
- Department of Food Science and Nutrition, Dong-A University, Pusan 602760, Republic of Korea;
| | - Seung Pil Pack
- Department of Biotechnology and Bioinformatics, Korea University, Sejong 30019, Republic of Korea; (T.-I.P.); (A.H.Y.)
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8
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Roig-Soriano J, Edo Á, Verdés S, Martín-Alonso C, Sánchez-de-Diego C, Rodriguez-Estevez L, Serrano AL, Abraham CR, Bosch A, Ventura F, Jordan BA, Muñoz-Cánoves P, Chillón M. Long-term effects of s-KL treatment in wild-type mice: Enhancing longevity, physical well-being, and neurological resilience. Mol Ther 2025; 33:1449-1465. [PMID: 39988871 PMCID: PMC11997498 DOI: 10.1016/j.ymthe.2025.02.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 09/30/2024] [Accepted: 02/19/2025] [Indexed: 02/25/2025] Open
Abstract
Aging is a major risk factor for pathologies including sarcopenia, osteoporosis, and cognitive decline, which bring suffering, disability, and elevated economic and social costs. Therefore, new therapies are needed to achieve healthy aging. The protein Klotho (KL) has emerged as a promising anti-aging molecule due to its pleiotropic actions modulating insulin, insulin-like growth factor-1, and Wnt signaling pathways and reducing inflammatory and oxidative stress. Here, we explored the anti-aging potential of the secreted isoform of this protein on the non-pathological aging progression of wild-type mice. The delivery of an adeno-associated virus serotype 9 (AAV9) coding for secreted KL (s-KL) efficiently increased the concentration of s-KL in serum, resulting in a 20% increase in lifespan. Notably, KL treatment improved physical fitness, related to a reduction in muscle fibrosis and an increase in muscular regenerative capacity. KL treatment also improved bone microstructural parameters associated with osteoporosis. Finally, s-KL-treated mice exhibited increased cellular markers of adult neurogenesis and immune response, with transcriptomic analysis revealing induced phagocytosis and immune cell activity in the aged hippocampus. These results show the potential of elevating s-KL expression to simultaneously reduce the age-associated degeneration in multiple organs, increasing both life and health span.
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Affiliation(s)
- Joan Roig-Soriano
- Institut de Neurociènces (INc), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Vall d'Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain
| | - Ángel Edo
- Institut de Neurociènces (INc), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Vall d'Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain
| | - Sergi Verdés
- Institut de Neurociènces (INc), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Vall d'Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain
| | - Carlos Martín-Alonso
- Institut de Neurociènces (INc), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | | | - Laura Rodriguez-Estevez
- Institut de Neurociènces (INc), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Vall d'Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain
| | - Antonio L Serrano
- Department of Medicine and Life Sciences, Pompeu Fabra University, 08003 Barcelona, Spain; Altos Labs, San Diego Institute of Science, San Diego, CA 92122, USA
| | | | - Assumpció Bosch
- Institut de Neurociènces (INc), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Vall d'Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain; Ciberned, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | | | - Bryen A Jordan
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Pura Muñoz-Cánoves
- Department of Medicine and Life Sciences, Pompeu Fabra University, 08003 Barcelona, Spain; ICREA, 08010 Barcelona, Spain; Altos Labs, San Diego Institute of Science, San Diego, CA 92122, USA
| | - Miguel Chillón
- Institut de Neurociènces (INc), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Vall d'Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain; ICREA, 08010 Barcelona, Spain; Unitat de Producció de Vectors (UPV), Universitat Autònoma de Barcelona, 08193 Barcelona, Spain.
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9
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Zhu T, Hu P, Mi Y, Zhang J, Xu A, Gao M, Zhang Y, Shen S, Yang G, Pan Y. Telomerase reverse transcriptase gene knock-in unleashes enhanced longevity and accelerated damage repair in mice. Aging Cell 2025; 24:e14445. [PMID: 39660787 PMCID: PMC11984681 DOI: 10.1111/acel.14445] [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: 04/22/2024] [Revised: 10/24/2024] [Accepted: 11/13/2024] [Indexed: 12/12/2024] Open
Abstract
While previous research has demonstrated the therapeutic efficacy of telomerase reverse transcriptase (TERT) overexpression using adeno-associated virus and cytomegalovirus vectors to combat aging, the broader implications of TERT germline gene editing on the mammalian genome, proteomic composition, phenotypes, lifespan extension, and damage repair remain largely unexplored. In this study, we elucidate the functional properties of transgenic mice carrying the Tert transgene, guided by precise gene targeting into the Rosa26 locus via embryonic stem (ES) cells under the control of the elongation factor 1α (EF1α) promoter. The Tert knock-in (TertKI) mice harboring the EF1α-Tert gene displayed elevated telomerase activity, elongated telomeres, and extended lifespan, with no spontaneous genotoxicity or carcinogenicity. The TertKI mice showed also enhanced wound healing, characterized by significantly increased expression of Fgf7, Vegf, and collagen. Additionally, TertKI mice exhibited robust resistance to the progression of colitis induced by dextran sodium sulfate (DSS), accompanied by reduced expression of disease-deteriorating genes. These findings foreshadow the potential of TertKI as an extraordinary rejuvenation force, promising not only longevity but also rejuvenation in skin and intestinal aging.
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Affiliation(s)
- Tian‐Yi Zhu
- School of PharmacyNanjing University of Chinese MedicineNanjingJiangsuChina
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain InstituteThe University of QueenslandBrisbaneQueenslandAustralia
| | - Po Hu
- School of PharmacyNanjing University of Chinese MedicineNanjingJiangsuChina
| | - Yu‐Hui Mi
- School of PharmacyNanjing University of Chinese MedicineNanjingJiangsuChina
| | - Jun‐Li Zhang
- School of PharmacyNanjing University of Chinese MedicineNanjingJiangsuChina
| | - An‐Na Xu
- School of PharmacyNanjing University of Chinese MedicineNanjingJiangsuChina
| | - Ming‐Tong Gao
- School of PharmacyNanjing University of Chinese MedicineNanjingJiangsuChina
| | - Ying‐Ying Zhang
- School of PharmacyNanjing University of Chinese MedicineNanjingJiangsuChina
| | - San‐Bing Shen
- Regenerative Medicine Institute, School of MedicineUniversity of GalwayGalwayIreland
| | - Guang‐Ming Yang
- School of PharmacyNanjing University of Chinese MedicineNanjingJiangsuChina
| | - Yang Pan
- School of PharmacyNanjing University of Chinese MedicineNanjingJiangsuChina
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10
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Huang X, Huang L, Lu J, Cheng L, Wu D, Li L, Zhang S, Lai X, Xu L. The relationship between telomere length and aging-related diseases. Clin Exp Med 2025; 25:72. [PMID: 40044947 PMCID: PMC11882723 DOI: 10.1007/s10238-025-01608-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 02/21/2025] [Indexed: 03/09/2025]
Abstract
The intensifying global phenomenon of an aging population has spurred a heightened emphasis on studies on aging and disorders associated with aging. Cellular senescence and aging are known to be caused by telomere shortening. Telomere length (TL) has emerged as a biomarker under intense scrutiny, and its widespread use in investigations of diseases tied to advancing age. This review summarizes the current knowledge of the association between telomeres and aging-related diseases, explores the important contribution of dysfunctional telomeres to the development and progression of these diseases, and aims to provide valuable insights for the development of novel therapeutic strategies.
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Affiliation(s)
- Xuanqi Huang
- Hangzhou Normal University School of Nursing, Hangzhou, China
| | - Leyi Huang
- Hangzhou Normal University School of Nursing, Hangzhou, China
| | - Jiaweng Lu
- Hangzhou Normal University School of Nursing, Hangzhou, China
| | - Lijuan Cheng
- Hangzhou Normal University School of Basic Medical Sciences, Hangzhou, China
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Hangzhou, China
| | - Du Wu
- Hangzhou Wuyunshan Hospital, Hangzhou, China
| | - Linmeng Li
- Department of Clinical Laboratory, Zhuji People's Hospital of Zhejiang Province, Shaoxing, China
| | - Shuting Zhang
- Hangzhou Normal University School of Nursing, Hangzhou, China
| | - Xinyue Lai
- Hangzhou Normal University School of Nursing, Hangzhou, China
| | - Lu Xu
- Hangzhou Normal University School of Nursing, Hangzhou, China.
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Hangzhou, China.
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11
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Otgaar TC, Bernert M, Morris G, Baichan P, Bignoux MJ, Letsolo B, Weiss SFT, Ferreira E. 37 kDa LRP::FLAG enhances telomerase activity and reduces ageing markers in vivo. Cell Mol Life Sci 2025; 82:83. [PMID: 39985566 PMCID: PMC11846807 DOI: 10.1007/s00018-025-05593-0] [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: 07/16/2024] [Revised: 12/30/2024] [Accepted: 01/13/2025] [Indexed: 02/24/2025]
Abstract
Ageing is a degenerative process characterised by a decline in physiological functioning of the organism. One of the core regulators of cellular ageing are telomeres, repetitive DNA sequences of TTAGGG that cap the ends of chromosomes and are maintained by the ribonucleoprotein complex, telomerase. Age-dependent progressive loss of the telomere ends eventually induces cell cycle arrest for the induction of either replicative senescence or apoptosis. It was previously established that overexpression of the 37 kDa/ 67 kDa laminin receptor (LRP/LR) increased telomerase activity and telomere length while concomitantly reducing senescence markers in aged normal cells in vitro. Therefore, it was hypothesized that elevating LRP/LR in vivo may increase telomerase activity and hinder the ageing process on an organism scale. To this end, aged C57BL/6J mice were treated/transfected to induce an overexpression of LRP::FLAG. Various physiological tests and histological analyses were performed to assess overall organism fitness as well as to discern the treatments' ability at reducing tissue degeneration and atrophy. It was found that mice overexpressing LRP::FLAG displayed improved physiological characteristics and markedly less tissue degeneration and atrophy when compared to control and non-treated mice. Alongside these improvements, certain organs displayed increased telomerase activity with a corresponding elongation in average telomere length. In addition the overexpression of LRP::FLAG significantly improved various proliferative and anti-ageing associated proteins while causing a concomitant decrease in senescence associated proteins. These findings are therefore indicative of a novel function of LRP/LR delaying the onset of senescence, while also promoting healthier ageing through elevating TERT and telomerase activity.
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Affiliation(s)
- Tyrone C Otgaar
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa
| | - Martin Bernert
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa
| | - Gavin Morris
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa
| | - Pavan Baichan
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa
| | - Monique J Bignoux
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa
| | - Boitelo Letsolo
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa
| | - Stefan F T Weiss
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa
| | - Eloise Ferreira
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa.
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12
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Zwi-Dantsis L, Mohamed S, Massaro G, Moeendarbary E. Adeno-Associated Virus Vectors: Principles, Practices, and Prospects in Gene Therapy. Viruses 2025; 17:239. [PMID: 40006994 PMCID: PMC11861813 DOI: 10.3390/v17020239] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 01/27/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Abstract
Gene therapy offers promising potential as an efficacious and long-lasting therapeutic option for genetic conditions, by correcting defective mutations using engineered vectors to deliver genetic material to host cells. Among these vectors, adeno-associated viruses (AAVs) stand out for their efficiency, versatility, and safety, making them one of the leading platforms in gene therapy. The enormous potential of AAVs has been demonstrated through their use in over 225 clinical trials and the FDA's approval of six AAV-based gene therapy products, positioning these vectors at the forefront of the field. This review highlights the evolution and current applications of AAVs in gene therapy, focusing on their clinical successes, ongoing developments, and the manufacturing processes required for the rapid commercial growth anticipated in the AAV therapy market. It also discusses the broader implications of these advancements for future therapeutic strategies targeting more complex and multi-systemic conditions and biological processes such as aging. Finally, we explore some of the major challenges currently confronting the field.
