Aging & Longevity

Aging is accompanied by widespread DNA methylation changes, yet their full genomic scope and parent-of-origin dynamics remain poorly understood. Here, we apply nanopore long-read sequencing to 7,284 whole blood samples enabling methylation measurements of 17,959,684 high-quality CpG units. Over 20% of the measured high quality CpG units undergo age-associated changes, predominantly hypomethylation. From these data, we construct a methylation aging clock from 1,373 high-quality CpG units, with...

The cholinergic system is central to attention, learning, and neuroplasticity and undergoes progressive degeneration with aging. Neuroplasticity-based computerized cognitive training is a scalable, non-pharmacological strategy to support cognitive health in older adults, yet its neurobiological mechanisms remain unclear. [18F]Fluoroethoxybenzovesamicol (FEOBV) positron emission tomography (PET) quantifies presynaptic cholinergic terminals via vesicular acetylcholine transporter (VACht) binding,...

Microtubules are well-researched components of the cytoskeleton, yet we lack a holistic understanding that bridges molecular and cellular details with the broader functions of the microtubule cytoskeleton in development, ageing and disease. For example, how microtubule properties and functions are affected by tubulin post-translational modifications, disease-related mutations or variation of the microtubule lattice remains unexplored. In this Roadmap, we argue that integrating various...

Breast cancer is among the leading causes of cancer mortality worldwide, with aging as a major risk factor. Caloric restriction (CR) is a well-established non-pharmaceutical intervention that extends healthspan and delays tumorigenesis, yet the systemic molecular mechanisms remain elusive. Both chronic and intermittent CR influence metabolic homeostasis, but their long-term effects on circulating miRNAs in breast cancer predisposition are unclear. Here, we examined how chronic and intermittent...

Secreted proteins are essential to modulate homeostasis in the extracellular space and facilitate communication to distal cells or tissues. Yet, the identity and functional importance of extracellular proteins in aging have been understudied. Here we use proximity labeling followed by quantitative proteomics to systematically characterize proteins along the intestinal secretory pathway in C. elegans, focusing on secreted proteins. We identify intestine-secreted proteins that are modulated with...

Can the skin microbiome shape healthy aging?

Skeletal muscle is the main motor organ and plays a vital role in regulating systemic metabolism and aging. Exercise interventions can address many metabolic and degenerative diseases associated with aging, though alternative strategies may be needed when exercise is contraindicated, inaccessible or insufficient. Here we developed subcutaneous transplantation of differentiated autologous myocytes (myografts). Myografts exhibited mature, vascularized structures that self-contract continuously in...

Inflammation is a pivotal driver of the progression from metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH), an aggressive form associated with substantial liver-related mortality. However, the molecular mechanisms underlying the initiation and persistence of liver inflammation remain poorly defined. Here, we demonstrated a previously unrecognized role for hepatic acetyl-CoA synthetase short-chain family member 2 (ACSS2) in...

Interest in aging 'omic' biomarkers has grown due to their ability to quantify biological age. Most of these biomarkers have been derived in blood and fall into many diverse categories, yet relatively little is known about their correlative patterns, especially between biomarkers from different categories. Here we present the OmniAge R and Python package, a collection of 413 aging omic biomarkers representing 12 different categories, including traditional epigenetic clocks, epigenetic mitotic...

Human cells utilize gut microbiota-derived metabolites to control systemic metabolism. Trimethylamine N-oxide (TMAO) is traditionally considered a hepatocyte-derived metabolite from microbial trimethylamine. Here we show that pancreatic β-cells also produce TMAO as an autocrine and intracellular metabolite to maintain β-cell function. β-cells synthesize TMAO via flavin-containing monooxygenase 3 (FMO3), but this machinery deteriorates in humans and rodents under diabetic and ageing conditions....

The genus Myotis is one of the largest clades of bats, and it exhibits some of the most extreme variation in lifespans among mammals, alongside unique adaptations to viral tolerance and immune defence^(1-3). Here, to study the evolution of these phenotypes, we generated cell lines and near-complete genome assemblies for eight closely related Myotis species. Using genome-wide screens of positive selection, analyses of structural variation and functional experiments in primary cells, we identify...

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Age-associated hematopoietic skewing results in an increase in the neutrophil-to-lymphocyte ratio, which serves as a strong predictor of all-cause mortality in older adults, although its causes are incompletely understood. Here we show that cytotoxic CD4^(+) T lymphocytes accumulate in the bone marrow of mice during aging and induce myelopoiesis, increasing the neutrophil-to-lymphocyte ratio. T cell receptor-dependent induction of mitochondrial stress and activation of STING upregulates the...

The associations between objectively measured sleep patterns, the hallmarks of aging, and their shared proteomic signatures remain poorly understood. In this study, we utilized wrist-worn accelerometer data, plasma proteomic profiles, and health records from the UK Biobank to examine the associations between six defined sleep patterns and nine established hallmarks of aging. We further identified proteins jointly associated with both sleep patterns and aging hallmarks. Longer total sleep...

Genotoxic stress induced by cancer therapies is increasingly recognized as a driver of accelerated aging in long-term cancer survivors, yet the mechanisms responsible for the emergence of age-related dysfunction months to years after treatment remain poorly understood. Here, we use sublethal whole-body irradiation as a model of systemic genotoxic stress to test whether senescent cells contribute to the progression of post-therapy age-related dysfunction and whether the benefits of senescent cell...

Sarcopenia is the age-related progressive decline in both skeletal muscle mass and function. It acts as an exacerbator of multimorbidity, engaging in bidirectional pathological cycles with multiple chronic diseases, and contributes substantially to increased mortality, disability and healthcare costs. Current nutritional support is often limited by a generic one-size-fits-all approach that fails to account for substantial inter-individual variation across genetics, metabolism, lifestyle, gut...

CONCLUSIONS: CNN-derived masseter muscle parameters from magnetic resonance imaging were inversely correlated with oral impairment in older adults. This approach enables scalable and objective oral phenotyping from imaging data and highlights its potential application in large-scale epidemiological studies of aging and functional decline.

Skin aging is a multifactorial, multiscale process driven by the interplay between intrinsic cellular decline and extrinsic environmental exposures. Increasing evidence positions the skin as a dynamic interface and sensitive "window" reflecting systemic aging. However, research remains fragmented across scales, and existing models fail to capture the full complexity of systemic regulation. In this review, we introduce a hierarchical four-dimension framework of skin aging to systematically...

Aging is associated with progressive cardiac dysfunction, characterized by increased myocardial fibrosis, chronic inflammation, and impaired myocardial structure. Exercise is a well-established, cost-effective intervention for age-related cardiovascular decline, yet the underlying epigenetic mechanisms remain to be fully elucidated. Recent studies have implicated histone lactylation as a regulatory mark that modulates macrophage polarization and inflammatory responses. Histone lactylation, a...

The musculoskeletal system is key to aging. Nonetheless, existing protein-based musculoskeletal aging clocks have limited predictive performance and fail to characterize genetic or environmental determinants. We first constructed a musculoskeletal protein pool by integrating transcriptomic enrichment, protein functional annotation, and literature expertise. Two musculoskeletal aging clocks-MSKAge and MSKAgeMort-were then developed using proteomic data of 21,070 UK Biobank participants....