Longevity Papers

Tissue-resident alveolar macrophages (AMs) rely on intrinsic stem-like programs for self-renewal and maintenance, yet the transcriptional networks that support these functions and their relevance to post-viral lung disease remain largely unknown. Here, we identify TCF4 (Tcf7l2) as a critical transcription factor that governs AM maturation and stemness. Loss of TCF4 impaired AM proliferation, shifted their identity toward a pro-inflammatory phenotype, and exacerbated host morbidity following influenza or SARS-CoV-2 infection. Conversely, enforced TCF4 expression promoted the expansion of mature AMs, and supported lung recovery, thereby protecting against severe acute viral disease. Mechanistically, TCF4 antagonized {beta}-catenin-driven inflammatory transcription while preserving oxidative phosphorylation, defining a reciprocal regulatory axis essential for AM function. Notably, respiratory viral infections and exuberant interferon signaling suppressed TCF4 expression, which remains chronically reduced in murine and human lungs with post-COVID fibrosis. This downregulation is associated with persistent KRT8hi dysplastic epithelium and collagen deposition. Moreover, aging diminished TCF4 levels and enforced TCF4 expression dampened age-associated decline of AM self-renewal. Furthermore, in vivo TCF4 overexpression after viral clearance enhanced mature AM accumulation, promoted lung epithelium regeneration, attenuated chronic tissue fibrosis and restored pulmonary physiologial function in aged lungs in a model of persistent pulmonary fibrosis post-acute viral infection. These findings have established TCF4 as a key regulator of AM stemness and identified a promising therapeutic target for long COVID and related chronic lung diseases through the modulation of embryonic-derived macrophage regenerative capacity by targeting TCF4.

Systemic chronic inflammation is a major determinant of aging and disease risk, yet current biomarkers such as the Inflammatory Age (iAge) clock and other proteomic assays remain costly, invasive, and poorly scalable. The skin, as both a visible marker and contributor to age-related inflammation (inflammaging), offers a potential non-invasive window into this health metric. Here, we developed Healthy Selfie, a digital predictor of iAge, from simple 2D frontal face photographs. We leveraged data from the Edifice Health Pre-Market trial, a clinical study of 750 participants aged 20 to 90 years, using a subset with available iAge measurements paired to facial images, demographic, clinical, and functional data. Facial embeddings from a pre-trained deep learning image model were combined with chronological age, sex and other easily obtainable metadata, and mapped to blood-derived iAge using regression within a leave-one-out cross-validation framework. Photo-predicted iAge values were significantly correlated with blood iAge values (r = 0.536) and were used to identify increased iAge acceleration (accuracy 66.39%, sensitivity 65.61%, specificity 67.24%). Validation on an external dataset containing ~100,000 images showed no significant demographic bias across ethnicities, including Asian, Black, Indian, Middle Eastern, and Latino populations. Beyond iAge, we also showed that facial features could predict blood levels of individual inflammaging proteins (CXCL9, CXCL1, CCL11, TNFSF10, and IFNG). Our findings suggest that ordinary facial photos can provide information on blood inflammation and can be used as a scalable, ultra low-cost tool for assessing biological aging and advancing precision health.

The consequences of harmful prenatal exposures for brain health may last a lifetime. Previous studies showed smaller adult brain volumes and altered perfusion at age 68 after prenatal famine exposure, particularly in men. To investigate whether the previously observed effects reflect persistent developmental effects or accelerated brain aging, we here studied longitudinal changes in brain volumes, white matter integrity, white matter hyperintensities and perfusion between ages 68 and 74 in individuals exposed and unexposed to famine in early gestation.

Aging, a universal biological process in complex organisms, is increasingly recognized to be driven by progressive loss of epigenetic information, as proposed in the Information Theory of Aging (ITOA). However, research on anti-aging peptides remains scarce, with most existing efforts confined to derivatives of natural proteins, while systematic design attempts are virtually absent. This limitation not only restricts discovery within the evolutionary sequence space but also hampers the identification of candidates with novel mechanisms and improved efficacy. Here, we present ElixirSeeker2, the first computational framework for de novo design of anti-aging peptides. By integrating modeling of known anti-aging peptides, activity scoring from the IC50 database, and penalty constraints from toxic peptides, ElixirSeeker2 enables large-scale virtual screening and identification of novel peptide candidates. Several lead peptides demonstrated significant effects in delaying cellular senescence, restoring cellular functions in vitro and in enhancing locomotor activity of aged Caenorhabditis elegans. This study not only validates the feasibility of de novo design in anti-aging interventions but also establishes a strategy for the development of next-generation biologics.

Mitochondrial dysfunction is a central driver of cellular senescence, a core hallmark of aging. While intrinsic mechanisms have been extensively reviewed, this article offers a novel paradigm by emphasizing the critical role of interorganellar communication in mitochondria-mediated senescence. We present a systematic dissection of the molecular mechanisms underlying functional crosstalk between mitochondria and key organelles, including the endoplasmic reticulum (ER), lysosomes, and peroxisomes. A particular focus is placed on established regulatory hubs such as mitochondria-associated ER membranes (MAMs), which orchestrate calcium signaling, lipid metabolism, and inflammatory responses. We further explore emerging pathways involving lysosomal mitochondrial coordination in nutrient sensing and mitophagy, and peroxisomal mitochondrial cooperation in redox balance and lipid homeostasis. By elucidating how defects in these dynamic networks propagate mitochondrial damage and execute senescence, this review establishes a unified framework for aging as integrated organelle network dysfunction. This synthesis advances fundamental aging biology and identifies novel molecular targets, providing a foundation for developing therapeutic strategies targeting organelle networks against age related pathologies.

Cells use information about their environments and internal states to decide whether to proliferate, differentiate, or enter non-proliferative states such as quiescence and senescence. But how do they integrate this information to make unambiguous decisions? Here, we describe how the interaction between two independent condensates, P-bodies and Whi3-dependent condensates, enables individual yeast cells to integrate information about their biological age and the presence of potential mates during fate decisions. Both formation and interaction of these condensates were necessary and sufficient to drive old cells into senescence and store age information in the yeast mother cell at mitosis. This same network also primed old cells to choose proliferation over mating when exposed to mating pheromone, demonstrating that it injects contextual information into multiple decisions. Thus, biomolecular condensates and their interactions can collect and integrate contextual information to adjust cellular decisions to overlapping life events.

Although they exhibit limited regenerative ability of some tissues and organs shortly after birth or towards the end of fetal development, humans and laboratory mammals quickly transition to producing scar tissue for tissue repair. In contrast, spiny mice exhibit complex tissue regeneration as adults and provide a blueprint for how regeneration can occur throughout adulthood in mammals. Fibroblasts are key mediators of wound healing outcomes and prior work uncovered that cells from highly regenerative mammals (spiny mice and rabbits) exhibit extreme resistance to oxidative stress compared to those from non-regenerating laboratory mice and rats. Using a battery of cellular tests in primary ear pinna fibroblasts from highly regenerative and non-regenerative mammals, we find that cells from spiny mice and rabbits exhibit a baseline preference for glycolysis supporting a lower ROS-producing basal state. Uniquely, spiny mouse fibroblasts exhibit large, spherical, depolarized mitochondria similar to megamitochondria identified in pathological tissues. The megamitochondria phenotype was present across lifespan in ear pinna fibroblasts from fetal, young and old spiny mice. While rabbit, mouse and rat fibroblasts had polarized tubular mitochondrial networks typical of adult mammalian fibroblasts, isolated rabbit and spiny mice fibroblasts shared lower oxygen consumption efficiency even in the absence of a potential gradient. Taken together, our results support that a shared metabolic signature exists in stromal cells from highly regenerative mammals, although possibly driven by different mechanisms, to converge on a ROS-resistant phenotype which ultimately helps supports tissue regeneration.