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Affiliation(s)
- Limor Zwi-Dantsis
- Department of Mechanical Engineering, Roberts Building, University College London, London WC1E 6BT, UK
| | - Saira Mohamed
- Department of Mechanical Engineering, Roberts Building, University College London, London WC1E 6BT, UK
| | - Giulia Massaro
- UCL School of Pharmacy, University College London, London WC1N 1AX, UK
| | - Emad Moeendarbary
- Department of Mechanical Engineering, Roberts Building, University College London, London WC1E 6BT, UK
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13
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Ullah S, Haider Z, Perera CD, Lee SH, Idrees M, Park S, Kong IK. Epitalon-activated telomerase enhance bovine oocyte maturation rate and post-thawed embryo development. Life Sci 2025; 362:123381. [PMID: 39788414 DOI: 10.1016/j.lfs.2025.123381] [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: 11/19/2024] [Revised: 01/03/2025] [Accepted: 01/06/2025] [Indexed: 01/12/2025]
Abstract
Telomerase is highly expressed in oocyte cumulus cells and plays a significant role in follicular development and oocyte maturation. In this study, we hypothesized that in vitro culture conditions may affect telomerase activity during in vitro embryo production (IVP) and that its activation may improve embryo quality. We first examined telomerase protein levels and localization in bovine cumulus-oocyte complexes via immunofluorescence assays. The results showed that healthy cumulus-oocyte complexes have the nuclear localization of the telomerase while the degraded cumulus-oocyte complex had reduced telomerase levels and that telomerase was localized in the cytoplasm. We activated telomerase via Epitalon, a tetrapeptide with the amino acid sequence Ala-Glut-Asp-Gly. We observed a significant improvement in the oocyte maturation rate compared with the control group (p < 0.05). Furthermore, telomerase activity was significantly compromised in post-thawed embryos, and Epitalon treatment significantly improved blastocyst hatching rate and implantation potential (p < 0.05). Moreover, we performed qPCR, reactive oxygen species, and JC-1 (ΔΨm) assays to evaluate the effect of Epitalon on the health of in vitro mature oocytes, cumulus cells, and post-thawed blastocysts, and the result showed that Epitalon highly enhances the quality and health of the oocyte, cumulus cell, and post-thawed blastocyst. Our results suggest that telomerase activation via Epitalon improves bovine in vitro embryo production.
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Affiliation(s)
- Safeer Ullah
- Division of Applied Life Science (BK21 Four), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea
| | - Zaheer Haider
- Division of Applied Life Science (BK21 Four), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea
| | - Chalani Dilshani Perera
- Division of Applied Life Science (BK21 Four), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea
| | - Su Hyeon Lee
- Division of Applied Life Science (BK21 Four), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea
| | - Muhammad Idrees
- Division of Applied Life Science (BK21 Four), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea; Institute of Agriculture and Life Science, Gyeongsang National University, Gyeongnam Province, Republic of Korea.
| | - Song Park
- Institute of Agriculture and Life Science, Gyeongsang National University, Gyeongnam Province, Republic of Korea; Division of Animal Science, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Il-Keun Kong
- Division of Applied Life Science (BK21 Four), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea; Institute of Agriculture and Life Science, Gyeongsang National University, Gyeongnam Province, Republic of Korea; Division of Animal Science, Gyeongsang National University, Jinju 52828, Republic of Korea; The King Kong Corp. Ltd., Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea.
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14
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Iskandar M, Xiao Barbero M, Jaber M, Chen R, Gomez-Guevara R, Cruz E, Westerheide S. A Review of Telomere Attrition in Cancer and Aging: Current Molecular Insights and Future Therapeutic Approaches. Cancers (Basel) 2025; 17:257. [PMID: 39858038 PMCID: PMC11764024 DOI: 10.3390/cancers17020257] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/09/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND/OBJECTIVES As cells divide, telomeres shorten through a phenomenon known as telomere attrition, which leads to unavoidable senescence of cells. Unprotected DNA exponentially increases the odds of mutations, which can evolve into premature aging disorders and tumorigenesis. There has been growing academic and clinical interest in exploring this duality and developing optimal therapeutic strategies to combat telomere attrition in aging and cellular immortality in cancer. The purpose of this review is to provide an updated overview of telomere biology and therapeutic tactics to address aging and cancer. METHODS We used the Rayyan platform to review the PubMed database and examined the ClinicalTrial.gov registry to gain insight into clinical trials and their results. RESULTS Cancer cells activate telomerase or utilize alternative lengthening of telomeres to escape telomere shortening, leading to near immortality. Contrarily, normal cells experience telomeric erosion, contributing to premature aging disorders, such as Werner syndrome and Hutchinson-Gilford Progeria, and (2) aging-related diseases, such as neurodegenerative and cardiovascular diseases. CONCLUSIONS The literature presents several promising therapeutic approaches to potentially balance telomere maintenance in aging and shortening in cancer. This review highlights gaps in knowledge and points to the potential of these optimal interventions in preclinical and clinical studies to inform future research in cancer and aging.
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Affiliation(s)
| | | | | | | | | | | | - Sandy Westerheide
- Department of Molecular Biosciences, University of South Florida, 4202 East Fowler Avenue, ISA2015, Tampa, FL 33620, USA; (M.I.); (M.X.B.); (M.J.); (R.C.); (R.G.-G.); (E.C.)
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15
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Ortega A, Chernicki B, Ou G, Parmar MS. From Lab Bench to Hope: Emerging Gene Therapies in Clinical Trials for Alzheimer's Disease. Mol Neurobiol 2025; 62:1112-1135. [PMID: 38958888 DOI: 10.1007/s12035-024-04285-3] [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: 02/29/2024] [Accepted: 06/05/2024] [Indexed: 07/04/2024]
Abstract
Alzheimer's disease is a progressive neurodegenerative disorder that affects memory and cognitive abilities, affecting millions of people around the world. Current treatments focus on the management of symptoms, as no effective therapy has been approved to modify the underlying disease process. Gene therapy is a promising approach that can offer disease-modifying treatment for AD, targeting various aspects of the pathophysiology of the disease. This review presents a comprehensive overview of the current state of gene therapy research for AD, with a specific focus on clinical trials and preclinical studies that have used nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), apolipoprotein E2 (APOE2), and human telomerase reverse transcriptase (hTERT) as therapeutic gene therapy approaches. These gene targets have shown potential to alleviate the neuropathology of AD in animal studies and have demonstrated feasibility and safety in non-human primates. Despite the failure of the NGF gene therapy approach in clinical trials, we have reviewed and highlighted the reported findings and evaluations from the trials. Furthermore, the review included the conclusions of postmortem brain tissue analysis of AD patients who received NGF gene therapy. The goal is to learn from the failed trials and improve the approach in the future. Although gene therapy shows promise, it faces several challenges and limitations, including optimizing gene delivery methods, enhancing safety and efficacy profiles, and determining long-term results. This review contributes to the growing body of literature on innovative treatments for AD and highlights the need for more research and development to advance gene therapy as a viable treatment option for AD.
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Affiliation(s)
- Angelica Ortega
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Clearwater, FL, USA
| | - Brendan Chernicki
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Clearwater, FL, USA
| | - Grace Ou
- College of Arts and Sciences, Cornell University, Ithaca, NY, USA
| | - Mayur S Parmar
- Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Clearwater, FL, USA.
- Department of Foundational Sciences, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Clearwater, FL, USA.
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16
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Pangrazzi L, Meryk A. Molecular and Cellular Mechanisms of Immunosenescence: Modulation Through Interventions and Lifestyle Changes. BIOLOGY 2024; 14:17. [PMID: 39857248 PMCID: PMC11760833 DOI: 10.3390/biology14010017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/17/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025]
Abstract
Immunosenescence, the age-related decline in immune function, is a complex biological process with profound implications for health and longevity. This phenomenon, characterized by alterations in both innate and adaptive immunity, increases susceptibility to infections, reduces vaccine efficacy, and contributes to the development of age-related diseases. At the cellular level, immunosenescence manifests as decreased production of naive T and B cells, accumulation of memory and senescent cells, thymic involution, and dysregulated cytokine production. Recent advances in molecular biology have shed light on the underlying mechanisms of immunosenescence, including telomere attrition, epigenetic alterations, mitochondrial dysfunction, and changes in key signaling pathways such as NF-κB and mTOR. These molecular changes lead to functional impairments in various immune cell types, altering their proliferative capacity, differentiation, and effector functions. Emerging research suggests that lifestyle factors may modulate the rate and extent of immunosenescence at both cellular and molecular levels. Physical activity, nutrition, stress management, and sleep patterns have been shown to influence immune cell function, inflammatory markers, and oxidative stress in older adults. This review provides a comprehensive analysis of the molecular and cellular mechanisms underlying immunosenescence and explores how lifestyle interventions may impact these processes. We will examine the current understanding of immunosenescence at the genomic, epigenomic, and proteomic levels, and discuss how various lifestyle factors can potentially mitigate or partially reverse aspects of immune aging. By integrating recent findings from immunology, gerontology, and molecular biology, we aim to elucidate the intricate interplay between lifestyle and immune aging at the molecular level, potentially informing future strategies for maintaining immune competence in aging populations.
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Affiliation(s)
- Luca Pangrazzi
- Institute for Biomedical Aging Research, Faculty of Biology, University of Innsbruck, 6020 Innsbruck, Austria;
| | - Andreas Meryk
- Department of Pediatrics, Medical University of Innsbruck, 6020 Innsbruck, Austria
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17
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Zhao H, Liu Z, Chen H, Han M, Zhang M, Liu K, Jin H, Liu X, Shi M, Pu W, Werner M, Meister M, Kauschke SG, Sun R, Wang J, Shen R, Wang QD, Ma X, Tchorz JS, Zhou B. Identifying specific functional roles for senescence across cell types. Cell 2024; 187:7314-7334.e21. [PMID: 39368477 DOI: 10.1016/j.cell.2024.09.021] [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: 03/08/2024] [Revised: 07/16/2024] [Accepted: 09/12/2024] [Indexed: 10/07/2024]
Abstract
Cellular senescence plays critical roles in aging, regeneration, and disease; yet, the ability to discern its contributions across various cell types to these biological processes remains limited. In this study, we generated an in vivo genetic toolbox consisting of three p16Ink4a-related intersectional genetic systems, enabling pulse-chase tracing (Sn-pTracer), Cre-based tracing and ablation (Sn-cTracer), and gene manipulation combined with tracing (Sn-gTracer) of defined p16Ink4a+ cell types. Using liver injury and repair as an example, we found that macrophages and endothelial cells (ECs) represent distinct senescent cell populations with different fates and functions during liver fibrosis and repair. Notably, clearance of p16Ink4a+ macrophages significantly mitigates hepatocellular damage, whereas eliminating p16Ink4a+ ECs aggravates liver injury. Additionally, targeted reprogramming of p16Ink4a+ ECs through Kdr overexpression markedly reduces liver fibrosis. This study illuminates the functional diversity of p16Ink4a+ cells and offers insights for developing cell-type-specific senolytic therapies in the future.
