Longevity Papers

In degenerated intervertebral discs, senescent nucleus pulposus cells increase and the senescence-associated secretory phenotype (SASP) is activated, causing abnormal proinflammatory factor and chemokine secretion, extracellular matrix degradation, and inflammation activation, accelerating intervertebral disc degeneration (IDD). DEP domain-containing mTOR-interacting protein (DEPTOR) inhibits SASP secretion through the mammalian target of rapamycin complex 1 (mTORC1) pathway and alleviates IDD. This study constructed an oxidized sodium alginate/carboxymethyl chitosan (OSA/CMCS) hydrogel with exosomes (EXOs) to treat IDD by sustained DEPTOR release via EXOs, addressing the limitations of traditional EXO carriers, including cytotoxicity, limited biocompatibility, and poor degradability. Moreover, the urine stem cell-derived EXO acquisition method is simple and noninvasive and has a high proliferation rate. In the prepared OSA/CMCS@EXO hydrogel, OSA forms a dynamic network with carboxymethyl chitosan through Schiff base bonds, encapsulating EXOs to promote DEPTOR release. This injectable hydrogel enables efficient and stable EXO delivery, resulting in sustained DEPTOR release. Finally, in a puncture-induced IDD rat model, OSA/CMCS@EXO hydrogel significantly alleviated intervertebral disc inflammation and slowed IDD progression, indicating that the DEPTOR/mTORC1/SASP pathway is an important target for IDD treatment. This novel hydrogel is a therapeutic target for IDD and has substantial potential for application in EXO-based therapies for various diseases.

The pregnane X receptor (Pxr) regulates metabolism and inflammation, but its roles in bone homeostasis remain elusive. This study demonstrates that Pxr deficiency in bones induces osteoporotic phenotypes, with reduced trabecular bone mass, impaired osteogenesis, increased inflammation, and apoptosis. RNA sequencing reveals downregulation of the PI3K/Akt signaling pathway in Pxr-deficient bones, a key pathway linked to cell survival and differentiation. In vitro, primary bone marrow mesenchymal stem cells (BMSCs) with Pxr deficiency exhibited inhibited antioxidant enzyme activity, elevated intracellular reactive oxygen species level, activated pro-inflammatory cytokines, suppressed PI3K/Akt pathway, enhanced apoptosis, and decreased osteogenic differentiation. Conversely, Pxr overexpression in BMSCs from aged mice restores PI3K/Akt activation, mitigates apoptosis, and rescues osteogenic differentiation, with these multidirectional beneficial effects abrogated by a PI3K/Akt inhibitor. Moreover, both genetical overexpression of Pxr and pharmacological activation of Pxr improve bone quality in aged mice. These findings identify Pxr as a key regulator of bone homeostasis via the PI3K/Akt pathway, suggesting Pxr as a potential treatment target for age-related bone loss.

Mitophagy is crucial for the selective autophagic degradation of damaged mitochondria, helping to maintain both mitochondrial and cellular homeostasis. Here, we report a fluoroalkylated polypyridinium that specifically targets mitochondria and exhibits high activity in mitophagy induction. The polymer effectively restores mitochondrial function and alleviates the inflammatory response in foam cells by activating mitophagy, and displays inherent red fluorescence under physiological conditions, allowing for direct tracing of its biodistribution in cells and in vivo. Besides, the polymer nanoparticle shows high serum stability due to the antifouling properties of fluoroalkyl tags. After intravenous administration, the nanoparticle reduces oxidative stress, promotes mitophagy, and decreases cellular senescence in atherosclerotic plaques, contributing to high therapeutic efficacy. This study presents an innovative and effective strategy for the treatment of atherosclerosis and other mitochondrial dysfunction-related inflammatory conditions.

The field of ageing science has gone through remarkable progress in recent decades, yet many fundamental questions remain unanswered or unexplored. Here we present a curated list of 100 open problems in ageing and longevity science. These questions were collected through community engagement and further analysed using Natural Language Processing to assess their prevalence in the literature and to identify both well-established and emerging research gaps. The final list is categorised into different topics, including molecular and cellular mechanisms of ageing, comparative biology and the use of model organisms, biomarkers and the development of therapeutic interventions. Both long-standing questions and more recent and specific questions are featured. Our comprehensive compilation is available to the biogerontology community on our website ( www.longevityknowledge.app ). Overall, this work highlights current key research questions in ageing biology and offers a roadmap for fostering future progress in biogerontology.

