Longevity Papers

Background: Telomere homeostasis is critical for normal cellular and organ function, and its dysregulation is implicated in aging and chronic diseases. Although telomere length (TL) is critical for normal telomere function, its functional status can also be altered by many other factors. The organization and protective status of telomere in failing human heart (FHH) remains incompletely understood. Methods: Using left ventricular tissues from patients with idiopathic dilated cardiomyopathy (IDC), ischemic heart disease (IHD), and non-failing heart (NFH), we performed a comprehensive analysis that included measurements of overall TL and 3\' overhang length in left ventricles and cardiomyocytes (CM), assessment of telomere-binding protein associations, and transcriptomic profiling through RNA sequencing. Results: Although TL varied among individuals, reduced median TL was observed only in IDC, while both IDC and IHD showed an increased frequency of very short telomeres, falling below the 5th percentile, in CMs. Strikingly, significant telomere 3\'-overhang attrition was detected in both disease groups and strongly correlated with elevated H2AX phosphorylated on serine 139 ({gamma}H2AX) in heart tissues, indicating DNA damage. This was accompanied by persistent activation of ataxia telangiectasia mutated (ATM) protein-mediated DNA damage responses and the formation of telomere dysfunction-induced foci (TIFs) in CMs from FHH. Concomitantly, the association of telomeres with the single-stranded telomere-binding protein, Protection of Telomeres 1 (POT1), and the double-stranded telomere-interacting protein, telomere repeat-binding factor 2 (TERF2), was markedly reduced, accompanied by an increase in association of {gamma}H2AX and ssDNA binding protein, RPA with telomeres in IDC and IHD relative to NFH, signifying telomere de-protection. Conclusions: CM telomere dysfunction, characterized by 3\' overhang attrition and de-protection, is a common feature in FHH, leading to persistent DNA damage response in telomeres. Better understanding of telomere biology throughout the progression of different heart diseases to heart failure will provide more effective prevention and treatment strategies.

Cellular senescence is the major hallmark and therapeutic target of aging and age-related diseases. The role of ALKBH5, one of the main m6A demethylases, in cellular senescence emerges however remains contentious. Herein, we show the reversible ALKBH5 aggregation in cytoplasm promotes cellular senescence. Mechanically, ALKBH5 aggregation causes cytosolic retention, resulting in the m6A dysregulation and m6A hypermethylation of Cdk2, which promotes Cdk2 RNA instability to drive senescence. In addition, m6A imbalance aggravates ALKBH5 cytosolic aggregation in a feedback loop. We further demonstrate that ALKBH5 nuclear translocation required the formation of ALKBH5 droplet phase via binding Nucleoporin p62 (Nup62), while the aggregation of ALKBH5 traps with Nup62 in the cytoplasm. Reduced Nup62 prevents ALKBH5 nuclear entry leading to cellular senescence. Importantly, administration of m6A labeled RNA efficiently reverses ALKBH5 cytosolic aggregates and restores its nuclear entry to alleviate cellular senescence. Forced nuclear entry by NLS-ALKBH5 can prevent senescence in vitro and in vivo. Taken together, these findings unravel a novel paradigm for m6A epigenetic regulation in cellular senescence and offer promising therapeutic targets and strategies for the intervention of aging and age-associated diseases.

Episodic memory, the ability to recall past events, is particularly vulnerable to ageing. A decline in episodic memory performance is generally considered part of ageing. However, the episodic memory performance of superagers -defined as individuals aged 80+ years old with episodic memory of people 30 years younger- is superior to that typical of their chronological age. The aim of this study was to determine whether the discrepancy between the superager's episodic memory and chronological age is also evident in their brain age. A BrainAGE (Brain Age Gap Estimation) approach, a multidimensional computational neuroanatomical method that uses structural neuroimaging data to estimate biological brain age, was applied. The study population comprised 64 superagers (mean age = 81.9 ± 1.9) and 55 age-matched typical older adults (82.4 ± 1.9). Cross-sectional analyses revealed a negative BrainAGE score for superagers (mean = -0.95 ± 2.36) indicating a deceleration of the ageing process. By contrast, typical older adults showed an average score close to zero (0.05 ± 3.03) consistent with their chronological age. The BrainAGE score of superagers was found to be lower relative to typical older adults, and the progression over a 5-year follow-up period was slower in superagers, in keeping with their youthful memory ability. Therefore, superagers have a younger brain than those of typical older adults, suggesting that their ageing mechanisms may involve resistance to age-related brain structural changes. However, despite a 30-year gap in episodic memory, their BrainAGE score differed by only one year, indicating that factors beyond brain structure contribute to the superager phenotype.

