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Errigo A, Dore MP, Mocci G, Pes GM. Lack of association between common polymorphisms associated with successful aging and longevity in the population of Sardinian Blue Zone. Sci Rep 2024; 14:30773. [PMID: 39730495 DOI: 10.1038/s41598-024-80497-w] [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: 02/15/2024] [Accepted: 11/19/2024] [Indexed: 12/29/2024] Open
Abstract
More than two decades ago, in the central-eastern region of the Mediterranean island of Sardinia, a mountain area was identified where the population displays exceptional longevity, especially among men (the Longevity Blue Zone, LBZ). This community was thoroughly investigated to understand the underlying causes of the phenomenon. The present study analyzed 11 genetic markers previously associated with increased survival in several long-lived populations. APOE (rs429358 and rs7412), APOE promoter (rs449647, rs769446, and rs405509), ACE1 (rs1799752), IL6 ‒174G/C (rs1800795), TNFα ‒308G/A (rs1800629), FOXO3A (rs2802292), KLOTHO (rs9536314) and G6PD (rs5030868) polymorphisms were investigated. PCR-based genotyping was performed following genomic DNA extraction from 150 nonagenarians living in the LBZ and 150 controls from a nearby area. No significant deviation in the frequency of the analyzed markers was detected between the two subgroups except for a weak association with the - 174G > C gene variant in the IL-6 gene (p = 0.040), which codes for a major modulator of the inflammatory response. Overall, the findings of this study do not support a significant association of known genetic variants on survival in the population of the Sardinian LBZ, suggesting that other genetic or epigenetic traits not yet identified might play a role.
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Affiliation(s)
- Alessandra Errigo
- Dipartimento di Medicina, Chirurgia e Farmacia, University of Sassari, Viale San Pietro 43, Sassari, 07100, Italy
| | - Maria Pina Dore
- Dipartimento di Medicina, Chirurgia e Farmacia, University of Sassari, Viale San Pietro 43, Sassari, 07100, Italy
- Baylor College of Medicine, One Baylor Plaza Blvd, Houston, TX, 77030, USA
| | - Giammarco Mocci
- Division of Gastroenterology, "Brotzu" Hospital, Cagliari, Italy
| | - Giovanni Mario Pes
- Dipartimento di Medicina, Chirurgia e Farmacia, University of Sassari, Viale San Pietro 43, Sassari, 07100, Italy.
- Sardinia Longevity Blue Zone Observatory, Ogliastra, 08040, Italy.
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Kallianpur KJ, Obhi HK, Donlon T, Masaki K, Willcox B, Martin P. Cross-sectional and longitudinal associations between late-life depressive symptoms and cognitive deficits: 20-year follow-up of the Kuakini Honolulu-Asia aging study. Arch Gerontol Geriatr 2024; 127:105551. [PMID: 38968756 PMCID: PMC11401759 DOI: 10.1016/j.archger.2024.105551] [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: 11/13/2023] [Revised: 06/15/2024] [Accepted: 06/24/2024] [Indexed: 07/07/2024]
Abstract
OBJECTIVE To examine depressed affect, somatic complaints, and positive affect as longitudinal predictors of fluid, crystallized and global cognitive performance in the Kuakini Honolulu-Asia Aging Study (HAAS), a large prospective cohort study of Japanese-American men. METHODS We assessed 3,088 dementia-free Kuakini-HAAS participants aged 71-93 (77.1 ± 4.2) years at baseline (1991-1993). Depressive symptoms were evaluated by the Center for Epidemiologic Studies Depression (CES-D) Scale. Baseline CES-D depression subscales (depressed and positive affects; somatic complaints) were computed. The Cognitive Abilities Screening Instrument (CASI) measured cognitive performance on a 100-point scale; fluid and crystallized cognitive abilities were derived from CASI factor analysis. Cognition was also evaluated at 4 follow-up examinations over a 20-year period. Multiple regression assessed baseline CES-D subscales as predictors of cognitive change. The baseline covariates analyzed were CASI, age, education, prevalent stroke, APOE ε4 presence, and the longevity-associated FOXO3 genotype. RESULTS Cross-sectionally, baseline CES-D subscales were related to cognitive measures; e.g., higher depressed affect was associated with lower crystallized ability (β = -0.058, p ≤ 0.01), and somatic complaints were linked to poorer fluid ability (β = -0.045, p ≤ 0.05) and to worse global cognitive function as measured by total CASI score (β = -0.038, p ≤ 0.05). However, depression subscales did not significantly or consistently predict fluid ability, crystallized ability, or global cognitive performance over time. CONCLUSION Psychological and physical well-being were associated with contemporaneous but not subsequent cognitive functioning. Assessment of depressive symptoms may identify individuals who are likely to benefit from interventions to improve mood and somatic health and thereby maintain or enhance cognition.
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Affiliation(s)
- Kalpana J Kallianpur
- Kuakini Center for Translational Research on Aging, Kuakini Medical Center, Honolulu, HI, United States; Department of Tropical Medicine, Medical Microbiology and Pharmacology, University of Hawaii-Manoa, Honolulu, HI, United States; Kamehameha Schools-Kapālama, Honolulu, HI, United States.
| | - Hardeep K Obhi
- School of Medicine Office of Research, University of California Davis, Sacramento, CA, United States
| | - Timothy Donlon
- Kuakini Center for Translational Research on Aging, Kuakini Medical Center, Honolulu, HI, United States; Department of Geriatric Medicine, University of Hawaii-Manoa, Honolulu, HI, United States
| | - Kamal Masaki
- Kuakini Center for Translational Research on Aging, Kuakini Medical Center, Honolulu, HI, United States; Department of Geriatric Medicine, University of Hawaii-Manoa, Honolulu, HI, United States
| | - Bradley Willcox
- Kuakini Center for Translational Research on Aging, Kuakini Medical Center, Honolulu, HI, United States; Department of Geriatric Medicine, University of Hawaii-Manoa, Honolulu, HI, United States
| | - Peter Martin
- Department of Human Development and Family Studies, Iowa State University, Ames, IA, United States
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Islam MA, Sehar U, Sultana OF, Mukherjee U, Brownell M, Kshirsagar S, Reddy PH. SuperAgers and centenarians, dynamics of healthy ageing with cognitive resilience. Mech Ageing Dev 2024; 219:111936. [PMID: 38657874 DOI: 10.1016/j.mad.2024.111936] [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: 04/08/2024] [Accepted: 04/16/2024] [Indexed: 04/26/2024]
Abstract
Graceful healthy ageing and extended longevity is the most desired goal for human race. The process of ageing is inevitable and has a profound impact on the gradual deterioration of our physiology and health since it triggers the onset of many chronic conditions like dementia, osteoporosis, diabetes, arthritis, cancer, and cardiovascular disease. However, some people who lived/live more than 100 years called 'Centenarians" and how do they achieve their extended lifespans are not completely understood. Studying these unknown factors of longevity is important not only to establish a longer human lifespan but also to manage and treat people with shortened lifespans suffering from age-related morbidities. Furthermore, older adults who maintain strong cognitive function are referred to as "SuperAgers" and may be resistant to risk factors linked to cognitive decline. Investigating the mechanisms underlying their cognitive resilience may contribute to the development of therapeutic strategies that support the preservation of cognitive function as people age. The key to a long, physically, and cognitively healthy life has been a mystery to scientists for ages. Developments in the medical sciences helps us to a better understanding of human physiological function and greater access to medical care has led us to an increase in life expectancy. Moreover, inheriting favorable genetic traits and adopting a healthy lifestyle play pivotal roles in promoting longer and healthier lives. Engaging in regular physical activity, maintaining a balanced diet, and avoiding harmful habits such as smoking contribute to overall well-being. The synergy between positive lifestyle choices, access to education, socio-economic factors, environmental determinants and genetic supremacy enhances the potential for a longer and healthier life. Our article aims to examine the factors associated with healthy ageing, particularly focusing on cognitive health in centenarians. We will also be discussing different aspects of ageing including genomic instability, metabolic burden, oxidative stress and inflammation, mitochondrial dysfunction, cellular senescence, immunosenescence, and sarcopenia.
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Affiliation(s)
- Md Ariful Islam
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Ujala Sehar
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Omme Fatema Sultana
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Upasana Mukherjee
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Malcolm Brownell
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Sudhir Kshirsagar
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Neurology, Departments of School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Nutritional Sciences Department, College of Human Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX 79409, USA.
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4
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Smulders L, Deelen J. Genetics of human longevity: From variants to genes to pathways. J Intern Med 2024; 295:416-435. [PMID: 37941149 DOI: 10.1111/joim.13740] [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: 11/10/2023]
Abstract
The current increase in lifespan without an equivalent increase in healthspan poses a grave challenge to the healthcare system and a severe burden on society. However, some individuals seem to be able to live a long and healthy life without the occurrence of major debilitating chronic diseases, and part of this trait seems to be hidden in their genome. In this review, we discuss the findings from studies on the genetic component of human longevity and the main challenges accompanying these studies. We subsequently focus on results from genetic studies in model organisms and comparative genomic approaches to highlight the most important conserved longevity-associated pathways. By combining the results from studies using these different approaches, we conclude that only five main pathways have been consistently linked to longevity, namely (1) insulin/insulin-like growth factor 1 signalling, (2) DNA-damage response and repair, (3) immune function, (4) cholesterol metabolism and (5) telomere maintenance. As our current approaches to study the relevance of these pathways in humans are limited, we suggest that future studies on the genetics of human longevity should focus on the identification and functional characterization of rare genetic variants in genes involved in these pathways.
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Affiliation(s)
- Larissa Smulders
- Max Planck Institute for Biology of Ageing, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Joris Deelen
- Max Planck Institute for Biology of Ageing, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
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5
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Zhang J, Pan L, Zhang S, Yang Y, Liang J, Ma S, Wu Q. CISD2 promotes lung squamous carcinoma cell migration and invasion via the TGF-β1-induced Smad2/3 signaling pathway. Clin Transl Oncol 2023; 25:3527-3540. [PMID: 37249759 DOI: 10.1007/s12094-023-03222-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 05/19/2023] [Indexed: 05/31/2023]
Abstract
BACKGROUND Although aberrant expression of CDGSH iron sulfur domain 2 (CISD2) contributes to the tumorigenesis and progression of numerous human cancers, the biological function of CISD2 and its specific prognostic value in lung squamous cell carcinoma (LUSC) have yet to be comprehensively explored. The current study aimed to elucidate the role of CISD2 in LUSC as well as the underlying molecular mechanisms. METHODS Immunohistochemistry was conducted to detect the protein expression of CISD2 and analyze whether high expression of CISD2 affects the overall survival (OS) of LUSC patients. Cell proliferation, colony formation, wound healing and Transwell invasion assays were performed to clarify whether CISD2 contributes to LUSC cell proliferation and disease progression. Quantitative real-time reverse transcription-PCR and western blot assays were used to detect the levels of transcription factors and key epithelial-mesenchymal transition (EMT)-related markers in LUSC cells after CISD2 knockdown and overexpression to determine whether CISD2 regulates transforming growth factor-beta (TGF-β)-induced EMT in LUSC. RESULTS Immunohistochemistry of human tissue microarrays containing 90 pairs of adjacent and cancerous tissues revealed that CISD2 is considerably overexpressed in LUSC and strongly linked to poor OS. Functional experiments suggested that silencing endogenous CISD2 inhibited the growth, colony formation, migration, and invasion of H2170 and H226 cell lines. Exogenous overexpression of CISD2 facilitated these phenotypes in SK-MES-1 and H2170 cells. Furthermore, CISD2 promoted EMT progression by increasing the expression of mesenchymal markers (N-cadherin, vimentin, Snail, and Slug) as well as SMAD2/3 and reducing the expression of the epithelial marker E-cadherin. Mechanistically, our studies provide the first evidence that CISD2 can promote EMT by enhancing TGF-β1-induced Smad2/3 expression in LUSC cells. CONCLUSION In conclusion, our research illustrates that CISD2 is highly expressed in LUSC and may facilitate LUSC proliferation and metastasis. Thus, CISD2 may serve as an independent prognostic marker and possible treatment target for LUSC.
