Longevity Papers

Senescent cells accumulate following chemotherapy and during aging, where they contribute to dysfunction through the pro-inflammatory arm of the senescence-associated secretory phenotype (SASP), termed NF-κB-associated SASP (NASP). Here we show that short-term inhibition of CDK4/6 with abemaciclib suppresses established NASP in pre-existing senescent cells both in vitro and in vivo. This senomorphic effect reduces the pro-tumorigenic activity of chemotherapy-induced senescent cells and improves physical function in mice following chemotherapy. Genetic knockdown of CDK4/6 phenocopied these effects, confirming a CDK4/6-dependent mechanism. Mechanistically, CDK4/6 inhibition suppressed retinoic acid signaling, and the RARα antagonist agn194310 similarly reduced NASP expression. CDK4 and CDK6 interacted with NF-κB, while CDK4 additionally bound RARα, and these interactions were disrupted by abemaciclib. In aged mice, abemaciclib and agn194310 reduced systemic NASP expression and improved physical performance. Together, these findings identify the CDK4/6-RARα-NF-κB axis as a therapeutic target for senomorphic interventions.

Aging of the hematopoietic system impairs hematopoietic stem cell (HSC) function and alters bone marrow niche behavior, increasing susceptibility to anemia, infections, and hematologic malignancies. Here, pharmacologic clearance of senescent cells with the PROTAC compound 753b simultaneously targeting BCL-xL and BCL-2 reverses key secretory, transcriptional, and functional hallmarks of hematopoietic aging with low toxicity, restoring balanced lineage output. Single-cell RNA sequencing further demonstrates that 753b treatment attenuates aging-associated transcriptional signatures in HSCs, while selectively eliminating senescent, pro-survival niche cells without grossly perturbing niche composition. Functionally, 753b suppresses pro-inflammatory cues from both niche and hematopoietic cells including those emanating from neutrophil progenitors, rebalancing global bone marrow secretory ecosystem across stromal and hematopoietic compartments. Collectively, we identify 753b-induced senescent cell clearance as a powerful strategy to rejuvenate aged hematopoiesis and re-establish homeostatic communication between HSCs and their microenvironment, with implications for mitigating age-related hematologic dysfunction and improving hematologic health in older individuals.

Proteostasis collapse, a hallmark of aging and neurodegeneration like Alzheimer's disease (AD), causes irreversible damage in late life. Whether late-life proteostasis capacity is developmentally programmed remains unclear, as mechanistic studies requiring lifelong tracking and molecular manipulation are challenging or impossible in long-lived species. Using C. elegans as a lifelong, genetically tractable AD model, we uncover a critical early-life window during which reducing TIP60/NuA4 acetyltransferase complex activity enduringly enhances proteostasis and extends lifespan. Mechanistically, NuA4 reduction depletes H4K16ac, triggering a compensatory, early-life-biased, XBP-1-mediated unfolded protein response (UPR

The anti-ageing response to Dietary Restriction (DR) is thought to be mechanistically ancient, reasoning from its phenotypic conservation. However, DR is implemented differently across species and evidence for conserved mechanisms remains limited. Here, we tested longevity and fecundity in response to DR across eight different Drosophila species, finding that DR is, on balance, phenotypically conserved. Next, we used comparative transcriptomics and found strongly concordant responses to DR. We studied the evolutionary history of the top concordantly differentially expressed orthologous genes and identified that many are "young" genes, suggesting that the genetic basis of DR is not widely conserved. To validate this hypothesis, we tested the longevity effects of the 15 most conserved genes that change in transcription in response to DR. Surprisingly, we found that 12 out of 15 genes tested had a lifespan phenotype, with 9 extending lifespan. Our findings suggest that while large parts of the DR response are taxonomically specific, some core mechanisms appear conserved. The comparative approaches we used here hold promise to identify shared mechanisms relevant to our own species.

Regenerative cells, also known as stem cells, exhibit transitioning between a resting state, crucial for long-term preservation with low metabolic activity, and an activation state defined by active proliferation and differentiation to repair old or damaged cells. Concomitant with stem cell transition, mitochondria also undergo a similar transition to support cell growth by providing energy and growth precursors. High mitochondrial activity during cell growth, however, results in reactive oxygen species (ROS). ROS function as signaling molecules and activate several metabolic pathways by rewiring key enzymes and proteins. During the resting state, often called quiescence, ROS production should be limited to prevent resumption of inappropriate growth and oxidation of essential components like DNA in a cell type whose main function is to divide and pass its genetic material to daughter cells for repair. Most stem cells in a resting state (also known as G0 phase) display reduced mitochondrial activity by suppressing oxidative phosphorylation (OXPHOS) due to active mitophagy maintained by quiescence regulators in cells. Mitogens and injury markers activate resting or quiescent stem cells to reenter the cell cycle and grow, a process that requires mitochondrial activity for the supply of nucleotides, non-essential amino acids, lipids and many more. Mitochondria undergo cell cycle-specific changes during the G1, S, and G2/M phases. This article examines how mitochondria regulate stem cell growth and control cell fate. Stem cell dysfunction leads to regeneration issues, contributing to premature aging and cancer. Understanding mitochondrial function can further enhance therapeutic interventions in cancer and aging, as highlighted at the end of the review.