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Affiliation(s)
- Huan Zhao
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, 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, China
| | - Zixin Liu
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, 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, China
| | - Hui Chen
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, 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, China
| | - Maoying Han
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, 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, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Mingjun Zhang
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, 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, China
| | - Kuo Liu
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, 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, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
| | - Hengwei Jin
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, 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, China
| | - Xiuxiu Liu
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, 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, China
| | - Mengyang Shi
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, 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, China
| | - Wenjuan Pu
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, 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, China
| | - Markus Werner
- Department of CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Michael Meister
- Department of CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Stefan G Kauschke
- Department of CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Ruilin Sun
- Shanghai Model Organisms Center, Inc., Shanghai, China
| | - Jinjin Wang
- Shanghai Model Organisms Center, Inc., Shanghai, China
| | - Ruling Shen
- Shanghai Laboratory Animal Research Center, Shanghai, China
| | - Qing-Dong Wang
- Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Xin Ma
- Department of Pharmacology, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Jan S Tchorz
- Biomedical Research, Novartis Pharma AG, Basel, Switzerland
| | - Bin Zhou
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, 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, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
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18
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Wu Z, Qu J, Liu GH. Roles of chromatin and genome instability in cellular senescence and their relevance to ageing and related diseases. Nat Rev Mol Cell Biol 2024; 25:979-1000. [PMID: 39363000 DOI: 10.1038/s41580-024-00775-3] [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: 08/12/2024] [Indexed: 10/05/2024]
Abstract
Ageing is a complex biological process in which a gradual decline in physiological fitness increases susceptibility to diseases such as neurodegenerative disorders and cancer. Cellular senescence, a state of irreversible cell-growth arrest accompanied by functional deterioration, has emerged as a pivotal driver of ageing. In this Review, we discuss how heterochromatin loss, telomere attrition and DNA damage contribute to cellular senescence, ageing and age-related diseases by eliciting genome instability, innate immunity and inflammation. We also discuss how emerging therapeutic strategies could restore heterochromatin stability, maintain telomere integrity and boost the DNA repair capacity, and thus counteract cellular senescence and ageing-associated pathologies. Finally, we outline current research challenges and future directions aimed at better comprehending and delaying ageing.
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Affiliation(s)
- Zeming Wu
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Jing Qu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
- Aging Biomarker Consortium, Beijing, China.
| | - Guang-Hui Liu
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
- Aging Biomarker Consortium, Beijing, China.
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, China.
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19
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Denham J, Bliss ES, Bryan TM, O'Brien BJ, Mills D. Exercise to combat cancer: focusing on the ends. Physiol Genomics 2024; 56:869-875. [PMID: 39374082 DOI: 10.1152/physiolgenomics.00075.2024] [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: 06/11/2024] [Revised: 09/26/2024] [Accepted: 09/27/2024] [Indexed: 10/09/2024] Open
Abstract
Cancer remains a leading cause of death worldwide and although prognosis and survivorship after therapy have improved significantly, current cancer treatments have long-term health consequences. For decades telomerase-mediated telomere maintenance has been an attractive anti-cancer therapeutic target due to its abundance and role in telomere maintenance, pathogenesis, and growth in neoplasms. Telomere maintenance-specific cancer therapies, however, are marred by off-target side effects that must be addressed before they reach clinical practice. Regular exercise training is associated with telomerase-mediated telomere maintenance in normal cells, which is associated with healthy aging. A single bout of endurance exercise training dynamically, but temporarily, increases TERT mRNA and telomerase activity, as well as several molecules that control genomic stability and telomere length (i.e., shelterin and TERRA). Considering the epidemiological findings and accumulating research highlighting that exercise significantly reduces the risk of many types of cancers and the anti-carcinogenic effects of exercise on tumor growth in vitro, investigating the governing molecular mechanisms of telomerase control in context with exercise and cancer may provide important new insights to explain these findings. Specifically, the molecular mechanisms controlling telomerase in both healthy cells and tumors after exercise could reveal novel therapeutic targets for tumor-specific telomere maintenance and offer important evidence that may refine current physical activity and exercise guidelines for all stages of cancer care.
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Affiliation(s)
- Joshua Denham
- School of Health and Medical Sciences, University of Southern Queensland, Toowoomba, Queensland, Australia
- Centre for Health Research, Toowoomba, Queensland, Australia
| | - Edward S Bliss
- School of Health and Medical Sciences, University of Southern Queensland, Toowoomba, Queensland, Australia
- Centre for Health Research, Toowoomba, Queensland, Australia
| | - Tracy M Bryan
- Children's Medical Research Institute, Faculty of Medicine and Health, University of Sydney, Westmead, New South Wales, Australia
| | - Brendan J O'Brien
- Institute of Health and Wellbeing, Federation University Australia, Ballarat, Victoria, Australia
| | - Dean Mills
- School of Health and Medical Sciences, University of Southern Queensland, Toowoomba, Queensland, Australia
- Centre for Health Research, Toowoomba, Queensland, Australia
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20
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Park K, Jeon MC, Lee D, Kim JI, Im SW. Genetic and epigenetic alterations in aging and rejuvenation of human. Mol Cells 2024; 47:100137. [PMID: 39433213 PMCID: PMC11625158 DOI: 10.1016/j.mocell.2024.100137] [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: 06/16/2024] [Revised: 09/19/2024] [Accepted: 10/16/2024] [Indexed: 10/23/2024] Open
Abstract
All the information essential for life is encoded within our genome and epigenome, which orchestrates diverse cellular states spatially and temporally. In particular, the epigenome interacts with internal and external stimuli, encoding and preserving cellular experiences, and it serves as the regulatory base of the transcriptome across diverse cell types. The emergence of single-cell transcriptomic and epigenomic data collection has revealed unique omics signatures in diverse tissues, highlighting cellular heterogeneity. Recent research has documented age-related epigenetic changes at the single-cell level, alongside the validation of cellular rejuvenation through partial reprogramming, which involves simultaneous epigenetic modifications. These dynamic shifts, primarily fueled by stem cell plasticity, have catalyzed significant interest and cross-disciplinary research endeavors. This review explores the genomic and epigenomic alterations with aging, elucidating their reciprocal interactions. Additionally, it seeks to discuss the evolving landscape of rejuvenation research, with a particular emphasis on dissecting stem cell behavior through the lens of single-cell analysis. Moreover, it proposes potential research methodologies for future studies.
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Affiliation(s)
- Kyunghyuk Park
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea
| | - Min Chul Jeon
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Dakyung Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Jong-Il Kim
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.
| | - Sun-Wha Im
- Department of Biochemistry and Molecular Biology, Kangwon National University School of Medicine, Gangwon, Korea.
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21
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Ciurleo GCV, de Azevedo OGR, Carvalho CGM, Vitek MP, Warren CA, Guerrant RL, Oriá RB. Apolipoprotein E4 and Alzheimer's disease causality under adverse environments and potential intervention by senolytic nutrients. Clin Nutr ESPEN 2024; 64:16-20. [PMID: 39251089 DOI: 10.1016/j.clnesp.2024.09.004] [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: 06/28/2024] [Revised: 08/16/2024] [Accepted: 09/05/2024] [Indexed: 09/11/2024]
Abstract
Apolipoprotein E (apoE) has a pivotal role in Alzheimer's Disease (AD) pathophysiology. APOE4 has been recognized as a risk factor for developing late-onset AD. Recently, APOE4 homozygosity was regarded as a new familial genetic trait of AD. In this opinion paper, we summarized the potential pleiotropic antagonism role of APOE4 in children living under early life adversity and afflicted with enteric infection/malnutrition-related pathogenic exposome. APOE4 was found to be neuroprotective early in life despite its increasing risk for AD with aging. We call for awareness of the potential burden this can bring to the public health system when APOE4 carriers, raised under adverse environmental conditions in early life and then aging with unhealthy lifestyles in later life may be at special risk for cognitive impairments and acquired AD. We postulate the importance of anti-senescence therapies to protect these individuals and remediate aging-related chronic illnesses.
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Affiliation(s)
- Gabriella C V Ciurleo
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, Brazil
| | - Orleâncio G R de Azevedo
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, Brazil
| | - Camila G M Carvalho
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, Brazil
| | - Michael P Vitek
- Department of Neurology, Duke University Medical Center, Durham, NC, USA
| | - Cirle A Warren
- Division of Infectious Diseases and International Health, Department of Medicine, School of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Richard L Guerrant
- Division of Infectious Diseases and International Health, Department of Medicine, School of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Reinaldo B Oriá
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, Brazil.
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22
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Martinović A, Mantovani M, Trpchevska N, Novak E, Milev NB, Bode L, Ewald CY, Bischof E, Reichmuth T, Lapides R, Navarini A, Saravi B, Roider E. Climbing the longevity pyramid: overview of evidence-driven healthcare prevention strategies for human longevity. FRONTIERS IN AGING 2024; 5:1495029. [PMID: 39659760 PMCID: PMC11628525 DOI: 10.3389/fragi.2024.1495029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 11/13/2024] [Indexed: 12/12/2024]
Abstract
Longevity medicine is an emerging and iterative healthcare discipline focusing on early detection, preventive measures, and personalized approaches that aim to extend healthy lifespan and promote healthy aging. This comprehensive review introduces the innovative concept of the "Longevity Pyramid." This conceptual framework delineates progressive intervention levels, providing a structured approach to understanding the diverse strategies available in longevity medicine. At the base of the Longevity Pyramid lies the level of prevention, emphasizing early detection strategies and advanced diagnostics or timely identification of potential health issues. Moving upwards, the next step involves lifestyle modifications, health-promoting behaviors, and proactive measures to delay the onset of age-related conditions. The Longevity Pyramid further explores the vast range of personalized interventions, highlighting the importance of tailoring medical approaches based on genetic predispositions, lifestyle factors, and unique health profiles, thereby optimizing interventions for maximal efficacy. These interventions aim to extend lifespan and reduce the impact and severity of age-related conditions, ensuring that additional years are characterized by vitality and wellbeing. By outlining these progressive levels of intervention, this review offers valuable insights into the evolving field of longevity medicine. This structured framework guides researchers and practitioners toward a nuanced strategic approach to advancing the science and practice of healthy aging.
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Affiliation(s)
- Anđela Martinović
- Maximon AG, Zug, Switzerland
- Department of Food Environmental and Nutritional Sciences (DeFENS), University of Milan, Milan, Italy
| | | | | | | | | | | | - Collin Y. Ewald
- Laboratory of Extracellular Matrix Regeneration, Institute of Translational Medicine, Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland
| | - Evelyne Bischof
- Shanghai University of Medicine and Health Sciences, Shanghai, China
- Sheba Longevity Center, Sheba Medical Center Tel Aviv, Ramat Gan, Israel
| | | | - Rebecca Lapides
- The Robert Larner, M.D., College of Medicine at the University of Vermont, Burlington, VT, United States
| | - Alexander Navarini
- Department of Dermatology, University Hospital Basel, Basel, Switzerland
| | - Babak Saravi
- Department of Orthopedics and Trauma Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Elisabeth Roider
- Maximon AG, Zug, Switzerland
- Department of Dermatology, University Hospital of Basel, Basel, Switzerland
- Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
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23
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Mani AK, Parvathi VD, Ravindran S. The Anti-Elixir Triad: Non-Synced Circadian Rhythm, Gut Dysbiosis, and Telomeric Damage. Med Princ Pract 2024:1-14. [PMID: 39536739 DOI: 10.1159/000542557] [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] [Received: 06/08/2024] [Accepted: 11/11/2024] [Indexed: 11/16/2024] Open
Abstract
Aging is an inevitable life process which is accelerated by lifestyle and environmental factors. It is an irreversible accretion of molecular and cellular damage associated with changes in the body composition and deterioration in physiological functions. Each cell (other than stem cells) reaches the limit of its ability to replicate, known as cellular or replicative senescence, and consequently, the organs lose their physiological functions, resulting in overall impairment. Other factors that promote aging include smoking, alcohol, UV rays, sleep habits, food, stress, sedentary lifestyle, and genetic abnormalities. These stress factors can alter our endogenous clock (the circadian rhythm) and the microbial commensals. As a result of the effect of these stressors, the microorganisms that generally support human physiological processes become baleful. The disturbance of natural physiology instigates many age-related pathologies, such as cardiovascular diseases, chronic obstructive pulmonary disorder, cerebrovascular diseases, opportunistic infections, high blood pressure, cancer, diabetes, kidney diseases, dementia, and Alzheimer's disease. The present review covers the three most essential processes of the circadian clock; the circadian gene mechanism and regulation, the mitotic clock (which plays a vital role in the telomere's attrition) and the gut microbiota and their metabolome that drive aging and lead to age-related pathologies. In conclusion, maintaining a synchronized circadian rhythm, a healthy gut microbiome, and telomere integrity is essential for mitigating the effects of aging and promoting longevity. The interplay among these factors underscores the importance of lifestyle choices in enhancing overall health and lifespan.