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Affiliation(s)
- Jingjing Zhang
- Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Lifang Pan
- Integrated Traditional Chinese and Western Medicine Oncology Laboratory, Zhejiang Cancer Hospital, Hangzhou, 310022, China
| | - Shirong Zhang
- Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yuhong Yang
- Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Jiafeng Liang
- Department of Radiation Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
| | - Shenglin Ma
- Department of Radiation Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China.
| | - Qiong Wu
- Integrated Traditional Chinese and Western Medicine Oncology Laboratory, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
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Yeh CH, Shen ZQ, Wang TW, Kao CH, Teng YC, Yeh TK, Lu CK, Tsai TF. Hesperetin promotes longevity and delays aging via activation of Cisd2 in naturally aged mice. J Biomed Sci 2022; 29:53. [PMID: 35871686 PMCID: PMC9310407 DOI: 10.1186/s12929-022-00838-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 07/19/2022] [Indexed: 11/18/2022] Open
Abstract
Abstract
Background
The human CISD2 gene is located within a longevity region mapped on chromosome 4q. In mice, Cisd2 levels decrease during natural aging and genetic studies have shown that a high level of Cisd2 prolongs mouse lifespan and healthspan. Here, we evaluate the feasibility of using a Cisd2 activator as an effective way of delaying aging.
Methods
Hesperetin was identified as a promising Cisd2 activator by herb compound library screening. Hesperetin has no detectable toxicity based on in vitro and in vivo models. Naturally aged mice fed dietary hesperetin were used to investigate the effect of this Cisd2 activator on lifespan prolongation and the amelioration of age-related structural defects and functional decline. Tissue-specific Cisd2 knockout mice were used to study the Cisd2-dependent anti-aging effects of hesperetin. RNA sequencing was used to explore the biological effects of hesperetin on aging.
Results
Three discoveries are pinpointed. Firstly, hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice. Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence. Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age.
Conclusions
Our findings indicate that a Cisd2 activator, hesperetin, represents a promising and broadly effective translational approach to slowing down aging and promoting longevity via the activation of Cisd2.
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Fu S, Hu J, Chen X, Li B, Shun H, Deng J, Zhang Y, Yao Y, Zhao Y. Mutant Single Nucleotide Polymorphism rs189037 in Ataxia-Telangiectasia Mutated Gene Is Significantly Associated With Ventricular Wall Thickness and Human Lifespan. Front Cardiovasc Med 2021; 8:658908. [PMID: 34124196 PMCID: PMC8187557 DOI: 10.3389/fcvm.2021.658908] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 04/20/2021] [Indexed: 11/13/2022] Open
Abstract
In the current study, we aimed to determine the association of single nucleotide polymorphism rs189037 in ataxia-telangiectasia mutated (ATM) gene with cardiac structure and human longevity. Based on the China Hainan Centenarian Cohort Study performed in 18 cities and counties of Hainan Province, China, the current study enrolled 547 centenarians, 250 young participants aged 20–45 years, and 250 middle-aged and elderly participants aged 46–90 years. The frequency of TT genotype was significantly higher and that of CC genotype was significantly lower in middle-aged and elderly participants than in young (P = 0.012) and centenarian (P = 0.041) participants. There were no significant differences in the genotype and allele frequencies of SNP rs189037 between young and centenarian participants. Compared with CT genotype, TT genotype was positively and significantly associated with interventricular septum thickness (IVST) and left ventricular posterior wall thickness (LVPWT) in centenarian (IVST: P = 0.049; LVPWT: P = 0.047) and middle-aged and elderly (IVST: P = 0.008; LVPWT: P = 0.004) participants. Compared with CC genotype, TT genotype was positively and significantly associated with LVPWT in centenarian (P = 0.030) and middle-aged and elderly (P = 0.013) participants. Compared with CC genotype, CT genotype was negatively and significantly associated with left ventricular end-diastolic diameter (LVEDD) in centenarian (P = 0.011) and middle-aged and elderly (P = 0.040) participants. The current study demonstrated that mutant rs189037 in the ATM gene was more commonly identified in middle-aged and elderly participants than in young and centenarian participants, was significantly associated with increased left ventricular wall thickness and volume, and could induce left ventricular eccentric hypertrophy and shorten human lifespan. Therefore, rs189037 without mutation might be an indicator of youth health and successful aging, whereas mutant rs189037 might hinder human longevity.
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Affiliation(s)
- Shihui Fu
- Department of Cardiology, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, China.,Department of Geriatric Cardiology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Jianqiu Hu
- Department of Ultrasound, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, China
| | - Xiaoping Chen
- Central Laboratory, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, China
| | - Bo Li
- Department of Cardiology, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, China
| | - Hongjuan Shun
- Department of Health Medicine, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, China
| | - Juelin Deng
- Department of Cardiology, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, China
| | - Yujie Zhang
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, China
| | - Yao Yao
- Center for the Study of Aging and Human Development and Geriatrics Division, Medical School of Duke University, Durham, NC, United States.,Center for Healthy Aging and Development Studies, National School of Development, Peking University, Beijing, China
| | - Yali Zhao
- Central Laboratory, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, China
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Liao HY, Liao B, Zhang HH. CISD2 plays a role in age-related diseases and cancer. Biomed Pharmacother 2021; 138:111472. [PMID: 33752060 DOI: 10.1016/j.biopha.2021.111472] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 03/03/2021] [Accepted: 03/04/2021] [Indexed: 12/12/2022] Open
Abstract
CDGSH iron-sulfur domain 2 (Cisd2) is an evolutionarily conserved protein that plays an important regulatory role in aging-related diseases and cancers. Since its discovery, Cisd2 has been identified as a regulatory factor for the aging of the human body and the regulation of mammalian lifespan. Cisd2 is also an oncoprotein that regulates the occurrence and development of cancer. Cisd2 mediates the occurrence of diseases related to human aging and the proliferation, differentiation, metastasis, and invasion of various cancer cells through various mechanisms. Multiple studies have shown that Cisd2 expression is related to the clinical characteristics of aging-related diseases and patients with cancer, and its expression profile is a novel diagnostic and prognostic biomarker for a variety of human diseases. Modulating the expression or function of Cisd2 may be a potential treatment strategy for different diseases. In this review, we summarize the role of Cisd2 in human aging-related diseases and various cancers, as well as the biological functions, underlying mechanisms, and potential clinical significance.
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Affiliation(s)
- Hai-Yang Liao
- The Second Clinical Medical College of Lanzhou University, 82 Cuiying Men, Lanzhou 730030, PR China; Orthopedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China.
| | - Bei Liao
- Orthopedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China; The First Clinical Medical College of Lanzhou University, 1 Donggang Road, Lanzhou 730000, PR China.
| | - Hai-Hong Zhang
- The Second Clinical Medical College of Lanzhou University, 82 Cuiying Men, Lanzhou 730030, PR China; Orthopedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China.
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Shen ZQ, Huang YL, Teng YC, Wang TW, Kao CH, Yeh CH, Tsai TF. CISD2 maintains cellular homeostasis. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1868:118954. [PMID: 33422617 DOI: 10.1016/j.bbamcr.2021.118954] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 12/29/2020] [Indexed: 02/07/2023]
Abstract
CDGSH Iron Sulfur Domain 2 (CISD2) is the causative gene for the disease Wolfram syndrome 2 (WFS2; MIM 604928), which is an autosomal recessive disorder showing metabolic and neurodegenerative manifestations. CISD2 protein can be localized on the endoplasmic reticulum (ER), outer mitochondrial membrane (OMM) and mitochondria-associated membrane (MAM). CISD2 plays a crucial role in the regulation of cytosolic Ca2+ homeostasis, ER integrity and mitochondrial function. Here we summarize the most updated publications and discuss the central role of CISD2 in maintaining cellular homeostasis. This review mainly focuses on the following topics. Firstly, that CISD2 has been recognized as a prolongevity gene and the level of CISD2 is a key determinant of lifespan and healthspan. In mice, Cisd2 deficiency shortens lifespan and accelerates aging. Conversely, a persistently high level of Cisd2 promotes longevity. Intriguingly, exercise stimulates Cisd2 gene expression and thus, the beneficial effects offered by exercise may be partly related to Cisd2 activation. Secondly, that Cisd2 is down-regulated in a variety of tissues and organs during natural aging. Three potential mechanisms that may mediate the age-dependent decrease of Cisd2, via regulating at different levels of gene expression, are discussed. Thirdly, the relationship between CISD2 and cell survival, as well as the potential mechanisms underlying the cell death control, are discussed. Finally we discuss that, in cancers, CISD2 may functions as a double-edged sword, either suppressing or promoting cancer development. This review highlights the importance of the CISD2 in aging and age-related diseases and identifies the urgent need for the translation of available genetic evidence into pharmaceutic interventions in order to alleviate age-related disorders and extend a healthy lifespan in humans.
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Affiliation(s)
- Zhao-Qing Shen
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Yi-Long Huang
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan; Aging and Health Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Yuan-Chi Teng
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Tai-Wen Wang
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Cheng-Heng Kao
- Center of General Education, Chang Gung University, Taoyuan, Taiwan
| | - Chi-Hsiao Yeh
- Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Linko, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung Branch, Keelung, Taiwan.
| | - Ting-Fen Tsai
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan; Aging and Health Research Center, National Yang-Ming University, Taipei, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
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Brd2 haploinsufficiency extends lifespan and healthspan in C57B6/J mice. PLoS One 2020; 15:e0234910. [PMID: 32559200 PMCID: PMC7304595 DOI: 10.1371/journal.pone.0234910] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 06/04/2020] [Indexed: 11/19/2022] Open
Abstract
Aging in mammals is the gradual decline of an organism's physical, mental, and physiological capacity. Aging leads to increased risk for disease and eventually to death. Here, we show that Brd2 haploinsufficiency (Brd2+/-) extends lifespan and increases healthspan in C57B6/J mice. In Brd2+/- mice, longevity is increased by 23% (p<0.0001), and, relative to wildtype animals (Brd2+/+), cancer incidence is reduced by 43% (p<0.001). In addition, relative to age-matched wildtype mice, Brd2 heterozygotes show healthier aging including: improved grooming, extended period of fertility, and lack of age-related decline in kidney function and morphology. Our data support a role for haploinsufficiency of Brd2 in promoting healthy aging. We hypothesize that Brd2 affects aging by protecting against the accumulation of molecular and cellular damage. Given the recent advances in the development of BET inhibitors, our research provides impetus to test drugs that target BRD2 as a way to understand and treat/prevent age-related diseases.
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Maurya PK. Animal biotechnology as a tool to understand and fight aging. Anim Biotechnol 2020. [DOI: 10.1016/b978-0-12-811710-1.00010-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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12
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Identification of novel genes associated with longevity in Drosophila melanogaster - a computational approach. Aging (Albany NY) 2019; 11:11244-11267. [PMID: 31794428 PMCID: PMC6932890 DOI: 10.18632/aging.102527] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 11/18/2019] [Indexed: 12/13/2022]
Abstract
Despite a growing number of studies on longevity in Drosophila, genetic factors influencing lifespan are still poorly understood. In this paper we propose a conceptually new approach for the identification of novel longevity-associated genes and potential target genes for SNPs in non-coding regions by utilizing the knowledge of co-location of various loci, governed by the three-dimensional architecture of the Drosophila genome. Firstly, we created networks between genes/genomic regions harboring SNPs deemed to be significant in two longevity GWAS summary statistics datasets using intra- and inter-chromosomal interaction frequencies (Hi-C data) as a measure of co-location. These networks were further extended to include regions strongly interacting with previously selected regions. Using various network measures, literature search and additional bioinformatics resources, we investigated the plausibility of genes found to have genuine association with longevity. Several of the newly identified genes were common between the two GWAS datasets and these possessed human orthologs. We also found that the proportion of non-coding SNPs in borders between topologically associated domains is significantly higher than expected by chance. Assuming co-location, we investigated potential target genes for non-coding SNPs. This approach therefore offers a stepping stone to identification of novel genes and SNP targets linked to human longevity.
