Biomarkers of aging

Science China Life Sciences, Год журнала: 2023, Номер 66(5), С. 893 - 1066

Опубликована: Апрель 11, 2023

Язык: Английский

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Quantifying the stochastic component of epigenetic aging

Nature Aging, Год журнала: 2024, Номер 4(6), С. 886 - 901

Опубликована: Май 9, 2024

Abstract DNA methylation clocks can accurately estimate chronological age and, to some extent, also biological age, yet the process by which age-associated (DNAm) changes are acquired appears be quasi-stochastic, raising a fundamental question: how much of an epigenetic clock’s predictive accuracy could explained stochastic DNAm change? Here, using data from sorted immune cells, we build realistic simulation models, subsequently demonstrating in over 22,770 and whole-blood samples 25 independent cohorts that approximately 66–75% underpinning Horvath’s clock driven process. This fraction increases 90% for more accurate Zhang’s clock, but is lower (63%) PhenoAge suggesting aging reflected nonstochastic processes. Confirming this, demonstrate acceleration males PhenoAge’s severe coronavirus disease 2019 cases smokers not increased rate change These results significantly deepen our understanding interpretation clocks.

Язык: Английский

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Epigenetic ageing clocks: statistical methods and emerging computational challenges

Nature Reviews Genetics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 13, 2025

Язык: Английский

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Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle

Aging Cell, Год журнала: 2023, Номер 23(1)

Опубликована: Май 2, 2023

Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates rodent muscle. Whether can decelerate, or reverse humans unknown. Here, we performed powerful meta-analysis of the methylome transcriptome an unprecedented number human skeletal samples (n = 3176). We show that: (1) individuals with higher baseline aerobic fitness have younger transcriptomic profiles, (2) leads to significant shifts patterns toward profile, (3) disuse "ages" transcriptome. Higher levels were associated attenuated differential methylation transcription during aging. Furthermore, both profiles shifted state after interventions, while older forced disuse. demonstrate that targets many transcripts DNA loci maintain specifically genes related structure, metabolism, mitochondrial Our comprehensive analysis will inform future studies aiming identify best combination therapeutics regimes optimize longevity.

Язык: Английский

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Histone mark age of human tissues and cell types

Science Advances, Год журнала: 2025, Номер 11(1)

Опубликована: Янв. 1, 2025

Aging is a complex and multifaceted process involving many epigenetic alterations. One key area of interest in aging research the role histone modifications, which can dynamically regulate gene expression. Here, we conducted pan-tissue analysis dynamics seven modifications during human aging. Our histone-specific age prediction models showed surprisingly accurate performance, proving resilient to experimental artificial noise. Simulation experiments for comparison with DNA methylation predictors revealed competitive performance. Moreover, set enrichment uncovered several critical developmental pathways prediction. Different from predictors, genes known be involved biology are among most important ones models. Last, developed pan-histone predictor, suggesting that age-related information degenerated across epigenome. This highlights power marks as input creating robust opens avenues understanding changes

Язык: Английский

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Epigenetic editing at individual age-associated CpGs affects the genome-wide epigenetic aging landscape

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 5, 2024

Summary Aging is reflected by genome-wide DNA methylation changes, but it largely unclear how these epigenetic modifications are regulated. In this study, we explored the possibility to interfere with clocks editing at individual CpG sites. CRISPR-guided approaches (dCas9-DNMT3A and CRISPRoff) facilitated targeted an age-associated genomic region in PDE4C that remained stable for more than three months. Furthermore, evoked many off-target effects, which were highly reproducible enriched other CpGs – thus, they not random seem resemble coregulated bystander modifications. 4C chromatin conformation analysis sites revealed increased interactions Subsequently, multiplexed HEK293T primary T cells five regions become either hypermethylated or hypomethylated upon aging. While age-hypomethylated appeared less stable, also resulted a clear enrichment of CpGs. Conversely, tend be accelerated up ten years after methylation, particularly These results demonstrate epigenome can modulate aging network its entirety thereby clocks.

