Longevity Papers

Aging is associated with progressive accumulation and dysregulation of dural immune cells, coinciding with impaired CSF drainage and lymphatic function. Prior work has shown that improving lymphatic function in aged mice is sufficient to ameliorate age-associated cognitive decline, and that local immune cells can directly regulate lymphatic draining function. Yet, the endothelial-intrinsic mechanisms driving lymphatic dysfunction remain unclear. Here we found that the integrin CD49a is upregulated in aged lymphatic endothelial cells and regulates CCL21 release. Accordingly, genetic deletion of CD49a in lymphatic endothelial cells broadly reverses age-associated immune dysfunction across dural myeloid, lymphoid and dendritic cell compartments, limits glial aging, and mitigates cognitive and social behavioral deficits, thereby revealing a targetable endothelial-intrinsic mechanism of lymphatic aging.

Impaired oligodendrocyte precursor cell (OPC) differentiation limits myelin renewal in aging and contributes to multiple sclerosis (MS) progression. How aging drives OPC deficits remains incompletely understood. We find dysregulation of genes associated with the circadian clock, including Bmal1, and metabolism in aged compared with young OPCs. Targeted loss of Bmal1 in OPCs drives metabolic dysfunction, leading to cellular senescence and impaired dynamics. OPC proliferation and differentiation occur at different rates throughout the day in young adult mice and become disrupted with aging. Chronotherapeutic targeting of BMAL1-controlled sirtuin signaling restores Bmal1-disrupted OPC dynamics after demyelination via sirtuin 2 (Sirt2)-dependent mechanisms. Induced pluripotent stem cell (iPSC)-derived OPCs from MS patients and MS lesion oligodendroglia recapitulate BMAL1 and SIRT2 disruptions. These findings establish BMAL1 as a key regulator of OPC energy metabolism, sirtuin homeostasis, and senescence. We anticipate that this work will provide a foundation for future studies investigating the interconnected roles of aging, circadian disruption, and myelin biology.

Age-related genome mosaicism is an inherent feature of multicellularity and genomic instability. It occurs because of DNA mutations, the accumulation of which leads to diverse genomic landscapes across different tissues. DNA mutations in the genome are consequences of DNA damage, changes in the chemical structure of DNA, such as strand breaks or loss of bases. DNA damage is very frequent and normally repaired quickly. However, errors intrinsic to DNA repair or replication can give rise to permanent changes in genome sequence information. Such DNA mutations are diverse and include single-nucleotide variants, small insertions and deletions, and larger genome structural variants. Since the 1950s, somatic mutations have been proposed to be a major cause of aging. Indeed, somatic mutations are the cause of cancer, the risk of which increases exponentially with age, and possibly other age-related diseases, such as neurodegenerative diseases and cardiomyopathies. Somatic mutations vary from cell to cell owing to the innate stochasticity of their occurrence, from error-prone processing of randomly inflicted DNA damage. With the emergence of single-cell and single-molecule sequencing, it has become possible to quantitatively analyze somatic mutations in human cells and tissues. Here, we discuss a possible causal relationship between mutation-driven mosaicism of the somatic genome and aging-related functional decline and disease by exploring several predictions of the somatic mutation theory of aging.

Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare premature aging disorder caused by progerin, a truncated lamin A variant generated by a silent de novo mutation activating a cryptic splice site in LMNA. The resulting morphological, epigenetic, genomic, and proteostasic defects closely recapitulate some hallmarks of cellular aging. Here, we identify the Parkinson's disease-associated kinase LRRK2 as a critical regulator of HGPS pathology and physiological aging. Rab29-mediated LRRK2 hyperactivation exacerbates progerin-induced cellular aging, whereas LRRK2 knockdown or overexpression of its opposing phosphatase, PPM1H, ameliorates progerin-induced defects. Progerin-expressing cells exhibit altered intracellular trafficking, which is regulated by LRRK2 and links diverse aging hallmarks. Consistent with these findings, reducing LRRK2 levels mitigates cellular aging phenotypes in physiologically aged cells, and loss of the C. elegans ortholog lrk-1 preserves aging-associated loss of motility and extends organismal lifespan. Together, our findings establish LRRK2 as a central node in cellular aging and position it as a potential therapeutic target for aging-related defects in both HGPS and physiological aging.

Diet plays a critical role in promoting wellness and longevity in both humans and canines. Epigenetic ageing clocks have emerged as accurate tools for assessing biological ageing and evaluating dietary and lifestyle interventions in humans and mice.