Peto's paradox, which describes the absence of a strong correlation between cancer risk, body size, and lifespan among species, raises intriguing questions about natural cancer resistance mechanisms. Elephants have evolved unique adaptations that reduce cancer susceptibility despite their large body size and long lifespan. Central to this phenomenon is p53, a key tumor suppressor regulated by MDM2. Our research investigates the structural and functional differences between elephantine MDM2 and its human counterpart. Utilizing human cellular models, we demonstrate that elephantine MDM2 variants enhance p53's activity, leading to increased p53 occupancy on its response elements, and modulate p53-mediated transcription in a stress-dependent manner. These findings shed light on the molecular basis of cancer resistance in elephants and provide a foundation for developing innovative cancer therapies targeting MDM2-p53 interactions.

Sarcopenia, the progressive loss of skeletal muscle mass and function with aging, is a growing public health concern. Conventional treatments such as exercise, pharmacological agents, and nutritional support offer limited efficacy, especially in older populations with reduced mobility or comorbidities. This study aimed to evaluate low-intensity pulsed ultrasound (LIPUS) as a novel, non-invasive therapeutic approach for age-related muscle atrophy. LIPUS was applied to the right hindlimbs of young (12-week), middle-aged (60-week), and aged (95-week) mice for 8 weeks. Muscle weights and mRNA expression levels were analyzed. In aged mice, LIPUS significantly increased gastrocnemius muscle mass and upregulated Fndc5 and Opa1 mRNA, genes associated with mitochondrial function and muscle regeneration. These findings suggest that LIPUS may serve as a safe, non-invasive intervention to counteract sarcopenia by promoting muscle growth and mitochondrial gene activation in aged skeletal muscle.

Resting-state functional MRI (fMRI) signals capture physiological processes, including systemic low-frequency oscillations (LFOs), respiration, and cardiac pulsation. These physiological oscillations-often treated as noise in functional connectivity analysis-reflect fundamental aspects of brain physiology and have recently been recognized as key drivers of brain waste clearance. However, these critical physiological signals are obscured in fMRI data due to slow sampling rates (typical repetition time (TR) > 0.8 s), which cause cardiac signal to alias into lower frequencies. To resolve physiological signals in fMRI datasets, we leveraged fast cross-slice sampling within each TR to hypersample the fMRI signal. A key novelty of this study is the development of a region-specific hypersampling approach, called HyPER (Hypersampling for Physiological signal Extraction in a Region-specific manner). HyPER enhances temporal resolution within coherently pulsating vascular and tissue compartments, including the major cerebral arteries, the superior sagittal sinus (SSS), gray matter (GM), and white matter (WM). This study is structured in three parts: (1) We developed and validated the HyPER approach using fast fMRI from a local dataset in four regions of interest: the major cerebral arteries, SSS, GM, and WM. (2) We applied this approach to the publicly available Human Connectome Project-Aging (HCP-A) dataset (ages 36-90 years), increasing the resolvable frequency by ninefold-from 0.625 Hz to 5.625 Hz-enabling clear separation of cardiac, respiration, and LFO oscillations. (3) We investigated how brain physiological pulsations change with age. Our findings revealed an age-related increase in cardiac and respiratory pulsations across all brain regions, likely reflecting an increased vessel stiffness and reduced dampening of high-frequency pulsations along the vascular network. In contrast, LFO pulsations generally declined with age, suggesting reduced vasomotion in the older brain. In summary, we demonstrated the feasibility and reliability of a region-specific hypersampling technique to resolve physiological pulsations in fMRI. This method can be broadly applied to existing fMRI datasets to uncover hidden physiological pulsations and advance our understanding of brain physiology and disease-related alterations.

Mesenchymal stem cells (MSCs) support tissue homeostasis and regeneration, yet their molecular signals remain largely enigmatic. In skeletal muscle (SkM), MSCs, known as fibroadipogenic progenitors (FAPs), are essential for maintenance and repair, orchestrating these processes through intricate cellular communication networks. Given the critical role of SkM in lifelong health and longevity, FAP signaling has drawn significant interest as a potential therapeutic target and a model for MSC interactions. However, deciphering FAP-derived regulatory signals remains challenging due to their pleiotropic complexity. Here, we employ a systems-based approach to construct a comprehensive FAP interactome in both homeostatic and regenerating SkM. By integrating unique single-cell RNA sequencing atlases with advanced computational analyses, we identify putative FAP-mediated signaling pathways and validate their biological relevance through FAP depletion experiments, assessing disruptions in key pathways. This approach reveals novel signaling networks across diverse SkM cell populations, corroborates key FAP interactions from recent studies, and provides a valuable dataset for modeling MSC interactions and their roles in SkM homeostasis and regeneration.

Across species, spatial memory declines with age, possibly reflecting altered hippocampal and medial entorhinal cortex (MEC) function. However, the integrity of cellular and network-level spatial coding in aged MEC is unknown. Here, we leveraged in vivo electrophysiology to assess MEC function in young, middle-aged, and aged mice navigating virtual environments. In aged grid cells, we observed impaired stabilization of context-specific spatial firing, correlated with spatial memory deficits. Additionally, aged grid networks shifted firing patterns often, but with poor alignment to context changes. Aged spatial firing was also unstable in an unchanging environment. In these same mice, we identified 458 genes differentially expressed with age in MEC, 61 of which had expression correlated with spatial coding quality. These genes were interneuron-enriched and related to synaptic plasticity, notably including a perineuronal net component. Together, these findings identify coordinated transcriptomic, cellular, and network changes in MEC implicated in impaired spatial memory in aging.

Accelerated aging is a dynamic process, yet few studies examined the association of changes in accelerated aging with cardiovascular disease (CVD) and mortality. This study aims to evaluate this association in three prospective cohorts from China and the UK.

The mechanisms for the age-related increase in fatigability of the elbow flexor muscles during dynamic contractions are unknown. The purpose of this study was to determine the contribution of supraspinal and contractile mechanisms for the age-related increase in fatigability of the elbow flexor muscles. Twenty-eight young (23.2 ± 2.6 years; 14 females) and 32 older adults (72.6 ± 5.6 years; 15 females) performed 80 maximal velocity contractions at 20% of maximal isometric strength. Voluntary activation and muscle contractile properties were assessed before and immediately following the fatiguing exercise using transcranial magnetic stimulation (TMS) and electrical stimulation. Fatigability (% reduction in power) was greater in older (49.2%) than in young adults (37.6%; p = 0.01) with no differences between males and females (p = 0.36). Reductions in voluntary activation following exercise did not differ between young and older adults (p = 0.96). Reductions in peak rates of torque relaxation induced by TMS were greater in older (44.4%) than in young adults (22.8%; p < 0.001) and were associated with fatigability (r = 0.51, p < 0.001). These data suggest that the age-related increase in fatigability of the elbow flexors is due primarily to mechanisms that impair muscle contractile function.