Advancing age is accompanied by an accumulation of senescent T cells that secrete pro-inflammatory senescence-associated secretory phenotype (SASP) molecules. Gut-microbiota-derived signals are increasingly recognised as immunomodulators. In the current study, we demonstrated that ageing and the accumulation of senescent T cells are accompanied by a reduction in microbial-derived short-chain fatty acids (SCFAs). Culturing aged T cells in the presence of butyrate suppresses the induction of a senescence phenotype and inhibits the secretion of pro-inflammatory SASP factors, such as IL6 and IL8. Administration of faecal supernatants from young mice rich in butyrate prevented in vivo accumulation of senescent spleen cells in aged mice. The molecular pathways governing butyrate's senomorphic potential include a reduced expression of DNA damage markers, lower mitochondrial ROS accumulation, and downregulation of mTOR activation, which negatively regulates the transcription factor NFκB. Our findings establish butyrate as a potent senomorphic agent and provide the evidence base for future microbiome restitution intervention trials using butyrate supplements for combating T cell senescence, ultimately reducing inflammation and combating age-related pathologies to extend lifelong health.

Histone H4K16 acetylation (H4K16ac) is a key epigenetic mark essential for chromatin structure and DNA repair, which is substantially reduced in the accelerated aging disorder Hutchinson-Gilford progeria syndrome (HGPS). The specific enzymes governing H4K16ac homeostasis, particularly the deacetylase responsible for its loss in HGPS, remain poorly defined. Here, we sought to identify the enzymes regulating H4K16ac and determine if their inhibition could rescue HGPS-associated cellular defects. Using systematic siRNA screening in HeLa and U2OS cells, we confirmed that KAT8/MOF is the principal H4K16 acetyltransferase. Surprisingly, we identified HDAC2 as the dominant class I histone deacetylase for H4K16ac; knockdown of the highly homologous HDAC1 had no effect. While SIRT1 knockdown also increased H4K16ac, its contribution was minimal in HGPS vascular smooth muscle cells (VSMCs) compared to HDAC2. Crucially, selective pharmacological inhibition of HDAC2, but not SIRT1, robustly restored H4K16ac levels in HGPS VSMCs. This restoration led to a significant rescue of premature aging phenotypes, including improvements in nuclear morphology, preservation of proliferative capacity (Ki67) at late passages, and a significant reduction in cellular senescence. The effects of HDAC2 inhibition on cellular senescence and nuclear morphology suggests that HDAC2-mediated histone deacetylation contributes directly to the pathological features of HGPS, extending the functional impact of HDAC2 inhibition beyond DNA repair defects to fundamental aspects of cellular aging.

This study investigated the relationship between plasma Interleukin-17A (IL-17A) and Interleukin-17F (IL-17F) levels and peripheral arterial disease (PAD), and explored the role of IL-17F in neovascularization in a preclinical PAD model of aged mice. Using an enzyme-linked immunosorbent assay, we found that plasma IL-17A levels were similar in young and aged groups in both PAD patients and mice with hindlimb ischemia. In contrast, IL-17F levels were elevated in the aged group. Spearman correlation analysis showed a positive correlation between IL-17F levels and PAD severity, onset risk, and cardiovascular outcome. Under simulated ischemic conditions, IL-17F induced endothelial cells (ECs) senescence and dysfunction in a dose-dependent manner. In aged male and female mice following left femoral artery ligation, results from Doppler imaging, ischemia and motor scores, and histology indicated that neutralization of IL-17F enhanced blood flow recovery, reduced ischemia scores, improved motor scores, and facilitated muscle regeneration and repair. Micro-CT, whole-mounting, and immunofluorescence staining results showed that neutralization of IL-17F promoted neovascularization and inhibited ischemic hindlimb muscle ECs' senescence and dysfunction. This study reveals for the first time that higher IL-17F levels were positively associated with PAD severity, onset risk, and cardiovascular outcome. Neutralization of IL-17F promoted postischemic neovascularization in aged mice, suggesting it represented a promising therapeutic strategy for elderly PAD patients.

This study applied multivariate ANOVA to investigate age-related microstructural changes in the brain tissues driven primarily by myelin, iron, and water content, as observed in MRI (semi-)quantitative R1, R2*, MTsat and PD maps. This is effectively a re-analysis of the data analyzed in a univariate way by Callaghan et al., 2014. Voxel-wise analyses were performed on gray matter (GM) and white matter (WM), in addition to region of interest (ROI) analyses. The multivariate approach identified brain regions showing coordinated alterations in multiple tissue properties and demonstrated bidirectional correlations between age and all examined modalities in various brain regions, including the caudate nucleus, putamen, insula, cerebellum, lingual gyri, hippocampus, and olfactory bulb. The multivariate model was more sensitive than univariate analyses, as evidenced by detecting a larger number of significant voxels within clusters in the supplementary motor area, frontal cortex, hippocampus, amygdala, occipital cortex, and cerebellum bilaterally. The examination of normalized, smoothed, and z-transformed maps within the ROIs revealed concurrent age-dependent alterations in myelin, iron, and water content. These findings contribute to our understanding of age-related brain differences and provide insights into the underlying mechanisms of aging. The study emphasizes the importance of multivariate analysis for detecting subtle microstructural changes associated with aging when dealing with multiple quantitative MRI parameter maps.

