Longevity Papers

Centenarians represent a human model of resilience to age-related decline, yet resiliency mechanisms remain elusive. Here, we establish an induced pluripotent stem cell (iPSC)-based platform to interrogate resilience signatures in centenarians. IPSC-derived neurons from centenarians exhibit transcriptional programs promoting synaptic integrity, calcium homeostasis, and cholesterol biosynthesis, while suppressing proteostatic stress pathways. Functionally, these neurons maintain stable calcium dynamics, reduced baseline mitochondrial activity, and energy-efficient homeostasis. Upon challenge, centenarian-derived neurons mount a robust stress response, in contrast to attenuated responses in non-centenarian controls. This resilience signature parallels adaptations in long-lived mammals and aligns with healthy brain aging, while showing erosion in Alzheimers disease and cancer. Our platform provides a scalable human model for dissecting resilience biology offering a framework to extend healthspan and mitigate age-related decline.

Biological aging is associated with progressively more severe genetic and epigenetic alterations. While these changes are expected to affect the transcriptional profile of cells, the magnitude of that effect is unknown as the aging transcriptome is still poorly understood. Understanding the aging transcriptional landscape will give us greater insight into how cells are affected by and/or respond to the aging process. To facilitate the large-scale exploration of the aging transcriptome, we report the development of the Human Cell Aging Transcriptome Atlas (HCATA). HCATA, contains single-cell RNA-sequencing datasets from 76 publications totaling 92 million cells and 3,475 tissue-level samples across more than 50 tissue types with ages ranging from 0 to 103 years. HCATA includes a genome browser that allows users to interactively explore age-related differential expression, as well as functions to explore related pathways at the tissue and cell-type level. HCATA is publicly accessible at http://hcata-xiaodonglab.org:3304 .

Extracellular vesicles present a promising alternative to stem cells in regenerative medicine and gerontology. They offer significant advantages over cell transplantation, demonstrating potential for slowing aging and treating age-related diseases. Extracellular vesicles secreted by diverse cell types modulate inflammation, stimulate tissue regeneration, and exhibit anti-inflammatory and immunomodulatory properties. This work explores the therapeutic potential of extracellular vesicles as alternatives to cell therapy, examining their key advantages and current limitations. It specifically focuses on their roles within established aging mechanisms and their dual utility as biomarkers and therapeutic agents. Critical aspects of extracellular vesicle translation are addressed, including standardized methods for production, storage stability optimization, and engineering strategies for cargo loading and targeting. Extracellular vesicles possess unique biological properties-inherent biocompatibility, low immunogenicity, ability to cross biological barriers, and high biological activity at low doses. Preclinical studies across various age-related pathologies (neurodegeneration, cardiovascular disease, sarcopenia) consistently report efficacy in reducing inflammation, promoting tissue repair, and improving functional outcomes. These findings strongly support the capacity of extracellular vesicles to mimic many therapeutic effects of parental cells while mitigating risks like tumorigenicity or immunorejection associated with whole-cell therapies. Overcoming challenges in scalable manufacturing, quality control, regulatory standardization, and targeted delivery is essential for the clinical translation of extracellular vesicles. Despite these hurdles, their compelling preclinical evidence and inherent advantages position them as a major future direction. They are expected to play a key role in combating age-related decline and advancing regenerative medicine, becoming a cornerstone of next-generation biomedical interventions over the next decade.

Efficient DNA repair might make possible the longevity of naked mole-rats. However, whether they have distinctive mechanisms to optimize functions of DNA repair suppressors is unclear. We find that naked mole-rat cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) lacks the suppressive function of human or mouse homologs in homologous recombination repair through the alteration of four amino acids during evolution. The changes enable cGAS to retain chromatin longer upon DNA damage by weakening TRIM41-mediated ubiquitination and interaction with the segregase P97. Prolonged chromatin binding of cGAS enhanced the interaction between repair factors FANCI and RAD50 to facilitate RAD50 recruitment to damage sites, thereby potentiating homologous recombination repair. Moreover, the four amino acids mediate the function of cGAS in antagonizing cellular and tissue aging and extending life span. Manipulating cGAS might therefore constitute a mechanism for life-span extension.

Background and aim: Aging significantly increases the risk of cardiovascular diseases, characterized by progressive cardiac dysfunction. The vascular niche is crucial for maintaining cardiac homeostasis, yet endothelial cell (EC) impairment during aging remains poorly understood. This study investigates epigenetically regulated mechanisms mediating EC-dependent cardiac aging and identifies a critical role of Zinc finger and BTB domain-containing protein 16 (ZBTB16). Methods: Chromatin accessibility (snATAC-seq) and transcriptomic (snRNA-seq) analyses were performed on aged hearts to identify age-related regulatory changes. Functional studies using genetic models, assessed cardiac aging phenotypes. In vitro assays examined EC senescence and secretory profiles, while co-culture experiments analyzed the impact of ZBTB16-deficient EC supernatants on fibroblasts, cardiomyocytes, and neurons. Overexpression experiments in vitro and in vivo tested the potential for ZBTB16 to mitigate aging-associated dysfunction. Results: Aged hearts exhibited decreased chromatin accessibility and expression of the transcription factor ZBTB16 in both human and mice. Loss of ZBTB16 in young mice, including Zbtb16 haploinsufficient and endothelial-specific knockout mice, led to premature aging, diastolic dysfunction, and increased secretion of pro-fibrotic and inflammatory factors. Supernatants from ZBTB16-deficient ECs activated fibroblasts, induced cardiomyocyte hypertrophy, and impaired neuronal sprouting. Overexpression of ZBTB16 reversed these effects in senescent ECs and aged mice and reduced diastolic dysfunction. Mechanistic studies identified key downstream targets of ZBTB16, including nuclear receptor-interacting protein 1 (NRIP1). ZBTB16 suppressed NRIP1 expression, limiting fibroblast activation and pro-fibrotic signaling. Conclusions: ZBTB16 is a key regulator of endothelial function, maintaining vascular niche homeostasis and mitigating aging-associated cardiac dysfunction. Its loss promotes EC senescence and pro-fibrotic signaling, contributing to diastolic dysfunction. Overexpression of ZBTB16 presents a potential therapeutic strategy for preserving cardiac function during aging. These findings establish a novel role for ZBTB16 in endothelial aging and cardiovascular disease prevention.