Aging affects lung function, predisposing older adults to respiratory diseases; however, the cellular and molecular mechanisms of lung aging are not fully understood. Leveraging single-cell and spatial transcriptomics data from 184 and 70 lung parenchyma samples, respectively, we present an analytical platform to dissect the cell composition, gene expression modules, and regulatory changes linked to multiple hallmarks of lung aging. Our findings show cell type-specific age-association of senescence markers and a decline in alveolar cell proliferation, autocrine WNT signaling, and stemness indicators with advancing age. Analysis of myeloid cells reveals a global reduction in macrophage subsets and a surge in mitochondrial dysfunction and inflammatory signaling. In contrast, lung parenchyma T cells expand with age and exhibit heightened interferon gamma expression, cytotoxic activity, and exhaustion in older lung and blood samples, indicative of age-related immune dysfunction. Cell interaction and spatial analysis demonstrate aberrant myeloid-T cell cross-talk, leading to an increase in T cell chemotaxis and activation. Lastly, we use machine learning to predict lung biological age and identify putative biomarkers of lung aging and disease risk.

Aging disrupts tissue homeostasis across organ systems. Here, we identify tissue-resident macrophages (TRMs) as central coordinators of age-related organ decline through impaired clearance of senescent neutrophils, a process regulated by the immunomodulatory prostaglandin E2 (PGE

Cardiovascular diseases remain the primary driver of global mortality, with advanced age serving the most significant risk factor for their development and progression. Emerging evidence suggests that chronic infections can act as potent catalysts for cardiac decline by prematurely inducing aging phenotypes. Pathogens, including viruses, bacteria, and parasites, that evade host clearance establish a state of permanent inflammaging: a chronic, low-grade inflammatory milieu characterized by persistent cytokine signaling and leukocyte infiltration. This environment directly mirrors the sterile inflammation that drives natural senescence. Mechanistically, chronic infection subverts the heart's homeostatic pathways, triggering cardiomyocyte senescence through the dysregulation of mTOR signaling and the impairment of autophagy. These infections further drive mitochondrial dysfunction and the overproduction of reactive oxygen species (ROS), leading to oxidative DNA damage and metabolic exhaustion within the myocardium. On a structural level, immune subversion, via macrophage polarization and the induction of autoimmunity, accelerates left ventricular hypertrophy, myocardial remodeling, and interstitial fibrosis. By characterizing chronic infection as a modifiable driver of biological aging, we can prioritize anti-infective strategies as essential components of cardiovascular longevity and geriatric care.

Regulatory T cells (Tregs) are essential for maintaining immune tolerance. We recently identified chaperone-mediated autophagy (CMA), a selective lysosomal degradation pathway, as a critical regulator of Treg function. Treg activation induces CMA, but this response is markedly diminished with aging. Mice lacking CMA specifically in Tregs develop systemic inflammation, impaired immune tolerance and reduced lifespan. We confirm that CMA is a fundamental mechanism supporting Treg suppressive function as CMA-deficient Tregs are unable to suppress intestinal inflammation in a model of inflammatory bowel disease and fail to block the anti-oncogenic immune response activated in a syngeneic tumor model. Mechanistically, CMA supports metabolic fitness, remodels immune-related protein networks, and promotes degradation of the m

Cellular senescence is a fundamental driver of aging and age-related diseases. While traditionally attributed to biochemical cues, accumulating evidence identifies cellular mechanics as a critical regulator of senescence. Cells continuously sense and transduce extracellular mechanical signals, which reshape cytoskeletal architecture, nuclear mechanics, and chromatin organization. In this review, we summarize multi-scale mechanical alterations associated with senescence, including altered cellular traction force, cytoskeletal disorganization, and impaired nuclear mechanotransduction. We further discuss key mechanosensitive pathways that govern senescence initiation and progression. Finally, we highlight emerging mechanical approaches for identifying senescent cells and discuss the therapeutic potential of mechanics-based interventions, including mechanical stimulation, microenvironment remodeling, and targeted modulation of mechanotransduction, for aging and regenerative medicine.