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Affiliation(s)
- Anup Kumar Mani
- Department of Biomedical Sciences, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, India
| | - Venkatachalam Deepa Parvathi
- Department of Biomedical Sciences, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, India
| | - Sumitha Ravindran
- Department of Biomedical Sciences, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, India
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24
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Portillo AM, García-Velasco JA, Varela E. An in-silico approach to the dynamics of proliferation potential in stem cells and the study of different therapies in cases of ovarian dysfunction. Math Biosci 2024; 377:109305. [PMID: 39366452 DOI: 10.1016/j.mbs.2024.109305] [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: 05/07/2024] [Revised: 09/26/2024] [Accepted: 09/27/2024] [Indexed: 10/06/2024]
Abstract
A discrete mathematical model based on ordinary differential equations and the associated continuous model formed by a partial differential equation, which simulate the generational and temporal evolution of a stem cell population, are proposed. The model parameters are the maximum proliferation potential and the rates of mitosis, death events and telomerase activity. The mean proliferation potential at each point in time is suggested as an indicator of population aging. The model is applied on hematopoietic stem cells (HSCs), with different telomerase activity rates, in a range of variation of maximum proliferation potential in healthy individuals, to study the temporal evolution of aging. HSCs express telomerase, however not at levels that are sufficient for maintaining constant telomere length with aging [1,2]. Women with primary ovarian insufficiency (POI) are known to have low telomerase activity in granulosa cells and peripheral blood mononuclear cells [3]. Extrapolating this to hematopoietic stem cells, the mathematical model shows the differences in proliferation potential of the cell populations when telomerase expression is activated using sexual steroids, though the endogenous promoter or with gene therapy using exogenous, stronger promoters within the adeno-associated virus. In the first case, proliferation potential of cells from POI condition increases, but when adeno-associated viruses are used, the proliferation potential reaches the levels of healthy cell populations.
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Affiliation(s)
- A M Portillo
- Instituto de Investigación en Matemáticas de la Universidad de Valladolid, Valladolid, Spain; Departamento de Matemática Aplicada, Escuela de Ingenierías Industriales, Universidad de Valladolid, Pso. Prado de la Magdalena 3-5, Valladolid, 47011, Spain.
| | - J A García-Velasco
- IVIRMA Global Research Alliance, The Health Research Institute La Fe (IIS La Fe), Edificio Biopolo. Av. Fernando Abril Martorell, 106 - Torre A, Planta 1, Valencia, 46026, Spain; IVIRMA Global Research Alliance, IVIRMA Madrid, Av. del Talgo, 68, Madrid, 28023, Spain; Rey Juan Carlos University, Department of Medical Specialties and Public Health, Edificio Departamental II. Av. de Atenas, s/n, Alcorcón, Madrid, 28922, Spain.
| | - E Varela
- IVIRMA Global Research Alliance, The Health Research Institute La Fe (IIS La Fe), Edificio Biopolo. Av. Fernando Abril Martorell, 106 - Torre A, Planta 1, Valencia, 46026, Spain; Rey Juan Carlos University, Department of Medical Specialties and Public Health, Edificio Departamental II. Av. de Atenas, s/n, Alcorcón, Madrid, 28922, Spain.
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25
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Ruetz TJ, Pogson AN, Kashiwagi CM, Gagnon SD, Morton B, Sun ED, Na J, Yeo RW, Leeman DS, Morgens DW, Tsui CK, Li A, Bassik MC, Brunet A. CRISPR-Cas9 screens reveal regulators of ageing in neural stem cells. Nature 2024; 634:1150-1159. [PMID: 39358505 PMCID: PMC11525198 DOI: 10.1038/s41586-024-07972-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 08/20/2024] [Indexed: 10/04/2024]
Abstract
Ageing impairs the ability of neural stem cells (NSCs) to transition from quiescence to proliferation in the adult mammalian brain. Functional decline of NSCs results in the decreased production of new neurons and defective regeneration following injury during ageing1-4. Several genetic interventions have been found to ameliorate old brain function5-8, but systematic functional testing of genes in old NSCs-and more generally in old cells-has not been done. Here we develop in vitro and in vivo high-throughput CRISPR-Cas9 screening platforms to systematically uncover gene knockouts that boost NSC activation in old mice. Our genome-wide screens in primary cultures of young and old NSCs uncovered more than 300 gene knockouts that specifically restore the activation of old NSCs. The top gene knockouts are involved in cilium organization and glucose import. We also establish a scalable CRISPR-Cas9 screening platform in vivo, which identified 24 gene knockouts that boost NSC activation and the production of new neurons in old brains. Notably, the knockout of Slc2a4, which encodes the GLUT4 glucose transporter, is a top intervention that improves the function of old NSCs. Glucose uptake increases in NSCs during ageing, and transient glucose starvation restores the ability of old NSCs to activate. Thus, an increase in glucose uptake may contribute to the decline in NSC activation with age. Our work provides scalable platforms to systematically identify genetic interventions that boost the function of old NSCs, including in vivo, with important implications for countering regenerative decline during ageing.
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Affiliation(s)
- Tyson J Ruetz
- Department of Genetics, Stanford University, Stanford, CA, USA
| | - Angela N Pogson
- Department of Genetics, Stanford University, Stanford, CA, USA
- Developmental Biology Graduate Program, Stanford University, Stanford, CA, USA
| | | | | | - Bhek Morton
- Department of Genetics, Stanford University, Stanford, CA, USA
| | - Eric D Sun
- Department of Genetics, Stanford University, Stanford, CA, USA
- Biomedical Informatics Graduate Program, Stanford University, Stanford, CA, USA
| | - Jeeyoon Na
- Department of Genetics, Stanford University, Stanford, CA, USA
- Stem Cell Biology & Regenerative Medicine Graduate Program, Stanford University, Stanford, CA, USA
| | - Robin W Yeo
- Department of Genetics, Stanford University, Stanford, CA, USA
| | - Dena S Leeman
- Department of Genetics, Stanford University, Stanford, CA, USA
| | - David W Morgens
- Department of Genetics, Stanford University, Stanford, CA, USA
| | - C Kimberly Tsui
- Department of Genetics, Stanford University, Stanford, CA, USA
| | - Amy Li
- Department of Genetics, Stanford University, Stanford, CA, USA
| | | | - Anne Brunet
- Department of Genetics, Stanford University, Stanford, CA, USA.
- Glenn Center for the Biology of Aging, Stanford University, Stanford, CA, USA.
- Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
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26
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Wang M, Hou C, Jia F, Zhong C, Xue C, Li J. Aging-associated atrial fibrillation: A comprehensive review focusing on the potential mechanisms. Aging Cell 2024; 23:e14309. [PMID: 39135295 PMCID: PMC11464128 DOI: 10.1111/acel.14309] [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: 02/29/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 10/11/2024] Open
Abstract
Atrial fibrillation (AF) has been receiving a lot of attention from scientists and clinicians because it is an extremely common clinical condition. Due to its special hemodynamic changes, AF has a high rate of disability and mortality. So far, although AF has some therapeutic means, it is still an incurable disease because of its complex risk factors and pathophysiologic mechanisms, which is a difficult problem for global public health. Age is an important independent risk factor for AF, and the incidence of AF increases with age. To date, there is no comprehensive review on aging-associated AF. In this review, we systematically discuss the pathophysiologic evidence for aging-associated AF, and in particular explore the pathophysiologic mechanisms of mitochondrial dysfunction, telomere attrition, cellular senescence, disabled macroautophagy, and gut dysbiosis involved in recent studies with aging-associated AF. We hope that by exploring the various dimensions of aging-associated AF, we can better understand the specific relationship between age and AF, which may be crucial for innovative treatments of aging-associated AF.
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Affiliation(s)
- Meng‐Fei Wang
- The Third Affiliated Hospital of Soochow UniversityThe First People's Hospital of ChangzhouChangzhouChina
| | - Can Hou
- The Third Affiliated Hospital of Soochow UniversityThe First People's Hospital of ChangzhouChangzhouChina
| | - Fang Jia
- The Third Affiliated Hospital of Soochow UniversityThe First People's Hospital of ChangzhouChangzhouChina
| | - Cheng‐Hao Zhong
- The Third Affiliated Hospital of Soochow UniversityThe First People's Hospital of ChangzhouChangzhouChina
| | - Cong Xue
- The Third Affiliated Hospital of Soochow UniversityThe First People's Hospital of ChangzhouChangzhouChina
| | - Jian‐Jun Li
- State Key Laboratory of Cardiovascular Diseases, Fu Wai Hospital, National Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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27
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Wölfel EM, Fernandez-Guerra P, Nørgård MØ, Jeromdesella S, Kjær PK, Elkjær AS, Kassem M, Figeac F. Senescence of skeletal stem cells and their contribution to age-related bone loss. Mech Ageing Dev 2024; 221:111976. [PMID: 39111640 DOI: 10.1016/j.mad.2024.111976] [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: 05/31/2024] [Revised: 07/30/2024] [Accepted: 08/03/2024] [Indexed: 08/18/2024]
Abstract
Human aging is linked to bone loss, resulting in bone fragility and an increased risk of fractures. This is primarily due to an age-related decline in the function of bone-forming osteoblastic cells and accelerated cellular senescence within the bone microenvironment. Here, we provide a detailed discussion of the hypothesis that age-related defective bone formation is caused by senescence of skeletal stem cells, as they are the main source of bone forming osteoblastic cells and influence the composition of bone microenvironment. Furthermore, this review discusses potential strategies to target cellular senescence as an emerging approach to treat age-related bone loss.
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Affiliation(s)
- Eva M Wölfel
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark.
| | - Paula Fernandez-Guerra
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark.
| | - Mikkel Ørnfeldt Nørgård
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark.
| | - Shakespeare Jeromdesella
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark.
| | - Pernille Kirkegaard Kjær
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark.
| | - Anna Sofie Elkjær
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark.
| | - Moustapha Kassem
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark; Institute of Cellular and Molecular Medicine (ICMM), Panum Institute, University of Copenhagen, 3B Blegdamsvej, Copenhagen N 2200, Denmark.
| | - Florence Figeac
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark.
