Universal DNA methylation age across mammalian tissues

Nature Aging, Год журнала: 2023, Номер 3(9), С. 1144 - 1166

Опубликована: Авг. 10, 2023

Abstract Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation pan-tissue epigenetic clocks. Here, we demonstrate development universal pan-mammalian clocks, 11,754 arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate age with high accuracy ( r > 0.96). Age deviations correlate human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines levels that change numerous sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated development, cancer, obesity longevity. Our findings offer new evidence suggesting aging is evolutionarily conserved intertwined developmental processes all mammals.

Язык: Английский

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Ageing as a software design flaw

Genome biology, Год журнала: 2023, Номер 24(1)

Опубликована: Март 27, 2023

Abstract Ageing is inherent to all human beings, yet why we age remains a hotly contested topic. Most mechanistic explanations of ageing posit that caused by the accumulation one or more forms molecular damage. Here, I propose not because inevitable damage hardware but rather intrinsic design flaws in software, defined as DNA code orchestrates how single cell develops into an adult organism. As developmental software runs, its sequence events reflected shifting cellular epigenetic states. Overall, suggest understand need decode our and flow information throughout life course.

Язык: Английский

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Aging clocks based on accumulating stochastic variation

Nature Aging, Год журнала: 2024, Номер 4(6), С. 871 - 885

Опубликована: Май 9, 2024

Abstract Aging clocks have provided one of the most important recent breakthroughs in biology aging, and may provide indicators for effectiveness interventions aging process preventive treatments age-related diseases. The reproducibility accurate has reinvigorated debate on whether a programmed underlies aging. Here we show that accumulating stochastic variation purely simulated data is sufficient to build clocks, first-generation second-generation are compatible with accumulation DNA methylation or transcriptomic data. We find predict chronological biological age, indicated by significant prediction differences smoking, calorie restriction, heterochronic parabiosis partial reprogramming. Although our simulations not explicitly rule out process, results suggest stochastically changes any set ground state at age zero generating clocks.

Язык: Английский

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A unified framework for evolutionary genetic and physiological theories of aging

PLoS Biology, Год журнала: 2024, Номер 22(2), С. e3002513 - e3002513

Опубликована: Фев. 27, 2024

Why and how we age are 2 intertwined questions that have fascinated scientists for many decades. However, attempts to answer these remain compartmentalized, preventing a comprehensive understanding of the aging process. We argue current lack knowledge about evolution mechanisms is due clarity regarding evolutionary theories explicitly involve physiological processes: disposable soma theory (DST) developmental (DTA). In this Essay, propose new hierarchical model linking genes vital rates, enabling us critically reevaluate DST DTA in terms their relationship genetic (mutation accumulation (MA) antagonistic pleiotropy (AP)). also demonstrate can be incorporated unified framework. The framework will help generate testable hypotheses hallmarks shaped by natural selection.

Язык: Английский

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Universal DNA methylation age across mammalian tissues

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2021, Номер unknown

Опубликована: Янв. 19, 2021

ABSTRACT Aging is often perceived as a degenerative process resulting from random accrual of cellular damage over time. Despite this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles almost any tissue the body. Since such pan-tissue have been successfully developed for several different species, we hypothesized that one build pan-mammalian measure in all mammalian species. To address generated data using 11,754 arrays, each profiling up to 36 thousand cytosines highly-conserved stretches DNA, 59 tissue-types derived 185 From these profiles, constructed three predictors, with single mathematical formula, termed universal are accurate estimating (r>0.96) tissue. Deviations between and chronological relate mortality risk humans, mutations affect somatotropic axis mice, caloric restriction. We characterized specific cytosines, whose levels change across most These greatly enriched polycomb repressive complex 2-binding sites, located regions gradually lose chromatin accessibility proximal genes play role development, cancer, human obesity, longevity. Collectively, results support notion aging indeed evolutionarily conserved coupled developmental processes species - was long-debated without benefit this new compelling evidence. SUMMARY This study identifies characterizes implicated mammals establishes pan clocks.