A new DNA methylation biomarker, Dunedin Pace of Aging Calculated from the Epigenome (DunedinPACE), is associated with healthy lifespan in several European ancestry cohorts. Few studies have examined the relation between dietary quality and DunedinPACE in African American and White adults with longitudinal assessments. To assess the relationship between diet quality and DunedinPACE, we used longitudinal data from African American and White 30-64 year old adults living above and below poverty. Participants' DunedinPACE scores and dietary assessments were calculated at two time points, approximately 5 years apart. Numbers of participants (n = 421; mean age 49 years) were balanced by race, sex, and poverty status. Diet quality was assessed using two different dietary indexes: Dietary Inflammatory Index (DII) and Healthy Eating Index-2010 (HEI). Linear mixed model regression examined the longitudinal association of DunedinPACE with DII and HEI adjusted by age, race, poverty status, BMI, and smoking status. Initial mean values of DII were 3.34 (SD = 2.16) and HEI was 40.67 (SD = 11.69), indicating a pro-inflammatory dietary pattern and low diet quality in this cohort. The initial mean DunedinPACE score was 1.07. We found that a higher DII score was associated with higher DunedinPACE score (β = 0.009; p < 0.001), higher HEI score was associated with lower DunedinPACE score (β =  - 0.001; p = 0.032), and that these relationships were consistent over time. Overall, lower dietary quality was associated with a faster pace of aging captured by DunedinPACE score. Our findings demonstrate the independent contribution of diet quality to healthy aging-related epigenetic mechanisms.

Transcriptome analysis has become increasingly utilized in aging research. However, the identification of the key molecular changes underlying aging processes and longevity-promoting regimens from transcriptome data remains challenging. Here, we present Transcriptomic CLassification via Adaptive learning of Signature States (T-CLASS), an online tool that identifies, from transcriptome data, gene sets of several hundred genes that provide an optimal representation of longevity and aging paradigms. We systematically evaluated the effectiveness of T-CLASS with diverse datasets, including longevity-promoting regimens in Caenorhabditis elegans, cellular senescence by different means in both cultured mouse primary cells and cultured human cells, and human sarcopenia. We found that T-CLASS exhibited robust and high classification performance across datasets compared to preexisting machine/deep learning-based gene selection tools. By focusing our further analysis on longevity-promoting regimens in C. elegans, we showed that T-CLASS successfully classified transcriptomic changes caused by ten lifespan-extending small molecules, among which we experimentally validated the effect of rifampicin and atracurium as a proof of principle. Overall, T-CLASS is an effective and practical tool for uncovering and classifying physiological changes caused by genetic and pharmacological interventions that affect aging.