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28
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Xu L, Yao S, Ding YE, Xie M, Feng D, Sha P, Tan L, Bei F, Yao Y. Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside. J Transl Med 2024; 22:866. [PMID: 39334366 PMCID: PMC11429861 DOI: 10.1186/s12967-024-05661-2] [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: 05/21/2024] [Accepted: 09/04/2024] [Indexed: 09/30/2024] Open
Abstract
Recombinant adeno-associated viruses (rAAVs) have emerged as an attractive tool for gene delivery, and demonstrated tremendous promise in gene therapy and gene editing-therapeutic modalities with potential "one-and-done" treatment benefits compared to conventional drugs. Given their tropisms for the central nervous system (CNS) across various species including humans, rAAVs have been extensively investigated in both pre-clinical and clinical studies targeting neurodegenerative disease. However, major challenges remain in the application of rAAVs for CNS gene therapy, such as suboptimal vector design, low CNS transduction efficiency and specificity, and therapy-induced immunotoxicity. Therefore, continuing efforts are being made to optimize the rAAV vectors from their "core" genetic payloads to their "coat" or capsid structure. In this review, we describe current approaches for rAAV vector design tailored for transgene expression in the CNS, summarize the development of CNS-targeting AAV serotypes, and highlight recent advancements in AAV capsid engineering, aimed at generating a new generation of rAAVs with improved CNS tropism. Additionally, we discuss various administration routes for delivering rAAVs to the CNS and provide an overview of AAV-mediated gene therapies currently under investigation in clinical trials for the treatment of neurodegenerative diseases.
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Affiliation(s)
- Liang Xu
- Clinical Research Center of Neurological Disease, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Shun Yao
- Department of Neurosurgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
| | - Yifan Evan Ding
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Mengxiao Xie
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dingqi Feng
- Center of Clinical Laboratory, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, 215123, China
| | - Pengfei Sha
- Clinical Research Center of Neurological Disease, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
| | - Lu Tan
- Clinical Research Center of Neurological Disease, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Fengfeng Bei
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Yizheng Yao
- Clinical Research Center of Neurological Disease, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
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29
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Verlinden SF. The genetic advantage of healthy centenarians: unraveling the central role of NLRP3 in exceptional healthspan. FRONTIERS IN AGING 2024; 5:1452453. [PMID: 39301197 PMCID: PMC11410711 DOI: 10.3389/fragi.2024.1452453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 08/19/2024] [Indexed: 09/22/2024]
Abstract
Despite extensive research into extending human healthspan (HS) and compressing morbidity, the mechanisms underlying aging remain elusive. However, a better understanding of the genetic advantages responsible for the exceptional HS of healthy centenarians (HC), who live in good physical and mental health for one hundred or more years, could lead to innovative health-extending strategies. This review explores the role of NLRP3, a critical component of innate immunity that significantly impacts aging. It is activated by pathogen-associated signals and self-derived signals that increase with age, leading to low-grade inflammation implicated in age-related diseases. Furthermore, NLRP3 functions upstream in several molecular aging pathways, regulates cellular senescence, and may underlie the robust health observed in HC. By targeting NLRP3, mice exhibit a phenotype akin to that of HC, the HS of monkeys is extended, and aging symptoms are reversed in humans. Thus, targeting NLRP3 could offer a promising approach to extend HS. Additionally, a paradigm shift is proposed. Given that the HS of the broader population is 30 years shorter than that of HC, it is postulated that they suffer from a form of accelerated aging. The term 'auto-aging' is suggested to describe accelerated aging driven by NLRP3.
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30
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Liu Y, Sheng Z, Sun L. Exosomes derived from hTERT-immortalized cells delay cellular senescence of human fibroblasts. Exp Gerontol 2024; 194:112508. [PMID: 38986855 DOI: 10.1016/j.exger.2024.112508] [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: 04/23/2024] [Revised: 06/21/2024] [Accepted: 07/01/2024] [Indexed: 07/12/2024]
Abstract
hTERT gene therapies hold significant promise for treating age-related diseases. However, further research is required to address the challenges of delivery and ethical considerations. We hypothesized that exosomes derived from hTERT-immortalized cells could function similarly to hTERT gene therapies by maintaining telomere length and attenuating cellular senescence biomarkers. In this study, we overexpressed the hTERT gene in Human Foreskin Fibroblast-1 cells (HFF cells) to produce hTERT-immortalized HFF cells (hT-HFF cells). We then used exosomes derived from these hT-HFF cells to treat human fibroblasts, HFF cells. Our results demonstrated that these exosomes effectively attenuated biomarkers of cellular senescence in HFF cells. Furthermore, analysis revealed that hTERT mRNA was indeed packaged into the exosomes from hT-HFF cells. This mRNA was capable of elongating telomeres and delaying cellular senescence in HFF cells. Therefore, exosomes from hT-HFF cells show potential as a treatment for age-related diseases.
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Affiliation(s)
- Yang Liu
- Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang, China
| | - Zhaoying Sheng
- Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang, China
| | - Linlin Sun
- Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang, China.
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31
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Panchin AY, Ogmen A, Blagodatski AS, Egorova A, Batin M, Glinin T. Targeting multiple hallmarks of mammalian aging with combinations of interventions. Aging (Albany NY) 2024; 16:12073-12100. [PMID: 39159129 PMCID: PMC11386927 DOI: 10.18632/aging.206078] [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: 11/01/2023] [Accepted: 06/28/2024] [Indexed: 08/21/2024]
Abstract
Aging is currently viewed as a result of multiple biological processes that manifest themselves independently, reinforce each other and in their totality lead to the aged phenotype. Genetic and pharmaceutical approaches targeting specific underlying causes of aging have been used to extend the lifespan and healthspan of model organisms ranging from yeast to mammals. However, most interventions display only a modest benefit. This outcome is to be expected if we consider that even if one aging process is successfully treated, other aging pathways may remain intact. Hence solving the problem of aging may require targeting not one but many of its underlying causes at once. Here we review the challenges and successes of combination therapies aimed at increasing the lifespan of mammals and propose novel directions for their development. We conclude that both additive and synergistic effects on mammalian lifespan can be achieved by combining interventions that target the same or different hallmarks of aging. However, the number of studies in which multiple hallmarks were targeted simultaneously is surprisingly limited. We argue that this approach is as promising as it is understudied.
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Affiliation(s)
- Alexander Y Panchin
- Sector of Molecular Evolution, Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow 127051, Russia
| | - Anna Ogmen
- Open Longevity, Sherman Oaks, CA 91403, USA
- Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, Turkey
| | - Artem S Blagodatski
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino 142290, Russia
| | | | | | - Timofey Glinin
- Open Longevity, Sherman Oaks, CA 91403, USA
- Department of Surgery, Endocrine Neoplasia Laboratory, University of California, San Francisco, CA 94143, USA
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32
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Roberts WS, Price S, Wu M, Parmar MS. Emerging Gene Therapies for Alzheimer's and Parkinson's Diseases: An Overview of Clinical Trials and Promising Candidates. Cureus 2024; 16:e67037. [PMID: 39286667 PMCID: PMC11405083 DOI: 10.7759/cureus.67037] [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: 06/24/2024] [Accepted: 08/14/2024] [Indexed: 09/19/2024] Open
Abstract
Gene therapy as a disease-modifying therapeutic approach for neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), is a promising avenue. Promising results in the preclinical studies involving rodents and nonhuman primates utilizing gene therapy have led to multiple clinical trials evaluating various genes of interest for AD and PD. In AD, clinical trials are assessing gene therapy involving brain-derived neurotrophic factor (BDNF) and other targets such as apolipoprotein E2 (APOE2) and human telomerase reverse transcriptase (hTERT). In PD, clinical trials are evaluating gene therapy delivering neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF). Additionally, gene therapy delivering enzymes aromatic L-amino acid decarboxylase (AADC) and glutamic acid decarboxylase (GAD) are also being evaluated for PD. All these trials primarily utilized adeno-associated virus (AAV) to deliver the above transgene of interest. This review summarizes the current clinical trials involving gene therapy for AD and PD. It also discusses the challenges and opportunities associated with the gene therapy approach in AD and PD and ongoing developments related to increasing the safety and efficacy of the gene therapy for long-term outcomes, which include evaluation of various serotypes and administration routes. This comprehensive review emphasizes translating preclinical findings into clinical trials, further directions, and the potential for this promising therapeutic approach to alleviate neurodegenerative disease.
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Affiliation(s)
- Will S Roberts
- Osteopathic Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine Nova Southeastern University, Clearwater, USA
| | - Shawn Price
- Osteopathic Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine Nova Southeastern University, Clearwater, USA
| | - Michael Wu
- Osteopathic Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine Nova Southeastern University, Clearwater, USA
| | - Mayur S Parmar
- Foundational Sciences, Dr. Kiran C. Patel College of Osteopathic Medicine Nova Southeastern University, Clearwater, USA
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Ye D, Chukwu C, Yang Y, Hu Z, Chen H. Adeno-associated virus vector delivery to the brain: Technology advancements and clinical applications. Adv Drug Deliv Rev 2024; 211:115363. [PMID: 38906479 PMCID: PMC11892011 DOI: 10.1016/j.addr.2024.115363] [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: 12/20/2023] [Revised: 05/13/2024] [Accepted: 06/18/2024] [Indexed: 06/23/2024]
Abstract
Adeno-associated virus (AAV) vectors have emerged as a promising tool in the development of gene therapies for various neurological diseases, including Alzheimer's disease and Parkinson's disease. However, the blood-brain barrier (BBB) poses a significant challenge to successfully delivering AAV vectors to the brain. Strategies that can overcome the BBB to improve the AAV delivery efficiency to the brain are essential to successful brain-targeted gene therapy. This review provides an overview of existing strategies employed for AAV delivery to the brain, including direct intraparenchymal injection, intra-cerebral spinal fluid injection, intranasal delivery, and intravenous injection of BBB-permeable AAVs. Focused ultrasound has emerged as a promising technology for the noninvasive and spatially targeted delivery of AAV administered by intravenous injection. This review also summarizes each strategy's current preclinical and clinical applications in treating neurological diseases. Moreover, this review includes a detailed discussion of the recent advances in the emerging focused ultrasound-mediated AAV delivery. Understanding the state-of-the-art of these gene delivery approaches is critical for future technology development to fulfill the great promise of AAV in neurological disease treatment.
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Affiliation(s)
- Dezhuang Ye
- Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, USA
| | - Chinwendu Chukwu
- Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, USA
| | - Yaoheng Yang
- Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, USA
| | - Zhongtao Hu
- Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, USA
| | - Hong Chen
- Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, USA; Department of Neurosurgery, Washington University School of Medicine, Saint Louis, MO 63110 USA; Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
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Shim HS, Iaconelli J, Shang X, Li J, Lan ZD, Jiang S, Nutsch K, Beyer BA, Lairson LL, Boutin AT, Bollong MJ, Schultz PG, DePinho RA. TERT activation targets DNA methylation and multiple aging hallmarks. Cell 2024; 187:4030-4042.e13. [PMID: 38908367 PMCID: PMC11552617 DOI: 10.1016/j.cell.2024.05.048] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 04/03/2024] [Accepted: 05/23/2024] [Indexed: 06/24/2024]
Abstract
Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. Together, these findings underscore TERT's critical role in aging processes and provide preclinical proof of concept for physiological TERT activation as a strategy to mitigate multiple aging hallmarks and associated pathologies.