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13
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Giuliani C, Garagnani P, Franceschi C. Genetics of Human Longevity Within an Eco-Evolutionary Nature-Nurture Framework. Circ Res 2019; 123:745-772. [PMID: 30355083 DOI: 10.1161/circresaha.118.312562] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Human longevity is a complex trait, and to disentangle its basis has a great theoretical and practical consequences for biomedicine. The genetics of human longevity is still poorly understood despite several investigations that used different strategies and protocols. Here, we argue that such rather disappointing harvest is largely because of the extraordinary complexity of the longevity phenotype in humans. The capability to reach the extreme decades of human lifespan seems to be the result of an intriguing mixture of gene-environment interactions. Accordingly, the genetics of human longevity is here described as a highly context-dependent phenomenon, within a new integrated, ecological, and evolutionary perspective, and is presented as a dynamic process, both historically and individually. The available literature has been scrutinized within this perspective, paying particular attention to factors (sex, individual biography, family, population ancestry, social structure, economic status, and education, among others) that have been relatively neglected. The strength and limitations of the most powerful and used tools, such as genome-wide association study and whole-genome sequencing, have been discussed, focusing on prominently emerged genes and regions, such as apolipoprotein E, Forkhead box O3, interleukin 6, insulin-like growth factor-1, chromosome 9p21, 5q33.3, and somatic mutations among others. The major results of this approach suggest that (1) the genetics of longevity is highly population specific; (2) small-effect alleles, pleiotropy, and the complex allele timing likely play a major role; (3) genetic risk factors are age specific and need to be integrated in the light of the geroscience perspective; (4) a close relationship between genetics of longevity and genetics of age-related diseases (especially cardiovascular diseases) do exist. Finally, the urgent need of a global approach to the largely unexplored interactions between the 3 genetics of human body, that is, nuclear, mitochondrial, and microbiomes, is stressed. We surmise that the comprehensive approach here presented will help in increasing the above-mentioned harvest.
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Affiliation(s)
- Cristina Giuliani
- From the Department of Biological, Geological, and Environmental Sciences (BiGeA), Laboratory of Molecular Anthropology and Centre for Genome Biology (C.G.), University of Bologna, Italy.,School of Anthropology and Museum Ethnography, University of Oxford, United Kingdom (C.G.).,Interdepartmental Centre 'L. Galvani' (CIG), University of Bologna, Italy (C.G.)
| | - Paolo Garagnani
- Department of Experimental, Diagnostic, and Specialty Medicine (DIMES) (P.G.), University of Bologna, Italy.,Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden (P.G.)
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14
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Morris BJ, Willcox BJ, Donlon TA. Genetic and epigenetic regulation of human aging and longevity. Biochim Biophys Acta Mol Basis Dis 2019; 1865:1718-1744. [PMID: 31109447 PMCID: PMC7295568 DOI: 10.1016/j.bbadis.2018.08.039] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 08/02/2018] [Accepted: 08/28/2018] [Indexed: 02/06/2023]
Abstract
Here we summarize the latest data on genetic and epigenetic contributions to human aging and longevity. Whereas environmental and lifestyle factors are important at younger ages, the contribution of genetics appears more important in reaching extreme old age. Genome-wide studies have implicated ~57 gene loci in lifespan. Epigenomic changes during aging profoundly affect cellular function and stress resistance. Dysregulation of transcriptional and chromatin networks is likely a crucial component of aging. Large-scale bioinformatic analyses have revealed involvement of numerous interaction networks. As the young well-differentiated cell replicates into eventual senescence there is drift in the highly regulated chromatin marks towards an entropic middle-ground between repressed and active, such that genes that were previously inactive "leak". There is a breakdown in chromatin connectivity such that topologically associated domains and their insulators weaken, and well-defined blocks of constitutive heterochromatin give way to generalized, senescence-associated heterochromatin, foci. Together, these phenomena contribute to aging.
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Affiliation(s)
- Brian J Morris
- Basic & Clinical Genomics Laboratory, School of Medical Sciences and Bosch Institute, University of Sydney, New South Wales 2006, Australia; Honolulu Heart Program (HHP)/Honolulu-Asia Aging Study (HAAS), Department of Research, Kuakini Medical Center, Honolulu, HI 96817, United States; Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Kuakini Medical Center Campus, Honolulu, HI 96813, United States.
| | - Bradley J Willcox
- Honolulu Heart Program (HHP)/Honolulu-Asia Aging Study (HAAS), Department of Research, Kuakini Medical Center, Honolulu, HI 96817, United States; Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Kuakini Medical Center Campus, Honolulu, HI 96813, United States.
| | - Timothy A Donlon
- Honolulu Heart Program (HHP)/Honolulu-Asia Aging Study (HAAS), Department of Research, Kuakini Medical Center, Honolulu, HI 96817, United States; Departments of Cell & Molecular Biology and Pathology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, United States.
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15
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Hook M, Roy S, Williams EG, Bou Sleiman M, Mozhui K, Nelson JF, Lu L, Auwerx J, Williams RW. Genetic cartography of longevity in humans and mice: Current landscape and horizons. Biochim Biophys Acta Mol Basis Dis 2018; 1864:2718-2732. [PMID: 29410319 PMCID: PMC6066442 DOI: 10.1016/j.bbadis.2018.01.026] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 01/24/2018] [Accepted: 01/28/2018] [Indexed: 12/14/2022]
Abstract
Aging is a complex and highly variable process. Heritability of longevity among humans and other species is low, and this finding has given rise to the idea that it may be futile to search for DNA variants that modulate aging. We argue that the problem in mapping longevity genes is mainly one of low power and the genetic and environmental complexity of aging. In this review we highlight progress made in mapping genes and molecular networks associated with longevity, paying special attention to work in mice and humans. We summarize 40 years of linkage studies using murine cohorts and 15 years of studies in human populations that have exploited candidate gene and genome-wide association methods. A small but growing number of gene variants contribute to known longevity mechanisms, but a much larger set have unknown functions. We outline these and other challenges and suggest some possible solutions, including more intense collaboration between research communities that use model organisms and human cohorts. Once hundreds of gene variants have been linked to differences in longevity in mammals, it will become feasible to systematically explore gene-by-environmental interactions, dissect mechanisms with more assurance, and evaluate the roles of epistasis and epigenetics in aging. A deeper understanding of complex networks-genetic, cellular, physiological, and social-should position us well to improve healthspan.
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Affiliation(s)
- Michael Hook
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Suheeta Roy
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Evan G Williams
- Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich CH-8093, Switzerland
| | - Maroun Bou Sleiman
- Interfaculty Institute of Bioengineering, Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH-1015, Switzerland
| | - Khyobeni Mozhui
- Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - James F Nelson
- Department of Cellular and Integrative Physiology and Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Lu Lu
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Johan Auwerx
- Interfaculty Institute of Bioengineering, Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH-1015, Switzerland
| | - Robert W Williams
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
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16
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Puca AA, Spinelli C, Accardi G, Villa F, Caruso C. Centenarians as a model to discover genetic and epigenetic signatures of healthy ageing. Mech Ageing Dev 2018; 174:95-102. [DOI: 10.1016/j.mad.2017.10.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/26/2017] [Accepted: 10/28/2017] [Indexed: 01/07/2023]
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17
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Sawaki K, Kanda M, Kodera Y. Review of recent efforts to discover biomarkers for early detection, monitoring, prognosis, and prediction of treatment responses of patients with gastric cancer. Expert Rev Gastroenterol Hepatol 2018; 12:657-670. [PMID: 29902383 DOI: 10.1080/17474124.2018.1489233] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Gastric cancer (GC) is the leading cause of cancer-related death worldwide. Despite recent advances in diagnosis and therapy, the prognosis of patients with GC is poor. Many patients have inoperable disease upon diagnosis or experience recurrent disease after curative gastrectomy. Unfortunately, tumor markers for GC, such as serum carcinoembryonic antigen and carbohydrate antigen 19-9, lack sufficient sensitivity and specificity. Therefore, effective biomarkers are required to detect early GC and to predict tumor recurrence and chemosensitivity. Areas covered: Here we aimed to review recent developments in techniques that improve the detection of aberrant expression of GC-associated molecules, including protein coding genes, microRNAs, long noncoding RNAs, and methylated promoter DNAs. Expert commentary: Detection of genetic and epigenetic alterations in gastric tissue or in the circulation will likely improve the diagnosis and management of GC to achieve significantly improved outcomes.
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Affiliation(s)
- Koichi Sawaki
- a Department of Gastroenterological Surgery (Surgery II) , Nagoya University Graduate School of Medicine , Nagoya , Japan
| | - Mitsuro Kanda
- a Department of Gastroenterological Surgery (Surgery II) , Nagoya University Graduate School of Medicine , Nagoya , Japan
| | - Yasuhiro Kodera
- a Department of Gastroenterological Surgery (Surgery II) , Nagoya University Graduate School of Medicine , Nagoya , Japan
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18
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S-nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy. Proc Natl Acad Sci U S A 2018; 115:E3388-E3397. [PMID: 29581312 DOI: 10.1073/pnas.1722452115] [Citation(s) in RCA: 142] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
S-nitrosylation, a prototypic redox-based posttranslational modification, is frequently dysregulated in disease. S-nitrosoglutathione reductase (GSNOR) regulates protein S-nitrosylation by functioning as a protein denitrosylase. Deficiency of GSNOR results in tumorigenesis and disrupts cellular homeostasis broadly, including metabolic, cardiovascular, and immune function. Here, we demonstrate that GSNOR expression decreases in primary cells undergoing senescence, as well as in mice and humans during their life span. In stark contrast, exceptionally long-lived individuals maintain GSNOR levels. We also show that GSNOR deficiency promotes mitochondrial nitrosative stress, including excessive S-nitrosylation of Drp1 and Parkin, thereby impairing mitochondrial dynamics and mitophagy. Our findings implicate GSNOR in mammalian longevity, suggest a molecular link between protein S-nitrosylation and mitochondria quality control in aging, and provide a redox-based perspective on aging with direct therapeutic implications.
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19
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La Spada A, Ntai A, Genovese S, Rondinelli M, De Blasio P, Biunno I. Generation of Human-Induced Pluripotent Stem Cells from Wolfram Syndrome Type 2 Patients Bearing the c.103 + 1G>A CISD2 Mutation for Disease Modeling. Stem Cells Dev 2018; 27:287-295. [PMID: 29239282 DOI: 10.1089/scd.2017.0158] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Wolfram syndrome (WFS) is a rare autosomal premature aging syndrome that shows signs of diabetes mellitus, optic atrophy, and deafness in addition to central nervous system and endocrine complications. The frequent form of WFS type 1 (WFS1) harbors causative mutations in the WFS1 gene, whereas the rare form or WFS type 2 (WFS2) involves CISD2. Mutations in these two genes are recognized by a subset of variable clinical symptoms and a set of overlapping features. In this study, we report on the generation of stable human-induced pluripotent stem cells (hiPSCs) derived from primary fibroblasts of a previously reported Italian family with CISD2 mutation (c.103 + 1G>A), occurring in the consensus intron 1 splicing site in two sisters, deleting the first exon of the transcript. The generated hiPSCs provide a cell model system to study the mutation's role in the multisystemic clinical disorders previously described and test eventual drug effects on the specific and associated clinical phenotype.
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Affiliation(s)
- Alberto La Spada
- 1 Institute of Genetic and Biomedical Research , National Research Council (IRGB-CNR), Department of Biomedicine, Milan, Italy
| | - Aikaterini Ntai
- 2 Integrated Systems Engineering S.r.l. (ISENET) , Milan, Italy
| | - Stefano Genovese
- 3 Diabetes Endocrine and Metabolic Diseases Unit, IRCCS MultiMedica , Milan, Italy
| | - Maurizio Rondinelli
- 3 Diabetes Endocrine and Metabolic Diseases Unit, IRCCS MultiMedica , Milan, Italy
| | | | - Ida Biunno
- 1 Institute of Genetic and Biomedical Research , National Research Council (IRGB-CNR), Department of Biomedicine, Milan, Italy .,4 IRCCS MultiMedica, Department of Stem Cell Research, Milan, Italy
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20
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Cattaneo M, La Sala L, Rondinelli M, Errichiello E, Zuffardi O, Puca AA, Genovese S, Ceriello A. A donor splice site mutation in CISD2 generates multiple truncated, non-functional isoforms in Wolfram syndrome type 2 patients. BMC MEDICAL GENETICS 2017; 18:147. [PMID: 29237418 PMCID: PMC5729406 DOI: 10.1186/s12881-017-0508-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 11/29/2017] [Indexed: 11/10/2022]
Abstract
BACKGROUND Mutations in the gene that encodes CDGSH iron sulfur domain 2 (CISD2) are causative of Wolfram syndrome type 2 (WFS2), a rare autosomal recessive neurodegenerative disorder mainly characterized by diabetes mellitus, optic atrophy, peptic ulcer bleeding and defective platelet aggregation. Four mutations in the CISD2 gene have been reported. Among these mutations, the homozygous c.103 + 1G > A substitution was identified in the donor splice site of intron 1 in two Italian sisters and was predicted to cause a exon 1 to be skipped. METHODS Here, we employed molecular assays to characterize the c.103 + 1G > A mutation using the patient's peripheral blood mononuclear cells (PBMCs). 5'-RACE coupled with RT-PCR were used to analyse the effect of the c.103 + 1G > A mutation on mRNA splicing. Western blot analysis was used to analyse the consequences of the CISD2 mutation on the encoded protein. RESULTS We demonstrated that the c.103 + 1G > A mutation functionally impaired mRNA splicing, producing multiple splice variants characterized by the whole or partial absence of exon 1, which introduced amino acid changes and a premature stop. The affected mRNAs resulted in either predicted targets for nonsense mRNA decay (NMD) or non-functional isoforms. CONCLUSIONS We concluded that the c.103 + 1G > A mutation resulted in the loss of functional CISD2 protein in the two Italian WFS2 patients.