Circadian clocks coordinate behaviour and physiology with daily cycles of light and nutrient availability, yet how metabolic signals tune brain timing remains unclear. Astrocytes integrate metabolic and hormonal cues and sustain cell-autonomous rhythms, implicating them as candidate links between energy state and central circadian control. Here we show that AMP-activated protein kinase (AMPK) in hypothalamic astrocytes exhibits intrinsic, calcium-dependent rhythmicity that persists under constant darkness and without feeding cues. This glial rhythm sustains time-of-day phosphorylation programmes in the hypothalamus and stabilises the clock protein PER2 via phosphorylation at a conserved serine residue, thereby linking metabolic state to period control beyond the canonical transcription-translation feedback loops. In the ventromedial hypothalamus, astrocytic AMPK-PER2 signalling is required for food-anticipatory activity, identifying a glial node within the food-entrainable timing system. Disrupting astrocytic AMPK rhythmicity alters circadian behaviour and energy homeostasis and shortens lifespan in a sex-dependent manner. These findings recast AMPK as a metabolically adaptive glial timekeeper that connects calcium signalling and phosphorylation rhythms to behaviour and metabolism. They also reveal a phosphorylation-based timing layer in central metabolic circuits, with implications for circadian-metabolic misalignment in contexts such as shift work and metabolic disorders.

Inflammaging is considered a driver of age-associated pathology across tissues. Similarly, intestinal permeability is a feature of ageing and underlies a range of inflammatory and age-related diseases. Increased intestinal permeability has been described as both a cause and a consequence of inflammation. Both intestinal permeability and inflammation are closely associated with microbial dysbiosis, epithelial dysplasia and mortality but dissecting the complex interplay between these phenotypes remains challenging. Here we genetically induce intestinal immune activation in Drosophila and stratify animals by their intestinal barrier status using the Smurf assay. We demonstrate that intestinal immune activation and barrier failure have distinct impacts on the microbiota. Further, intestinal immune activation drives intestinal barrier failure and mortality even in the absence of the microbiota. Importantly, immune-induced intestinal barrier failure takes time to develop and is closely associated with the onset of mortality. Our work adds to building evidence that the impact of intestinal permeability on the microbiota and on animal health needs to be considered independently of its relationship with inflammation.

Nowadays, aptamers have transitioned into valuable antibody alternatives. We present the first anti-glucosepane aptamer targeting a key glycation product linked to aging and diabetes. Glu3, with high specificity and affinity, enabled the first-ever direct, fluorescence-based histological staining of glucosepane in murine tissue, distinguishing diabetic samples from wild-type samples without secondary reagents.

Cardiovascular diseases (CVDs) are life-threatening conditions with multifactorial causes. As the most abundant cells in the vascular wall, vascular smooth muscle cells (VSMCs) play a crucial role in regulating vascular tone. Under physiological conditions, VSMCs predominantly demonstrate a contractile phenotype. However, this phenotype can be altered in response to microenvironmental stimuli, particularly during injury or pathological conditions. We performed a systematic literature review to examine the phenotypic switching of VSMCs from a contractile state to a dedifferentiated state, as well as the role of senescence in VSMC dysfunction. Special attention was given to the impact of microenvironmental stress on VSMCs transdifferentiation into multiple phenotypes, including macrophage-like cells, foam cells, and mesenchymal stem cells. Prolonged or excessive phenotypic switching of VSMCs leads to cellular senescence, characterized by decreased proliferative capacity, increased secretion of inflammatory factors (SASP), and a tendency toward calcification. Senescent VSMCs undergo transdifferentiation into multiple phenotypes, which promote arterial calcification and fibrosis, thereby exacerbating cardiovascular disease progression. Emerging evidence reveals that VSMC phenotypic switching and senescence share common molecular pathways, offering new opportunities for developing dual-target therapies against age-related cardiovascular diseases by simultaneously modulating cellular plasticity and aging processes.

Cognitive impairment and dementia in older adults represent significant global health challenges. Although the bidirectional relationship between physical function and brain health is well established, the mechanistic drivers of this link remain poorly understood. Muscle function and quality are central to physical function, and muscle's secretome is increasingly recognized for its systemic health effects-supporting the potential for muscle-to-brain crosstalk. This concept was explored at the 3rd International Research Symposium on Brain Health, jointly hosted by Vancouver Coastal Health and the University of British Columbia. We present the findings of this symposium, which reviewed the current state of the literature on muscle-to-brain crosstalk from multiple perspectives, spanning population studies to preclinical models. A key focus was the muscle secretome, particularly myokines and extracellular vesicles, as potential messengers influencing brain health. The symposium also identified critical takeaways and proposed next steps to further elucidate the underlying mechanisms of muscle-to-brain crosstalk and explore how these pathways might be harnessed through exercise or pharmacologic interventions to promote brain health in older adults.