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Affiliation(s)
- Hong Seok Shim
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jonathan Iaconelli
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Xiaoying Shang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jiexi Li
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zheng D Lan
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Shan Jiang
- Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kayla Nutsch
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Brittney A Beyer
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Luke L Lairson
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Adam T Boutin
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Michael J Bollong
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Peter G Schultz
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Ronald A DePinho
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Tregub PP, Komleva YK, Kulikov VP, Chekulaev PA, Tregub OF, Maltseva LD, Manasova ZS, Popova IA, Andriutsa NS, Samburova NV, Salmina AB, Litvitskiy PF. Relationship between Hypoxia and Hypercapnia Tolerance and Life Expectancy. Int J Mol Sci 2024; 25:6512. [PMID: 38928217 PMCID: PMC11204369 DOI: 10.3390/ijms25126512] [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: 05/02/2024] [Revised: 06/05/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
The review discusses the potential relationship between hypoxia resistance and longevity, the influence of carbon dioxide on the mechanisms of aging of the mammalian organism, and intermittent hypercapnic-hypoxic effects on the signaling pathways of aging mechanisms. In the article, we focused on the potential mechanisms of the gero-protective efficacy of carbon dioxide when combined with hypoxia. The review summarizes the possible influence of intermittent hypoxia and hypercapnia on aging processes in the nervous system. We considered the perspective variants of the application of hypercapnic-hypoxic influences for achieving active longevity and the prospects for the possibilities of developing hypercapnic-hypoxic training methods.
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Affiliation(s)
- Pavel P. Tregub
- Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
- Brain Science Institute, Research Center of Neurology, 125367 Moscow, Russia; (Y.K.K.)
- Scientific and Educational Resource Center “Innovative Technologies of Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis”, RUDN University, 117198 Moscow, Russia
| | - Yulia K. Komleva
- Brain Science Institute, Research Center of Neurology, 125367 Moscow, Russia; (Y.K.K.)
| | - Vladimir P. Kulikov
- Department of Ultrasound and Functional Diagnostics, Altay State Medical University, 656040 Barnaul, Russia
| | - Pavel A. Chekulaev
- Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | | | - Larisa D. Maltseva
- Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Zaripat Sh. Manasova
- Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Inga A. Popova
- Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Natalia S. Andriutsa
- Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Natalia V. Samburova
- Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Alla B. Salmina
- Brain Science Institute, Research Center of Neurology, 125367 Moscow, Russia; (Y.K.K.)
| | - Peter F. Litvitskiy
- Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
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Vedunova M, Borysova O, Kozlov G, Zharova AM, Morgunov I, Moskalev A. Candidate molecular targets uncovered in mouse lifespan extension studies. Expert Opin Ther Targets 2024; 28:513-528. [PMID: 38656034 DOI: 10.1080/14728222.2024.2346597] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 04/19/2024] [Indexed: 04/26/2024]
Abstract
INTRODUCTION Multiple interventions have demonstrated an increase in mouse lifespan. However, non-standardized controls, sex or strain-specific factors, and insufficient focus on targets, hinder the translation of these findings into clinical applications. AREAS COVERED We examined the effects of genetic and drug-based interventions on mice from databases DrugAge, GenAge, the Mouse Phenome Database, and publications from PubMed that led to a lifespan extension of more than 10%, identifying specific molecular targets that were manipulated to achieve the maximum lifespan in mice. Subsequently, we characterized 10 molecular targets influenced by these interventions, with particular attention given to clinical trials and potential indications for each. EXPERT OPINION To increase the translational potential of mice life-extension studies to clinical research several factors are crucial: standardization of mice lifespan research approaches, the development of clear criteria for control and experimental groups, the establishment of criteria for potential geroprotectors, and focusing on targets and their clinical application. Pinpointing the targets affected by geroprotectors helps in understanding species-specific differences and identifying potential side effects, ensuring the safety and effectiveness of clinical trials. Additionally, target review facilitates the optimization of treatment protocols and the evaluation of the clinical feasibility of translating research findings into practical therapies for humans.
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Affiliation(s)
- Maria Vedunova
- Institute of Biomedicine, Institute of Biogerontology, National Research Lobachevsky State University of Nizhni Novgorod (Lobachevsky University), Nizhny Novgorod, Russia
| | | | - Grigory Kozlov
- Institute of Biomedicine, Institute of Biogerontology, National Research Lobachevsky State University of Nizhni Novgorod (Lobachevsky University), Nizhny Novgorod, Russia
| | - Anna-Maria Zharova
- Institute of Biomedicine, Institute of Biogerontology, National Research Lobachevsky State University of Nizhni Novgorod (Lobachevsky University), Nizhny Novgorod, Russia
| | | | - Alexey Moskalev
- Institute of Biomedicine, Institute of Biogerontology, National Research Lobachevsky State University of Nizhni Novgorod (Lobachevsky University), Nizhny Novgorod, Russia
- Longaevus Technologies LTD, London, United Kingdom
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University, Moscow, Russia
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Lewis CJ, de Grey AD. Combining rejuvenation interventions in rodents: a milestone in biomedical gerontology whose time has come. Expert Opin Ther Targets 2024; 28:501-511. [PMID: 38477630 DOI: 10.1080/14728222.2024.2330425] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 03/11/2024] [Indexed: 03/14/2024]
Abstract
INTRODUCTION Longevity research has matured to the point where significantly postponing age-related decline in physical and mental function is now achievable in the laboratory and foreseeable in the clinic. The most promising strategies involve rejuvenation, i.e. reducing biological age, not merely slowing its progression. AREAS COVERED We discuss therapeutic strategies for rejuvenation and results achieved thus far, with a focus on in vivo studies. We discuss the implications of interventions which act on mean or maximum lifespan and those showing effects in accelerated disease models. While the focus is on work conducted in mice, we also highlight notable insights in the field from studies in other model organisms. EXPERT OPINION Rejuvenation was originally proposed as easier than slowing aging because it targets initially inert changes to tissue structure and composition, rather than trying to disentangle processes that both create aging damage and maintain life. While recent studies support this hypothesis, a true test requires a panel of rejuvenation interventions targeting multiple damage categories simultaneously. Considerations of cost, profitability, and academic significance have dampened enthusiasm for such work, but it is vital. Now is the time for the field to take this key step toward the medical control of aging.
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Affiliation(s)
- Caitlin J Lewis
- Longevity Escape Velocity Foundation, San Francisco, CA, USA
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Fossel M. Curing age-related disease, transforming global medicine. Expert Opin Ther Targets 2024; 28:481-485. [PMID: 37902505 DOI: 10.1080/14728222.2023.2277223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 10/26/2023] [Indexed: 10/31/2023]
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Gao Z, Santos RB, Rupert J, Van Drunen R, Yu Y, Eckel‐Mahan K, Kolonin MG. Endothelial-specific telomerase inactivation causes telomere-independent cell senescence and multi-organ dysfunction characteristic of aging. Aging Cell 2024; 23:e14138. [PMID: 38475941 PMCID: PMC11296101 DOI: 10.1111/acel.14138] [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: 11/02/2023] [Revised: 01/31/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
It has remained unclear how aging of endothelial cells (EC) contributes to pathophysiology of individual organs. Cell senescence results in part from inactivation of telomerase (TERT). Here, we analyzed mice with Tert knockout specifically in EC. Tert loss in EC induced transcriptional changes indicative of senescence and tissue hypoxia in EC and in other cells. We demonstrate that EC-Tert-KO mice have leaky blood vessels. The blood-brain barrier of EC-Tert-KO mice is compromised, and their cognitive function is impaired. EC-Tert-KO mice display reduced muscle endurance and decreased expression of enzymes responsible for oxidative metabolism. Our data indicate that Tert-KO EC have reduced mitochondrial content and function, which results in increased dependence on glycolysis. Consistent with this, EC-Tert-KO mice have metabolism changes indicative of increased glucose utilization. In EC-Tert-KO mice, expedited telomere attrition is observed for EC of adipose tissue (AT), while brain and skeletal muscle EC have normal telomere length but still display features of senescence. Our data indicate that the loss of Tert causes EC senescence in part through a telomere length-independent mechanism undermining mitochondrial function. We conclude that EC-Tert-KO mice is a model of expedited vascular senescence recapitulating the hallmarks aging, which can be useful for developing revitalization therapies.
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Affiliation(s)
- Zhanguo Gao
- The Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science CenterHoustonTexasUSA
| | - Rafael Bravo Santos
- The Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science CenterHoustonTexasUSA
| | - Joseph Rupert
- The Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science CenterHoustonTexasUSA
| | - Rachel Van Drunen
- The Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science CenterHoustonTexasUSA
| | - Yongmei Yu
- The Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science CenterHoustonTexasUSA
| | - Kristin Eckel‐Mahan
- The Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science CenterHoustonTexasUSA
| | - Mikhail G. Kolonin
- The Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science CenterHoustonTexasUSA
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40
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Butts B, Hope C, Herring C, Mueller K, Gary RA. The Effects of Exercise on Telomere Length in Persons With Heart Failure. J Cardiovasc Nurs 2024; 39:E86-E92. [PMID: 37801568 PMCID: PMC10997734 DOI: 10.1097/jcn.0000000000001044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/08/2023]
Abstract
BACKGROUND Telomere length is reduced in persons with heart failure (HF). Inflammation is a putative mechanism contributing to telomere shortening. Although physical activity is known to increase telomere length, its effects in HF are unknown. OBJECTIVE The aim of this study was to examine the effects of exercise on telomere length and its relationship with interleukin (IL)-1β in persons with HF. METHODS This secondary analysis of a 3-month home-based aerobic exercise intervention measured total telomere length and IL-1β levels in persons with HF (69% with reduced ejection fraction). RESULTS Total telomere length increased and plasma IL-1β levels decreased in the exercise group from baseline to 3 months. Total telomere length was negatively associated with IL-1β at baseline ( r = -0.441 P = .001). CONCLUSIONS The association between telomere length and IL-1β suggests a relationship between inflammation and cellular aging. Moderate-intensity exercise may help maintain cellular functions. Further research is needed to examine the effects on outcomes in persons with HF.
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Chatterjee S, Leach-Mehrwald M, Huang CK, Xiao K, Fuchs M, Otto M, Lu D, Dang V, Winkler T, Dunbar CE, Thum T, Bär C. Telomerase is essential for cardiac differentiation and sustained metabolism of human cardiomyocytes. Cell Mol Life Sci 2024; 81:196. [PMID: 38658440 PMCID: PMC11043037 DOI: 10.1007/s00018-024-05239-7] [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: 10/24/2023] [Revised: 03/29/2024] [Accepted: 04/12/2024] [Indexed: 04/26/2024]
Abstract
Telomeres as the protective ends of linear chromosomes, are synthesized by the enzyme telomerase (TERT). Critically short telomeres essentially contribute to aging-related diseases and are associated with a broad spectrum of disorders known as telomeropathies. In cardiomyocytes, telomere length is strongly correlated with cardiomyopathies but it remains ambiguous whether short telomeres are the cause or the result of the disease. In this study, we employed an inducible CRISPRi human induced pluripotent stem cell (hiPSC) line to silence TERT expression enabling the generation of hiPSCs and hiPSC-derived cardiomyocytes with long and short telomeres. Reduced telomerase activity and shorter telomere lengths of hiPSCs induced global transcriptomic changes associated with cardiac developmental pathways. Consequently, the differentiation potential towards cardiomyocytes was strongly impaired and single cell RNA sequencing revealed a shift towards a more smooth muscle cell like identity in the cells with the shortest telomeres. Poor cardiomyocyte function and increased sensitivity to stress directly correlated with the extent of telomere shortening. Collectively our data demonstrates a TERT dependent cardiomyogenic differentiation defect, highlighting the CRISPRi TERT hiPSCs model as a powerful platform to study the mechanisms and consequences of short telomeres in the heart and also in the context of telomeropathies.