Males and females are known to have dramatically different health and lifespan trajectories, but the underlying basis for these differences is only now being fully investigated. In the Caenorhabditis elegans nematode model system, most aging studies have been conducted with hermaphrodites, and little is known about male-specific responses to pro-longevity mutations. Several previous studies have used the auxin-inducible degron system to degrade the insulin-like DAF-2/IGF-1 receptor in hermaphrodites, finding that both ubiquitous and tissue-specific degradation can extend lifespan. Here we show that ubiquitous degradation of DAF-2 in male C. elegans increases median lifespan by more than 440%, one of the longest lifespan extensions by a single intervention to date. Conversely, degrading DAF-2 in the male germline decreased lifespan, opposite of its effect in hermaphrodites. Using male mating and reproductive success as a meaningful ecological and neurophysiological measure of healthspan, we found that ubiquitous degradation of DAF-2 greatly prolongs reproductive health, likely by prolonging function of the male intromittent organ in the tail. This work highlights the importance of studying sex differences in aging and highlights the utility of using C. elegans males to understand the underlying basis of enhanced lifespan and healthspan.

The hippocampus, a brain region critical for memory, undergoes significant age-related changes at both the macroscopic and microstructural levels. This study investigates these changes using high-gradient diffusion MRI (dMRI) data analyzed in an unfolded hippocampal space. We applied the Soma and Neurite Density Imaging (SANDI) model to quantify microstructural alterations in 72 cognitively healthy participants aged 19-85 years, scanned on a 3 T Connectome MRI scanner with a maximum gradient strength of 300 mT/m. By combining SANDI with a super-resolution algorithm and the HippUnfold toolbox, we achieved high spatial fidelity in our analysis. We observed significant age-related reductions in soma fraction and soma radius, particularly in the subiculum and dentate gyrus, alongside increases in extracellular diffusivity and extracellular fraction, indicating a decline in cellular density and structural integrity. These microstructural changes occur alongside macroscopic alterations such as reduced hippocampal volume and cortical thickness, decreased gyrification, and increased curvature in specific subfields. The spatial correlations between microstructural and macroscopic metrics across the unfolded hippocampal space are weak, both in their mean values and in how they change with age. Our findings suggest that SANDI metrics provide sensitive and complementary information to traditional structural measures, offering new insights into the microstructural underpinnings of hippocampal aging. This study highlights the potential of advanced dMRI techniques to detect subtle age-related changes in hippocampal microstructure, which may contribute to our understanding of aging and its impact on memory and cognition.

Aging is associated with genome-wide changes in DNA methylation in humans, facilitating the development of epigenetic age prediction models. However, these models have been trained primarily on European-ancestry individuals and none account for the impact of methylation quantitative trait loci (meQTL). To address these gaps, we analyze the relationships between age, genotype, and CpG methylation in 3 understudied populations: central African Baka (n = 35), southern African ‡Khomani San (n = 52), and southern African Himba (n = 51). We show that published prediction methods yield higher mean errors in these cohorts compared to European-ancestry individuals and find that unaccounted-for DNA sequence variation may be a significant factor underlying this loss of accuracy. We leverage information about the associations between DNA genotype and CpG methylation to develop an age predictor that is minimally influenced by meQTL and show that this model remains accurate across a broad range of genetic backgrounds. Intriguingly, we also find that the older individuals and those with lower epigenetic age acceleration carry more genetic variants linked to reduced epigenetic age. These findings support the hypothesis that multiple heritable factors collectively influence healthspan and longevity in human populations.

Astrocytes are central to brain homeostasis, supporting neuronal metabolism, synaptic activity, and the blood-brain barrier. With aging, these glial cells undergo molecular and functional changes that weaken support functions and promote neuroinflammation, contributing to neurodegeneration. Yet the systems-level mechanisms of astrocytic aging remain poorly defined in human models. Because aging also heightens risk for cardiovascular disease, cognitive impairment, type 2 diabetes, and systemic inflammation, clarifying shared astrocytic pathways is critical for understanding brain-body crosstalk. Using an in vitro human astrocyte model exposed to sublethal oxidative stress (10 M H2O2), we profiled transcriptomic changes and identified differentially expressed genes across antioxidant defences, proteostasis, transcriptional regulation, vesicular trafficking, and inflammatory signalling. We then performed seven network-prioritization analyses on a curated human protein-protein interactome: one seeded with the astrocyte H2O&2-responsive genes and six with phenotype-associated gene sets (Alzheimer\'s disease, cardiovascular disease, cognitive impairment, type 2 diabetes, oxidative stress, and inflammation). Intersecting the top 5% scoring genes from each run yielded a 127-gene core shared across all seven, enriched for proteostasis, DNA repair, mitochondrial regulation, and telomere and nuclear envelope maintenance. Structure-guided analyses highlighted vulnerable interfaces, including lamin A/C-lamin B1, -actinin-filamins, 14-3-3 dimers, and aminoacyl-tRNA synthetase assemblies, where pathogenic variants are predicted to destabilize or aberrantly stabilize protein interactions. Structure-based interface predictions also highlight potential interactions between APP-VCP/p97 and p53-14-3-3{zeta} that link proteostasis and stress signalling. Together, these findings define a conserved astrocytic vulnerability network that may couple neurodegeneration with cardiovascular disease and nominate structurally testable targets for biomarkers and interventions.