Herein, we extracted a polyphenol-polysaccharide complex (HPC) from Hizikia fusiforme through enzyme-assisted alkali extraction. This complex had total phenol and carbohydrate contents of 57.99 mg GAE∙g

Senolytic therapy, which targets and selectively eliminates senescent cells, has emerged as a promising strategy for treating various age-related diseases. However, its clinical application is often limited by poor bioavailability, off-target toxicity, and the need for invasive administration routes. To overcome these challenges, we developed N201-gal, a novel β-galactosidase-reactive senolytic prodrug that self-assembles into stable nanoparticles, enabling oral administration and improved systemic bioavailability. Once internalized by senescent cells, N201-gal responds to β-galactosidase overexpression, triggering controlled drug release and inducing selective apoptosis in senescent cells while sparing normal cells. The nanoparticle formulation exhibited favorable physicochemical properties, including uniform particle size and pH stability suitable for gastrointestinal absorption. In vitro study shows that N201-gal demonstrated potent senolytic activity and reduced the expression of senescence-associated markers in retinal pigment epithelial (RPE) cells. In addition, in vivo study also shows that oral administration of N201-gal in a mouse model of doxorubicin-induced retinal senescence model significantly restored retinal tissue integrity and visual function through the targeted clearance of senescent cells. These findings highlight the potential of self-assembling senolytic prodrugs as a noninvasive and targeted therapeutic platform for age-related degenerative diseases.

Prior research suggests that meditation may slow brain aging and reduce the risk of Alzheimer's disease (AD). However, we lack research systematically examining what aspect(s) of meditation may drive such benefits. In particular, it is unknown how breathing patterns during meditation might influence health outcomes associated with AD. In this study, we examined whether two types of mindfulness meditation practice, one with slow breathing and one with normal breathing, differently affect plasma amyloid beta (A{beta}) relative to a no-intervention control group. One week of daily mindfulness practice with slow breathing decreased plasma A{beta} levels whereas one week of daily mindfulness practice with normal breathing increased plasma A{beta} levels. The no-intervention control group showed no changes in plasma A{beta} levels. Slow breathing appears to be a factor through which meditative practices can influence pathways relevant for AD.

Innate immune defense relies on post-translational modifications (PTMs) to protect against viral infections. SUMOylation plays complex roles in viral replication and antiviral defenses in mammals and has been implicated in age-associated diseases. Whether PTMs and SUMOylation contribute to age-induced immunosenescence is unknown. We find that antiviral defense in Caenorhabditis elegans is regulated through SUMOylation of DRH-1, ortholog of the cytosolic pattern recognition receptor RIG-I. The SUMO isopeptidase ULP-4 is essential for deSUMOylation of DRH-1 and activation of the intracellular pathogen response (IPR) after exposure to Orsay virus (OV). ULP-4 stabilizes DRH-1, which translocates to the mitochondria to activate the IPR. Loss of drh-1 or ulp-4 compromises antiviral defense; mutant animals fail to clear OV and develop intestinal pathogenesis. During aging, ulp-4 expression decreases, which promotes DRH-1 proteosomal degradation and IPR loss. Mutating the DRH-1 SUMOylated lysines partially rescued the age-associated lost inducibility of the IPR. Our work establishes that aging results in dysregulated SUMOylation and loss of DRH-1, which compromises antiviral defense and creates a physiological shift to favor chronic pathological infection in older animals.

Acer truncatum is a unique tree species indigenous to northern China. The Chinese government approved the utilization of Acer truncatum leaves as a raw material for food. These leaves have been traditionally used in Inner Mongolia as a form of anti-aging medicine. However, the specific mechanism responsible for the anti-aging properties of Acer truncatum leaves remains unidentified. In this study, an aqueous extract of Acer truncatum leaves (AAL) was prepared and analyzed using UPLC-QTOF-MS/MS. the UPLC-MS/MS profile detected a total of 989 compounds in AAL, with 5 compounds of high concentration selected for quantitative analysis via UPLC-QTOF-MS/MS employing the internal standard method. Subsequently, Drosophila melanogaster served as a model organism to assess the impact of AAL on the lifespan and locomotor abilities. The results demonstrated a significant extension of the lifespan of D. melanogaster in response to AAL supplementation. Moreover, the addition of AAL to the medium enhanced the physical and anti-stress abilities of D. melanogaster, while preserving the integrity of their intestinal barrier. Gut microbiome analysis revealed that AAL administration positively influenced the structure and composition of gut microbes in aged D. melanogaster, notably reducing the prevalence of detrimental bacteria like Enterococcus and increasing beneficial bacteria such as Lactococcus. Metabolomic analysis annotated 30 potentially significant metabolites in AAL that contribute to delaying aging, predominantly associated with Phenylalanine metabolic pathways. Through a comprehensive multi-omics correlation analysis, a strong link was established between gut microbiota and metabolites following AAL treatment, highlighting how AAL prolongs the lifespan of D. melanogaster by modulating metabolic pathways via the gut microbiota. This study offers valuable insights into the anti-aging properties of AAL, emphasizing its ability to delay aging primarily through the regulation of metabolic pathways mediated by the gut microbiota and sets a foundation for the potential future application of AAL as a functional food.

Bone marrow health is central to transplantations, blood formation, and cancer progression. However, the bone marrow niche deteriorates with age, impairing haematopoietic stem cell function. Contrary to a recent report1 suggesting skull marrow resists ageing, our multi-laboratory investigation reveals the opposite: the skull marrow is among the vulnerable sites of age-related decline. Ageing skull niches consistently show loss of mesenchymal and osteoprogenitors, suppression of angiogenic and lymphatic programs, adipocyte accumulation, vascular senescence, DNA replication stress, mitochondrial dysfunction, cellular senescence, and heightened inflammation. Proteomic profiling further highlights this vulnerability, demonstrating that vertebral niches, unlike the skull are relatively spared from these ageing hallmarks. Together, these convergent datasets overturn the notion of skull-specific resilience and instead establish the skull marrow as a fragile, degenerating environment. These findings redefine marrow ageing and highlight the skull as a critical, clinically relevant target for sustaining blood and immune health and reducing vulnerability to haematological disease.

Neuroimaging studies have shown that age-related dysregulation of the locus coeruleus-noradrenaline (LC-NA) system is associated with cognitive decline. However, due to limitations in directly measuring LC function in vivo, it remains unclear whether age-related alterations in humans reflect tonic LC-NA system hyper- or hypoactivity, constraining our understanding of underlying mechanisms and hampers the development of targeted preventative interventions. In this study, we tested the hypothesis that cognitively healthy older adults sustain tonic LC hyperactivity, by acquiring electrophysiological, pupillometric, and behavioral measures during a passive and active auditory oddball paradigm. We capitalized on the LC-NA system's role in arousal regulation and manipulated state arousal using the unpredictable threat of electric shock. We hypothesized that if older adults maintain elevated LC activity compared with young adults, task-evoked noradrenergic responses would be less responsive to arousal in older adults. Consistent with this hypothesis, arousal elicited weaker behavioral responses, pupil dilation responses, and P300 event-related potentials in older adults compared with young adults. Linear mixed models revealed an arousal by modality interaction, showing that arousal differentially modulated attentional control to salient but task-irrelevant distractors between both age groups. Collectively, these findings support the hypothesis that aging is associated with tonic LC-NA system hyperactivity in humans, with neuromodulatory consequences for mechanisms of attentional control. Furthermore, the multimodal approach underscores the potential of non-invasive physiological markers to assess LC-NA system function throughout aging and identify individuals at elevated risk for neurodegenerative progression prior to the emergence of clinical biomarkers.

