Aging & Longevity

A growing body of preclinical research is demonstrating the therapeutic potential of chronic, continuous hypoxia (11% FIO(2)) for rare and common diseases. However, the chronic delivery of hypoxic gas poses both practical challenges and long-term safety concerns. We previously introduced a small-molecule, "hypoxia-in-a-pill" combining a hemoglobin affinity enhancer (GBT440) to limit oxygen delivery with a HIF-2α inhibitor (PT2399) to prevent detrimental compensatory erythropoiesis. Although this...

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are standard therapies for estrogen receptor-positive breast cancer, but their efficacy is limited by drug resistance. While dysregulation of alternative splicing has been implicated in cancer progression, the underlying mechanisms remain unclear. Here, we uncover a splicing-mediated mechanism whereby exon 2 inclusion in SUV39H2 drives its overexpression in CDK4/6i-resistant breast cancer cells. Clinically, elevated exon 2 inclusion in SUV39H2...

As an important component of biomimetic drug delivery systems, cell membrane-coated nanoparticles are widely used for subcellular delivery. However, the influence of cell membranes at different life cycles on subcellular delivery remains unexplored. Our previous study demonstrated that senescent tumor cell membrane-coated nanoparticles (SNP) displayed superior endoplasmic reticulum (ER) targeting efficiency in tumor cells. After inducing tumor cells into senescence, SNP showed greater...

The proteostasis network (PN) safeguards the integrity of proteins by promoting various cellular activities. However, with aging, the PN's competence declines and aggregated proteins accrue within cells. This process underlies the development of neurodegenerative disorders such as Alzheimer's and Huntington's diseases. While the PN functions within cells, proteostasis is regulated across the organism by intertissue communication, which is partially governed by neurons. We previously found that...

Early-life nutrition may influence long-term health, but its impact on organ-specific biological aging is unclear. We investigated associations of birthweight and breastfeeding with multi-organ aging and potential mediating pathways in adulthood. Using UK Biobank data, we examined associations of retrospectively reported birthweight (n = 21,446) and breastfeeding history (n = 29,713) with 19 proteomics-derived aging indices, comprising 18 organ-specific indices and one composite index....

CONCLUSION: Opioid use is associated with significantly poorer HrQoL in community-dwelling older adults, highlighting the importance of routinely assessing quality of life, functional status, and psychosocial factors among persons who use opioids.

Aging is associated with cognitive deterioration accompanied by a reduction in hippocampal neurogenesis. Murine models have been widely used to study aging and age-related cognitive decline, as they recapitulate many of the key features of the degenerative process. Among these, the SAMP8 strain represents a well-established model of accelerated aging, characterized by early-onset and progressive cognitive impairment, Alzheimer's disease-like neuropathology, and an initial increase in hippocampal...

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...