Sarcopenia, a progressive age-related decline in skeletal muscle mass and function, is closely linked to impaired regenerative capacity of satellite cells (SCs), also known as satellite cells. Age-dependent SCs dysfunction, driven by intrinsic senescence and niche dysregulation, disrupts activation, proliferation, and differentiation, thereby exacerbating regenerative deficits in sarcopenia. The SCs niche undergoes age-related remodeling, characterized by immune cell infiltration, ECM stiffening, and aberrant FAPs differentiation toward Fibro-Adipogenic lineages. Immune subsets orchestrate inflammation resolution and SCs activation during regeneration, while FAPs exhibit dual roles: transient pro-regenerative WISP1 secretion and chronic fibrotic conversion. Concurrently, vascular-neural networks sustain SCs quiescence and neuromuscular junction integrity, with age-related degradation of these systems exacerbating regenerative decline. Single-cell omics and 3D genomic studies have revealed heterotypic interactions and chromatin structural changes underlying SCs dysfunction in aging. Emerging therapeutic strategies targeting SCs rejuvenation and niche restoration-including metabolic regulation, endocrine interventions, and cell-based therapies-are complemented by advances in single-cell omics and 3D modeling technologies, which offer unprecedented opportunities to dissect niche complexity and identify novel therapeutic targets for sarcopenia. This review synthesizes recent advancements in understanding the role of SCs and their dynamic niche microenvironment in sarcopenia pathogenesis, exploring novel therapeutic strategies while underscoring the critical importance of deciphering their bidirectional interplay for developing effective interventions against age-related muscle loss.

The exposome, an individual's lifelong environmental exposure, profoundly impacts health. Somatic tissues undergo functional decline with age, exhibiting characteristic ageing phenotypes, including hair greying and cancer. However, the specific genotoxins, signals and cellular mechanisms underlying each phenotype remain largely unknown. Here we report that melanocyte stem cells (McSCs) and their niche coordinately determine individual stem cell fate through antagonistic, stress-responsive pathways, depending on the type of genotoxic damage incurred. McSC fate tracking in mice revealed that McSCs undergo cellular senescence-coupled differentiation (seno-differentiation) in response to DNA double-strand breaks, resulting in their selective depletion and hair greying, and effectively protecting against melanoma. Conversely, carcinogens can suppress McSC seno-differentiation, even in cells harbouring double-strand breaks, by activating arachidonic acid metabolism and the niche-derived KIT ligand, thereby promoting McSC self-renewal. Collectively, the fate of individual stem cell clones-expansion versus exhaustion-cumulatively and antagonistically governs ageing phenotypes through interaction with the niche.

Methionine restriction (MetR) attenuates the severity of numerous age-related diseases and extends lifespan across multiple species. Implementing MetR in humans remains challenging due to the low palatability of MetR diets, unfavorable side effects associated with continuous dietary MetR, and interindividual variation in factors that can diminish its efficacy, including microbiota activity, compensatory effects from cysteine, and methionine transfer from neighboring cells. Several novel approaches that target methionine metabolism have been developed - including small molecules, synthetic biotics, and xenotopic tools - with some already translated into early-stage clinical trials. In this review, we discuss a variety of approaches that either produce or mimic MetR, as well as their potential applications for human healthspan improvement.

Tissue structure, the organization of cells, vasculature and extracellular matrix, determines organ function. Yet how tissue structure changes with aging remains largely unknown. Current aging research primarily focuses on molecular changes, missing this structural dimension. Here, we present PathStAR, Pathology based Structural Aging Rate, the first computational framework that captures when and how tissue structure changes during aging from histopathology images. We applied it to 25,306 postmortem tissues covering 40 tissue types from individuals aged 21 - 70, connecting structural aging to molecular data, health records and genotype data. Without any training on chronological age, PathStAR captured non-linear functional decline of ovary, undetectable by bulk-molecular profiling. Applying it across 40 tissues, it revealed that structural aging occurs through discrete phases of rapid change (accelerated periods), with tissue-specific trajectories following three patterns: Early Aging Tissues (vascular system with major changes during the 30s), Late Aging Tissues (uterus and vagina with major changes during menopause (50s)) and Biphasic Aging Tissues (digestive, male reproductive tissues, and ovary with two periods of major changes). During these accelerated phases, most tissues exhibited shared aging hallmarks of inflammation and energy production decline, coupled with disruption of pathways governing their specialized functions. Cross-organ analysis revealed coordinated aging within organ systems and an unexpected link between digestive and male reproductive tissues. We next identified 123 germline variants associated with organ-specific accelerated structural aging, including SIRT6 variants linked to accelerated vascular decline. Finally, individuals with systemic autoimmune disease, as well as tissues with classical aging pathologies (atrophy, calcification, fibrosis), showed elevated structural aging scores. We demonstrate that structural aging is measurable from histology scans and provide the first systematic framework for studying it, revealing organ-specific aging processes.