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Affiliation(s)
- Monica Cattaneo
- Cardiovascular Research Unit, IRCCS MultiMedica, Via G. Fantoli 16/15, 20138, Milan, Italy.
| | - Lucia La Sala
- Cardiovascular Research Unit, IRCCS MultiMedica, Via G. Fantoli 16/15, 20138, Milan, Italy
| | - Maurizio Rondinelli
- Diabetes Endocrine and Metabolic Diseases Unit, IRCCS MultiMedica, 20099 Sesto San Giovanni, Milan, Italy.,IRCCS Centro Cardiologico Monzino Diabetes, Endocrine and Metabolic Diseases Unit, 20138, Milan, Italy
| | | | - Orsetta Zuffardi
- Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy
| | - Annibale Alessandro Puca
- Cardiovascular Research Unit, IRCCS MultiMedica, Via G. Fantoli 16/15, 20138, Milan, Italy.,Department of Medicine and Surgery, University of Salerno, 84084, Salerno, Italy
| | - Stefano Genovese
- Diabetes Endocrine and Metabolic Diseases Unit, IRCCS MultiMedica, 20099 Sesto San Giovanni, Milan, Italy.,IRCCS Centro Cardiologico Monzino Diabetes, Endocrine and Metabolic Diseases Unit, 20138, Milan, Italy
| | - Antonio Ceriello
- Cardiovascular Research Unit, IRCCS MultiMedica, Via G. Fantoli 16/15, 20138, Milan, Italy.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomedica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
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21
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Sebastiani P, Gurinovich A, Bae H, Andersen S, Malovini A, Atzmon G, Villa F, Kraja AT, Ben-Avraham D, Barzilai N, Puca A, Perls TT. Four Genome-Wide Association Studies Identify New Extreme Longevity Variants. J Gerontol A Biol Sci Med Sci 2017; 72:1453-1464. [PMID: 28329165 DOI: 10.1093/gerona/glx027] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 02/14/2017] [Indexed: 01/10/2023] Open
Abstract
The search for the genetic determinants of extreme human longevity has been challenged by the phenotype's rarity and its nonspecific definition by investigators. To address these issues, we established a consortium of four studies of extreme longevity that contributed 2,070 individuals who survived to the oldest one percentile of survival for the 1900 U.S. birth year cohort. We conducted various analyses to discover longevity-associated variants (LAV) and characterized those LAVs that differentiate survival to extreme age at death (eSAVs) from those LAVs that become more frequent in centenarians because of mortality selection (eg, survival to younger years). The analyses identified new rare variants in chromosomes 4 and 7 associated with extreme survival and with reduced risk for cardiovascular disease and Alzheimer's disease. The results confirm the importance of studying truly rare survival to discover those combinations of common and rare variants associated with extreme longevity and longer health span.
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Affiliation(s)
- Paola Sebastiani
- Department of Biostatistics, Boston University School of Public Health, Massachusetts
| | | | - Harold Bae
- College of Public Health and Human Sciences, Oregon State University, Corvallis
| | - Stacy Andersen
- Geriatrics Section, Department of Medicine, Boston University School of Medicine & Boston Medical Center, Massachusetts
| | - Alberto Malovini
- Laboratory of Informatics and Systems Engineering for Clinical Research, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy
| | - Gil Atzmon
- Department of Natural Science, University of Haifa, Israel.,Department of Medicine.,Department of Genetics, Albert Einstein College of Medicine, Bronx, New York
| | - Francesco Villa
- IRCCS MultiMedica, Milan, Italy.,Department of Medicine and Surgery, University of Salerno, Baronissi, Italy
| | - Aldi T Kraja
- Division of Statistical Genomics, Washington University School of Medicine, Saint Louis, Missouri
| | - Danny Ben-Avraham
- Department of Medicine.,Department of Genetics, Albert Einstein College of Medicine, Bronx, New York
| | - Nir Barzilai
- Department of Medicine.,Department of Genetics, Albert Einstein College of Medicine, Bronx, New York
| | - Annibale Puca
- IRCCS MultiMedica, Milan, Italy.,Department of Medicine and Surgery, University of Salerno, Baronissi, Italy
| | - Thomas T Perls
- Geriatrics Section, Department of Medicine, Boston University School of Medicine & Boston Medical Center, Massachusetts
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22
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Rouzier C, Moore D, Delorme C, Lacas-Gervais S, Ait-El-Mkadem S, Fragaki K, Burté F, Serre V, Bannwarth S, Chaussenot A, Catala M, Yu-Wai-Man P, Paquis-Flucklinger V. A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions. Hum Mol Genet 2017; 26:1599-1611. [PMID: 28335035 PMCID: PMC5411739 DOI: 10.1093/hmg/ddx060] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 02/14/2017] [Indexed: 12/26/2022] Open
Abstract
Wolfram syndrome (WS) is a progressive neurodegenerative disease characterized by early-onset optic atrophy and diabetes mellitus, which can be associated with more extensive central nervous system and endocrine complications. The majority of patients harbour pathogenic WFS1 mutations, but recessive mutations in a second gene, CISD2, have been described in a small number of families with Wolfram syndrome type 2 (WFS2). The defining diagnostic criteria for WFS2 also consist of optic atrophy and diabetes mellitus, but unlike WFS1, this phenotypic subgroup has been associated with peptic ulcer disease and an increased bleeding tendency. Here, we report on a novel homozygous CISD2 mutation (c.215A > G; p.Asn72Ser) in a Moroccan patient with an overlapping phenotype suggesting that Wolfram syndrome type 1 and type 2 form a continuous clinical spectrum with genetic heterogeneity. The present study provides strong evidence that this particular CISD2 mutation disturbs cellular Ca2+ homeostasis with enhanced Ca2+ flux from the ER to mitochondria and cytosolic Ca2+ abnormalities in patient-derived fibroblasts. This Ca2+ dysregulation was associated with increased ER-mitochondria contact, a swollen ER lumen and a hyperfused mitochondrial network in the absence of overt ER stress. Although there was no marked alteration in mitochondrial bioenergetics under basal conditions, culture of patient-derived fibroblasts in glucose-free galactose medium revealed a respiratory chain defect in complexes I and II, and a trend towards decreased ATP levels. Our results provide important novel insight into the potential disease mechanisms underlying the neurodegenerative consequences of CISD2 mutations and the subsequent development of multisystemic disease.
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Affiliation(s)
- Cécile Rouzier
- Université Côte d'Azur, CHU, Inserm, CNRS, IRCAN, France
| | - David Moore
- Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
| | - Cécile Delorme
- Fédération de Neurologie, Université Pierre et Marie Curie et Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Sandra Lacas-Gervais
- Joint Centre for Applied Electron Microscopy, Nice Sophia-Antipolis University, Nice, France
| | | | | | - Florence Burté
- Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
| | - Valérie Serre
- UMR7592 CNRS, Jacques Monod Institute, Paris Diderot University, Paris, France
| | | | | | - Martin Catala
- UMR 7622 CNRS et UPMC et Fédération de Neurologie, Université Pierre et Marie Curie et Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Patrick Yu-Wai-Man
- Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.,Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK.,NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK
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23
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Kheirbek RE, Fokar A, Shara N, Bell-Wilson LK, Moore HJ, Olsen E, Blackman MR, Llorente MD. Characteristics and Incidence of Chronic Illness in Community-Dwelling Predominantly Male U.S. Veteran Centenarians. J Am Geriatr Soc 2017; 65:2100-2106. [PMID: 28422270 DOI: 10.1111/jgs.14900] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
OBJECTIVES To assess the incidence of chronic illness and its effect on veteran centenarians. DESIGN Retrospective longitudinal cohort study. SETTING United States Veterans Affairs Corporate Data Warehouse (CDW). PARTICIPANTS Community-dwelling veterans born between 1910 and 1915 who survived to at least age 80 (N = 86,892; 31,121 octogenarians, 52,420 nonagenarians, 3,351 centenarians). MEASUREMENTS The Kaplan-Meier method was used to estimate cumulative incidence of chronic conditions according to age group. Incidence rates were compared using the log-rank test. Cox proportional hazards models were used to estimate unadjusted hazard ratios. RESULTS Ninety-seven percent of Centenarians were male, 88.0% were white, 31.8% were widowed, 87.5% served in World War II, and 63.9% did not have a service-related disability. The incidence rates of chronic illnesses were higher in octogenarians than centenarians (atrial fibrillation, 15.0% vs 0.6%, P < .001; heart failure, 19.3% vs 0.4%, P < .001; chronic obstructive pulmonary disease, 17.9% vs 0.6%, P < .001; hypertension, 29.6% vs 3.0%, P < .001; end-stage renal disease, 7.2% vs 0.1%, P < .001; malignancy, 14.1% vs 0.6%, P < .001; diabetes mellitus, 11.1% vs 0.4%, P < .001; stroke, 4.6% vs 0.4%, P < .001) and in nonagenarians than centenarians (atrial fibrillation, 13.2% vs 3.5%, P < .001; heart failure, 15.8% vs 3.3%, P < .001; chronic obstructive pulmonary disease, 11.8% vs 3.5%, P < .001; hypertension, 27.2% vs 12.8%, P < .001; end-stage renal disease, 11.9% vs 4.5%, P < .001; malignancy, 8.6% vs 2.3%, P < .001; diabetes mellitus, 7.5% vs 2.2%, P < .001; and stroke, 3.5% vs 1.3%, P < .001). CONCLUSION In a large cohort of predominantly male community-dwelling elderly veterans, centenarians had a lower incidence of chronic illness than those in their 80s and 90s, demonstrating similar compression of morbidity and extension of health span observed in other studies.
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Affiliation(s)
- Raya Elfadel Kheirbek
- Washington DC Veterans Affairs Medical Center, Washington, District of Columbia.,School of Medicine and Health Sciences, George Washington University, Washington, District of Columbia.,School of Medicine, Georgetown University, Washington, District of Columbia
| | - Ali Fokar
- Washington DC Veterans Affairs Medical Center, Washington, District of Columbia
| | - Nawar Shara
- MedStar Health Research Institute, Hyattsville, Maryland.,Georgetown-Howard Universities Center for Clinical and Translational Sciences, Washington, District of Columbia
| | | | - Hans J Moore
- Washington DC Veterans Affairs Medical Center, Washington, District of Columbia.,School of Medicine, Georgetown University, Washington, District of Columbia.,Uniformed Services University of the Health Sciences, Bethesda, Maryland
| | - Edwin Olsen
- Miller School of Medicine, University of Miami, Miami, Florida
| | - Marc R Blackman
- Washington DC Veterans Affairs Medical Center, Washington, District of Columbia.,School of Medicine and Health Sciences, George Washington University, Washington, District of Columbia.,School of Medicine, Georgetown University, Washington, District of Columbia.,Georgetown-Howard Universities Center for Clinical and Translational Sciences, Washington, District of Columbia
| | - Maria D Llorente
- Washington DC Veterans Affairs Medical Center, Washington, District of Columbia.,School of Medicine, Georgetown University, Washington, District of Columbia
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24
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Bioactive Nutrients and Nutrigenomics in Age-Related Diseases. Molecules 2017; 22:molecules22010105. [PMID: 28075340 PMCID: PMC6155887 DOI: 10.3390/molecules22010105] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 12/20/2016] [Accepted: 01/03/2017] [Indexed: 01/10/2023] Open
Abstract
The increased life expectancy and the expansion of the elderly population are stimulating research into aging. Aging may be viewed as a multifactorial process that results from the interaction of genetic and environmental factors, which include lifestyle. Human molecular processes are influenced by physiological pathways as well as exogenous factors, which include the diet. Dietary components have substantive effects on metabolic health; for instance, bioactive molecules capable of selectively modulating specific metabolic pathways affect the development/progression of cardiovascular and neoplastic disease. As bioactive nutrients are increasingly identified, their clinical and molecular chemopreventive effects are being characterized and systematic analyses encompassing the "omics" technologies (transcriptomics, proteomics and metabolomics) are being conducted to explore their action. The evolving field of molecular pathological epidemiology has unique strength to investigate the effects of dietary and lifestyle exposure on clinical outcomes. The mounting body of knowledge regarding diet-related health status and disease risk is expected to lead in the near future to the development of improved diagnostic procedures and therapeutic strategies targeting processes relevant to nutrition. The state of the art of aging and nutrigenomics research and the molecular mechanisms underlying the beneficial effects of bioactive nutrients on the main aging-related disorders are reviewed herein.