Despite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWH) experience persistent inflammation, immune dysfunction, and premature onset of cardiovascular and aging related comorbidities. To define the underlying mechanisms, we performed longitudinal transcriptomic profiling in peripheral blood mononuclear cells (PBMCs) from a cohort of simian immunodeficiency virus (SIV) infected rhesus macaques spanning four key stages: preinfection, acute infection, short term ART, and long term ART. Bulk RNA sequencing revealed dynamic immune remodeling across infection and treatment. Acute SIV infection induced robust antiviral and inflammatory programs, with upregulation of interferon-stimulated genes (ISGs), IL-27, JAK/STAT, and NFkB signaling, coupled with suppression of T cell and B cell activation pathways. Short term ART effectively reversed these transcriptional perturbations, restoring adaptive immune gene expression and reducing innate antiviral responses to near baseline levels. In contrast, chronic SIV infection on long term ART maintained viral suppression but was characterized by reactivation of innate immune pathways, including TLR2/TLR4/MYD88, NFkB, and inflammasome (NLRP3 or NLRP12, caspase1) signaling, along with sustained macrophage activation, platelet/coagulation signaling, and senescence-associated secretory phenotype. Protein analyses confirmed persistent CASPASE1 and NFkB activation in spleen tissue. Pathologic evaluation of a carotid artery from an SIV infected, long term ART treated macaque revealed macrophages in plaques with p21 expressing; senescent cells with intraluminal thrombus formation, recapitulating key features of HIV associated atherogenesis. Together, these findings demonstrate that while ART normalizes acute infection induced immune dysregulation, chronic SIV infection sustains a chronic, macrophage and TLR driven inflammatory state linked to vascular injury and aging process regardless of long term suppression of viremia. Targeting inflammasome, NFkB, and senescence pathways may mitigate nonAIDS comorbidities in PLWH.

The skin is one of the earliest organs in the human body to exhibit signs of aging, with photoaging mainly caused by chronic ultraviolet (UV) exposure and recognized as a major form of extrinsic aging. Small extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hucMSC-sEVs) have been shown to delay skin aging by upregulating pregnancy zone protein (PZP), which modulates inflammatory responses, oxidative stress, and extracellular matrix remodeling. However, the core regulatory network underlying these effects remains unclear. Focusing on PZP, this study integrated bioinformatics to identify GATA2 as a potential upstream transcriptional regulator and GRP75 as a possible downstream target, indicating a GATA2/PZP/GRP75 signaling axis that may regulate photoaging. ChIP assays and dual-luciferase reporter analyses confirmed that GATA2 binds to the promoter region of PZP and upregulates its transcription. Knockdown and overexpression experiments further demonstrated that GATA2 suppresses or promotes PZP expression, thereby significantly influencing the senescence phenotype of dermal fibroblasts under UV irradiation. In addition, protein docking, co-immunoprecipitation (CoIP), and immunofluorescence colocalization assays validated the interaction between PZP and GRP75. PZP alleviates mitochondrial calcium overload and dysfunction by inhibiting the abnormal elevation of GRP75, thus delaying photoaging. These findings offer novel insights and targets for skin-aging intervention.

Aging disrupts physiological homeostasis, impairing thermoregulation, metabolism, and water balance, but the underlying neural mechanisms remain unclear. Here, we identify arginine vasopressin (AVP) neurons in the supraoptic nucleus (SON) of the hypothalamus as a critical driver of these changes. Using single-nucleus RNA-sequencing of the anterior hypothalamus in young and aged mice, we found Avp to be one of the most upregulated neuronal transcripts with age. Aged SON-AVP neurons displayed enlarged size and heightened excitability, features consistent with hyperactivity. Functionally, chemogenetic activation of SON-AVP neurons in young mice reproduced aging-associated phenotypes including hypothermia, reduced energy expenditure, and suppressed water intake. Conversely, knockdown of Avp in the SON of aged mice restored water balance, partially improved thermoregulation and systemic metabolism. Pharmacological inhibition of AVP receptors revealed that neuroendocrine release of AVP drives homeostatic deficits, with distinct roles for V1A and V2 receptors. Senolytic drug treatment improved systemic metabolism and reduced inflammaging but does not rescue hypothalamic AVP dysfunction, underscoring a brain autonomous mechanism of age-related physiological failure. Together, our findings establish SON-AVP neuronal hyperactivity as a driver of impaired homeostasis with age and suggest that targeted modulation of neuroendocrine AVP signaling may offer a therapeutic strategy to alleviate age-associated water balance defects.