Vascular aging is considered now to be the first factor of multiorgan aging in what is called "the vascular theory of aging". Clinical understanding of vascular aging has long been limited to arterial hypertension and arterial stiffness. The effects of age on arterial mechanical properties have always been difficult to interpret for reasons linked to the non-linear behaviour of the stiffness/pressure function and the complex interactions between vascular cells and the matrix. Even new methodologies for decoding aging at the single-cell level are equally difficult to interpret. This objectives of this review are: (i) to introduce new computational approaches in biomechanics and mechanobiology; (ii) to revisit the role of oxidative stress and cellular senescence; (iii) to summarize some of the main molecular, cellular and mechanistic contributions to vascular aging; (iv) to present the latest human studies of accelerated arterial aging with particular reference to cognitive impairment and functional decline; (v) to propose some future directions for research related to vascular aging.

The immune system comprises multiple cell lineages and subsets maintained in tissues throughout the lifespan, with unknown effects of tissue and age on immune cell function. Here we comprehensively profiled RNA and surface protein expression of over 1.25 million immune cells from blood and lymphoid and mucosal tissues from 24 organ donors aged 20-75 years. We annotated major lineages (T cells, B cells, innate lymphoid cells and myeloid cells) and corresponding subsets using a multimodal classifier and probabilistic modeling for comparison across tissue sites and age. We identified dominant site-specific effects on immune cell composition and function across lineages; age-associated effects were manifested by site and lineage for macrophages in mucosal sites, B cells in lymphoid organs, and circulating T cells and natural killer cells across blood and tissues. Our results reveal tissue-specific signatures of immune homeostasis throughout the body, from which to define immune pathologies across the human lifespan.

Aging is characterized by a decreased autophagic activity contributing to the intracellular deposition of damaged organelles and macromolecules. Autophagy is particularly challenging in neurons since autophagic vesicles are formed at the axonal tip and must be transported to the soma where final degradation occurs. Here, we examined if axonal transport of autophagic vesicles is altered during aging. We employed two-photon microscopy for in vivo imaging in the optic nerve of young and aged rats. In old animals (> 18 months old), retrograde autophagic vesicle transport was significantly reduced with regard to motility and velocity. While activation of autophagy was decreased, expression of key proteins of the autophagy-lysosomal pathway including p62 and procathepsin D and the number of autophagolysosomes was increased. Maturation of autophagic vesicles was shifted to more distal regions of the axon and axonal lysosomal clearing was impaired. In a pull-down assay, the protein binding between dynein and dynactin was decreased by half, which could explain the retrograde axonal transport effects. Taken together, retrograde axonal autophagic vesicle transport in vivo is diminished during aging accompanied by decreased autophagy activation, alterations of the lysosomal pathway, and a reduced dynein-dynactin binding.

Mild distress of mitochondria extends animal lifespan, yet the underlying mechanisms are not completely understood. Here we screened mitochondrial proteins for effects on longevity and found that flies mutant in Uncoupling protein 4a (Ucp4a), which encodes a mitochondrial aspartate transporter, have extended lifespans. Tissue-specific experiments revealed knockdown of Ucp4a in muscles, but not neurons, fat, or intestine, to extend lifespan and also eliminate polyubiquitinated protein aggregates, which accumulate with aging and are associated with lifespan. These findings suggest a retrograde mitochondrial signaling process initiated by reduced cytosol aspartate level culminates in muscle protein aggregate removal and lifespan extension.