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25
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Li HH, Lin SL, Huang CN, Lu FJ, Chiu PY, Huang WN, Lai TJ, Lin CL. miR-302 Attenuates Amyloid-β-Induced Neurotoxicity through Activation of Akt Signaling. J Alzheimers Dis 2016; 50:1083-98. [PMID: 26890744 DOI: 10.3233/jad-150741] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Deficiency of insulin signaling has been linked to diabetes and ageing-related neurodegenerative diseases such as Alzheimer's disease (AD). In this regard, brains exhibit defective insulin receptor substrate-1 (IRS-1) and hence result in alteration of insulin signaling in progression of AD, the most common cause of dementia. Consequently, dysregulation of insulin signaling plays an important role in amyloid-β (Aβ)-induced neurotoxicity. As the derivation of induced pluripotent stem cells (iPSC) involves cell reprogramming, it may provide a means for regaining the control of ageing-associated dysfunction and neurodegeneration via affecting insulin-related signaling. To this, we found that an embryonic stem cell (ESC)-specific microRNA, miR-302, silences phosphatase and tensin homolog (PTEN) to activate Akt signaling, which subsequently stimulates nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) elevation and hence inhibits Aβ-induced neurotoxicity. miR-302 is predominantly expressed in iPSCs and is known to regulate several important biological processes of anti-oxidative stress, anti-apoptosis, and anti-aging through activating Akt signaling. In addition, we also found that miR-302-mediated Akt signaling further stimulates Nanog expression to suppress Aβ-induced p-Ser307 IRS-1 expression and thus enhances tyrosine phosphorylation and p-Ser 473-Akt/p-Ser 9-GSK3β formation. Furthermore, our in vivo studies revealed that the mRNA expression levels of both Nanog and miR-302-encoding LARP7 genes were significantly reduced in AD patients' blood cells, providing a novel diagnosis marker for AD. Taken together, our findings demonstrated that miR-302 is able to inhibit Aβ-induced cytotoxicity via activating Akt signaling to upregulate Nrf2 and Nanog expressions, leading to a marked restoration of insulin signaling in AD neurons.
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Affiliation(s)
- Hsin-Hua Li
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Shi-Lung Lin
- Division of Regenerative Medicine, WJWU & LYNN Institute for Stem Cell Research, Santa Fe Springs, CA, USA
| | - Chien-Ning Huang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Fung-Jou Lu
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Pai-Yi Chiu
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Neurology, Show Chwan Memorial Hospital, Changhua, Taiwan
| | - Wen-Nung Huang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Te-Jen Lai
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Psychiatry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chih-Li Lin
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
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26
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Wang L, Ouyang F, Liu X, Wu S, Wu HM, Xu Y, Wang B, Zhu J, Xu X, Zhang L. Overexpressed CISD2 has prognostic value in human gastric cancer and promotes gastric cancer cell proliferation and tumorigenesis via AKT signaling pathway. Oncotarget 2016; 7:3791-805. [PMID: 26565812 PMCID: PMC4826170 DOI: 10.18632/oncotarget.6302] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 10/30/2015] [Indexed: 12/12/2022] Open
Abstract
CDGSH iron sulfur domain 2 (CISD2) is localized in the outer mitochondrial membrane and mediates mitochondrial integrity and lifespan in mammals, but its role in cancer is unknown. In the current study, we reported that CISD2 mRNA and protein expression levels were significantly upregulated in gastric cancer cells compared to normal gastric epithelial cells (P < 0.001). Immunohistochemical analysis of 261 paraffin-embedded archived gastric cancer tissues showed that high CISD2 expression was significantly associated with clinical stage, TNM classifications, venous invasion and lymphatic invasion. Univariate and multivariate analysis indicated that high CISD2 expression was an independent prognostic factor for poorer overall survival in the entire cohort. Overexpressing CISD2 promoted, while silencing CISD2 inhibited, the proliferation of gastric cancer cells. Furthermore, we found that silencing endogenous CISD2 also significantly inhibited the proliferation and tumorigenicity of MGC-803 and SGC-7901 cells not only in vitro but also in vivo in NOD/SCID mice (P < 0.05). Furthermore, we found that CISD2 affected cell proliferation and tumorigenicity of gastric cancer cells through mediating the G1-to-S phase transition. Moreover, we demonstrated that the pro-proliferative effect of CISD2 on gastric cancer cells was associated with downregulation of cyclin-dependent kinase inhibitor p21Cip1 and p27Kip1, and activation of AKT signaling. The findings of this study indicate that CISD2 may promote proliferation and tumorigenicity, potentially representing a novel prognostic marker for overall survival in gastric cancer.
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Affiliation(s)
- Lan Wang
- Department of Pathogen Biology and Immunology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, China
| | - Fei Ouyang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaobo Liu
- Department of Pathogen Biology and Immunology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, China
| | - Shu Wu
- State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Hong-Mei Wu
- Department of Pathogen Biology and Immunology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yuandong Xu
- Gastrointestinal Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Bin Wang
- Laura Biotech Co, Ltd., Guangzhou, Guangdong Province, China
| | - Jinrong Zhu
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xuehu Xu
- Gastrointestinal Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Liang Zhang
- State Key Laboratory of Oncology in South China, Guangzhou, China.,Center of Medical Imaging and Image-Guided Therapy, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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27
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Kim S, Welsh DA, Myers L, Cherry KE, Wyckoff J, Jazwinski SM. Non-coding genomic regions possessing enhancer and silencer potential are associated with healthy aging and exceptional survival. Oncotarget 2016; 6:3600-12. [PMID: 25682868 PMCID: PMC4414140 DOI: 10.18632/oncotarget.2877] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 12/08/2014] [Indexed: 01/04/2023] Open
Abstract
We have completed a genome-wide linkage scan for healthy aging using data collected from a family study, followed by fine-mapping by association in a separate population, the first such attempt reported. The family cohort consisted of parents of age 90 or above and their children ranging in age from 50 to 80. As a quantitative measure of healthy aging, we used a frailty index, called FI34, based on 34 health and function variables. The linkage scan found a single significant linkage peak on chromosome 12. Using an independent cohort of unrelated nonagenarians, we carried out a fine-scale association mapping of the region suggestive of linkage and identified three sites associated with healthy aging. These healthy-aging sites (HASs) are located in intergenic regions at 12q13-14. HAS-1 has been previously associated with multiple diseases, and an enhancer was recently mapped and experimentally validated within the site. HAS-2 is a previously uncharacterized site possessing genomic features suggestive of enhancer activity. HAS-3 contains features associated with Polycomb repression. The HASs also contain variants associated with exceptional longevity, based on a separate analysis. Our results provide insight into functional genomic networks involving non-coding regulatory elements that are involved in healthy aging and longevity.
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Affiliation(s)
- Sangkyu Kim
- Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
| | - David A Welsh
- Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Leann Myers
- Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
| | - Katie E Cherry
- Department of Psychology, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Jennifer Wyckoff
- Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
| | - S Michal Jazwinski
- Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
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28
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MicroRNA-302b Enhances the Sensitivity of Hepatocellular Carcinoma Cell Lines to 5-FU via Targeting Mcl-1 and DPYD. Int J Mol Sci 2015; 16:23668-82. [PMID: 26457704 PMCID: PMC4632720 DOI: 10.3390/ijms161023668] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 08/24/2015] [Accepted: 09/01/2015] [Indexed: 02/07/2023] Open
Abstract
MiR-302b is a member of miR-302-367 cluster. The miR-302-367 cluster played important roles in maintaining pluripotency in human embryonic stem cells (hESCs) and has been proved to be capable of suppressing cell growth in several types of cancer cell lines including Hepatocellular Carcinoma (HCC) Cell lines. However, the role that miR-302b plays in the 5-Fluorouracil (5-FU) sensitivity of HCC has not been known. This study showed that miR-302b could enhance the sensitivity to 5-FU in HCC cell lines and verified its two putative targeted genes responsible for its 5-FU sensitivity.
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29
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Chen B, Shen S, Wu J, Hua Y, Kuang M, Li S, Peng B. CISD2 associated with proliferation indicates negative prognosis in patients with hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:13725-13738. [PMID: 26722601 PMCID: PMC4680546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Accepted: 09/23/2015] [Indexed: 06/05/2023]
Abstract
BACKGROUND An evolutionarily conserved gene, the CDGSH iron sulfur domain 2 (CISD2), functions to control mammalian life span and regulates human cells proliferation. However, the role of CISD2 in HCC remains unclear. This study was aimed at investigating the expression pattern and clinicopathological significance of CISD2 in patients with HCC. METHODS The mRNA and protein expression levels of CISD2 were analyzed in six HCC lines and eight paired hepatic cancer tumors by real-time PCR, Western blotting and immunohistochemical staining. Statistical analysis was used to evaluate the clinicopathological significance of CISD2 expression. Short hairpin RNA interfering approach was employed to suppress endogenous CISD2 expression in hepatic cancer cells to determine its role in proliferation. RESULTS CISD2 expression in liver cancer cell lines and tissues was significantly up-regulated at both the RNA and protein levels compared with that in normal cells and adjacent non-tumorous liver tissues (ANT). CISD2 was an independent prognostic factor for poor prognosis. It was correlated with tumor size (P=0.001), number of tumors (P=0.003), surgical margin (P=0.006), hepatitis B surface antigen (HBsAg) infection (P=0.002) and recurrence (P<0.001) of liver cancer. Multivariate analysis suggested that CISD2 expression was an independent prognostic indicator for the survival of patients with HCC. HCC patients with high CISD2 expression displayed a shorter overall survival and a higher recurrence rate than those with low CISD2 expression (P<0.05, respectively). Additionally, stable down-expression of CISD2 in hepatoma cells suppressed cell proliferation in vitro. Similarly, an in vivo assay showed that CISD2 down-regulation in hepatoma cells inhibited remarkably tumorigenic potential in tumor size and weight. CONCLUSIONS CISD2 protein may serve as a candidate prognostic marker and a novel therapeutic target for HCC and play an important role in promoting proliferation and enhanced progression of HCC.