The Asian Working Group for Sarcopenia (AWGS) presents an updated 2025 consensus reframing sarcopenia management through a life-course approach to muscle health promotion. While aligning with the Global Leadership Initiative in Sarcopenia (GLIS), this update provides healthcare providers with Asia-specific guidance. The consensus introduces three key refinements: first, expanding sarcopenia diagnosis to middle-aged adults (50‒64 years) with validated diagnostic thresholds; second, simplifying the diagnostic algorithm to require only concurrent low muscle mass and strength, with physical performance as an outcome measure; and third, introducing an enhanced muscle health framework recognizing skeletal muscle as vital for healthy longevity, emphasizing cross-talk with brain, bone, adipose tissue and immune systems. This framework leverages the World Health Organization's Integrated Care for Older People (ICOPE) implementation for enhanced case-finding through natural overlap between muscle health and ICOPE's intrinsic capacity domains. The consensus provides evidence-based recommendations for multimodal interventions that combine resistance exercise with nutritional supplementation, representing advancement toward proactive muscle health promotion and establishing a framework for reducing age-related decline in Asian populations.

Age-related protein aggregation drives senile osteoporosis. Aberrant tRNA modifications exacerbate the progression, yet mechanisms linking these to bone loss remain unclear. In this study, we identify Nsun2 (m5C methyltransferase) as key regulator: age-dependent Nsun2 downregulation in BMSCs reduces m5C levels of tRNAs, destabilizing tRNAs and impairing translation efficiency of specific transcripts. This directly disrupts the protein synthesis of molecular chaperone and pro-osteogenic factors, accelerating misfolded protein aggregates and activating unfolded protein response, inducing BMSCs senescence and impairing osteogenesis. Mice specifically depleted of Nsun2 exhibited reduced bone mass, whereas mice overexpressing Nsun2 alleviated age-associated bone loss. Notably, the exacerbated protein aggregation and bone mass loss in Nsun2-deficient mice were ameliorated following treatment with the molecular chaperone activator-ML346. Remarkably, ML346 administration proved sufficient to reverse age-related functional deficits in aged mice. Overall, our findings demonstrate that aberrant tRNA-m5C modification alters protein synthesis and induces proteostasis collapse, which constitute a novel contributor to the pathogenesis of senile osteoporosis. Additionally, reduction of protein aggregation through the activation of molecular chaperones presents a promising therapeutic strategy for this disease.

Yeast replicative lifespan is a crucial part of aging research, yet its quantification remains labor-intensive and time-consuming, particularly when using time-lapse imaging and microfluidics. Manual counting methods for cell division events are prone to bias and inefficiency, while existing automated approaches often require extensive annotated datasets. These limitations hinder the adaptability of such tools across different microfluidic setups. To address these challenges, we propose a versatile image analysis approach that accurately detects yeast cell division events. To reduce the burden of requiring a large cell division annotated dataset, we pretrained a Masked Auto-Encoder on large-scale segmented yeast cell images. This substantially reduced the annotated data needed to train the transformer model for detecting cellular division events. Additionally, the model is trained directly on budding event detection, circumventing reliance on arbitrary heuristics, such as changes in cell area. By leveraging self-supervised pretraining, we reduced the training data requirement to fewer than 50 mother cells (~1,000 divisions), representing a >5-fold reduction compared to prior methods while maintaining comparable accuracy.

Hematopoiesis changes over the lifetime to adapt to the physiology of development, maturation, and aging. Temporal changes in hematopoiesis parallel age-dependent incidences of certain blood diseases. Several heterochronic regulators of hematopoiesis have been identified, but how the master transcription factor (TF) circuitry of definitive hematopoietic stem cells (HSCs) adapts to changes in physiology over the lifespan is unknown. Here, we show that programmed upregulation of expression of the ETS family TF Erg during prenatal to adult maturation is evolutionarily conserved and required for implementation of adult patterns of HSC self-renewal and myeloid, erythroid, and lymphoid differentiation. Erg deficiency maintains fetal transcriptional and epigenetic programs in adulthood, and persistent juvenile phenotypes in Erg haploinsufficient mice are at least in part dependent on deregulation of the fetal-biased factor Hmga2. Overall, we identify a mechanism whereby master HSC TF networks are rewired to specify stage-specific hematopoiesis, a finding directly relevant to age-biased blood diseases.