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Affiliation(s)
- Shambhabi Chatterjee
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
- Center of Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
| | - Megan Leach-Mehrwald
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Cheng-Kai Huang
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Ke Xiao
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
| | - Maximilian Fuchs
- Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
| | - Mandy Otto
- Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
| | - Dongchao Lu
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
- Center of Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Vinh Dang
- Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Thomas Winkler
- Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Cynthia E Dunbar
- Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
- Center of Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Christian Bär
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.
- Center of Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany.
- Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.
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Córdova-Oriz I, Polonio AM, Cuadrado-Torroglosa I, Chico-Sordo L, Medrano M, García-Velasco JA, Varela E. Chromosome ends and the theory of marginotomy: implications for reproduction. Biogerontology 2024; 25:227-248. [PMID: 37943366 DOI: 10.1007/s10522-023-10071-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 09/21/2023] [Indexed: 11/10/2023]
Abstract
Telomeres are the protective structures located at the ends of linear chromosomes. They were first described in the 1930s, but their biology remained unexplored until the early 70s, when Alexey M. Olovnikov, a theoretical biologist, suggested that telomeres cannot be fully copied during DNA replication. He proposed a theory that linked this phenomenon with the limit of cell proliferation capacity and the "duration of life" (theory of marginotomy), and suggested a potential of telomere lenghthening for the prevention of aging (anti-marginotomy). The impact of proliferative telomere shortening on life expectancy was later confirmed. In humans, telomere shortening is counteracted by telomerase, an enzyme that is undetectable in most adult somatic cells, but present in cancer cells and adult and embryonic stem and germ cells. Although telomere length dynamics are different in male and female gametes during gametogenesis, telomere lengths are reset at the blastocyst stage, setting the initial length of the species. The role of the telomere pathway in reproduction has been explored for years, mainly because of increased infertility resulting from delayed childbearing. Short telomere length in ovarian somatic cells is associated to decreased fertility and higher aneuploidy rates in embryos. Consequently, there is a growing interest in telomere lengthening strategies, aimed at improving fertility. It has also been observed that lifestyle factors can affect telomere length and improve fertility outcomes. In this review, we discuss the implications of telomere theory in fertility, especially in oocytes, spermatozoa, and embryos, as well as therapies to enhance reproductive success.
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Affiliation(s)
- Isabel Córdova-Oriz
- IVIRMA Global Research Alliance, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Alba M Polonio
- IVIRMA Global Research Alliance, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Isabel Cuadrado-Torroglosa
- IVIRMA Global Research Alliance, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Lucía Chico-Sordo
- IVIRMA Global Research Alliance, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Marta Medrano
- IVIRMA Global Research Alliance, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Juan A García-Velasco
- IVIRMA Global Research Alliance, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
- IVIRMA Global Research Alliance, IVIRMA Madrid, Madrid, Spain
- Department of Medical Specialties and Public Health, Edificio Departamental II, Rey Juan Carlos University, Av. de Atenas, s/n, 28922, Alcorcón, Madrid, Spain
| | - Elisa Varela
- IVIRMA Global Research Alliance, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain.
- Department of Medical Specialties and Public Health, Edificio Departamental II, Rey Juan Carlos University, Av. de Atenas, s/n, 28922, Alcorcón, Madrid, Spain.
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Lipskaia L, Breau M, Cayrou C, Churikov D, Braud L, Jacquet J, Born E, Fouillade C, Curras-Alonso S, Bauwens S, Jourquin F, Fiore F, Castellano R, Josselin E, Sánchez-Ferrer C, Giovinazzo G, Lachaud C, Gilson E, Flores I, Londono-Vallejo A, Adnot S, Géli V. mTert induction in p21-positive cells counteracts capillary rarefaction and pulmonary emphysema. EMBO Rep 2024; 25:1650-1684. [PMID: 38424230 PMCID: PMC10933469 DOI: 10.1038/s44319-023-00041-1] [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: 10/06/2023] [Revised: 12/12/2023] [Accepted: 12/14/2023] [Indexed: 03/02/2024] Open
Abstract
Lung diseases develop when telomeres shorten beyond a critical point. We constructed a mouse model in which the catalytic subunit of telomerase (mTert), or its catalytically inactive form (mTertCI), is expressed from the p21Cdkn1a locus. Expression of either TERT or TERTCI reduces global p21 levels in the lungs of aged mice, highlighting TERT non-canonical function. However, only TERT reduces accumulation of very short telomeres, oxidative damage, endothelial cell (ECs) senescence and senile emphysema in aged mice. Single-cell analysis of the lung reveals that p21 (and hence TERT) is expressed mainly in the capillary ECs. We report that a fraction of capillary ECs marked by CD34 and endowed with proliferative capacity declines drastically with age, and this is counteracted by TERT but not TERTCI. Consistently, only TERT counteracts decline of capillary density. Natural aging effects are confirmed using the experimental model of emphysema induced by VEGFR2 inhibition and chronic hypoxia. We conclude that catalytically active TERT prevents exhaustion of the putative CD34 + EC progenitors with age, thus protecting against capillary vessel loss and pulmonary emphysema.
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Affiliation(s)
- Larissa Lipskaia
- Institute for Lung Health, Justus Liebig University, Giessen, Germany
- INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, FHU SENEC, AP-HP, 94010, Créteil, and Université Paris-Est Créteil (UPEC), Paris, France
| | - Marielle Breau
- Marseille Cancer Research Centre (CRCM), U1068 INSERM, UMR7258 CNRS, UM105 Aix-Marseille University, Institut Paoli-Calmettes, Ligue Nationale Contre le Cancer (Equipe labellisée), Team Telomeres and Chromatin, Marseille, France
| | - Christelle Cayrou
- Marseille Cancer Research Centre (CRCM), U1068 INSERM, UMR7258 CNRS, UM105 Aix-Marseille University, Institut Paoli-Calmettes, Ligue Nationale Contre le Cancer (Equipe labellisée), Team Telomeres and Chromatin, Marseille, France
| | - Dmitri Churikov
- Marseille Cancer Research Centre (CRCM), U1068 INSERM, UMR7258 CNRS, UM105 Aix-Marseille University, Institut Paoli-Calmettes, Ligue Nationale Contre le Cancer (Equipe labellisée), Team Telomeres and Chromatin, Marseille, France
| | - Laura Braud
- Marseille Cancer Research Centre (CRCM), U1068 INSERM, UMR7258 CNRS, UM105 Aix-Marseille University, Institut Paoli-Calmettes, Ligue Nationale Contre le Cancer (Equipe labellisée), Team Telomeres and Chromatin, Marseille, France
| | - Juliette Jacquet
- Institute for Lung Health, Justus Liebig University, Giessen, Germany
| | - Emmanuelle Born
- Institute for Lung Health, Justus Liebig University, Giessen, Germany
| | - Charles Fouillade
- Institut Curie, Inserm U1021, CNRS UMR 3347, University Paris-Saclay, PSL Research University, Orsay, France
| | - Sandra Curras-Alonso
- Institut Curie, PSL Research University, CNRS UMR3244, Sorbonne Université, Telomeres and Cancer, 75005, Paris, France
| | - Serge Bauwens
- Université Côte d'Azur, CNRS, Inserm, IRCAN, Faculty of Medicine, Nice, France
| | - Frederic Jourquin
- Marseille Cancer Research Centre (CRCM), U1068 INSERM, UMR7258 CNRS, UM105 Aix-Marseille University, Institut Paoli-Calmettes, Ligue Nationale Contre le Cancer (Equipe labellisée), Team Telomeres and Chromatin, Marseille, France
| | - Frederic Fiore
- Centre d'Immunophénomique, Aix Marseille Université, INSERM, CNRS UMR, Marseille, France
| | - Rémy Castellano
- Marseille Cancer Research Centre (CRCM), TrGET Preclinical Platform, Institut Paoli-Calmettes, Inserm, CNRS, Aix Marseille Université, Marseille, France
| | - Emmanuelle Josselin
- Marseille Cancer Research Centre (CRCM), TrGET Preclinical Platform, Institut Paoli-Calmettes, Inserm, CNRS, Aix Marseille Université, Marseille, France
| | | | - Giovanna Giovinazzo
- Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029, Madrid, Spain
| | - Christophe Lachaud
- Marseille Cancer Research Centre (CRCM), U1068 INSERM, UMR7258 CNRS, UM105 Aix-Marseille University, Institut Paoli-Calmettes, Team DNA Interstrand Crosslink Lesions and Blood Disorders, Marseille, France
| | - Eric Gilson
- Université Côte d'Azur, CNRS, Inserm, IRCAN, Faculty of Medicine, Nice, France
| | - Ignacio Flores
- Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029, Madrid, Spain
- Centro de Biologia Molecular Severo Ochoa, CSIC-UAM, Cantoblanco, Madrid, Spain
| | - Arturo Londono-Vallejo
- Institut Curie, PSL Research University, CNRS UMR3244, Sorbonne Université, Telomeres and Cancer, 75005, Paris, France
| | - Serge Adnot
- Institute for Lung Health, Justus Liebig University, Giessen, Germany.
- INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, FHU SENEC, AP-HP, 94010, Créteil, and Université Paris-Est Créteil (UPEC), Paris, France.
| | - Vincent Géli
- Marseille Cancer Research Centre (CRCM), U1068 INSERM, UMR7258 CNRS, UM105 Aix-Marseille University, Institut Paoli-Calmettes, Ligue Nationale Contre le Cancer (Equipe labellisée), Team Telomeres and Chromatin, Marseille, France.
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44
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Tenchov R, Sasso JM, Wang X, Zhou QA. Antiaging Strategies and Remedies: A Landscape of Research Progress and Promise. ACS Chem Neurosci 2024; 15:408-446. [PMID: 38214973 PMCID: PMC10853939 DOI: 10.1021/acschemneuro.3c00532] [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: 08/12/2023] [Revised: 12/01/2023] [Accepted: 12/04/2023] [Indexed: 01/13/2024] Open
Abstract
Aging is typified by a gradual loss of physiological fitness and accumulation of cellular damage, leading to deteriorated functions and enhanced vulnerability to diseases. Antiaging research has a long history throughout civilization, with many efforts put forth to understand and prevent the effects of aging. Multiple strategies aiming to promote healthy aging and extend the lifespan have been developed including lifestyle adjustments, medical treatments, and social programs. A multitude of antiaging medicines and remedies have also been explored. Here, we use data from the CAS Content Collection to analyze the publication landscape of recent research related to antiaging strategies and treatments. We review the recent advances and delineate trends in research headway of antiaging knowledge and practice across time, geography, and development pipelines. We further assess the state-of-the-art antiaging approaches and explore their correlations with age-related diseases. The landscape of antiaging drugs has been outlined and explored. Well-recognized and novel, currently evaluated antiaging agents have also been summarized. Finally, we review clinical applications of antiaging products with their development pipelines. The objective of this review is to summarize current knowledge on preventive strategies and treatment remedies in the field of aging, to outline challenges and evaluate growth opportunities, in order to further efforts to solve the problems that remain.