Aging involves processes spanning orders of magnitude in time, from fast events that occur at the molecular scale to the slow decrease of physiological function. Whether and how fast molecular events lead to the slow progression of aging, and what ultimately sets the timescale of aging, is not understood. Here, by focusing on dynamic changes in DNA methylation, we show how aging phenomena on long timescales emerge from the kinetics of fast molecular processes, providing a bridge between temporal scales. By combining DNA methylation sequencing data across a range of timescales with a statistical modeling-based approach, we show that DNA methylation aging is governed by a three-fold hierarchy of processes that dominate on distinct timescales: individual stochastic events in which enzymes interact with the DNA and with each other (milliseconds); the convergence of molecular concentrations to steady states (days to months); and stochastic transitions between these steady states (years to decades). Our findings provide a unified picture of how DNA methylation aging arises across temporal scales.

The focal adhesion (FA) is the structural basis of the cell-extracellular matrix crosstalk and plays important roles in control of organ formation and function. Here we show that expression of FA protein vinculin is dramatically reduced in osteocytes in patients with aging-related osteoporosis. Vinculin loss severely impaired osteocyte adhesion and dendrite formation. Deleting vinculin using the mouse 10-kb Dmp1-Cre transgenic mice causes dramatic bone loss in the weight-bearing long bones and spine, but not in the skull, in both young and aged mice by impairing osteoblast formation and function without markedly affecting bone resorption. Vinculin loss impairs the anabolic response of skeleton to mechanical loading in mice. Vinculin knockdown increases, while vinculin overexpression decreases, sclerostin expression in osteocytes without impacting expression of Mef2c, a major transcriptional regulator of the Sost gene, which encodes sclerostin. Vinculin interacts with Mef2c and retains the latter in the cytoplasm. Thus, vinculin loss enhances Mef2c nuclear translocation and binding to the Sost enhancer ECR5 to promote sclerostin expression in osteocytes and reduces bone formation. Consistent with this notion, deleting Sost expression in osteocytes reverses the osteopenic phenotypes caused by vinculin loss in mice. Finally, we find that estrogen is a novel regulator of vinculin expression in osteocytes and that vinculin-deficient mice are resistant to ovariectomy-induced bone loss. Thus, we demonstrate a novel mechanism through which vinculin inhibits the Mef2c-driven sclerostin expression in osteocytes to promote bone formation.

Cytoskeleton-Associated Protein 4 (CKAP4) is a multifunctional protein implicated in diverse cellular processes, including cytoskeletal organization, signal transduction, and extracellular matrix remodeling. Recent studies have highlighted the dual role of CKAP4 in regulating cell growth and aging. On one hand, CKAP4 can promote cell proliferation and survival by activating signaling pathways such as PI3K/Akt, thereby delaying cellular senescence under physiological conditions. On the other hand, under chronic stress or pathological stimuli, CKAP4 may induce cell cycle arrest and accelerate aging by interacting with ligands such as antiproliferative factor (APF) and Dickkopf-1 (DKK1), leading to the upregulation of cell cycle inhibitors and the suppression of autophagy. Moreover, CKAP4 has emerged as a key mediator linking extracellular matrix remodeling to inflammatory responses, which are closely associated with age-related diseases. This review comprehensively summarizes the current understanding of CKAP4's molecular mechanisms in cell longevity and aging, discusses its involvement in inflammation and tissue homeostasis, and explores its potential as a therapeutic target for aging-related disorders.

Aging is a major risk factor in amyotrophic lateral sclerosis (ALS) and other adult-onset neurodegenerative disorders. Whereas young neurons are capable of buffering disease-causing stresses, mature neurons lose this ability and degenerate over time. We hypothesized that the resilience of young motor neurons could be restored by reexpression of the embryonic motor neuron selector transcription factors ISL1 and LHX3. We found that viral reexpression of ISL1 and LHX3 selectively in postnatal motor neurons reactivates aspects of their youthful gene expression program and alleviates key disease-relevant phenotypes in the SOD1