Язык: Английский

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Epistemic uncertainty challenges aging clock reliability in predicting rejuvenation effects

Aging Cell, Год журнала: 2024, Номер 23(11)

Опубликована: Июль 28, 2024

Abstract Epigenetic aging clocks have been widely used to validate rejuvenation effects during cellular reprogramming. However, these predictions are unverifiable because the true biological age of reprogrammed cells remains unknown. We present an analytical framework consider from uncertainty perspective. Our analysis reveals that DNA methylation profiles across reprogramming poorly represented in data train clock models, thus introducing high epistemic estimations. Moreover, different published inconsistent, with some even suggesting zero or negative rejuvenation. While not questioning possibility reversal, we show challenges reliability observed vitro before pluripotency and throughout embryogenesis. Conversely, our method a significant increase after vivo recommend including estimation future models avoid risk misinterpreting results prediction.

Язык: Английский

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Precise and interpretable neural networks reveal epigenetic signatures of aging across youth in health and disease

Frontiers in Aging, Год журнала: 2025, Номер 5

Опубликована: Янв. 23, 2025

Introduction DNA methylation (DNAm) age clocks are powerful tools for measuring biological age, providing insights into aging risks and outcomes beyond chronological age. While traditional models effective, their interpretability is limited by dependence on small potentially stochastic sets of CpG sites. Here, we propose that the reliability DNAm should stem from capacity to detect comprehensive targeted signatures. Methods We compiled publicly available whole-blood samples (n = 17,726) comprising entire human lifespan (0–112 years). used a pre-trained network-coherent autoencoder (NCAE) compress data embeddings, with which trained interpretable neural network epigenetic clocks. then retrieved age-specific signatures examined functional enrichments in age-associated processes. Results introduce NCAE-CombClock, novel highly precise (R 2 0.978, mean absolute error 1.96 years) deep clock integrating data-driven embeddings established markers. Additionally, developed suite NCAE-Age classifiers tailored adolescence young adulthood. These can accurately classify individuals at critical developmental ages youth (AUROC 0.953, 0.972, 0.927, 15, 18, 21 capture fine-grained, single-year enriched processes associated anatomic neuronal development, immunoregulation, metabolism. showcased practical applicability this approach identifying candidate mechanisms underlying altered pace observed pediatric Crohn’s disease. Discussion In study, present clock, named improves prediction accuracy large datasets, explainable robust classification across youth. Our offer broad applications personalized medicine research, valuable resource interpreting trajectories health

Язык: Английский

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Senolytic compounds reduce epigenetic age of blood samples in vitro

npj Aging, Год журнала: 2025, Номер 11(1)

Опубликована: Фев. 4, 2025

Abstract Senolytic drugs raise the expectation that they can specifically eliminate a subset of senescent cells in given tissue. In this study, we have exemplarily analyzed if 3-day treatment human blood samples vitro would reduce age-associated biomarkers, with particular focus on epigenetic age-predictions. Of eight tested compounds, JQ1, RG7112, nutlin-3a, and AMG232 reduced age, indicating approach may be useful drug screening for senolytic compounds.

Язык: Английский

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Mechanistic target of rapamycin/blood-testes barrier mechanism mediates acceleration of sperm epigenetic aging by environmental factors

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Abstract Our previous research suggested that mechanistic target of rapamycin (mTOR)/blood-testis barrier (BTB) mechanism is involved in the regulation rates epigenetic aging sperm, where increased activity mTORC1 opens BTB and accelerates mTORC2 produces opposite results – increases integrity rejuvenates sperm epigenome. In present study, we use our newly developed clock model to investigate whether mTOR/BTB reprogramming mice exposed heat stress (HS) cadmium (Cd). findings show both mTOR-dependent disruption caused by HS mTOR-independent due Cd exposure accelerate aging, resulting similar changes DNA methylation patterns. These suggest a novel molecular pathway through which environmental stressors influence this may be relevant broad range factors, including environmental, lifestyle, dietary, health influences.

Язык: Английский

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