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Affiliation(s)
- Rumiana Tenchov
- CAS, a Division of the American
Chemical Society, 2540 Olentangy River Road, Columbus, Ohio 43202, United States
| | - Janet M. Sasso
- CAS, a Division of the American
Chemical Society, 2540 Olentangy River Road, Columbus, Ohio 43202, United States
| | - Xinmei Wang
- CAS, a Division of the American
Chemical Society, 2540 Olentangy River Road, Columbus, Ohio 43202, United States
| | - Qiongqiong Angela Zhou
- CAS, a Division of the American
Chemical Society, 2540 Olentangy River Road, Columbus, Ohio 43202, United States
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45
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Macip CC, Hasan R, Hoznek V, Kim J, Lu YR, Metzger LE, Sethna S, Davidsohn N. Gene Therapy-Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice. Cell Reprogram 2024; 26:24-32. [PMID: 38381405 PMCID: PMC10909732 DOI: 10.1089/cell.2023.0072] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2024] Open
Abstract
Aging is a complex progression of changes best characterized as the chronic dysregulation of cellular processes leading to deteriorated tissue and organ function. Although aging cannot currently be prevented, its impact on life- and healthspan in the elderly can potentially be minimized by interventions that aim to return these cellular processes to optimal function. Recent studies have demonstrated that partial reprogramming using the Yamanaka factors (or a subset; OCT4, SOX2, and KLF4; OSK) can reverse age-related changes in vitro and in vivo. However, it is still unknown whether the Yamanaka factors (or a subset) are capable of extending the lifespan of aged wild-type (WT) mice. In this study, we show that systemically delivered adeno-associated viruses, encoding an inducible OSK system, in 124-week-old male mice extend the median remaining lifespan by 109% over WT controls and enhance several health parameters. Importantly, we observed a significant improvement in frailty scores indicating that we were able to improve the healthspan along with increasing the lifespan. Furthermore, in human keratinocytes expressing exogenous OSK, we observed significant epigenetic markers of age reversal, suggesting a potential reregulation of genetic networks to a younger potentially healthier state. Together, these results may have important implications for the development of partial reprogramming interventions to reverse age-associated diseases in the elderly.
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Affiliation(s)
| | | | | | - Jihyun Kim
- Rejuvenate Bio, San Diego, California, USA
| | - Yuancheng Ryan Lu
- Department of Biology, Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
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46
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de Magalhães JP. Distinguishing between driver and passenger mechanisms of aging. Nat Genet 2024; 56:204-211. [PMID: 38242993 DOI: 10.1038/s41588-023-01627-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 11/28/2023] [Indexed: 01/21/2024]
Abstract
Understanding why we age is a long-standing question, and many mechanistic theories of aging have been proposed. Owing to limitations in studying the aging process, including a lack of adequate quantitative measurements, its mechanistic basis remains a subject of debate. Here, I explore theories of aging from the perspective of causal relationships. Many aging-related changes have been observed and touted as drivers of aging, including molecular changes in the genome, telomeres, mitochondria, epigenome and proteins and cellular changes affecting stem cells, the immune system and senescent cell buildup. Determining which changes are drivers and not passengers of aging remains a challenge, however, and I discuss how animal models and human genetic studies have been used empirically to infer causality. Overall, our understanding of the drivers of human aging is still inadequate; yet with a global aging population, elucidating the causes of aging has the potential to revolutionize biomedical research.
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Affiliation(s)
- João Pedro de Magalhães
- Genomics of Ageing and Rejuvenation Lab, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
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47
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Schellnegger M, Hofmann E, Carnieletto M, Kamolz LP. Unlocking longevity: the role of telomeres and its targeting interventions. FRONTIERS IN AGING 2024; 5:1339317. [PMID: 38333665 PMCID: PMC10850353 DOI: 10.3389/fragi.2024.1339317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 01/11/2024] [Indexed: 02/10/2024]
Abstract
Average life expectancy has been steadily increasing in developed countries worldwide. These demographic changes are associated with an ever-growing social and economic strain to healthcare systems as well as society. The aging process typically manifests as a decline in physiological and cognitive functions, accompanied by a rise in chronic diseases. Consequently, strategies that both mitigate age-related diseases and promote healthy aging are urgently needed. Telomere attrition, characterized by the shortening of telomeres with each cell division, paradoxically serves as both a protective mechanism and a contributor to tissue degeneration and age-related ailments. Based on the essential role of telomere biology in aging, research efforts aim to develop approaches designed to counteract telomere attrition, aiming to delay or reduce age-related diseases. In this review, telomere biology and its role in aging and age-related diseases is summarized along with recent approaches to interfere with telomere shortening aiming at well- and healthy-aging as well as longevity. As aging research enters a new era, this review emphasizes telomere-targeting therapeutics, including telomerase activators and tankyrase inhibitors, while also exploring the effects of antioxidative and anti-inflammatory agents, along with indirectly related approaches like statins.
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Affiliation(s)
- Marlies Schellnegger
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
- COREMED–Centre for Regenerative and Precision Medicine, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Graz, Austria
| | - Elisabeth Hofmann
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
- COREMED–Centre for Regenerative and Precision Medicine, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Graz, Austria
- Research Unit for Tissue Regeneration, Repair and Reconstruction, Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Martina Carnieletto
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
- COREMED–Centre for Regenerative and Precision Medicine, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Graz, Austria
| | - Lars-Peter Kamolz
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
- COREMED–Centre for Regenerative and Precision Medicine, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Graz, Austria
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48
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Orabi MAA, Abdelhamid RA, Elimam H, Elshaier YAMM, Ali AA, Aldabaan N, Alhasaniah AH, Refaey MS. Furofuranoid-Type Lignans and Related Phenolics from Anisacanthus virgularis (Salisb.) Nees with Promising Anticholinesterase and Anti-Ageing Properties: A Study Supported by Molecular Modelling. PLANTS (BASEL, SWITZERLAND) 2024; 13:150. [PMID: 38256704 PMCID: PMC10820861 DOI: 10.3390/plants13020150] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 12/23/2023] [Accepted: 01/03/2024] [Indexed: 01/24/2024]
Abstract
Lignan phytomolecules demonstrate promising anti-Alzheimer activity by alleviating dementia and preserving nerve cells. The purpose of this work is to characterize the lignans of Anisacanthus virgularis and explore their potential anti-acetylcholinesterase and anti-ageing effects. Phytochemical investigation of A. virgularis aerial parts afforded a new furofuranoid-type lignan (1), four known structural analogues, namely pinoresinol (2), epipinoresinol (3), phillyrin (4), and pinoresinol 4-O-β-d-glucoside (5), in addition to p-methoxy-trans-methyl cinnamate (6) and 1H-indole-3-carboxaldehyde (7). The structures were established from thorough spectroscopic analyses and comparisons with the literature. Assessment of the anticholinesterase activity of the lignans 1-5 displayed noticeable enzyme inhibition of 1 (IC50 = 85.03 ± 4.26 nM) and 5 (64.47 ± 2.75 nM) but lower activity of compounds 2-4 as compared to the reference drug donepezil. These findings were further emphasized by molecular docking of 1 and 5 with acetylcholinesterase (AChE). Rapid overlay chemical similarity (ROCS) and structure-activity relationships (SAR) analysis highlighted and rationalized the anti-AD capability of these compounds. Telomerase activation testing of the same isolates revealed 1.64-, 1.66-, and 1.72-fold activations in cells treated with compounds 1, 5, and 4, respectively, compared to untreated cells. Our findings may pave the way for further investigations into the development of anti-Alzheimer and/or anti-ageing drugs from furofuranoid-type lignans.
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Affiliation(s)
- Mohamed A. A. Orabi
- Department of Pharmacognosy, College of Pharmacy, Najran University, Najran 66454, Saudi Arabia
| | - Reda A. Abdelhamid
- Department of Pharmacognosy, Faculty of Pharmacy, Al-Azhar University, Assiut-Branch, Assiut 71524, Egypt;
| | - Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City 32958, Egypt;
| | - Yaseen A. M. M. Elshaier
- Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City 32958, Egypt;
| | - Ahmed A. Ali
- Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt;
| | - Nayef Aldabaan
- Department of Pharmacology, College of Pharmacy, Najran University, Najran 66454, Saudi Arabia;
| | - Abdulaziz Hassan Alhasaniah
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran 66454, Saudi Arabia;
| | - Mohamed S. Refaey
- Department of Pharmacognosy, Faculty of Pharmacy, University of Sadat City, Sadat City 32958, Egypt
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49
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Dunn PL, Logeswaran D, Chen JJL. Telomerase-Mediated Anti-Ageing Interventions. Subcell Biochem 2024; 107:1-20. [PMID: 39693017 DOI: 10.1007/978-3-031-66768-8_1] [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] [Indexed: 12/19/2024]
Abstract
The ageing process involves a gradual decline of chromosome integrity throughout an organism's lifespan. Telomeres are protective DNA-protein complexes that cap the ends of linear chromosomes in eukaryotic organisms. Telomeric DNA consists of long stretches of short "TTAGGG" repeats that are conserved across most eukaryotes including humans. Telomeres shorten progressively with each round of DNA replication due to the inability of conventional DNA polymerase to completely replicate the chromosome ends, known as the "end-replication problem". The telomerase enzyme counteracts the telomeric DNA loss by de novo addition of telomeric repeats onto chromosomal ends. Germline and stem cells maintain significant levels of telomerase activity to maintain telomere length and can divide almost indefinitely. However, the differentiation of stem cells accompanies the inactivation of telomerase gene expression, resulting in the progressive shortening of telomeres in somatic cells over successive divisions. Critically short telomeres elicit and sustain a persistent DNA damage response leading to permanent growth arrest of cells known as cellular senescence, a hallmark of cellular ageing. The accumulation of senescent cells in tissues and organs contributes to organismal ageing. Thus, the prevention of telomere shortening is a promising means to delay or even reverse cellular ageing. In this chapter, we summarize potential anti-ageing interventions that mitigate telomere shortening through increasing telomerase level or activity and discuss these strategies' risks, benefits, and future outlooks.
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Affiliation(s)
- Phoebe L Dunn
- School of Life Sciences, Arizona State University, Tempe, Arizona, USA
| | | | - Julian J-L Chen
- School of Molecular Sciences, Arizona State University, Tempe, Arizona, USA.
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50
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Saad FA. Gene Therapy for Skin Aging. Curr Gene Ther 2024; 25:2-9. [PMID: 38529607 DOI: 10.2174/0115665232286489240320051925] [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: 10/09/2023] [Revised: 02/27/2024] [Accepted: 03/05/2024] [Indexed: 03/27/2024]
Abstract
Extrinsic and intrinsic factors contribute to skin aging; nonetheless, they are intertwined. Moreover, intrinsic skin aging mirrors age-related declines in the entire human body's internal organs. There is evidence that skin appearance is an indicator of the general health of somebody or a visual certificate of health. Earlier, it was apparent that the intrinsic factors are unalterable, but the sparkling of skin aging gene therapy on the horizon is changing this narrative. Skin aging gene therapy offers tools for skin rejuvenation, natural beauty restoration, and therapy for diseases affecting the entire skin. However, skin aging gene therapy is an arduous and sophisticated task relying on precise interim stimulation of telomerase to extend telomeres and wend back the biological clock in the hopes to find the fountain of youth, while preserving cells innate biological features. Finding the hidden fountain of youth will be a remarkable discovery for promoting aesthetics medicine, genecosmetics, and healthy aging. Caloric restriction offers ultimate health benefits and a reproducible way to promote longevity in mammals, while delaying age-related diseases. Moreover, exercise further enhances these health benefits. This article highlights the potential of skin aging gene therapy and foretells the emerging dawn of the genecosmetics era.
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Affiliation(s)
- Fawzy A Saad
- Department of Gene Therapy, Saad Pharmaceuticals, Juhkentali 8, Tallinn, 10132, Estonia
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