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Affiliation(s)
- Bin Chen
- Department of Hepatic Surgery, The First Affiliated Hospital, Sun Yat-sen University Guangzhou, China
| | - Shunli Shen
- Department of Hepatic Surgery, The First Affiliated Hospital, Sun Yat-sen University Guangzhou, China
| | - Jian Wu
- Department of Hepatic Surgery, The First Affiliated Hospital, Sun Yat-sen University Guangzhou, China
| | - Yunpeng Hua
- Department of Hepatic Surgery, The First Affiliated Hospital, Sun Yat-sen University Guangzhou, China
| | - Ming Kuang
- Department of Hepatic Surgery, The First Affiliated Hospital, Sun Yat-sen University Guangzhou, China
| | - Shaoqiang Li
- Department of Hepatic Surgery, The First Affiliated Hospital, Sun Yat-sen University Guangzhou, China
| | - Baogang Peng
- Department of Hepatic Surgery, The First Affiliated Hospital, Sun Yat-sen University Guangzhou, China
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30
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Carnes MU, Campbell T, Huang W, Butler DG, Carbone MA, Duncan LH, Harbajan SV, King EM, Peterson KR, Weitzel A, Zhou S, Mackay TFC. The Genomic Basis of Postponed Senescence in Drosophila melanogaster. PLoS One 2015; 10:e0138569. [PMID: 26378456 PMCID: PMC4574564 DOI: 10.1371/journal.pone.0138569] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 09/01/2015] [Indexed: 12/30/2022] Open
Abstract
Natural populations harbor considerable genetic variation for lifespan. While evolutionary theory provides general explanations for the existence of this variation, our knowledge of the genes harboring naturally occurring polymorphisms affecting lifespan is limited. Here, we assessed the genetic divergence between five Drosophila melanogaster lines selected for postponed senescence for over 170 generations (O lines) and five lines from the same base population maintained at a two week generation interval for over 850 generations (B lines). On average, O lines live 70% longer than B lines, are more productive at all ages, and have delayed senescence for other traits than reproduction. We performed population sequencing of pools of individuals from all B and O lines and identified 6,394 genetically divergent variants in or near 1,928 genes at a false discovery rate of 0.068. A 2.6 Mb region at the tip of the X chromosome contained many variants fixed for alternative alleles in the two populations, suggestive of a hard selective sweep. We also assessed genome wide gene expression of O and B lines at one and five weeks of age using RNA sequencing and identified genes with significant (false discovery rate < 0.05) effects on gene expression with age, population and the age by population interaction, separately for each sex. We identified transcripts that exhibited the transcriptional signature of postponed senescence and integrated the gene expression and genetic divergence data to identify 98 (175) top candidate genes in females (males) affecting postponed senescence and increased lifespan. While several of these genes have been previously associated with Drosophila lifespan, most are novel and constitute a rich resource for future functional validation.
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Affiliation(s)
- Megan Ulmer Carnes
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
| | - Terry Campbell
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
| | - Wen Huang
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
- Program in Genetics, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
| | - Daniel G. Butler
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
| | - Mary Anna Carbone
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
- Program in Genetics, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
- W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
| | - Laura H. Duncan
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
| | - Sasha V. Harbajan
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
| | - Edward M. King
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
| | - Kara R. Peterson
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
| | - Alexander Weitzel
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
| | - Shanshan Zhou
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
- Program in Genetics, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
- W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
| | - Trudy F. C. Mackay
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
- Program in Genetics, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
- W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, North Carolina, 27695, United States of America
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31
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Sood S, Gallagher IJ, Lunnon K, Rullman E, Keohane A, Crossland H, Phillips BE, Cederholm T, Jensen T, van Loon LJC, Lannfelt L, Kraus WE, Atherton PJ, Howard R, Gustafsson T, Hodges A, Timmons JA. A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status. Genome Biol 2015; 16:185. [PMID: 26343147 PMCID: PMC4561473 DOI: 10.1186/s13059-015-0750-x] [Citation(s) in RCA: 155] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 08/12/2015] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Diagnostics of the human ageing process may help predict future healthcare needs or guide preventative measures for tackling diseases of older age. We take a transcriptomics approach to build the first reproducible multi-tissue RNA expression signature by gene-chip profiling tissue from sedentary normal subjects who reached 65 years of age in good health. RESULTS One hundred and fifty probe-sets form an accurate classifier of young versus older muscle tissue and this healthy ageing RNA classifier performed consistently in independent cohorts of human muscle, skin and brain tissue (n = 594, AUC = 0.83-0.96) and thus represents a biomarker for biological age. Using the Uppsala Longitudinal Study of Adult Men birth-cohort (n = 108) we demonstrate that the RNA classifier is insensitive to confounding lifestyle biomarkers, while greater gene score at age 70 years is independently associated with better renal function at age 82 years and longevity. The gene score is 'up-regulated' in healthy human hippocampus with age, and when applied to blood RNA profiles from two large independent age-matched dementia case-control data sets (n = 717) the healthy controls have significantly greater gene scores than those with cognitive impairment. Alone, or when combined with our previously described prototype Alzheimer disease (AD) RNA 'disease signature', the healthy ageing RNA classifier is diagnostic for AD. CONCLUSIONS We identify a novel and statistically robust multi-tissue RNA signature of human healthy ageing that can act as a diagnostic of future health, using only a peripheral blood sample. This RNA signature has great potential to assist research aimed at finding treatments for and/or management of AD and other ageing-related conditions.
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Affiliation(s)
- Sanjana Sood
- XRGenomics Ltd, London, UK
- Division of Genetics & Molecular Medicine, King's College London, 8th Floor, Tower Wing, Guy's Hospital, London, SE1 9RT, UK
| | - Iain J Gallagher
- XRGenomics Ltd, London, UK
- School of Health, Stirling University, Stirling, Scotland, UK
| | - Katie Lunnon
- Department of Old Age Psychiatry, King's College London, London, UK
- Present address: University of Exeter Medical School, Exeter, UK
| | - Eric Rullman
- Division of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden
| | - Aoife Keohane
- Department of Old Age Psychiatry, King's College London, London, UK
| | - Hannah Crossland
- Division of Genetics & Molecular Medicine, King's College London, 8th Floor, Tower Wing, Guy's Hospital, London, SE1 9RT, UK
- School of Medicine, Derby Royal Hospital, Derbyshire, UK
| | | | - Tommy Cederholm
- Department of Public Health, Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden
| | | | | | - Lars Lannfelt
- Department of Public Health and Caring Sciences/Molecular Geriatrics, Uppsala University, Uppsala, Sweden
| | - William E Kraus
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA
| | | | - Robert Howard
- Department of Old Age Psychiatry, King's College London, London, UK
| | - Thomas Gustafsson
- Division of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden
| | - Angela Hodges
- Department of Old Age Psychiatry, King's College London, London, UK
| | - James A Timmons
- XRGenomics Ltd, London, UK.
- Division of Genetics & Molecular Medicine, King's College London, 8th Floor, Tower Wing, Guy's Hospital, London, SE1 9RT, UK.
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Exome and Whole Genome Sequencing in Aging and Longevity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 847:127-39. [DOI: 10.1007/978-1-4939-2404-2_6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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33
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Stallard E. Underlying and Multiple Case Mortality Advanced Ages: United States 1980-1998. ACTA ACUST UNITED AC 2014. [DOI: 10.1080/10920277.2002.11073999] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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34
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CISD2 expression is a novel marker correlating with pelvic lymph node metastasis and prognosis in patients with early-stage cervical cancer. Med Oncol 2014; 31:183. [PMID: 25134919 DOI: 10.1007/s12032-014-0183-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Accepted: 08/11/2014] [Indexed: 10/24/2022]
Abstract
The CDGSH iron sulfur domain2 (CISD2) is an evolutionarily conserved gene. It functions to control mammalian life span and regulate human breast cancer cells proliferation. However, the characteristics of CISD2 expression and its clinical/prognostic significance are unclear in human tumor. Our study aimed to investigate the expression pattern and clinicopathological significance of CISD2 in patients with early-stage cervical cancer. The mRNA and protein expression levels of CISD2 were analyzed in eight cervical cancer cell lines and eight paired cervical cancer tumors by real-time PCR and Western blotting, respectively. Immunohistochemistry was performed to examine CISD2 protein expression in paraffin-embedded tissues from 149 early-stage cervical cancer patients. Statistical analyses were used to evaluate the clinicopathological significance of CISD2 expression. CISD2 expression was significantly upregulated in cervical cancer cells at both the mRNA and protein levels. Statistical analysis showed a significant correlation of CISD2 expression with the squamous cell carcinoma antigen (P = 0.000), myometrium invasion (P = 0.003), recurrence (P = 0.012), lymphovascular space involvement (P = 0.019) and especially pelvic lymph node metastasis (PLNM; P = 0.000). Patients with higher CISD2 expression had shorter overall survival duration than patients with lower CISD2 expression. Multivariate analysis suggested that CISD2 expression might be an independent prognostic indicator for the survival of patients with early-stage cervical cancer. Our results for the first time suggested that high CISD2 expression was closely correlated with PLNM and poor prognosis in early-stage cervical cancer patients. CISD2 protein might be a novel biomarker for early-stage cervical cancer progression.
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35
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Burke MK, King EG, Shahrestani P, Rose MR, Long AD. Genome-wide association study of extreme longevity in Drosophila melanogaster. Genome Biol Evol 2014; 6:1-11. [PMID: 24259311 PMCID: PMC3914684 DOI: 10.1093/gbe/evt180] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Human genome-wide association studies (GWAS) of longevity attempt to identify alleles at different frequencies in the extremely old, relative to a younger control sample. Here, we apply a GWAS approach to “synthetic” populations of Drosophila melanogaster derived from a small number of inbred founders. We used next-generation DNA sequencing to estimate allele and haplotype frequencies in the oldest surviving individuals of an age cohort and compared these frequencies with those of randomly sampled individuals from the same cohort. We used this case–control strategy in four independent cohorts and identified eight significantly differentiated regions of the genome potentially harboring genes with relevance for longevity. By modeling the effects of local haplotypes, we have more power to detect regions enriched for longevity genes than marker-based GWAS. Most significant regions occur near chromosome ends or centromeres where recombination is infrequent, consistent with these regions harboring unconditionally deleterious alleles impacting longevity. Genes in regions of normal recombination are enriched for those relevant to immune function and a gene family involved in oxidative stress response. Genetic differentiation between our experimental cohorts is comparable to that between human populations, suggesting in turn that our results may help explain heterogeneous signals in human association studies of extreme longevity when panels have diverse ancestry.
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Affiliation(s)
- Molly K Burke
- Department of Ecology and Evolutionary Biology, University of California, Irvine
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36
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Tian XL, Li Y. Endothelial cell senescence and age-related vascular diseases. J Genet Genomics 2014; 41:485-95. [PMID: 25269674 DOI: 10.1016/j.jgg.2014.08.001] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Revised: 07/31/2014] [Accepted: 08/06/2014] [Indexed: 10/24/2022]
Abstract
Advanced age is an independent risk factor for ageing-related complex diseases, such as coronary artery disease, stroke, and hypertension, which are common but life threatening and related to the ageing-associated vascular dysfunction. On the other hand, patients with progeria syndromes suffer from serious atherosclerosis, suggesting that the impaired vascular functions may be critical to organismal ageing, or vice versa. However, it remains largely unknown how vascular cells, particularly endothelial cell, become senescent and how the senescence impairs the vascular functions and contributes to the age-related vascular diseases over time. Here, we review the recent progress on the characteristics of vascular ageing and endothelial cell senescence in vitro and in vivo, evaluate how genetic and environmental factors as well as autophagy and stem cell influence endothelial cell senescence and how the senescence contributes to the age-related vascular phenotypes, such as atherosclerosis and increased vascular stiffness, and explore the possibility whether we can delay the age-related vascular diseases through the control of vascular ageing.
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Affiliation(s)
- Xiao-Li Tian
- Department of Human Population Genetics and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine (IMM), Peking University, Beijing 100871, China.
| | - Yang Li
- Department of Human Population Genetics and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine (IMM), Peking University, Beijing 100871, China
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Wang CH, Kao CH, Chen YF, Wei YH, Tsai TF. Cisd2 mediates lifespan: is there an interconnection among Ca2+homeostasis, autophagy, and lifespan? Free Radic Res 2014; 48:1109-14. [DOI: 10.3109/10715762.2014.936431] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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We are ageing. BIOMED RESEARCH INTERNATIONAL 2014; 2014:808307. [PMID: 25045704 PMCID: PMC4090574 DOI: 10.1155/2014/808307] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/11/2014] [Revised: 05/27/2014] [Accepted: 05/27/2014] [Indexed: 02/01/2023]
Abstract
Ageing and longevity is unquestioningly complex. Several thoughts and mechanisms of ageing such as pathways involved in oxidative stress, lipid and glucose metabolism, inflammation, DNA damage and repair, growth hormone axis and insulin-like growth factor (GH/IGF), and environmental exposure have been proposed. Also, some theories of ageing were introduced. To date, the most promising leads for longevity are caloric restriction, particularly target of rapamycin (TOR), sirtuins, hexarelin and hormetic responses. This review is an attempt to analyze the mechanisms and theories of ageing and achieving longevity.