Aging is increasingly recognized as a systemic process, yet the mechanisms by which senescent cells signal from peripheral tissues accelerate brain aging remain poorly defined. Here, we used chronic exposure of human cerebral organoids to the secretome of senescent osteocytes to investigate how peripheral aging signals reshape brain tissue architecture. We combined spatially resolved optical fiber-based interferometry nanoindentation with transcriptomic and immunofluorescence profiling, demonstrating that bone-derived senescence-associated secretory phenotype (SASP) factors induce a biphasic mechanical response, early global tissue softening, followed by the emergence of discrete hyper-stiff microdomains. This spatially heterogeneous biomechanical remodeling was accompanied by upregulation of extracellular matrix (ECM), inflammatory, and senescence pathways, and suppression of neurodevelopmental and synaptic gene networks. Our results reveal that chronic paracrine SASP exposure from senescent osteocytes drives localized ECM reorganization and mechanical vulnerability in human brain tissue, providing mechanistic insight into how peripheral cellular senescence may contribute to regional brain fragility during aging.

Resting and maximal exercise respiratory rates (V̇O

Mass spectrometry (MS)-based metabolomics is a key technology for the interrogation of exogenous and endogenous small molecule mediators that influence human health and disease. To date, however, low throughput of MS systems have largely precluded large-scale metabolomics studies of human populations, limiting power to discover physiological roles of metabolites. Here, we introduce a fully automated rapid liquid chromatography-mass spectrometry (rLC-MS) system coupled to an AI-enabled computational pipeline that enables high-throughput, reproducible, non-targeted metabolite measurements across tens of thousands of samples. This system captures thousands of polar, amphipathic and nonpolar (lipid) metabolites in a human plasma sample in 53 seconds of analytical time, enabling analysis of greater than 1,000 samples per day per instrument. To demonstrate the discovery power of the rLC-MS platform, a subset of samples from Sapient\'s DynamiQ biorepository -- comprised of 62,039 total plasma samples collected longitudinally from 11,045 individuals -- were selected for deep analysis by rLC-MS to capture a rich, dynamic landscape of chemical variation that reflects both physiological processes and environmental influences. 26,042 plasma samples with matched real-world data (RWD) were chosen for the study, representing 6,935 individuals with diverse demographic backgrounds and disease profiles. Unbiased exploratory analysis revealed human metabotypes that correlate with heterogenous disease phenotypes, including key sub-populations of cardiometabolic and other human diseases. Moreover, a metabolic aging clock machine learning model trained on healthy individuals in this dataset accurately predicted accelerated aging in various chronic diseases, with dynamic reversal of metabolic aging following definitive therapy. These data demonstrate that the rLC-MS platform enables prediction of clinically relevant physiological states from plasma metabolomics at scale in human populations.

Aging significantly influences host immune responses to viral infections, including Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV), which is associated with high mortality in elderly patients. Despite its high fatality rate and pandemic potential, effective therapies remain unavailable, and the age-dependent mechanisms underlying SFTSV pathogenesis are not fully understood. To address this gap, we employed a ferret model (an immunocompetent animal model that mimics human SFTSV infections) and performed multi-tissue single-cell RNA sequencing and histopathological analyses. Our results reveal that, upon SFTSV infection, aged ferrets experience extensive decrease of critical immune cells (particularly B and T cells) due to infection-induced cell death and excessive hemophagocytosis in hematopoietic organs, whereas young-adult ferrets rapidly clear the virus with minimal lymphocyte changes. Notably, aged ferrets display marked immune dysregulation, characterized by non-specific activation of T-bet ⁺ age-associated memory B cells (T-bet+ ABCs) and the proliferation of defective plasmablasts (MKI67 ⁺ PB1), which serve as major viral reservoirs and drive systemic viral dissemination. Comparative analysis further demonstrated that the MKI67 ⁺ PB1 subset dominates SFTSV⁺ cells in both aged ferrets and human fatal cases, exhibiting the highest per-cell viral UMI counts. Moreover, monocytes and macrophages in aged ferrets exhibit heightened inflammatory gene expression, contributing to the hyper-inflammatory state observed during infection. Collectively, these insights underscore the critical role of dysregulated memory B cell responses and hyper-inflammation in age-dependent SFTSV pathogenesis, highlighting potential targets for interventions in elderly populations.