The female longevity advantage (averaging 4 to 6 years globally) stems from reduced susceptibility to inflammaging, the chronic, low-grade inflammation driving age-related diseases like fibrosis and cardiovascular decline [10]. Interleukin 11 (IL-11), a gp130-family cytokine, has emerged as a pivotal inflammaging mediator: Its genetic or pharmacological inhibition extends mouse median lifespan by 22.5% in males and 25% in females, with enhanced healthspan benefits in the latter [20-29]. Here, we propose that estrogen\'s direct suppression of IL-11 transcription via estrogen receptor-alpha (ERalpha)-mediated interference with NF-kappa B/AP-1 on the IL-11 promoter in osteoblasts, fibroblasts, and endothelial cells establishes a premenopausal \"hormonal firewall\" against IL-11-driven senescence and multi-organ fibrosis [0-9]. In contrast, testosterone exhibits neutral or permissive effects, correlating with elevated IL-11 in hyperandrogenic states like polycystic ovary syndrome (PCOS) [30-40]. To test this, we developed an ordinary differential equation (ODE) model integrating IL-11 dynamics with upstream triggers (e.g., Ang II, c-Myc/miR-23 derepression) and suppressors (SIRT1 deacetylates IL-11 promoter histones; p53 represses IL-11/c-Myc; NRF2 quenches NF-kappa B) [10, 12]. In persistent inflammaging simulations (impaired degradation, k_deg=0.1), high estrogen (1.0 arbitrary units) reduced steady-state IL-11 by 63% (179.96 to 65.77 at t=20 days), cascading to 40-50% lower STAT3/NF-kappa B activation and triad cytokines (TNF-alpha/IL-6/IL-1beta). [11,13]. Synergy with high SIRT1/p53/NRF2 amplified suppression to [~]74% for IL-11 [16,17]. Post-menopausal estrogen decline erodes this buffer, but cumulative pre-menopausal protection persists, explaining sustained sex gaps post-65. [32,34]. This framework predicts estrogen replacement therapy (HRT) could mitigate inflammaging equitably, narrowing longevity disparities. [35]. Validation via sex-stratified IL-11 cohorts and HRT-fibrosis trials is warranted, positioning IL-11 as a sex-specific therapeutic nexus.

Understanding the genetic and epigenetic regulation of mitochondrial DNA (mtDNA) is essential for elucidating mechanisms of aging and disease. Long-read sequencing can span the entire mitochondrial genome and directly capture base-modification signals, yet analytical tools for such data remain limited. We developed Himito, a graph-based toolkit for analyzing mitochondrial genome using long reads. Himito filters reads originating from nuclear mitochondrial insertions (NUMTs), constructs a sequence graph to represent mtDNA diversity, assembles primary haplotypes, calls variants, and analyzes 5-methylcytosine (5mC) modifications within a unified framework. Benchmarking on high-quality reference datasets shows Himito achieves superior performance in assembly and variant calling compared with existing tools. Applied to the All of Us (AoU) v8 dataset, Himito identified pathogenic mtDNA variants, revealed population-scale haplogroup diversity, and uncovered age-related genetic and epigenetic patterns. These results demonstrate that long-read sequencing, combined with graph-based analysis, enables integrated characterization of mitochondrial genomic and epigenomic variation. Himito is available at https://github.com/broadinstitute/Himito.

Lipid-droplet (LD) accumulation emerges in microglia and neurons with age. Because neither cell type is specialized for lipid storage, LDs are linked to dysfunction. The upstream drivers of LD formation and their effects on neighboring cells remain unclear. Here, we identify a mitochondrial-iron axis that promotes LD formation in aging microglia via reactive oxygen species (ROS), which secondarily reshapes neuronal iron handling. LD-enriched microglia show reduced mitochondrial mass and increased labile iron, ROS, and lipid peroxidation. Chelating labile iron or scavenging ROS suppresses LD formation. Conditioned media from iron-stressed microglia alter neuronal iron homeostasis, indicating transcellular coupling. In primary neurons, iron overload increases LDs and activates coordinated iron, ROS, and lipogenesis programs, whereas antioxidant treatment attenuates iron-driven LD accumulation. Together, these findings position iron overload as an upstream regulator of ROS-dependent LD biogenesis in microglia and neurons and reveal a microglia

A mechanistic network of ovarian aging, highlighting mitochondrial dysfunction as a central hub interconnected with genetic, metabolic, and inflammatory pathways.

Metabolic diseases, including obesity, Type 2 diabetes (T2D), and metabolic syndrome, are increasingly prevalent worldwide, driven by sedentary lifestyles, aging populations, and complex genetic and environmental factors. Traditionally understood as disorders of glucose and lipid metabolism, a growing body of evidence now implicates cellular senescence as a central, age-related contributor to metabolic dysfunction. Senescent cells (SCs) accumulate in key metabolic tissues where they disrupt tissue function through the senescence-associated secretory phenotype (SASP), a pro-inflammatory and fibrogenic secretome. SASP factors exacerbate insulin resistance, chronic inflammation, and tissue remodeling, advancing the progression and complications of metabolic diseases. These insights have catalyzed the development of senotherapeutics, a class of interventions that includes senolytics (to eliminate SCs), senomorphics (to suppress SASP), and senosensitizers (to render resistant SCs more vulnerable to clearance). Although preclinical studies show promise, translation into clinical practice faces significant challenges, including identifying reliable biomarkers, understanding SC heterogeneity, and optimizing treatment timing and safety. As research advances, senotherapeutics may offer a transformative approach not only to managing metabolic diseases but also to mitigating associated comorbidities. The recognition that antidiabetic agents already in clinical use can modulate key features of senescence highlights a unique translational opportunity, suggesting that prevention of age-related metabolic disorders may be achievable with therapies already available in routine clinical practice. Medicine is poised to enter a new era in which targeting cellular senescence could fundamentally reshape the prevention and treatment of age-related metabolic disorders, offering the potential for improved healthspan and reduced disease burden across the lifespan.