Loss of skeletal muscle mass and strength with age drives sarcopenia, a syndrome affecting >100 million people worldwide that leads to loss of mobility, independence, and increased mortality. Mechanical overload induces hypertrophy in young muscle, but this response is markedly attenuated with age - a poorly understood phenomenon termed anabolic resistance. Here we test whether impaired paracrine communication between myofibers and their niche underlies this loss of plasticity in geriatric mice. In aged muscle, pharmacological inhibition of 15-PGDH restores prostaglandin E2 (PGE2) bioavailability and rescues the anabolic response, increasing muscle growth and contractile strength. Single-nuclei RNA-seq revealed a paracrine circuit: PGE2 drives IGF1 synthesis in type IIb myonuclei, which signals to stromal, myogenic, myonuclear, and immune cells. Blocking IGF1 receptor signaling abolished these gains, placing PGE2 upstream of an IGF1-mediated circuit that coordinates multicellular hypertrophy. Thus, 15-PGDH inhibition is a pharmacological strategy to overcome the anabolic resistance and rebuild muscle in aging.

Aging-related functional decline in hematopoietic stem cells (HSCs) is closely associated with mitochondrial dysfunction and impaired mitophagy. This study aimed to investigate whether targeted restoration of mitophagy

Mosaic chromosomal alterations (mCAs) increase with age and are associated with multiple diseases, yet the cell types and states that harbor these alterations remain largely unknown. Because mCAs arise in individual cells prior to clonal expansion, they are typically rare and obscured in bulk data. We develop CHASM, a method for detecting chromosomal copy number alterations (CNA) from single-cell chromatin accessibility (scATAC-seq) data, a scalable modality that captures both cell state and chromosomal alterations. CHASM estimates a CNA-null background for each cell, providing an individualized expectation for chromosomal accessibility, which is critical in non-neoplastic tissues where alteration-carrying cells are not readily distinguishable from normal. By comparing each cell against its expected background, CHASM distinguishes chromosomal alterations from background variation and achieves more stringent control of false positives. We validate CHASM using in silico spike-in experiments, cross-modality comparisons with matched single-cell DNA and RNA data, and established genome-instability contrasts, including p53 deficiency and chromosome Y loss. Applied to multiple aging data sets, CHASM consistently recovers mCA burden in age-susceptible cell populations and reveals aging-associated signatures not detected by existing methods. In a cohort of 99 human kidney samples spanning age and disease conditions, CHASM identifies enrichment of mCAs in injury-associated cell states (VCAM1-high proximal tubule cells). Notably, CHASM detects the age-associated emergence of mCAs in cancer-relevant genomic regions, including chromosomes 3 gains and losses and chromosome 7 gain, in ostensibly normal cell populations. Cells harboring mCAs exhibit activation of injury-response regulatory programs and reduced epithelial identity programs, while elevated mCA burden in specific epithelial populations are associated with increased immune and stromal infiltration. Overall, we develop CHASM for high-specificity detection of CNA at single cell resolution. Applied across tissues, CHASM reveals aging-patterns of genome instability within cell types and implicates mCAs in early, pre-disease cellular states.

Progressive aging of bone marrow hematopoietic stem cells (HSCs) underlies clonal hematopoiesis and age-associated hematologic disorders. Defining early molecular events driving HSC functional decline is essential for rejuvenation strategies. Here, we identify P-selectin (Selp) as a surface marker that stratifies HSCs into conserved functional and transcriptional states during organismal aging in humans and mice. P-selectin expression increases early during aging and remains elevated in old HSCs. Selp

Agingis characterized by chronic low-grade inflammation ("inflammaging"), a key driver of functional decline and age-related diseases. The cGAS-STING pathway, which senses cytosolic DNA, has emerged as a central mediator of this sterile inflammation. Here, we systematically review the mechanisms of cGAS-STING activation in aging-including mitochondrial DNA leakage, nuclear envelope disruption, and retrotransposon activation-and its role in driving cellular senescence and the senescence-associated secretory phenotype (SASP). We examine the pathway's pathological contributions across multiple systems, including the nervous, cardiovascular, musculoskeletal, metabolic, reproductive, and sensory systems. We also discuss therapeutic strategies targeting cGAS-STING, encompassing small-molecule inhibitors, natural products, nanomedicine, and gene therapy. Furthermore, we integrate AlphaFold3-based structural modeling and CB-DOCK2 molecular docking analyses to characterize the binding modes and affinities of key inhibitors (e.g., H-151, RU.521, VBIT-4, Mdivi-1) to cGAS, STING, VDAC1, and DRP1, providing a structural rationale for their therapeutic potential. Finally, we address current challenges, including tissue-specific effects and pathway complexity, and highlight future directions for translating these insights into clinical interventions for aging and age-associated disorders.