To gain a more comprehensive understanding of the relationships among immunoscenescence and inflammaging, and subsequent epigenetic aging, we measured a panel of 43 immune cell phenotypes and 68 inflammatory proteins collected from blood samples provided by participants in the Framingham Heart Study Offspring Cohort at Exam 7 (1998-2001) and principal component-based DNA methylation (DNAm)-based biologic clocks measured at the subsequent exam (Exam 8 2005-2008), an average of 6 years later. A total of 24 of the 43 immune cell phenotypes and 55 of the 68 inflammatory proteins investigated were significantly associated with at least one of six DNAm aging metrics in age and sex adjusted models. The immune cell associations persisted after accounting for cardiovascular disease and its risk factors, but the protein associations were attenuated. The effects of the inflammatory proteins were larger in the subset of individuals who were < 60 at the protein measurement, compared to those ≥ 60. Immune cell measurements had more associations with age acceleration measures from the 1st generation DNAm clocks and the 2nd generation PhenoAge, while the inflammatory proteins were primarily associated with age acceleration measures based on PhenoAge, GrimAge, and the Dunedin Pace of Aging metric. This study is one of the first attempts to investigate prospective relationships between baseline immune cell composition measured via flow cytometry and inflammatory protein levels and DNAm age measured several years later and represents one of the most comprehensive mappings of immune and inflammatory contributions to DNAm-based age acceleration and pace of aging metrics to date.

Disentangling normal aging from disease driven transcriptional change remains a major obstacle for spatial genomics. We introduce the Delta-Delta ({Delta}{Delta}) Method, a contrastive trajectory framework that resolves a four-dimensional progression (genes x cell types x brain regions x time) by subtracting the wild type (WT) aging trajectory from the transgenic (TG) trajectory to yield a pure disease trajectory ({Delta}{Delta}log2FC). The method is platform agnostic, integrates with common spatial transcriptomics workflows, and outputs direction and speed of change summaries, enriched pathways, and region and cell type specific maps. In a demonstration using G2-3 -synuclein TG mice and age matched WT controls at 6 and 10 months across hippocampus and midbrain, {Delta}{Delta} uncovered opposite regional dynamics in glutamatergic neurons and a convergent enrichment of RNA splicing pathways, corroborated by alternative splicing analyses. By explicitly modeling time while controlling for aging within each region and cell type, the {Delta}{Delta} Method isolates disease specific molecular programs that are obscured in conventional bulk or single cell analyses, and provides a generalizable framework for trajectory aware mechanistic target prioritization in neurodegeneration and other progressive conditions.

Cellular senescence has gradually been recognized as a key process, which not only inhibits the occurrence of early tumors but also promotes advanced malignant progression through secretory and immunomodulatory functions. Initially, cellular senescence manifested as irreversible cell cycle arrest, but now it encompasses a broader phenotype regulated by the p53-p21CIP1 and p16INK4A-Rb pathways. Although secretory phenotypes related to aging can recruit immune effectors to clear new tumor cells, persistent senescent cell populations often trigger chronic inflammation, promoting immune escape and fibrosis. In this review, we first discuss the molecular underpinnings of cellular senescence, highlighting its induction pathways and diverse physiological or pathological roles. We then examine the composition of the tumor microenvironment, where senescent cells accumulate and secrete pro-inflammatory cytokines, reshaping immune surveillance and extracellular matrix architecture. Against this backdrop, we explore how aging clocks refine our understanding of individual susceptibility to malignancy by distinguishing biological from chronological aging. We also present current therapeutic prospects, including senolytic agents targeting senescent stromal cells that promote tumor growth, and the utilization of aging clock metrics to tailor immunotherapies more effectively for older patients. Finally, we consider the major challenges facing clinical translation, from standardizing multi-omics data pipelines to clarifying the ethical implications of measuring biological age. By bridging senescence biology with geroscience and cutting-edge oncology, we posit that aging clocks may catalyze a transformation in cancer care, enabling more personalized, effective, and age-conscious treatment strategies.

Maintaining skeletal muscle mass is crucial for health, as muscle atrophy caused by drugs, cancer, or aging poses serious risks. However, there are few effective pharmacological interventions targeting muscle atrophy, highlighting the need for new therapeutic strategies. In this study, in vivo self-assembled siRNA is designed to silence myostatin (MSTN), a key regulator of muscle growth and atrophy, aiming to prevent muscle atrophy. Using synthetic constructs and the host liver as a scaffold, the assembly of MSTN-siRNA is guided into muscle-specific peptide MSP-tagged small extracellular vesicles (sEVs). These MSP-tagged sEVs selectively deliver MSTN-siRNA to muscle tissue. Treatment significantly reduces MSTN protein levels in skeletal muscle, promotes muscle mass gain in healthy mice, and protectes skeletal muscles from atrophy in cancer- and dexamethasone-induced muscle atrophy models. Notably, the sEV-encapsulated MSTN-siRNA is produced in a nontoxic, nonimmunogenic, and biocompatible manner. This study offers a promising therapeutic approach for muscle atrophy, addressing a key gap in current treatment options and potentially improving outcomes for patients with muscle-wasting conditions.

Dietary restriction (DR) refers to a broad set of interventions that limit the intake of specific nutrients or overall food consumption, either in quantity or timing, without causing malnutrition. DR has long been considered the most robust intervention for increasing healthspan and lifespan. This includes, not exhaustively, caloric restriction (CR), protein restriction (PR), amino acid restriction (AAR), intermittent fasting (IF), and time-restricted fasting (TRF), each with overlapping but distinct metabolic and physiological effects. This brief review examines the current scientific understanding of how some of the most commonly employed DR regimens may impact metabolism, lifespan, and healthspan. Particular attention is given to the underlying biological mechanisms and supporting evidence derived from both human clinical studies and fundamental biological research conducted with model organisms ranging from yeast to non-human primates.

Much focus has shifted towards understanding how glial dysfunction contributes to age-related neurodegeneration due to the critical roles glial cells play in maintaining healthy brain function. Cell-cell interactions, which are largely mediated by cell-surface proteins, control many critical aspects of development and physiology; as such, dysregulation of glial cell-surface proteins in particular is hypothesized to play an important role in age-related neurodegeneration. However, it remains technically difficult to profile glial cell-surface proteins in intact brains. Here, we applied a cell-surface proteomic profiling method to glial cells from intact brains in

The aging population presents significant challenges for healthcare and social services, emphasizing the need for innovative solutions that support independent living. This study explores the feasibility of identifying Instrumental Activities of Daily Living (IADLs) through power consumption data collected from smart plug-based system. Using a combination of unsupervised and supervised machine learning techniques, including K-Means clustering and Long Short-Term Memory (LSTM) networks, we developed a method to classify and predict IADLs based on energy usage patterns. The REFIT dataset was used to train and validate the models, ensuring generalizability across different households. Results demonstrate that K-means clustering effectively group energy consumption patterns with Silhouette & DB algorithms in a reasonable time (Silhouette score of 0.88 and a Davies-Bouldin Index of 0.29), while LSTM models trained on monthly household data, demonstrated high rates of activities classified over time (with F1-Score of 0.99). IADLs like cooking, cleaning, and entertainment showed the highest classification accuracy due to their distinct energy features. This approach enables non-intrusive monitoring of daily routines, offering potential applications in Ambient Assisted Living (AAL) environments. Despite limitations in detecting activities without direct energy consumption, this study highlights the potential of energy-based activity recognition for promoting independent aging. Future work will focus on refining abnormal behavior detection and integrating additional contextual factors to improve accuracy.