Aging causes significant changes in gene expression and metabolic function of cells in various organs. Although it is known that liver regeneration is delayed by aging, the effects of aging on changes in gene expression and metabolic functions in liver regeneration need further investigation. In this study, we comprehensively analyzed changes in gene expression and metabolic function by liver regeneration in young and old mice to examine the effects of aging on these changes. During the process of liver regeneration, the gene expression profiles of hepatocytes from young and old mice changed significantly in a stepwise manner while each remained close together. After the completion of liver regeneration, the genes with aging-specific expression patterns in old mouse hepatocytes changed to expression levels close to those in young mouse hepatocytes. In contrast to the results of these transcriptome analyses, the aging-specific changes in metabolic state detected in old mouse livers were found to be largely maintained after the completion of liver regeneration. These results demonstrated that the gene expression state in the liver of old mice is flexibly altered by liver regeneration, whereas their metabolic state is robust. This finding helps to elucidate the relationship between aging and liver regeneration and to determine the basis of the increased incidence of liver disease with aging.

Aging is increasingly understood as a multifactorial process involving mitochondrial dysfunction, epigenetic drift, and chronic inflammation. While many age-related pathologies have been linked to impaired mitophagy and transcriptional deregulation, the upstream mechanisms driving these phenomena remain elusive. Here, a unifying hypothesis is proposed: that the progressive reactivation of human endogenous retroviruses (HERVs), combined with latent viral infections acquired during life, imposes an escalating burden on the epigenetic regulatory system. This "virome pressure" demands continuous silencing via DNA methylation, histone deacetylation, and NAD⁺-dependent pathways. With age, these silencing mechanisms deteriorate, leading to HERV reactivation, disruption of key mitochondrial quality control genes, and activation of innate immune responses. This is likened to a molecular peat bog, a simmering threat buried beneath the surface, where silencing mechanisms struggle to contain viral elements until pressure builds and erupts as the organism ages. This model integrates virology, epigenetics, and mitochondrial biology to offer novel insights into the aging process and suggests new targets for therapeutic intervention research.

Skeletal muscle stem cells (MuSCs) have strong regenerative abilities, but as we age, their ability to regenerate decreases, leading to a decline in muscle function. Although the methylation reprogramming of super-enhancers (SEs) plays a pivotal role in regulating gene expression associated with the aging process, our understanding of the molecular diversity of stem cells during aging remains limited. This study aimed to identify the methylation profile of SEs in MuSCs and explore potential therapeutic molecular targets associated with aging.

Persistent genomic instability compromises cellular viability while also triggers non-cell-autonomous responses that drive dysfunction across tissues, contributing to aging. Recent evidence suggests that DNA damage activates secretory programs, including the release of inflammatory cytokines, damage-associated molecular patterns, and extracellular vesicles, that reshape immune homeostasis, stem cell function, and metabolic balance. Although these responses may initially support tissue integrity and organismal survival, their chronic activation has been associated with tissue degenerative changes and systemic decline. Here, we discuss how nuclear DNA damage responses trigger the activation of cytoplasmic sensing pathways, promote secretory phenotypes, and affect organismal physiology. Targeting DNA damage-driven mechanisms may help buffer harmful systemic responses while preserving regeneration and immune surveillance, offering new ways to delay aging-related decline.

