Aging & Longevity

Epigenetic clocks have emerged as potential biomarkers of aging due to their association with morbidity and mortality. They have recently gained traction as outcome measurements for anti-aging interventions. However, as the number of new epigenetic clocks continues to grow, different clocks may not agree on the effect of an intervention. This raises the question of when researchers can trust epigenetic clock results. In this study, we find that when extending previously published single-clock...

Vitamin D deficiency has been implicated in biological processes linked to aging and organismal resilience, yet its relationship to long-term systemic aging trajectories remains incompletely characterized. We analyzed longitudinal electronic health record data from two large healthcare systems: Leumit Health Services (LHS), a nationwide Israeli health organization, and TriNetX, a federated US research network. We examined more than 1.67 million serum 25-hydroxyvitamin D [25(OH)D] measurements...

Chronological age accounts for much of the variance in structural brain measures, yet aging is spatially distributed, modality-dependent and often nonlinear, features that conventional T1-only brain-age models overlook. We introduce a population-calibrated, multimodal framework in 2,796 adults that integrates gray-matter volume with diffusion-derived metrics to fit linear and quadratic age-association profiles across cortical and subcortical regions. We define the Age of Structural Transition...

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Oocyte activation and follicular development are fundamental for fertility in mammals, yet the dynamics of activated oocytes (Act-Oos) remain unclear. Here we use a Zp3-based lineage-tracing mouse model to label Act-Oos and reconstruct their developmental trajectories and folliculogenesis across the lifespan. We uncovered age-dependent heterogeneity in Act-Oo longevity: some oocytes activated in early adulthood progressed rapidly, whereas others persisted into late or even terminal reproductive...

Hematopoiesis depends on the sustained function of hematopoietic stem and progenitor cells (HSPCs). However, aging progressively impairs HSPC function, contributing to immunosenescence, hematologic malignancies, and degenerative disorders. Therefore, elucidating the mechanisms underlying HSPC aging is essential for developing strategies to alleviate age-related dysfunction. Here, we identify angiopoietin-like 8 (ANGPTL8), a secreted glycoprotein known for its role in glucose and lipid...

The retina is an extension of the central nervous system and a recognized indicator of systemic health, yet the link between the brain care score (BCS) and retinal health remains unclear. In this study, we aimed to assess the associations of BCS with retinal layer thickness and retinal biological age and to evaluate potential metabolic mediation for retinal thickness. A total of 28,657 UK Biobank participants with optical coherence tomography (OCT) imaging at baseline were included, of whom...

Aging biology still lacks a fully mechanistic explanation for why functional decline accelerates after sexual maturity in the absence of a single initiating pathology. Here, we integrate cross-species epigenetic, transcriptomic, and proteomic datasets to test whether aging is associated with a post-maturity imbalance between two genome partitions: housekeeping genes (HG), which encode the cellular maintenance infrastructure, and integrative genes (IntG), which support specialized tissue...

Proteome integrity is continuously challenged by diverse forms of molecular damage, yet, in contrast to DNA, proteins have long been considered largely disposable rather than repairable. This view has shaped the prevailing paradigm of proteostasis, in which damaged proteins are primarily eliminated and replaced. However, emerging evidence from both prokaryotic and eukaryotic systems indicates that enzymatic protein repair is more widespread and functionally significant than previously...

Cellular senescence, characterized by irreversible cell cycle arrest and the acquisition of a senescence-associated secretory phenotype (SASP), is a fundamental hallmark of aging and a key driver of numerous age-related diseases. However, conventional two-dimensional cell cultures and animal models fail to fully replicate the complex cellular architecture, multicellular interactions, and tissue-specific microenvironments in which senescence develops in vivo. Organoids, three-dimensional tissue...

CONCLUSION: In conclusion, exosome-mediated delivery of a dual miRNA sponge represents a mechanism-driven strategy to reprogram senescence-associated gene networks and restore MSC function. This approach provides a promising cell-free nucleic acid therapeutic platform for regenerative medicine applications.

INTRODUCTION: Gait alterations have been proposed as functional indicators of neural dysfunction in Alzheimer's disease; however, their ability to capture disease-associated locomotor changes in preclinical models remains insufficiently characterized.

As organisms age, mitochondrial metabolic activity declines, and disrupted gene expression regulation mediated by histone acetylation induces the emergence of senescent physiological phenotypes in tissues. In this study, we found that periodic exposure to red light significantly increased histone H3 Lys9 acetylation (H3K9ac) levels in the tissues and organs of aged mice. Following red light exposure, silent information regulation factor 4 (SIRT4) protein levels in keratinocytes were notably...

Cellular quiescence is a low metabolic, non-proliferative state critical for tissue maintenance and regenerative capacity, with broad implications for aging and age-related diseases. In Caenorhabditis elegans, L1 developmental arrest upon hatching in the absence of food provides a robust in vivo model to study quiescence. Here, we investigate the roles of the transcription factors HLH-30/TFEB and DAF-16/FOXO during L1 arrest. We show that HLH-30 and DAF-16 collaborate to ensure survival under...

Proteostasis is essential for cellular health, with its disruption contributing to aging, neurodegeneration, and metabolic disorders. While the upstream proteotoxic stress-sensing and protein-folding mechanisms in the ER and cytosol are well studied, the transcriptional regulation of proteostasis remains incompletely understood, particularly concerning the temporal epigenome dynamics, chromatin landscapes, and co-regulatory networks underlying dynamic proteostasis control. Traditionally,...

The DNA damage response (DDR) pathway has emerged as the central signaling network that preserves genome stability by using sensors to monitor the genome for aberrant structures and establishing signaling centers that promote organismal homeostasis. This review revisits the formative years of DDR research, focusing on the genetic dissection of the pathway in Saccharomyces cerevisiae and its evolution into a broadly conserved eukaryotic signaling system. Early studies of ribonucleotide reductase...

The extraordinary lifespan variation in domestic dogs provides a natural experiment for testing how intrinsic rates of biological aging shape lifespan. Using 1640 methylomes from 894 dogs, we developed an epigenetic clock that predicted mortality and demonstrated that epigenetic aging is fastest early in life. At orthologs of human age-associated genes, dogs exhibited concordant age effects on promoter methylation, highlighting conserved remodeling of immune pathways. We found that larger and...

Time-restricted feeding (TRF) restricts food intake to daily windows, yet its efficacy against vascular aging and underlying mechanisms remain unclear. Here, we demonstrate that TRF attenuates angiotension II -induced accelerated vascular aging by reshaping gut microbiota, stabilizing microbial diversity, and elevating the Firmicutes/Bacteroidetes ratio. TRF preserved intestinal barrier integrity, upregulated tight junction proteins (Occludin, ZO-1, MUC2), reduced serum lipopolysaccharide, and...

Aging-associated β-cell senescence is a key driver of type 2 diabetes mellitus (T2DM). However, its associated molecular mechanisms remain poorly explored. This study identifies Chromobox 4 (CBX4), a Polycomb group protein with SUMO E3 ligase activity, as an essential regulator of β-cell aging and function. The results show that CBX4 expression progressively downregulates in both aged and diabetic pancreatic islets. Targeted deletion of Cbx4 in β-cell accelerates cellular senescence, impairs...

The pursuit of high-energy-density lithium metal batteries is often hampered by severe safety hazards and limited cycle life, leading to increased environmental impact and higher costs. Here, we demonstrate that tuning the underappreciated miscibility between electrolyte components could provide an effective approach. By introducing a non-coordinating, non-flammable cyclic fluorinated diluent, we minimize diluent-ion pair intermolecular forces, thereby enabling the formation of isolated...