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Manayi A, Saeidnia S, Gohari AR, Abdollahi M. Methods for the discovery of new anti-aging products--targeted approaches. Expert Opin Drug Discov 2014; 9:383-405. [PMID: 24494592 DOI: 10.1517/17460441.2014.885014] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Aging is considered to be one of the most complicated and heterogeneous phenomena and is the main risk factor for most chronic diseases, disabilities and declining health. Aging cells cease to divide and drive the progression of illness through various pathways. Over the years, a number of anti-aging medicines of natural and synthetic origin have been introduced. Indeed, some studies have identified senescent cells as potential therapeutic targets in the treatment of aging and age-related diseases. AREAS COVERED In this review, the authors highlight and critically review the possible mechanisms of the aging process and related illnesses. The authors give particular attention to illnesses, including Alzheimer's disease, Parkinson's disease, skin aging and cardiovascular diseases. EXPERT OPINION Several reports have highlighted that mitochondria are a key factor in the progression of aging and neurodegenerative illnesses. This is due to their production of extra amounts of reactive oxygen species, which leads into progressive caspase-dependent apoptosis and cell death. Therefore, strategies to prevent/reduce oxidative stress-mediated aging, whether environmental, nutritional and pharmacological, need to be taken into account. Presently, Drosophila melanogaster and Caenorhabditis elegans, which focus on the evolutionary and genetic foundations of aging, have helped to establish the screening of several synthetic and natural compounds with large cohorts in a quick manner. However, there is yet to be any efficient experimental evidence to prove the exact role of senescent cells in age-related dysfunction and further studies are required to better understand these processes.
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Affiliation(s)
- Azadeh Manayi
- Tehran University of Medical Sciences, Faculty of Pharmacy, Medicinal Plants Research Center , Tehran 1417614411 , Iran
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Bendjilali N, Hsueh WC, He Q, Willcox DC, Nievergelt CM, Donlon TA, Kwok PY, Suzuki M, Willcox BJ. Who are the Okinawans? Ancestry, genome diversity, and implications for the genetic study of human longevity from a geographically isolated population. J Gerontol A Biol Sci Med Sci 2014; 69:1474-84. [PMID: 24444611 DOI: 10.1093/gerona/glt203] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Isolated populations have advantages for genetic studies of longevity from decreased haplotype diversity and long-range linkage disequilibrium. This permits smaller sample sizes without loss of power, among other utilities. Little is known about the genome of the Okinawans, a potential population isolate, recognized for longevity. Therefore, we assessed genetic diversity, structure, and admixture in Okinawans, and compared this with Caucasians, Chinese, Japanese, and Africans from HapMap II, genotyped on the same Affymetrix GeneChip Human Mapping 500K array. Principal component analysis, haplotype coverage, and linkage disequilibrium decay revealed a distinct Okinawan genome-more homogeneity, less haplotype diversity, and longer range linkage disequilibrium. Population structure and admixture analyses utilizing 52 global reference populations from the Human Genome Diversity Cell Line Panel demonstrated that Okinawans clustered almost exclusively with East Asians. Sibling relative risk (λs) analysis revealed that siblings of Okinawan centenarians have 3.11 times (females) and 3.77 times (males) more likelihood of centenarianism. These findings suggest that Okinawans are genetically distinct and share several characteristics of a population isolate, which are prone to develop extreme phenotypes (eg, longevity) from genetic drift, natural selection, and population bottlenecks. These data support further exploration of genetic influence on longevity in the Okinawans.
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Affiliation(s)
| | - Wen-Chi Hsueh
- Departments of Medicine and Epidemiology & Biostatistics, University of California, San Francisco
| | - Qimei He
- Pacific Health Research and Education Institute, Honolulu, Hawaii. Department of Research, Kuakini Medical Center, Honolulu, Hawaii
| | | | | | - Timothy A Donlon
- Pacific Health Research and Education Institute, Honolulu, Hawaii. Ohana Genetics, Honolulu, Hawaii
| | - Pui-Yan Kwok
- Department of Dermatology, Institute for Human Genetics, and Cardiovascular Research Institute, University of California, San Francisco
| | - Makoto Suzuki
- Okinawa Research Center for Longevity Science, Urasoe, Okinawa, Japan. Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan
| | - Bradley J Willcox
- Pacific Health Research and Education Institute, Honolulu, Hawaii. Department of Research, Kuakini Medical Center, Honolulu, Hawaii. Okinawa Research Center for Longevity Science, Urasoe, Okinawa, Japan. Department of Geriatric Medicine, John A Burns School of Medicine, University of Hawaii, Honolulu, Hawaii
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Lee JH, Cheng R, Honig LS, Feitosa M, Kammerer CM, Kang MS, Schupf N, Lin SJ, Sanders JL, Bae H, Druley T, Perls T, Christensen K, Province M, Mayeux R. Genome wide association and linkage analyses identified three loci-4q25, 17q23.2, and 10q11.21-associated with variation in leukocyte telomere length: the Long Life Family Study. Front Genet 2014; 4:310. [PMID: 24478790 PMCID: PMC3894567 DOI: 10.3389/fgene.2013.00310] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Accepted: 12/20/2013] [Indexed: 11/13/2022] Open
Abstract
Leukocyte telomere length is believed to measure cellular aging in humans, and short leukocyte telomere length is associated with increased risks of late onset diseases, including cardiovascular disease, dementia, etc. Many studies have shown that leukocyte telomere length is a heritable trait, and several candidate genes have been identified, including TERT, TERC, OBFC1, and CTC1. Unlike most studies that have focused on genetic causes of chronic diseases such as heart disease and diabetes in relation to leukocyte telomere length, the present study examined the genome to identify variants that may contribute to variation in leukocyte telomere length among families with exceptional longevity. From the genome wide association analysis in 4,289 LLFS participants, we identified a novel intergenic SNP rs7680468 located near PAPSS1 and DKK2 on 4q25 (p = 4.7E-8). From our linkage analysis, we identified two additional novel loci with HLOD scores exceeding three, including 4.77 for 17q23.2, and 4.36 for 10q11.21. These two loci harbor a number of novel candidate genes with SNPs, and our gene-wise association analysis identified multiple genes, including DCAF7, POLG2, CEP95, and SMURF2 at 17q23.2; and RASGEF1A, HNRNPF, ANF487, CSTF2T, and PRKG1 at 10q11.21. Among these genes, multiple SNPs were associated with leukocyte telomere length, but the strongest association was observed with one contiguous haplotype in CEP95 and SMURF2. We also show that three previously reported genes-TERC, MYNN, and OBFC1-were significantly associated with leukocyte telomere length at p empirical < 0.05.
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Affiliation(s)
- Joseph H Lee
- Sergievsky Center, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Taub Institute, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Department of Epidemiology, School of Public Health, Columbia University New York, NY, USA
| | - Rong Cheng
- Sergievsky Center, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Taub Institute, College of Physicians and Surgeons, Columbia University New York, NY, USA
| | - Lawrence S Honig
- Sergievsky Center, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Taub Institute, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Department of Neurology, College of Physicians and Surgeons, Columbia University New York, NY, USA
| | - Mary Feitosa
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine St. Louis, MO, USA
| | - Candace M Kammerer
- Department of Epidemiology, University of Pittsburgh Pittsburgh, PA, USA ; Department of Human Genetics, University of Pittsburgh Pittsburgh, PA, USA ; Center for Aging and Population Health, University of Pittsburgh Pittsburgh, PA, USA
| | - Min S Kang
- Taub Institute, College of Physicians and Surgeons, Columbia University New York, NY, USA
| | - Nicole Schupf
- Sergievsky Center, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Taub Institute, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Department of Epidemiology, School of Public Health, Columbia University New York, NY, USA ; Department of Psychiatry, College of Physicians and Surgeons, Columbia University New York, NY, USA
| | - Shiow J Lin
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine St. Louis, MO, USA
| | - Jason L Sanders
- Department of Epidemiology, University of Pittsburgh Pittsburgh, PA, USA ; Center for Aging and Population Health, University of Pittsburgh Pittsburgh, PA, USA
| | - Harold Bae
- Department of Biostatistics, Boston University Medical Center Boston, MA, USA
| | - Todd Druley
- Department of Pediatrics and Genetics, Washington University School of Medicine St. Louis, MO, USA
| | - Thomas Perls
- Department of Medicine, Boston University Medical Center Boston, MA, USA
| | - Kaare Christensen
- The Danish Aging Research Center, Epidemiology, University of Southern Denmark Odense, Denmark
| | - Michael Province
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine St. Louis, MO, USA
| | - Richard Mayeux
- Sergievsky Center, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Taub Institute, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Department of Epidemiology, School of Public Health, Columbia University New York, NY, USA ; Department of Neurology, College of Physicians and Surgeons, Columbia University New York, NY, USA ; Department of Psychiatry, College of Physicians and Surgeons, Columbia University New York, NY, USA
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Brooks-Wilson AR. Genetics of healthy aging and longevity. Hum Genet 2013; 132:1323-38. [PMID: 23925498 PMCID: PMC3898394 DOI: 10.1007/s00439-013-1342-z] [Citation(s) in RCA: 214] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 07/15/2013] [Indexed: 12/17/2022]
Abstract
Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may ‘buffer’ the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.
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Affiliation(s)
- Angela R Brooks-Wilson
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada,
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Di Cianni F, Campa D, Tallaro F, Rizzato C, De Rango F, Barale R, Passarino G, Canzian F, Gemignani F, Montesanto A, Landi S, Rose G. MAP3K7 and GSTZ1 are associated with human longevity: a two-stage case-control study using a multilocus genotyping. AGE (DORDRECHT, NETHERLANDS) 2013; 35:1357-1366. [PMID: 22576335 PMCID: PMC3705096 DOI: 10.1007/s11357-012-9416-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Accepted: 04/17/2012] [Indexed: 05/31/2023]
Abstract
The pathways that regulate energy homeostasis, the mechanisms of damage repair, and the signaling response to internal environmental changes or external signals have been shown to be critical in modulating lifespan of model organisms and humans. In order to investigate whether genetic variation of genes involved in these pathways contribute to longevity, a two-stage case-control study in two independent sets of long-lived individuals from Calabria (Italy) was performed. In stage 1, 317 SNPs in 104 genes were analyzed in 78 cases (median age 98 years) and 71 controls (median age 67 years). In stage 2, 31 candidate SNPs identified in stage 1 (π markers = 0.1) were analyzed in an independent sample composed by 288 cases (median age 92 years) and 554 controls (median age 67 years). Two SNPs, rs282070 located in intron 1 of the MAP3K7 gene, and rs2111699 located in intron 1 of the GSTZ1 gene, were significantly associated (after adjustment for multiple testing) with longevity in stage 2 (p = 1.1 × 10(-3) and p = 1.4 × 10(-3), respectively). Interestingly, both genes are implicated in the cellular response to internal and external environmental changes, playing a crucial role in the inflammation processes that accompany aging. Our data confirm that long-lived subjects are endowed with genetic variants that allow them to optimize these cellular responses and to better deal with environmental and internal stresses.
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Affiliation(s)
- Fausta Di Cianni
- />Department of Cell Biology, University of Calabria, 87036 Rende, Italy
| | - Daniele Campa
- />Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Federica Tallaro
- />Department of Cell Biology, University of Calabria, 87036 Rende, Italy
| | - Cosmeri Rizzato
- />Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Francesco De Rango
- />Department of Cell Biology, University of Calabria, 87036 Rende, Italy
| | - Roberto Barale
- />Department of Biology, University of Pisa, Pisa, Italy
| | - Giuseppe Passarino
- />Department of Cell Biology, University of Calabria, 87036 Rende, Italy
| | - Federico Canzian
- />Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Alberto Montesanto
- />Department of Cell Biology, University of Calabria, 87036 Rende, Italy
| | - Stefano Landi
- />Department of Biology, University of Pisa, Pisa, Italy
| | - Giuseppina Rose
- />Department of Cell Biology, University of Calabria, 87036 Rende, Italy
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Insulin/IGF-1-mediated longevity is marked by reduced protein metabolism. Mol Syst Biol 2013; 9:679. [PMID: 23820781 PMCID: PMC3734508 DOI: 10.1038/msb.2013.35] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Accepted: 05/27/2013] [Indexed: 12/20/2022] Open
Abstract
Mutations in the daf-2 gene of the conserved Insulin/Insulin-like Growth Factor (IGF-1) pathway double the lifespan of the nematode Caenorhabditis elegans. This phenotype is completely suppressed by deletion of Forkhead transcription factor daf-16. To uncover regulatory mechanisms coordinating this extension of life, we employed a quantitative proteomics strategy with daf-2 mutants in comparison with N2 and daf-16; daf-2 double mutants. This revealed a remarkable longevity-specific decrease in proteins involved in mRNA processing and transport, the translational machinery, and protein metabolism. Correspondingly, the daf-2 mutants display lower amounts of mRNA and 20S proteasome activity, despite maintaining total protein levels equal to that observed in wild types. Polyribosome profiling in the daf-2 and daf-16;daf-2 double mutants confirmed a daf-16-dependent reduction in overall translation, a phenotype reminiscent of Dietary Restriction-mediated longevity, which was independent of germline activity. RNA interference (RNAi)-mediated knockdown of proteins identified by our approach resulted in modified C. elegans lifespan confirming the importance of these processes in Insulin/IGF-1-mediated longevity. Together, the results demonstrate a role for the metabolism of proteins in the Insulin/IGF-1-mediated extension of life.
