Genetic Factors and Epigenetic Mechanisms of Longevity: Current Perspectives

Lazarus, Jessica; Mather, Karen A.; Thalamuthu, Anbupalam

doi:10.2217/epi.15.80

Cited by 7 publications

(4 citation statements)

References 74 publications

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“…Recent studies on stem cells suggest that mutations and epigenetic changes influence stem cell functionality leading to cellular ageing [41]. Epigenetic changes in CR factors have been thought to cause cellular ageing [42][43][44], but the relationship between the epigenetic changes and ageing-dependent genome instability or mutation has remained unknown. While cellular senescence is a model for cellular ageing [45], the way in which genetic or epigenetic damage accumulates with age, the basis for cellular ageing, has also remained elusive.…”

Section: Relationships Among Nucleosome Remodelling Dna Repair and Transcription And Cellular Ageingmentioning

confidence: 99%

Nucleosome remodelling, DNA repair and transcriptional regulation build negative feedback loops in cancer and cellular ageing

Watanabe¹,

Kanno²,

Roushandeh³

et al. 2017

Phil. Trans. R. Soc. B

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Nucleosome remodelling (NR) regulates transcription in an ATP-dependent manner, and influences gene expression required for development and cellular functions, including those involved in anti-cancer and anti-ageing processes. ATP-utilizing chromatin assembly and remodelling factor (ACF) and Brahma-associated factor (BAF) complexes, belonging to the ISWI and SWI/SNF families, respectively, are involved in various types of DNA repair. Suppression of several BAF factors makes U2OS cells significantly sensitive to X-rays, UV and especially to cisplatin, and these BAF factors contribute to the accumulation of repair proteins at various types of DNA damage and to DNA repair. Recent cancer genome sequencing and expression analysis has shown that BAF factors are frequently mutated or, more frequently, silenced in various types of cancer cells. Thus, those cancer cells are potentially X-ray- and especially cisplatin-sensitive, suggesting a way of optimizing current cancer therapy. Recent single-stem cell analysis suggests that mutations and epigenetic changes influence stem cell functionality leading to cellular ageing. Genetic and epigenetic changes in the BAF factors diminish DNA repair as well as transcriptional regulation activities, and DNA repair defects in turn negatively influence NR and transcriptional regulation. Thus, they build negative feedback loops, which accelerate both cellular senescence and transformation as common and rare cellular events, respectively, causing cellular ageing.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'.

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Section: Relationships Among Nucleosome Remodelling Dna Repair and Transcription And Cellular Ageingmentioning

confidence: 99%

Nucleosome remodelling, DNA repair and transcriptional regulation build negative feedback loops in cancer and cellular ageing

Watanabe¹,

Kanno²,

Roushandeh³

et al. 2017

Phil. Trans. R. Soc. B

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“…FoxO3 interference induces reactive oxygen radical overproduction, inhibiting the osteogenic differentiation capacity of mesenchymal stem cells [ 42 ]. The methylation status of the FoxO3 gene correlates with human tissue aging [ 43 ]. In addition, a reciprocal regulation was present in miR-29a and Dnmt3b.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-29a Mitigates Osteoblast Senescence and Counteracts Bone Loss through Oxidation Resistance-1 Control of FoxO3 Methylation

Lian

Chen

et al. 2021

Antioxidants

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Senescent osteoblast overburden accelerates bone mass loss. Little is understood about microRNA control of oxidative stress and osteoblast senescence in osteoporosis. We revealed an association between microRNA-29a (miR-29a) loss, oxidative stress marker 8-hydroxydeoxyguanosine (8-OHdG), DNA hypermethylation marker 5-methylcystosine (5mC), and osteoblast senescence in human osteoporosis. miR-29a knockout mice showed low bone mass, sparse trabecular microstructure, and osteoblast senescence. miR-29a deletion exacerbated bone loss in old mice. Old miR-29a transgenic mice showed fewer osteoporosis signs, less 5mC, and less 8-OHdG formation than age-matched wild-type mice. miR-29a overexpression reversed age-induced senescence and osteogenesis loss in bone-marrow stromal cells. miR-29a promoted transcriptomic landscapes of redox reaction and forkhead box O (FoxO) pathways, preserving oxidation resistance protein-1 (Oxr1) and FoxO3 in old mice. In vitro, miR-29a interrupted DNA methyltransferase 3b (Dnmt3b)-mediated FoxO3 promoter methylation and senescence-associated β-galactosidase activity in aged osteoblasts. Dnmt3b inhibitor 5′-azacytosine, antioxidant N-acetylcysteine, or Oxr1 recombinant protein attenuated loss in miR-29a and FoxO3 to mitigate oxidative stress, senescence, and mineralization matrix underproduction. Taken together, miR-29a promotes Oxr1, compromising oxidative stress and FoxO3 loss to delay osteoblast aging and bone loss. This study sheds light on a new antioxidation mechanism by which miR-29a protects against osteoblast aging and highlights the remedial effects of miR-29a on osteoporosis.

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“…Previous studies have focused on the association of gene polymorphism with aging and longevity, while epigenetics also plays an important role in this field. DNA methylation is well characterized among 3 epigenetic mechanisms (DNA methylation, histone modification, and noncoding RNA changes) [2].…”

Section: Introductionmentioning

confidence: 99%

Association between SIRT6 Methylation and Human Longevity in a Chinese Population

Tang

Wei

Wang

et al. 2020

Public Health Genomics

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Background: Sirtuin 6 gene (SIRT6) is a longevity gene that is involved in a variety of metabolic pathways, but the relationship between SIRT6 methylation and longevity has not been clarified. Methods: We conducted a case-control study on 129 residents with a family history of longevity (1 of parents, themselves, or siblings aged ≥90 years) and 86 individuals without a family history of exceptional longevity to identify the association. DNA pyrosequencing was performed to analyze the methylation status of SIRT6 promoter CpG sites. qRT-PCR and ELISA were used to estimate the SIRT6 messenger RNA (mRNA) levels and protein content. Six CpG sites (P1–P6) were identified as methylation variable positions in the SIRT6 promoter region. Results: At the P2 and P5 CpG sites, the methylation rates of the longevity group were lower than those of the control group (p < 0.001 and p = 0.009), which might be independent determinants of longevity. The mRNA and protein levels of SIRT6 decreased in the control group (p < 0.0001 and p = 0.038). The mRNA level negatively correlated with the methylation rates at the P2 (rs = −0.173, p = 0.011) and P5 sites (rs = −0.207, p = 0.002). Furthermore, the protein content positively correlated with the methylation rate at the P5 site (rs = 0.136, p = 0.046) but showed no significant correlation with the methylation rate at the P2 site. Conclusion: The low level of SIRT6 methylation may be a potential protective factor of Chinese longevity.

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Genetic Factors and Epigenetic Mechanisms of Longevity: Current Perspectives

Cited by 7 publications

References 74 publications

Nucleosome remodelling, DNA repair and transcriptional regulation build negative feedback loops in cancer and cellular ageing

Nucleosome remodelling, DNA repair and transcriptional regulation build negative feedback loops in cancer and cellular ageing

MicroRNA-29a Mitigates Osteoblast Senescence and Counteracts Bone Loss through Oxidation Resistance-1 Control of FoxO3 Methylation

Association between <b><i>SIRT6</i></b> Methylation and Human Longevity in a Chinese Population

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