Cellular senescence is a key driver of age-associated tissue dysfunction through the secretion of pro-inflammatory and pro-senescent factors (SASP). Among these, insulin-like growth factor binding proteins (IGFBPs) have emerged as causal mediators of senescence propagation. Piceatannol (PCT), a naturally occurring stilbene and resveratrol metabolite with superior pharmacokinetic properties, exhibits senomorphic activity in vitro, but its in vivo senotherapeutic potential remains poorly defined. We established a murine model of mild aging using sublethal X-ray irradiation, in which organ function remains largely preserved but molecular and cellular hallmarks of aging, such as senescent cell accumulation, SASP factor elevation, tissue remodeling, and low-grade inflammation, are detectable. This controlled model mimics the early stage of aging seen in many healthy middle-aged individuals, particularly prevalent in Western societies, and provides a relevant platform for testing preventive senotherapeutics. Mice were treated with oral PCT at a human-translatable dose and evaluated for behavioral performance, circulating SASP factors, tissue senescence, inflammation and fibrosis. PCT significantly improved motor coordination and spatial memory while reducing systemic inflammation and circulating SASP factors, including the senescence-propagating IGFBPs IGFBP4, IGFBP5, and IGFBP7. In kidney and heart, the organs most affected by radiation-induced aging, PCT reduced senescent cell burden, CD68⁺ inflammatory foci, fibrotic remodeling, and the senescence markers P53 and P21. PCT also preserved mesenchymal stromal cell clonogenic capacity. These multi-organ benefits were achieved without detectable toxicity in healthy animals. Our findings position PCT as a promising, safe, nutritionally derived senotherapeutic candidate for delaying aging-associated deterioration. This mild aging model, capturing preclinical senescence without overt organ failure, may accelerate the development of interventions aimed at preserving health span in middle-aged populations.

The accumulation of advanced glycation end products (AGEs) in long-lived proteins is a hallmark of mammalian aging and implicated as a driver of metabolic dysfunction. Among these adducts, N

The blood-brain barrier (BBB) experiences dysfunction during physiological aging, potentially leading to cognitive decline and the onset of neurodegenerative diseases. Recent research highlights brain endothelial cell (BEC) senescence as a key factor contributing to BBB impairment. In this study, polymeric nanoparticles (NPs) loaded with a senolytic agent - Navitoclax - were designed to selectively eliminate senescent cells more effectively. These NPs are taken up by both proliferative and senescent BECs, but are only degraded in the latter due to the presence of senescence-associated beta-galactosidase (SA-β-gal), releasing the drug to induce cell death. NPs effectively and selectively eliminate senescent BECs at lower doses, without affecting proliferative cells, outperforming the soluble senolytic. NPs were then evaluated in a chronologically aged rat model exhibiting BEC senescence, increased BBB permeability, and diminished exploratory behavior. In comparison to high-dose soluble senolytic, the NPs successfully restored BBB integrity by reducing permeability, diminishing the burden of senescent BECs, and partially improving rat exploratory performance. Notably, only the NPs were able to reduce the presence of p21

Spatial chromatin organization dictates cellular function and resilience, yet scalable imaging methods to quantify chromatin states in situ across aging and interventions are lacking. While ATAC-see can visualize accessible chromatin, its broader application is hindered by protocol variability, low throughput, and incompatibility with complex tissues. Here, we systematically optimize the ATAC-see workflow for robust, high-throughput quantitative imaging in fixed, adherent mammalian cells and fresh frozen tissues. We validate the platform's sensitivity to pharmacologic remodeling and apply it to replicative, chronological, and pathological aging in primary human fibroblasts, revealing progressive age-associated chromatin opening and heterochromatin remodeling. Furthermore, we demonstrate that our optimized ATAC-see captures rapid, reversible chromatin reorganization during OSK(M)-driven partial reprogramming of aged fibroblasts. Finally, we extend a cost-effective and accessible protocol to murine tissue sections, quantifying in situ age-dependent remodeling. This standardized framework establishes chromatin accessibility as a highly scalable, sequencing-compatible imaging biomarker for evaluating aging and rejuvenation.

The urokinase-type plasminogen activator receptor (uPAR) is a glycosylphosphatidylinositol-anchored membrane protein that regulates fibrinolysis, cell adhesion, migration, and intracellular signaling. Elevated uPAR expression is linked to numerous pathological conditions, including cancer, inflammation, and metabolic dysfunction. In obesity and aging, increased uPAR levels are associated with chronic inflammation, adipose tissue impairment, and systemic metabolic disturbances. uPAR also modulates adipocyte differentiation and contributes to the progression of inflammatory obesity, while serving as a key regulator of cellular senescence triggered by oncogenic stress, chemotherapy, or aging. These characteristics position uPAR as a compelling therapeutic target for metabolic and age-related diseases. To address this, we developed a nanoparticle-based targeted therapy optimized for senolytic delivery, which enhances accumulation in uPAR-overexpressing cells and improves drug stability. Dasatinib and quercetin, two established senolytic agents, were co-encapsulated into uPAR-targeted hybrid nanoparticles to selectively eliminate senescent cells, reduce inflammation, and restore metabolic homeostasis, presenting a promising therapeutic strategy for obesity- and aging-associated disorders.