Aging is a universal, continuous, and complex process in which an animal's biological ability to resist, react to, and recover from environmental stressors declines and there is an alteration of physiological processes in response to accumulating cellular damage. In companion dogs and cats, aging is often perceived as an unmodifiable decline in physical and mental capabilities combined with increased morbidity, all aligned with chronological age. An insufficient understanding of healthy aging means missed opportunities to alter the trajectory of health span and maintain overall quality of life despite those changes that are inevitable. We believe that the course of aging is modifiable throughout an individual's entire life, with healthy, or successful, aging being an achievable goal. We explored herein 3 aspects of healthy aging: the need for a better scientific understanding of aging processes in dogs and cats and practical potential of biological aging clocks; a meaningful definition of healthy aging; and greater use of validated clinical monitoring tools and resources. A universal, meaningful, and actionable definition of healthy aging is needed to dissociate aging from declining health and poor quality of life in all their manifestations. The unique relationship between pets and their caregivers may demand a more expansive definition than that for humans. We propose that healthy aging in dogs and cats should be regarded as aging in which the individual maintains functional capabilities and develops resilience sufficient to meet their own physical, behavioral, social, and emotional needs throughout all adult life stages, while sustaining the human-animal bond.

Objective:Spontaneous intracerebral hemorrhage (ICH) occurs later in life in women compared to men. Although previous studies have demonstrated epigenetic age acceleration (EAA) differences in ischemic stroke (IS) patients - a measure of an individual's biological aging -it remains unknown whether this sex dimorphism also applies to ICH patients. Approach and Results: We joined two ICH cohorts (N= 200, 45% women: 76.8{+/-}13 years; 55% men: 67.9{+/-}14 years). DNAm levels were obtained from whole blood samples using Illumina EPIC array. We evaluated three age-predictor clocks (Horvath, Hannum and Zang-BLUP) and one health-status clock (Levine) and their respective EAA metrics including extrinsic EAA (EEAA) and intrinsic EAA (IEAA) measures. We compared aging measures between women and men, then performed an ICH-subtype stratification, a specificity analysis evaluating sex differences in non-stroke samples (N= 350, 54% women 60.8{+/-}8 years, men: 60.8{+/-}10 years) and replication of previous result in a new IS cohort (N= 657, 43% women 73.6{+/-}12 years, men: 70.1{+/-}11 years). Women at time of ICH present lower EAA values than men (Horvath-EAA, p-value=1x10-04; Hannum-EAA, p-value=8.1x10-06; BLUP-EAA, p-value=4.4x10-04) as well as lower extrinsic EAA values (Horvath-IEAA, p-value=3.1x10-03; Hannum-IEAA, p-value=6.5x10-04). These differences seemed to be driven by differences in deep-ICH patients. Non-ICH females have lower acceleration values (Hannum-EAA: -10,37) than non-ICH men (Hannum-EAA: -8,01), but the differences are smaller than in ICH cases (ICH-women Hannum-EAA: -9,26, ICH-men Hannum-EAA: -2,6). This pattern was consistent in the IS cohort, where women were chronologically older than men but had similar biological age and significantly lower epigenetic age acceleration across multiple measures (Horvath-EAA, p = 2.6x10^-3; Hannum-EAA, p = 7.1x10^-3; Horvath-IEAA, p = 1.6x10^-2; Hannum-IEAA, p = 4.5x10^-2). Conclusion:This study shows that biological age difference between women and men are not exclusive of ischemic stroke but also observed in ICH.

The local breast environment is a valuable research focus for identifying the etiological and biological factors that contribute to the development of breast cancer. Single-cell RNA sequencing shows that the increased availability of the medium-chain fatty acid octanoic acid induces changes typical of the aged mammary gland, including downregulation of cell-cell junctions, altered extracellular matrix (ECM)-receptor interactions, and upregulation of aging markers like MDK and GDF15. Ex vivo exposure to medium-chain fatty acids compromises cell-cell junctions leading to cell dissemination. As aging is associated with an increased risk of developing breast cancer, it is crucial to identify the factors driving these age-related changes in the mammary gland to develop effective cancer prevention strategies. Given that the proportion of breast adipocytes increases with age, we propose that the remodeling of the mammary gland associated with aging is partly due to the increase in adipocytes and fatty-acid release.

Cognitive impairment has become a major challenge to health aging all over the world, and evidence shows that transportation infrastructure affects the elderly's cognitive health. However, little is known about the effects of high-speed rail (HSR) on cognitive health. Based on the panel data from 2011 to 2018, this study employs the double machine learning (ML) approach to examine the relationship between HSR and cognitive health among 11,572 middle-aged and aged adults in China. The result shows that the opening of HSR significantly improved global cognition, with an estimated treatment effect coefficient of 0.198 (95 % confidence interval, [0.088, 0.309]). The effect of HSR varies in dimensions of cognitive health, only promoting mental intactness rather than episodic memory. The main result remains robust after conducting a series of robustness tests such as introducing instrumental variables, replacing the HSR measurements and ML method. Further analysis shows that HSR has heterogeneous effects on cognitive health across gender, ages, education levels, rural-urban areas, and geographic regions. For instance, HSR has narrowed the cognitive health inequalities between individuals with elementary or middle school education and those with higher education, but widened the gap between rural and urban residents. Additionally, mediation analysis indicates that HSR may enhance cognitive health by reducing PM2.5 exposure, improving individual earnings, and alleviating depressive symptoms. This study provides beneficial insights for China and other countries to develop transportation infrastructure and promote healthy cognitive aging.

Physical activity (PA) enhances physical health as well as cognitive and brain health, yet motivating older adults to initiate and sustain PA remains challenging, a difficulty exacerbated by the COVID-19 pandemic. Active augmented reality (AAR) games, integrating digital gameplay with real-world physical movement, provide an enjoyable and accessible means for PA promotion among older adults in independent living environments, mitigating barriers such as poor weather and unfavorable neighborhood environments. However, limited research has explored the feasibility and impact of AAR interventions in this population.

The human brain develops and matures over an exceptionally prolonged period of time that spans nearly two decades of life. Processes that govern species-specific aspects of human postnatal brain development are difficult to study in animal models. While human brain organoids offer a promising in vitro model, they have thus far been shown to largely mimic early stages of brain development. Here, we developed human brain organoids for an unprecedented 5 years in culture, optimizing growth conditions able to extend excitatory neuron viability beyond previously-known limits. Using module scores of maturation-associated genes derived from a time course of endogenous human brain maturation, we show that brain organoids transcriptionally age with cell type-specificity through these many years in culture. Whole-genome methylation profiling reveals that the predicted epigenomic age of organoids sampled between 3 months and 5 years correlates precisely with time spent in vitro, and parallels epigenomic aging in vivo. Notably, we show that in chimeric organoids generated by mixing neural progenitors derived from "old" organoids with progenitors from "young" organoids, old progenitors rapidly produce late neuronal fates, skipping the production of earlier neuronal progeny that are instead produced by their young counterparts in the same co-cultures. The data indicate that human brain organoids can mature and record the passage of time over many years in culture. Progenitors that age in organoids retain a memory of the time spent in culture reflected in their ability to execute age-appropriate, late developmental programs.