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Balistreri CR, Candore G, Accardi G, Colonna-Romano G, Lio D. NF-κB pathway activators as potential ageing biomarkers: targets for new therapeutic strategies. Immun Ageing 2013; 10:24. [PMID: 23786653 PMCID: PMC3695812 DOI: 10.1186/1742-4933-10-24] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2012] [Accepted: 06/02/2013] [Indexed: 12/17/2022]
Abstract
Chronic inflammation is a major biological mechanism underpinning biological ageing process and age-related diseases. Inflammation is also the key response of host defense against pathogens and tissue injury. Current opinion sustains that during evolution the host defense and ageing process have become linked together. Thus, the large array of defense factors and mechanisms linked to the NF-κB system seem to be involved in ageing process. This concept leads us in proposing inductors of NF-κB signaling pathway as potential ageing biomarkers. On the other hand, ageing biomarkers, represented by biological indicators and selected through apposite criteria, should help to characterize biological age and, since age is a major risk factor in many degenerative diseases, could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. In this report, some inflammatory biomarkers will be discussed for a better understanding of the concept of biological ageing, providing ideas on eventual working hypothesis about potential targets for the development of new therapeutic strategies and improving, as consequence, the quality of life of elderly population.
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Affiliation(s)
- Carmela R Balistreri
- Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Corso Tukory 211, Palermo 90134, Italy
| | - Giuseppina Candore
- Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Corso Tukory 211, Palermo 90134, Italy
| | - Giulia Accardi
- Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Corso Tukory 211, Palermo 90134, Italy
| | - Giuseppina Colonna-Romano
- Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Corso Tukory 211, Palermo 90134, Italy
| | - Domenico Lio
- Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Corso Tukory 211, Palermo 90134, Italy
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Wiley SE, Andreyev AY, Divakaruni AS, Karisch R, Perkins G, Wall EA, van der Geer P, Chen YF, Tsai TF, Simon MI, Neel BG, Dixon JE, Murphy AN. Wolfram Syndrome protein, Miner1, regulates sulphydryl redox status, the unfolded protein response, and Ca2+ homeostasis. EMBO Mol Med 2013; 5:904-18. [PMID: 23703906 PMCID: PMC3779451 DOI: 10.1002/emmm.201201429] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2012] [Revised: 03/26/2013] [Accepted: 03/27/2013] [Indexed: 01/21/2023] Open
Abstract
Miner1 is a redox-active 2Fe2S cluster protein. Mutations in Miner1 result in Wolfram Syndrome, a metabolic disease associated with diabetes, blindness, deafness, and a shortened lifespan. Embryonic fibroblasts from Miner1(-/-) mice displayed ER stress and showed hallmarks of the unfolded protein response. In addition, loss of Miner1 caused a depletion of ER Ca(2+) stores, a dramatic increase in mitochondrial Ca(2+) load, increased reactive oxygen and nitrogen species, an increase in the GSSG/GSH and NAD(+)/NADH ratios, and an increase in the ADP/ATP ratio consistent with enhanced ATP utilization. Furthermore, mitochondria in fibroblasts lacking Miner1 displayed ultrastructural alterations, such as increased cristae density and punctate morphology, and an increase in O2 consumption. Treatment with the sulphydryl anti-oxidant N-acetylcysteine reversed the abnormalities in the Miner1 deficient cells, suggesting that sulphydryl reducing agents should be explored as a treatment for this rare genetic disease.
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Affiliation(s)
- Sandra E Wiley
- Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA
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Beekman M, Blanché H, Perola M, Hervonen A, Bezrukov V, Sikora E, Flachsbart F, Christiansen L, De Craen AJM, Kirkwood TBL, Rea IM, Poulain M, Robine JM, Valensin S, Stazi MA, Passarino G, Deiana L, Gonos ES, Paternoster L, Sørensen TIA, Tan Q, Helmer Q, van den Akker EB, Deelen J, Martella F, Cordell HJ, Ayers KL, Vaupel JW, Törnwall O, Johnson TE, Schreiber S, Lathrop M, Skytthe A, Westendorp RGJ, Christensen K, Gampe J, Nebel A, Houwing-Duistermaat JJ, Slagboom PE, Franceschi C. Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study. Aging Cell 2013; 12:184-93. [PMID: 23286790 DOI: 10.1111/acel.12039] [Citation(s) in RCA: 118] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/27/2012] [Indexed: 01/04/2023] Open
Abstract
Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10(-5) , respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.
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Affiliation(s)
| | | | - Markus Perola
- The National Institute for Health and Welfare; THL; Helsinki; FI-00271; Finland
| | - Anti Hervonen
- Tampere School of Public Health; Tampere; FI-33014; Finland
| | | | - Ewa Sikora
- Nencki Istitute for Experimental Biology; NENCKI; Warszawa; 02-093; Poland
| | - Friederike Flachsbart
- Institute of Clinical Molecular Biology; Christian-Albrechts-University Kiel (CAU); Kiel; 24118; Germany
| | - Lene Christiansen
- Danish Aging Research Center; Institute of Public Health; University of Southern Denmark; Odense; DK-5230; Denmark
| | | | - Tom B. L. Kirkwood
- Institute for Ageing and Health; Newcastle University; UNEW; Newcastle; NE1 7RU; UK
| | - Irene Maeve Rea
- Queens University of Belfast; QUB; Belfast; Northern Ireland; BT7 1NN; UK
| | | | | | - Silvana Valensin
- Interdepartmental Centre “Luigi Galvani” CIG; University of Bologna UNIBO; Bologna; 40126; Italy
| | | | | | - Luca Deiana
- UNISS; University of Sassari; 07100; Sassari; Italy
| | | | | | | | | | - Quinta Helmer
- Medical Statistics and Bioinformatics; Leiden University Medical Centre; Leiden; ZC; 2333; The Netherlands
| | | | - Joris Deelen
- Molecular Epidemiology; Leiden University Medical Centre; Leiden; ZC; 2333; The Netherlands
| | | | - Heather J. Cordell
- Institute for Ageing and Health; Newcastle University; UNEW; Newcastle; NE1 7RU; UK
| | - Kristin L. Ayers
- Institute for Ageing and Health; Newcastle University; UNEW; Newcastle; NE1 7RU; UK
| | - James W. Vaupel
- Max Planck Institute for Demographic Research; MPIDR; 18057; Rostock; Germany
| | - Outi Törnwall
- The National Institute for Health and Welfare; THL; Helsinki; FI-00271; Finland
| | - Thomas E. Johnson
- Institute for Behavioral Genetics; University of Colorado at Boulder; Boulder; CO 80309-0447; USA
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology; Christian-Albrechts-University Kiel (CAU); Kiel; 24118; Germany
| | - Mark Lathrop
- Foundation Jean Dausset; CEPH; 75010; Paris; France
| | - Axel Skytthe
- Danish Aging Research Center; Institute of Public Health; University of Southern Denmark; Odense; DK-5230; Denmark
| | - Rudi G. J. Westendorp
- Gerontology and Geriatrics; Leiden University Medical Centre; Leiden; ZA; 2333; The Netherlands
| | | | - Jutta Gampe
- Max Planck Institute for Demographic Research; MPIDR; 18057; Rostock; Germany
| | - Almut Nebel
- Institute of Clinical Molecular Biology; Christian-Albrechts-University Kiel (CAU); Kiel; 24118; Germany
| | | | | | - Claudio Franceschi
- Interdepartmental Centre “Luigi Galvani” CIG; University of Bologna UNIBO; Bologna; 40126; Italy
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Deelen J, Beekman M, Capri M, Franceschi C, Slagboom PE. Identifying the genomic determinants of aging and longevity in human population studies: progress and challenges. Bioessays 2013; 35:386-96. [PMID: 23423909 PMCID: PMC3633240 DOI: 10.1002/bies.201200148] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Human lifespan variation is mainly determined by environmental factors, whereas the genetic contribution is 25–30% and expected to be polygenic. Two complementary fields go hand in hand in order to unravel the mechanisms of biological aging: genomic and biomarker research. Explorative and candidate gene studies of the human genome by genetic, transcriptomic, and epigenomic approaches have resulted in the identification of a limited number of interesting positive linkage regions, genes, and pathways that contribute to lifespan variation. The possibilities to further exploit these findings are rapidly increasing through the use of novel technologies, such as next-generation sequencing. Genomic research is progressively being integrated with biomarker studies on aging, including the application of (noninvasive) deep phenotyping and omics data – generated using novel technologies – in a wealth of studies in human populations. Hence, these studies may assist in obtaining a more holistic perspective on the role of the genome in aging and lifespan regulation.
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Affiliation(s)
- Joris Deelen
- Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
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Glessner JT, Smith AV, Panossian S, Kim CE, Takahashi N, Thomas KA, Wang F, Seidler K, Harris TB, Launer LJ, Keating B, Connolly J, Sleiman PMA, Buxbaum JD, Grant SFA, Gudnason V, Hakonarson H. Copy number variations in alternative splicing gene networks impact lifespan. PLoS One 2013; 8:e53846. [PMID: 23382853 PMCID: PMC3559729 DOI: 10.1371/journal.pone.0053846] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2012] [Accepted: 12/06/2012] [Indexed: 01/01/2023] Open
Abstract
Longevity has a strong genetic component evidenced by family-based studies. Lipoprotein metabolism, FOXO proteins, and insulin/IGF-1 signaling pathways in model systems have shown polygenic variations predisposing to shorter lifespan. To test the hypothesis that rare variants could influence lifespan, we compared the rates of CNVs in healthy children (0–18 years of age) with individuals 67 years or older. CNVs at a significantly higher frequency in the pediatric cohort were considered risk variants impacting lifespan, while those enriched in the geriatric cohort were considered longevity protective variants. We performed a whole-genome CNV analysis on 7,313 children and 2,701 adults of European ancestry genotyped with 302,108 SNP probes. Positive findings were evaluated in an independent cohort of 2,079 pediatric and 4,692 geriatric subjects. We detected 8 deletions and 10 duplications that were enriched in the pediatric group (P = 3.33×10−8–1.6×10−2 unadjusted), while only one duplication was enriched in the geriatric cohort (P = 6.3×10−4). Population stratification correction resulted in 5 deletions and 3 duplications remaining significant (P = 5.16×10−5–4.26×10−2) in the replication cohort. Three deletions and four duplications were significant combined (combined P = 3.7×10−4−3.9×10−2). All associated loci were experimentally validated using qPCR. Evaluation of these genes for pathway enrichment demonstrated ∼50% are involved in alternative splicing (P = 0.0077 Benjamini and Hochberg corrected). We conclude that genetic variations disrupting RNA splicing could have long-term biological effects impacting lifespan.
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Affiliation(s)
- Joseph T. Glessner
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Albert Vernon Smith
- Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Kopavogur, Iceland
- University of Iceland, Reykjavik, Iceland
| | - Saarene Panossian
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Cecilia E. Kim
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Nagahide Takahashi
- Laboratory of Molecular Neuropsychiatry, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Kelly A. Thomas
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Fengxiang Wang
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Kallyn Seidler
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Tamara B. Harris
- Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Lenore J. Launer
- Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Brendan Keating
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - John Connolly
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Patrick M. A. Sleiman
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Joseph D. Buxbaum
- Laboratory of Molecular Neuropsychiatry, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Struan F. A. Grant
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Division of Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Vilmundur Gudnason
- Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Kopavogur, Iceland
- University of Iceland, Reykjavik, Iceland
| | - Hakon Hakonarson
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Division of Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
- * E-mail:
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