Diabetes mellitus (DM) is characterized by chronic metabolic stress that promotes oxidative damage, genomic instability, and premature cellular aging, with adipose tissue senescence being a pivotal contributor to metabolic dysfunction. Yet the impact on DNA damage repair (DDR) and telomere maintenance in adipose tissue remains poorly defined. This study investigated DDR capacity, telomere integrity, and the senescence-associated secretory phenotype (SASP) in adipose tissue and adipose-derived stromal cells (ADSCs) under diabetic conditions. Using an obese diabetic (ob/ob) mouse model, we confirmed whole-blood telomere shortening, significant adipose tissue hypertrophy, metabolic dysregulation, and elevated DNA damage, evidenced by increased γH2AX-positive staining. In vitro, ADSCs exposed to a diabetic microenvironment (AGEs and TNFα) exhibited increased reactive oxygen species and DNA damage without a corresponding activation of DDR pathways, as indicated by unchanged PARP1 levels and broad downregulation of key DNA repair genes, including sensors (ATM, ABL1, RAD17) and effectors across MMR, NER, HR, and NHEJ pathways. This impaired genomic surveillance was accompanied by premature cellular senescence and significant repression of genes involved in telomere protection (shelterin complex), telomerase activity, and telomere maintenance, together with marked telomere shortening following prolonged exposure. Furthermore, diabetic conditions increased the secretion of pro-inflammatory cytokines, chemokines, and growth factors. Collectively, these findings demonstrate that the diabetic microenvironment is associated with maladaptive DDR responses, telomere dysfunction, cellular senescence, and a pro-inflammatory secretory phenotype. This study highlights compromised genomic maintenance as a potential key mechanism underpinning adipose tissue dysfunction in DM and emphasizes the need for future investigations into the mechanisms underlying dysregulated DDR and telomere biology.

Much focus has shifted towards understanding how glial dysfunction contributes to age-related neurodegeneration due to the critical roles glial cells play in maintaining brain health. Cell-cell interactions, which are largely mediated by cell-surface proteins, control many critical aspects of development and physiology; as such, dysregulation of glial cell-surface proteins is hypothesized to play an important role in age-related neurodegeneration. However, it remains technically difficult to profile glial cell-surface proteins in intact brains. Here, we applied an in-situ cell-surface proteomic profiling method to glial cells from intact fly brains. Applying this platform to young and old flies, we identified candidate genes predicted to be involved in brain aging. Through a genetic screen, we identified one surface protein, DIP-β, which is down-regulated in old flies and can increase fly lifespan when overexpressed in adult glial cells. We performed whole-head single-nucleus RNA-seq and revealed that DIP-β overexpression mainly impacts glial and fat cells. We also found that glial DIP-β overexpression was associated with improved cell-cell communication. Our study is the first to apply in-situ cell-surface proteomics to glial cells in

Nutrient-sensing pathways, including mTOR, AMPK, Sirtuins, and insulin/IGF-1 signaling, are central regulators orchestrating adult stem cell (ASC) fate by dynamically modulating cellular metabolism. This review proposes a framework that integrates these pathways into a cohesive network that dictates the metabolic transitions between quiescence, activation, and differentiation in ASCs. Age-related dysregulation of this network leads to metabolic imbalance and stem cell exhaustion, underpinning tissue degeneration. Interventions such as mTOR inhibitors, AMPK activators, NAD

Age-associated thymic involution is a major driver of immunosenescence, yet the cellular and spatial mechanisms coordinating age-related thymic remodeling remain incompletely understood. Combining single-cell transcriptomics, chromatin accessibility profiling, and spatial transcriptomics, we generated a spatially resolved multi-omic atlas of the aging mouse thymus. We show that thymic aging is not simply a process of epithelial loss, but a spatial reorganization of the stroma into new microenvironments, including age-associated epithelial states, a fibroblast-supported epithelial progenitor niche, and tertiary lymphoid structures. This remodeling displaces niches supporting positive and negative thymocyte selection and coincides with an intrinsic decline in cortical thymic epithelial cell function. Ligand-receptor mapping identifies medullary fibroblasts as a signaling hub sustaining epithelial progenitors and promoting tertiary lymphoid structure neogenesis, linking these hallmarks of thymic aging. Together, our findings reframe thymic involution as spatial stromal reorganization that links stromal remodeling to impaired thymopoiesis, central tolerance, and immune aging.