Aging is commonly associated with a decline in memory abilities, yet some individuals remain resilient to such changes. Memory processing has been shown to rely on adult neurogenesis, a form of hippocampal plasticity, but whether the integration and role of long-lived adult-born neurons (ABNs) generated during early adult life also contribute to cognitive resilience and to such inter-individual differences remain unknown. Using a pseudo-longitudinal approach in rats characterized as resilient or vulnerable to cognitive aging, we examined the survival, senescence, morphology, glutamatergic connectivity, and mitochondrial health of ABNs. To achieve this, we combined approaches based on thymidine analogues and retroviral labeling using Moloney murine leukemia viruses. While ABNs survival, entry into senescence and dendritic gross morphology did not differ between resilient and vulnerable rats, resilient animals exhibited preserved glutamatergic synaptic input and maintained mitochondrial homeostasis in the proximal dendrites of ABNs. Interestingly, bypassing this reduction in glutamatergic inputs in vulnerable rats through direct optogenetic stimulation was sufficient to rescue their memory retrieval abilities, indicating that ABNs themselves remain intrinsically functional despite reduced input. Overall, our data indicate that maintaining long-lived ABNs within the neuronal network is essential for successful cognitive aging, highlighting their potential as a therapeutic target for restoring cognitive functions in old age.

Being a major contributor to cell senescence and aging, DNA damage activates macroautophagy/autophagy, but how this process is affected by aging-rewired metabolism in normal biological systems remains to be explored. Here in cultured human umbilical cord-derived mesenchymal stem cells (HsMSCs) and the mouse liver that accumulate DNA damage during aging, we found an elevation of DRAM1 (DNA damage regulated autophagy modulator 1) and DRAM1-mediated pro-senescent autophagy (DMPA). Confirming that DRAM1 activated AMPK, we sought DMPA-associated metabolic features and noted substantial enrichment of N-acetylhistamine (N-AcHA) and phosphatidylethanolamine (PE) products in the aging HsMSCs and mouse liver. Elevating DNA damage and senescence, N-AcHA supplements were sufficient to upregulate DRAM1 and DMPA in primary hepatocytes from young mice but not even in pre-senescent HsMSCs, hence reflecting the differential tolerance of these cell models toward cytotoxic metabolic cues. The effects of N-AcHA were further verified in mouse aging and post-hepatectomy liver regeneration models. In contrast, accumulating cellular PE contents via ethanolamine supplements augmented autophagy but not DNA damage and senescence despite tending to induce DRAM1. Combined treatments with N-AcHA and ethanolamine were sufficient to trigger DMPA in HsMSCs. Despite their differential cellular responses toward N-AcHA and ethanolamine supplements, in primary HsMSCs and mouse hepatocytes DMPA did not notably downregulate SQSTM1/p62 proteins, which differed from general macroautophagy and may constitutively support the fusion of SQSTM1-modified cargo-containing autophagosomes with lysosomes. Overall, this study reveals DMPA-promoting metabolic and molecular features. Thus, targeting certain metabolic pathways and DMPA may promote DNA repair and delay senescence/aging.

Life expectancy has been increasing over the last decades, which is not matched by an increase in healthspan. Besides genetic composition, environmental and nutritional factors influence both health- and lifespan. Diet is thought to be a major factor for healthy ageing. Here, we show that dietary RNA species improve proteostasis in C. elegans. Inherent bacterial-derived double stranded RNA reduces protein aggregation in a C. elegans muscle proteostasis model. This beneficial effect depends on low levels of systemic selective autophagy, the RNAi machinery in the germline, even when the RNA is delivered through ingestion in the intestine and the integrity of muscle cells. Our data suggest a requirement of inter-organ communication between the intestine, the germline and muscles. Our results demonstrate that bacterial-derived RNAs elicit a systemic response in C. elegans, which protects the animal from protein aggregation during ageing, which might extend healthspan.

Hematopoietic stem cells require tight regulation to rapidly initiate emergency hematopoiesis in response to pathogens, but chronic activation leads to proliferation induced exhaustion. Timely reentry into quiescence after inflammatory stimuli is essential for long term sustained HSC maintenance. We identify IL-10R signaling, an established negative feedback regulator in mature myeloid cells, as critical for returning HSCs to quiescence. IL-10R blockade prolongs HSC cycling and sustains activated transcriptional programs after acute inflammation. With chronic exposure, blockade increases cumulative divisions and accelerates aging hallmarks, including myeloid bias, loss of polarity, and functional defects, under conditions that do not otherwise exhaust HSCs when IL-10R signaling is intact. Jak2V617F mutant HSCs resist the aging acceleration induced by blockade. Consistent with this resistance, IL-10R blocking antibody promotes Jak2V617F clonal expansion and augments the myeloproliferative neoplasm phenotype. Together, these findings identify IL-10R signaling as a key coordinator of post inflammatory return to quiescence and suggest that modulating this axis could preserve HSCs and shape clonal hematopoiesis. SummaryWadley et al. show that IL-10 receptor signaling restrains inflammation-induced hematopoietic stem cell cycling and exhaustion; its blockade prolongs cycling, accelerates aging-related decline, and selectively favors Jak2V617F mutant HSCs, establishing IL-10 signaling as a critical regulator of inflammatory HSC exhaustion and malignant clonal evolution.

Aging is the greatest risk factor for AD, ALS, PD, FTD, and HD. Neurons in the brain experience many changes as people age, negatively affecting their structure and function. It examines the key processes behind brain aging, such as age-related death of cells, failure of the cells' powerhouses, oxidative stress, incorrect protein shapes, brain inflammation, difficulty in cleaning the brain, and deterioration of blood vessels, and shows their impact on neurodegeneration. With age, there are difficulties in brain-blood circulation, less synaptic change, and fewer new neurons, which make the disease even worse. Informed by human and animal trials, we see that mitochondria work less efficiently in aging brain cells, while oxidative damage to DNA increases doubly to triply. In addition, too much tau, amyloid-β, and α-synuclein building up is tied to declining mental abilities in the elderly. We further evaluate new tests that help with early detection and classification, for example, using biomarkers in cerebrospinal fluid (CSF), blood panels, detailed brain scans, and AI algorithms. It stresses that more aging-specific trials, better integration of multi-omics, and increased interest in research on the gut-brain axis are important. The communication between the aging of the body and the brain is also explained. This article covers the main cellular, molecular, and clinical issues linked to brain aging and highlights important future research areas needed to develop effective treatments for aging people.

Centenarians comprise an age group characterized by exceptional longevity and low age-associated pathologies. However, they still experience physiological decline, and different studies have linked frailty to this population. Exercise interventions reverse frailty and improve functional capacity, but no studies have addressed the effect of an intervention in centenarians. In this study, we assessed the impact of a 12-week resistance exercise intervention in a group of centenarians and characterized their functional capacity as well as the expression of several molecular biomarkers associated with frailty.

All organisms have evolved survival strategies to cope with changes in environmental conditions. Nutrient deprivation, one of the most frequently encountered stresses in nature, causes haploid budding yeast to enter a reversible state of non-proliferation known as quiescence, which entails extensive remodeling of gene expression, metabolism and the cellular biophysical properties. Yeast cells can adapt to and survive long periods of time in glucose starvation-induced quiescence, provided they are able to respire in the early stages of glucose withdrawal. When respiration is blocked during glucose withdrawal, cells prematurely age and exhibit markedly reduced survival and cytoplasmic diffusion. We find here that respiration is required to induce a quiescence-related gene expression program. Induction of this program prior to withdrawing glucose in respiration-inhibited cells bypasses the need for respiration and rescues survival and biophysical properties to levels seen in glucose-starved but respiration-competent cells. This rescue effect relies on proteomic adaptation, which partially occurs through inactivation of Ras/PKA signaling and activation of the environmental stress response via the transcription factors Msn2/4. This signaling cascade triggers the expression of stress response genes and modulates the cytoplasmic diffusion state of cells, ensuring long-term survival in quiescence even in the absence of respiration. Our results highlight the importance of stress adaptation in quiescence and aging, integrating gene expression control and modulation of cytoplasmic properties to maintain cell fitness.