Язык: Английский

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Cell senescence, rapamycin and hyperfunction theory of aging

Cell Cycle, Год журнала: 2022, Номер 21(14), С. 1456 - 1467

Опубликована: Март 31, 2022

A hallmark of cellular senescence is proliferation-like activity growth-promoting pathways (such as mTOR and MAPK) in non-proliferating cells. When the cell cycle arrested, these convert arrest to (geroconversion), rendering cells hypertrophic, beta-Gal-positive hyperfunctional. The senescence-associated secretory phenotype (SASP) one numerous hyperfunctions. Figuratively, geroconversion a continuation growth Rapamycin, reversible inhibitor growth, slows down mTOR-driven geroconversion. Developed two decades ago, this model had accurately predicted that rapamycin must extend life span animals. However, notion senescent directly cause organismal aging oversimplified. Senescent contribute but are not strictly required. Cell can be linked indirectly via same underlying cause, namely hyperfunctional signaling such mTOR.

Язык: Английский

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Aging as a loss of morphostatic information: A developmental bioelectricity perspective

Ageing Research Reviews, Год журнала: 2024, Номер 97, С. 102310 - 102310

Опубликована: Апрель 17, 2024

Язык: Английский

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Epigenetic clocks and programmatic aging

Ageing Research Reviews, Год журнала: 2024, Номер 101, С. 102546 - 102546

Опубликована: Окт. 16, 2024

The last decade has seen remarkable progress in the characterization of methylation clocks that can serve as indicators biological age humans and many other mammalian species. While processes aging underlie these have remained unclear, several clues pointed to a link developmental mechanisms. These include presence vicinity clock CpG sites genes specify development, including those Hox (homeobox) polycomb classes. Here we discuss how recent advances programmatic theories provide framework within which be understood part process aging. This includes such evolve, mechanisms cause aging, they give rise late-life disease. combination ideas from evolutionary biology, biogerontology biology open path new discipline, gerontology (devo-gero). Drawing on properties clocks, offer hypotheses exemplify devo-gero thinking. We suggest controls trade-off between earlier fidelity later plasticity. also propose existence an evolutionarily-conserved sequence spanning ontogenesis, adult development both constrains determines evolution

Язык: Английский

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Programmed ageing: decline of stem cell renewal, immunosenescence, and Alzheimer's disease

Biological reviews/Biological reviews of the Cambridge Philosophical Society, Год журнала: 2023, Номер 98(4), С. 1424 - 1458

Опубликована: Апрель 17, 2023

ABSTRACT The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that lifespan, and the ageing process itself dictates are large extent genetically determined. Although controversial, this is supported by firm evidence semelparous display evolutionarily programmed in response reproductive environmental cues. Parabiosis experiments reveal orchestrated systemically through circulation, accompanied changes hormone levels lifetime. implies that, like circadian circannual clocks, there master ‘clock age’ (circavital clock) located limbic brain mammals modulates systemic growth factor secretion over as well alterations gene expression revealed genomic methylation analysis. Studies on accelerated mice, human longevity genes, converge conserved fibroblast factors (FGFs) their receptors, including KLOTHO, insulin‐like (IGFs) steroid hormones, key players mediating effects ageing. Age‐related these multiple other inferred cause progressive decline tissue maintenance failure stem cell replenishment. most severely affects immune system, which requires constant renewal bone marrow cells. increases risk infection whereas can be extended germfree animals. suggests major death higher organisms. Immune also associated with age‐related diseases. Taking example Alzheimer's disease (AD), we assess AD caused immunosenescence infection. signature protein brain, Aβ, now known an antimicrobial peptide, Aβ deposits may rather than disease. Because some cognitively normal elderly individuals show extensive neuropathology, argue location pathology crucial – specifically, lesions likely accentuate immunosenescence, could thus underlie vicious cycle microbial proliferation culminates AD. general model extend diseases, propose paradigm organismal senescence declining leads mortality.

Язык: Английский

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C. elegans ageing is accelerated by a self-destructive reproductive programme

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 20, 2023

In post-reproductive C. elegans, destructive somatic biomass repurposing supports production of yolk which, it was recently shown, is vented and can serve as a foodstuff for larval progeny. This reminiscent the suicidal reproductive effort (reproductive death) typical semelparous organisms such Pacific salmon. To explore possibility that elegans exhibits death, we have compared sibling species pairs genera Caenorhabditis Pristionchus with hermaphrodites females. We report venting constitutive, early pathology involving major anatomical changes occur only in hermaphrodites, which are also shorter lived. Moreover, does germline removal suppress senescent markedly increase lifespan. consistent hypothesis exhibit death suppressed by ablation. If correct, this would imply difference ageing process between most higher organisms, potentially explain exceptional plasticity ageing.

Язык: Английский

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