Sleep disruption is a hallmark of aging and a plausible driver of Alzheimer's disease vulnerability. Reduced slow-wave sleep, increased fragmentation, and circadian instability may facilitate amyloid-β accumulation, tau propagation, neuroinflammation, oxidative stress, and impaired glymphatic clearance. Yet the physiological factors that predispose older adults to unstable sleep remain insufficiently integrated into models of brain aging. This Review advances a sleep-muscle-brain framework in which sarcopenia, sarcopenic obesity, and insulin resistance are conceptualized as modifiable muscle-metabolic conditions that may bias sleep continuity and shape the biological impact of sleep disruption. We examine irisin/FNDC5-BDNF signaling as a hypothesis-generating candidate modifier of metabolic regulation, neurotrophic support, and brain resilience, while emphasizing that direct evidence for a causal role in human sleep regulation remains insufficient. Irisin-related pathways intersect with insulin sensitivity, inflammatory control, and BDNF-dependent synaptic plasticity, all of which are relevant to the physiological context in which sleep disruption may influence Alzheimer's disease pathophysiology. We propose that age-related attenuation of muscle endocrine signaling, together with insulin resistance and low-grade inflammation, may lower the threshold at which sleep fragmentation translates into amyloid/tau dyshomeostasis, glial activation, and network dysfunction. Rather than treating sleep disturbance as an isolated brain-centered risk factor, this framework positions sleep as a biobehavioral hub through which peripheral aging processes can modulate neurodegenerative resilience. The Review integrates evidence from sleep neuroscience, geroscience, metabolism, and neurodegeneration, and identifies experimentally testable predictions. A sleep-muscle-brain perspective may help refine risk stratification and guide multimodal interventions combining sleep optimization, resistance exercise, metabolic targeting, and Alzheimer's disease biomarker monitoring.

Interventions targeting conserved aging pathways can markedly extend lifespan in model organisms, yet their efficacy declines with increasing organismal complexity. While this phenomenon is well documented, the underlying constraints remain poorly defined. Here, we integrate comparative experimental data with mechanistic insights to propose a unifying framework explaining the declining ceiling of lifespan extension. We show that in simple organisms, aging is governed by a limited number of high-leverage pathways, whereas in mammals it emerges from distributed, multi-tissue regulatory systems characterized by redundancy, feedback, and competing physiological constraints. By synthesizing findings from Caenorhabditis elegans, Drosophila melanogaster, and rodent models, we identify key determinants of this transition, including metabolic organization, genetic redundancy, endocrine regulation, microbiome interactions, and pharmacokinetic complexity.

Lysosomal dysfunction is a prominent feature of neurodegeneration and aging, yet how primary defects in lysosomal trafficking are converted into progressive cellular decline remains poorly understood. Niemann Pick disease type C (NPC), caused by impaired NPC1 dependent cholesterol export, provides a genetically defined model to address this question. Here, we show that NPC1 deficiency activates a lysosome, genome, immune axis linking cholesterol trafficking failure to neurodegeneration and hallmarks of cellular aging. In Npc1 mutant mice, NPC1 loss triggered DNA damage, neuroinflammation, microglial and astrocytic activation, Purkinje neuron degeneration, and motor dysfunction. Consistently, NPC patient-derived fibroblasts exhibited mitochondrial abnormalities and widespread DNA double-strand breaks. Genome-wide DNA break mapping and transcriptomic analyses revealed extensive genomic instability at regulatory regions, including enrichment of DNA breaks at transcription start sites and G quadruplex associated loci, accompanied by widespread transcriptional reprogramming, activation of innate immune pathways, disruption of fibroblast identity, and induction of cellular aging signatures. We further identify Fingolimod, an FDA approved sphingosine - 1 phosphate receptor modulator, as a potent modifier of this disease network. Fingolimod improved lysosomal cholesterol trafficking, increased LAMP1 abundance, attenuated STING associated inflammatory signaling, normalized mitochondrial function, reduced neuroinflammatory and neurodegenerative phenotypes in Npc1 mutant mice, and broadly shifted disease-associated transcriptional programs toward a healthier state. Extending these findings beyond NPC, Fingolimod improved age-associated phenotypes in C. elegans and prolonged lifespan in aged male mice. Together, these findings identify genome instability and chronic innate immune activation as major downstream consequences of lysosomal cholesterol trafficking failure and establish Fingolimod as a clinically actionable modulator of lysosomal dysfunction, neurodegeneration, and aging-related decline.