Blood vessels exhibit a pronounced vulnerability to aging and are often at the forefront of systemic aging processes. Vascular endothelial cells, which line blood vessels and directly contact blood flow, are susceptible to damage and play a key role in vascular aging; however, the underlying mechanisms of their aging remain unclear. Here, we identify TRPM7 as a key molecule in vascular endothelial aging. Endothelial deletion of TRPM7 significantly accelerates premature vascular aging in mice. Mechanistically, TRPM7 deficiency reduces lactate production and inhibits the lactylation writer protein p300, leading to decreased histone H3K18 lactylation. This induces a gene expression profile reprogramming, increasing the expression of the senescence gene p21 and decreasing the expression of angiogenesis genes. Inhibiting p21 or supplementing lactate reversed premature vascular endothelial aging caused by TRPM7 deficiency. This study reveals the critical role of the TRPM7-H3K18la axis in vascular aging, offering potential therapeutic targets for vascular anti-aging interventions.

Aplysia californica has been a useful model system for studies of the neural basis of behavior, learning, and aging. While the latter topic has been explored with respect to several of its simple reflex behaviors, this study represents the first examination of how one of Aplysia's more complex behaviors, escape locomotion, is affected in animals nearing the end of their natural lifespan. Old animals (12-13mo) showed a greatly reduced gallop response compared with middle-aged adults (5-7mo), together with a loss of locomotion onset latency sensitization. Large-scale VSD imaging was used to record motor programs in isolated brain preparations from middle-aged vs. elderly animals. Old brains displayed the same loss of onset latency sensitization seen in the intact old animal behavior, and also a reduced number of cycles per locomotion episode. Brains from middle-aged animals showed an unchanged number of motor program cycles from that observed in intact animals, but a much more transient motor program onset latency sensitization. A further age-related finding was that while in middle-aged brains repeatedly eliciting the motor program led to progressively increasing cumulative activity across trials, in old brains this same procedure led to progressively decreasing activity. Some of our results are consistent with peripheral processes working in concert with the CNS as animals age to support healthy locomotion behavior and its modification by learning, or with early changes in the brain that are not yet expressed in behavior.

With the advent of an aging society, the lack of physical activity has become a major concern, leading to various age-related diseases. To prevent such issues, research on wearable robots aimed at improving gait has been actively pursued. Among them, exoskeleton robots, a widely used approach, require an accurate understanding of the user's gait cycle for effective control. Various studies have explored gait cycle detection and prediction methods depending on the type of gait robot platform and the use of sensors. However, a major challenge in gait cycle prediction algorithms remains the issue of nonlinear predictive trajectories. In the study, a robotic hip exoskeleton (RHE) was utilized to implement an enhanced gait phase estimation (GPE) algorithm integrated with a muscle support system. Participants were divided into two groups (Group A and Group B) based on their initial gait performance, and the effectiveness of gait rehabilitation training was evaluated. The results showed that in the 10-meter walk test (10MWT), walking time decreased by approximately 5% in Group A and 27% in Group B. In the 6-minute walk test (6MinWT), walking distance increased by approximately 1% in Group A and 14% in Group B. Group B, which had lower initial gait performance, showed a greater gait performance improvement rate compared to Group A, which had higher initial gait performance. Through the gait performance results of the two groups, the applicability of the GPE based muscle support algorithm was confirmed.

The progression of sarcopenia with aging may be related to mitochondrial dysfunction due in part to altered mitochondrial dynamics (fusion, fission, mitophagy, and biogenesis). Previous work has identified altered expression of proteins associated with these processes in with aging, but whether further changes occur in sarcopenia remains unclear.

Before human genome sequencing, a genome-wide study of sibling centenarian pairs identified a longevity-associated locus on chromosome 4. Here, we mapped the genes in this locus and identified a collagen gene, COL25A1. Introducing an SNP linked to longevity that changes a serine predicted to be phosphorylated to leucine in COL25A1, into col-99, the C. elegans ortholog, extended lifespan. These col-99(gk694263[S106L]) SNP-mutants exhibited enhanced innate immune-related transcriptional responses, and their lifespan extension was abolished by inhibiting the p38 MAPK pathway. YAP-1, a transcriptional co-activator responsive to extracellular matrix changes, was essential for this longevity. Mechanistically, we find that this SNP modifies furin-mediated cleavage of this transmembrane collagen in vitro, and expressing the cleaved extracellular domain of COL-99 alone was sufficient to prolong C. elegans' lifespan. These findings reveal a potential mechanism by which a human centenarian-associated SNP in COL25A1 influences furin cleavage and shedding of the collagen ectodomain to promote healthy longevity.

Women over 35 experience a marked reduction in fertility. The origin of these fertility defects appears to reside in the implantation capacity of the embryo itself, but the mechanistic basis of this impairment is not well-understood. Here, we identify a core mechanical defect in embryos from aged mothers that impairs the process of implantation. Using mouse models, we find that reproductive aging yields increased contractility in the extra-embryonic trophectoderm, the outer epithelial tissue responsible for mediating uterine attachment and embryo implantation. This hypercontractile state elevates tissue surface tension and viscosity in the blastocyst, culminating in defective spreading during implantation. Enhanced contractility is necessary and sufficient for this age-related defect in implantation, and early embryo mechanics can be used to predict successful implantation for embryos from both young and aged mothers. Our work represents a potential foundation for improving embryo selection in Assisted Reproductive Technologies to resolve age-related defects in female fertility.

Telomere shortening is a well-established marker of cellular aging and genomic instability. While the relationship between leukocyte telomere length and cardiovascular diseases has long been of interest, their genetic interplay remains incompletely understood. In this study, we observe substantial genetic overlap beyond genome-wide correlations and identify a potential causal relationship between leukocyte telomere length and coronary artery disease. Specifically, we discover 248 pleiotropic loci, 22 of which show strong evidence of colocalization. Some shared loci implicate multiple pleiotropic genes across different trait pairs, including ALDH2, ACAD10, TMEM116, SH2B3 (all at 12q24.12), TMED6 (16q22.1), SERPINF1 (17p13.3), and XPO7 (8p21.3). Functional analysis highlights key pathways involved in DNA biosynthesis and telomere maintenance. Notably, SH2B3 is validated through proteome-wide Mendelian randomization analysis, suggesting its potential as a therapeutic target. Here we report the shared genetic basis between leukocyte telomere length and cardiovascular diseases, providing valuable insights into future therapeutic developments.

Aging is a complex biological process, and some individuals are aging faster or slower than expected. This phenomenon of aging acceleration occurs when biological age exceeds chronological age and can be assessed by epigenetic clock estimation. As aging acceleration is known to occur in response to some environmental exposures as well as trauma, we hypothesized that World Trade Center (WTC) exposures may have led to epigenetic aging acceleration. WTC-exposed women were selected from the World Trade Center Environmental Health Center (WTC EHC) clinic, with peripheral blood collected during routine clinical monitoring visits. The reference group was selected from the NYU Women's Health Study (NYUWHS), a prospective cohort study that collected blood samples before 9/11/2001. Epigenomes of WTC-exposed vs. unexposed women were profiled using the Infinium MethylationEPIC array. DNA-based epigenetic aging was estimated using Hannum, Horvath, PhenoAge and GrimAge epigenetic clocks. Age acceleration was defined as the residual from regressing estimated epigenetic age on chronological age. Ordinary least squares regression was used to investigate the relationship between WTC exposure and accelerated aging. After adjustment for race/ethnicity, smoking status, Body Mass Index (BMI), batch and cell type composition, WTC exposure was associated with epigenetic aging acceleration using the Hannum epigenetic clock (β