Aging is associated with a chronic, low-grade inflammatory state referred to as inflammaging, which contributes to impaired immune regulation and increased susceptibility to disease. While regulatory T (Treg) cells are key mediators of immune homeostasis, their role in the context of age-related inflammation remains poorly understood. Here we demonstrate that age-related changes in the microbiota promote impaired Treg cell function, resulting in the differentiation of inflammatory T cells. In agreement, we find that aged germ-free (GF) mice exhibited a more balanced immune profile, where the Treg cells are functional and pro-inflammatory mediators are reduced, suggesting that microbial exposure is essential for the establishment of inflammaging. Furthermore, we show that the use of old microbiota in young animals was sufficient to induce pro-inflammatory T cell responses and impaired mucosal Treg cell proliferation, while young microbiota restored Treg cell function in old animals. Mechanistically, we show that exposure to aged microbiota was associated with sustained TNF signaling, elevated oxidative stress, DNA damage, and increased expression of senescence markers such as {gamma}H2AX and p16 in Treg cells. These findings uncover a microbiota-TNF- dependent mechanism by which age-associated microbial dysbiosis drives Treg cell dysfunction and promotes immune aging, highlighting the therapeutic potential of microbiota-targeted strategies to restore immune homeostasis in the elderly.

Evidence connecting skin aging to functional decline and systemic aging biomarkers is lacking. This study investigated how skin-aging biomechanics were associated with changes in intrinsic capacity (IC), a marker of healthy aging. We also explored their links with biological aging clocks (epigenetic and inflammatory clocks) and potential moderating effects on the skin-IC relationship. Baseline skin elasticity and viscoelasticity were measured in 441 INSPIRE-T participants aged 20 to 93 (59.9% women) using Cutometer parameters. IC was evaluated over 3 years as a five-domain score covering cognition, locomotion, psychology, vitality, and sensory (a higher score indicated better). Biological aging was measured at baseline using six epigenetic clocks (Horvath pan-tissue, Horvath skin & blood, Hannum, PhenoAge, GrimAge, and DunedinPACE) and inflammatory clock (iAge). Poor skin elasticity and viscoelasticity in older adults were associated with lower baseline IC after controlling for demographic, medical, and lifestyle factors. Longitudinally, older men with a higher viscoelastic ratio (R6) experienced a faster decline in IC (a standardized coefficient [95% CI] ranged from -0.37 [-0.72, -0.03] at age 62 to -1.32 [-1.91, -0.73] at age 93). Accelerated iAge was associated with reduced skin elasticity (R2, R5, R7). Moreover, the association between parameters related to elastic recovery (R5, R7) and baseline IC became more pronounced as accelerated iAge increased. This is the first study demonstrating the association between skin-aging biomechanics and IC. Poor skin elasticity was associated with higher systemic inflammation. Therefore, skin biomechanical properties may reflect overall functional aging, with inflammation serving as a common underlying factor.

The transcriptional complex Mondo/Max-like, MML-1/MXL-2, acts as a convergent transcriptional regulatory output of multiple longevity pathways in

Optimal sleep plays a vital role in promoting healthy aging and enhancing longevity. This study proposes a Sleep Chart to assess the relationship between sleep duration and 23 biological aging clocks across 17 organ systems or tissues and 3 omics data types (imaging, proteomics, and metabolomics). First, a systemic, U-shaped pattern shows that both short (<6 hours) and long (>8 hours) sleep duration are linked to elevated biological age gaps (BAGs) across 9 brain and body systems and 3 omics types, with optimal sleep time varying by organ and sex ([6.4-7.8] hours). Furthermore, short and long sleep duration, compared to a normal sleep duration ([6-8] hours), are consistently linked to increased risk of systemic diseases beyond the brain and all-cause mortality, with evidence from genetic correlations and time to incident disease predictions, such as migraine, depression, and diabetes. Finally, short and long sleep duration are associated with late-life depression via distinct pathways: long sleep may contribute indirectly through biological aging processes, while short sleep shows a more direct link. Although our Mendelian randomization does not show strong causal effects from disease to sleep disturbances, it does not fully rule out the possibility that sleep disturbances may, in part, reflect underlying disease burden. Our findings suggest that the U-shaped relationship is likely driven by modifiable sleep disturbances rather than genetic predisposition, highlighting the potential of sleep optimization to support healthy aging, lower disease risk, and extend longevity. An interactive web portal is available to explore the Sleep Chart at: https://labs-laboratory.com/sleepchart.