Skin aging is a multifactorial biological process driven by the cumulative effects of oxidative stress, chronic low-grade inflammation, and progressive deterioration of barrier function. Among its pivotal regulatory nodes, the Vitamin D-Vitamin D receptor (VDR) signaling axis acts as an integrative hub that senses and coordinates photic, redox, and metabolic cues to regulate immune homeostasis and structural integrity, thereby shaping the skin's defensive and reparative capacity throughout aging. Disruption of this axis amplifies inflammaging, accelerates dermal and epidermal structural decline, and compromises cutaneous resilience against environmental insults. Phenotypic shifts in keratinocytes, melanocytes, Langerhans cells, and T lymphocytes during aging are tightly linked to VDR-governed transcriptional programs and pathway crosstalk. Mechanistically, Nrf2-mediated antioxidant networks, Wnt/β-catenin and NF-κB signal interplay, stabilization of E-cadherin/β-catenin complexes, lipid metabolic remodeling, and reprogramming of immune tolerance collectively constitute the molecular basis through which Vitamin D mitigates skin aging. This review systematically delineates the critical role of the VDR axis in the onset and progression of skin aging and proposes its repositioning as a programmable molecular node for intervention, aiming to modulate inflammaging and maintain barrier homeostasis to slow the structural and functional decline of aging skin.

Long duration spaceflight is associated with neurological symptoms in astronauts, yet the underlying molecular mechanisms remain unclear. Using human brain organoids cultured aboard the International Space Station, we analyzed three independent spaceflights to demonstrate that exposure to the space environment triggers Space Induced Neural Senescence (SINS), characterized by chromatin remodeling, mitochondrial dysfunction, and activation of viral-like transcriptional programs in the absence of infection. Multiomics analyses identified upregulation of endogenous LINE-1 (L1) retroelements, whose activity was markedly enhanced in organoids lacking MECP2, a known L1 repressor implicated in Rett syndrome. The resulting accumulation of cytoplasmic L1 DNA elicited an IL6 mediated inflammatory and neurotoxic response, which was reversed by reverse transcriptase inhibitors (RTi) such as lamivudine or stavudine. Parallel preclinical experiments in Mecp2-deficient mice confirmed that RTi treatment restored neuronal morphology, synaptogenesis, function, cognition, and survival. These findings reveal that the space environment reactivates dormant genomic retroelements, providing an unexpected mechanistic insight into astronaut neurobiology and identifying a potential therapeutic strategy for both space-induced and terrestrial neurological conditions. Our pioneering study demonstrates the value of space-enabling research in accelerating drug discovery and the treatment of diseases on Earth.

Female reproductive aging is accompanied by a sharp increase in egg aneuploidy rates. Premature loss of chromosome cohesion proteins and early separation of chromosomes are thought to cause high aneuploidy rates during maternal aging. However, because cohesion loss occurs gradually throughout a woman's reproductive lifespan, and because cytoskeletal defects alone can lead to chromosomal abnormalities, the main causes of the rapid rise in aneuploidy at older reproductive ages are still unclear. In this study, we created a versatile and tunable cohesion manipulation system that enables rapid, dose-dependent degradation of the meiotic cohesin REC8 in live mouse oocytes. By coupling this system with quantitative high-resolution live imaging, we directly observed cohesion protein behavior during meiosis and tested the longstanding threshold model of aneuploidy development. Our results show that premature sister chromatid separation sharply increases only when REC8 levels drop below a critical threshold, supporting the idea of a nonlinear, vulnerability-triggering cohesion limit. We also used our system to examine how other age-related issues, such as cytoskeletal disruption and partial centromere dysfunction, can exacerbate chromatid separation in the context of weakened cohesion. This work provides a tractable oocyte platform for modeling and dissecting the multifactorial mechanisms driving female reproductive age-related egg aneuploidy.

The corpus callosum (CC) is the major tract connecting the two hemispheres in placental mammals and diffusion-weighted (DWI) MRI has revealed the meso/macroscopic organization of human CC and its organization of connectivity with the cortex. Here, we applied longitudinal DWI probabilistic tractography to study the CC fibers of mice across the adult lifespan. Our results reveal that connections of eight cortical areas can be delineated within the CC. The mouse CC organization aligns with the human topographical organization with frontal areas occupying the genus and parieto-occipital the posterior splenium region. A further regional analysis of passage fields showed stable field sizes in many of the studied areas over time. In contrast, several areas of the mouse default mode network and motor cortical regions show a decline in size with advancing age. Our analysis also identifies sex differences in the CC with female mice showing a larger orbitofrontal commissural connection. In summary, we confirm a mammalian-like organization of the CC in mice. Furthermore, we confirm an aging-related decline in the integrity of mouse white matter that aligns with previous findings in humans, thus opening up the possibility for future developmental in vivo studies across the entire lifespan using a mouse model.

Non-lethal exposure to mitochondrial stress has been shown to have beneficial effects due to activation of signaling pathways, including the mitochondrial unfolded protein response (UPR

The renin-angiotensin-aldosterone system (RAAS) is a central regulator of cardiovascular, renal, and fluid homeostasis. Over the past century, our understanding of RAAS has evolved from a unidimensional circulatory hormone system to a complex network that includes local and intracellular signaling pathways. Aging profoundly impacts this system, influencing both systemic and tissue-specific RAAS activity. While levels of systemic RAAS components, such as plasma renin and aldosterone, decline with age, local RAAS components, particularly the proinflammatory angiotensin (Ang)II/AngII type 1 receptor (AT1R) axis, are upregulated in aging tissues, contributing to vasoconstriction, oxidative stress, inflammation, and fibrosis. Conversely, the protective arms of RAAS, the AngII/AT2R and Ang-(1-7)/Mas receptor pathways, are downregulated. Recent advances in geroscience have further illuminated how RAAS intersects with fundamental aging mechanisms, providing a mechanistic framework for understanding RAAS not only as a driver of age-related disease but also as a modifiable contributor to the aging process itself. In this Review, we summarize the evolution of RAAS biology, examine the molecular and functional consequences of aging on RAAS activity, and discuss the translational relevance of these findings. Finally, we explore emerging therapeutic strategies targeting RAAS components as potential interventions to promote healthy aging and reduce age-related disease burden, emphasizing a translational arc moving from bedside to bench and back, with the ultimate goal of improving patient outcomes.

Single-cell DNA sequencing offers a powerful means of studying somatic mosaicism but requires careful analysis to mitigate DNA amplification-related artifacts. We performed primary template-directed amplification (PTA) and sequencing of 102 nuclei from postmortem lung and colon tissues of a 74-year-old male. Single-cell mutation burdens and spectra were validated by duplex sequencing and revealed heterogeneity across organs and cells, including signatures of APOBEC activity and tobacco exposure. Cells from both tissues exhibited chromosomal aneuploidies, loss of chromosome Y, and chromosomal rearrangements including rearrangements of the T-cell receptor loci indicative of T-cells. Shared embryonic mutations between cells enabled reconstruction of cellular ancestries from the zygote, which were validated by bulk sequencing. Collectively, we demonstrate a comprehensive approach for single-cell genomics that yields an expansive view of diverse somatic mutation types from development through aging across diverse tissues--insights that are obscured in bulk sequencing and only partially captured by other single-cell methods.

The endoplasmic reticulum (ER) and mitochondria are known to affect myriad cellular mechanisms. More recently, dynamic association between them has been identified in different eukaryotes; these interactions vary in their composition and involvement in regulation of intracellular machineries. FAM134B or RETREG1, originally identified as an oncogene, regulates ER membrane shape and curvature. It is a key ER-phagy or reticulophagy receptor, which promotes autophagy of not only the ER but also simultaneous dual autophagy of ER and mitochondria. While it is known that FAM134B can potentiate contact with mitochondria, its direct involvement in affecting mitochondrial dynamics remains unexplored. Here we show that FAM134B can interact with the canonical fission-promoting protein, DRP1. Functional depletion of FAM134B leads to local Actin rearrangement and reduced DRP1 recruitment onto mitochondria, resulting in hyperfusion. A decrease in FAM134B levels is observed with aging in rat brains, cell and mouse models of Parkinson's disease and patient-derived samples. Our study establishes FAM134B as the ER partner that helps in maintaining mitochondrial morphology and dynamics.

Age-related functional decline has emerged as a major challenge to human health and societal development. Safe and effective anti-aging interventions, particularly those involving natural products, offer promising strategies to delay aging and promote healthy longevity. In this study, we used Caenorhabditis elegans (C. elegans) models to investigate the anti-aging effects and underlying mechanisms of Liu Jun Zi Decoction (LJZD), a traditional Chinese herbal formula. The results showed that LJZD extended lifespan and enhanced stress resistance and locomotion in C. elegans. Serum pharmacochemistry, network pharmacology, and molecular docking identified key bioactive compounds that target the IIS/mTOR and p16/p21 pathways. Furthermore, we found that LJZD promoted longevity by improving mitochondrial function via the IIS-mTOR axis. Notably, LJZD also conferred neuroprotection in Aβ-/tau-expressing models. These findings provide mechanistic insights into multi-target herbal interventions for aging and neurodegeneration.