Aged tissue is characterized by chronic inflammation known as "inflammaging". While this aging immune phenotype supposedly drives some of the most common diseases affecting the elderly, little is known about the structural drivers of inflammaging. In this study, we demonstrate that age-dependent activation of NF-kB in tissue fibroblasts remodels the immune architecture, promoting the emergence of an exhausted T cell population (GZMK+/CD8+) recently identified in normal aging, as well as autoimmunity and cancer. Fibroblast-specific NF-kB activation triggered a fibroblast-macrophage-T cell circuit to form tertiary lymphoid structures in the lung and promoted the emergence of exhausted GZMK+ T cells. Fibroblastic activation of NF-kB increased host susceptibility to acute lung injury and mimics severe pneumonia commonly seen in elderly patients, which was alleviated by deletion of GZMK+ T cells. Our data provide a structural basis for inflammaging, where fibroblasts orchestrate the complex immune aging phenotype in non-immune tissues, increasing susceptibility to age-related diseases. Highlights- Bronchus-associated lymphoid tissue (BALT) enriched for GZMK+ T cells develop with age - Lung adventitial fibroblasts demonstrate increased NF-kB activation with age. - Fibroblast activation of NF-kB in young animals recapitulates multiple features of normal lung immune aging - Depletion of GZMK+ cells decreases lung inflammation in a mouse model of acute respiratory distress syndrome (ARDS)

To estimate biological age, we developed a proteomic aging clock in cancer-free participants (CaPAC) and examined its association with mortality in long-term cancer survivors (LTCS, >2 years between cancer diagnosis and blood collection) and cancer-free participants in the Atherosclerosis Risk in Communities (ARIC) and Multi-Ethnic Study of Atherosclerosis (MESA) studies.

Known as immunosenescence, the major dysregulation of the immune system with age is associated with poor vaccination efficacy, and increased susceptibility to infections, age-related pathologies, and neoplasms, with incidences exacerbated with age. Cellular senescence is a crucial process that puts cells in an irreversible cell-cycle arrest which prevents damaged or stressed cells from uncontrolled propagation and eventually potential malignancy. Paradoxically, senescence also contributes to the occurrence of cancer and increases the risk of metastasis through different secretory mediators. Altogether, the recent use of senotherapy to eliminate senescent cells has been shown to delay tumorigenesis, attenuate age-related deterioration of organs, and promote healthy aging. Interestingly, immune cells have been shown to specifically interact with, and kill senescent cells, thus opening new opportunities for the development of specific therapeutic strategies similar to immunotherapy in cancer. Through its detrimental impact on the immune system, immunosenescence is also leading to the accumulation of senescent cells with age thus further contributing to the occurrence and worsening of multiple age-related pathologies such as cancer. Understanding the molecular and cellular events occurring during the aging process, and triggering immunosenescence as well as the mechanisms by which senescent cells escape immune surveillance would help to improve immune responses to senescent cells and their clearance. In this review, we highlight how senescent cells interact with immune cells, and how immunosenescence-associated phenotypical and functional deregulation hinder the ability of immune cells to clear senescent cells. We further characterize strategies aimed at promoting the clearance of senescent cells by the immune system.

Cellular senescence refers to a state in which cells stop dividing and can no longer proliferate because of various factors, such as DNA damage and oxidative stress. It is implicated as a key driver of aging and age-related diseases.

Aging impairs glucose counterregulatory function by unknown mechanisms. Ventromedial hypothalamic nucleus/dorsomedial division (VMNdm) growth hormone-releasing hormone (Ghrh) neurons control counterregulation through Ghrh-modulated discharge of structurally diverse co-expressed neurochemicals. Current research used gene silencing and single-cell laser-catapult-microdissection/multiplex qPCR tools to investigate whether aging alters eu- and/or hypoglycemic patterns of co-produced counterregulatory-inhibiting (γ-aminobutyric acid) or -stimulating (Ghrh; glutamate; nitric oxide) neurotransmitter marker genes in this cell population. Data document basal Ghrh mRNA diminution in older, i.e., middle-aged rats of each sex and age-specific Ghrh transcriptional responses to hypoglycemia in females. Older rats showed Ghrh repression of glutamate decarboxylase

Muscle-specific strength (MSS), defined as grip strength normalized to arm muscle mass, may better reflect muscle efficiency than grip strength. Despite its potential utility in diagnosing sarcopenia, longitudinal studies evaluating MSS as a predictor of sarcopenia-related outcomes remain limited. This study investigated the associations of MSS with physical performance deterioration and biomarker profiles in community-dwelling older adults, compared it with conventional measures, determined whether MSS-defined sarcopenia offers superior predictive utility versus traditional diagnostic criteria and examined associations with key cardiometabolic and inflammatory biomarkers.

Aging is a universal and inevitable biological process that affects all living organisms at different rates. Both internal and external factors contribute to the aging of human skin. Intrinsic ageing is primarily determined by genetic predisposition and physiological changes over time, leading to the gradual loss of skin elasticity, thinning, and the development of wrinkles. Conversely, extrinsic ageing is largely attributed to environmental stressors, with ultraviolet (UV) radiation being a key factor in accelerating oxidative damage, collagen degradation, and an increased risk of cutaneous malignancies such as melanoma. One of the primary mechanisms driving skin ageing is oxidative stress, which is caused by an overproduction of reactive oxygen species (ROS). This disrupts enzymatic homeostasis, particularly affecting elastase, an enzyme responsible for maintaining skin elasticity, thereby contributing to visible signs of ageing. The rising awareness of age-related dermatological concerns has led to a growing demand for natural, safe, and cost-effective strategies to mitigate skin ageing. Herbal compounds have gained significant attention due to their therapeutic potential and minimal adverse effects, making plant-based formulations increasingly popular in anti-ageing research. This review examines the molecular pathways of extrinsic skin ageing and explores phytoconstituents with promising anti-ageing properties. These bioactive compounds are categorised based on their mechanisms of action. Several plant-derived molecules, including mangiferin, lutein, curcumin, and resveratrol, exert potent antioxidant and anti-inflammatory effects. Compounds such as quercetin, apigenin, and gingerol also demonstrate inhibitory activity against collagenase and elastase, preserving skin integrity and function. The growing body of research supporting these natural agents highlights their potential role in the development of effective anti-aging interventions.

Kidney aging is characterized by a loss of glomeruli, predominately in the superficial cortex, with a resultant decline in glomerular filtration rate and an increased risk of various kidney-related diseases. The early molecular alterations in glomeruli associated with the aging process are not well studied.

The roles of cells in systemic aging have been systematically investigated, while the roles of the extracellular matrix (ECM) and its degradation have been largely overlooked. Herein, we show that the serum contents of elastin-, hyaluronic acid- and fibronectin-derived fragments are all positively correlated with age. Elastin-derived fragments exhibited the most potent lifespan-shortening effects in mice and a positive correlation with various aging indicators in a human cohort (n = 1,068). Mechanistically, the VGVAPG oligopeptide (E-motif) in elastin-derived fragments activated monocytes and macrophages through NEU1, a component of the elastin receptor complex, which consequently caused an inflammatory response. Therapeutically, a NEU1 inhibitor extended lifespan by up to 17% in wild-type naturally aged mice and alleviated aging-related phenotypes in wild-type mice, immune-humanized mice and pigs. This study uncovers that degraded ECM acts as a circulating driver of aging, providing an anti-aging intervention strategy focused on particular elastin fragment signals.

Centenarians provide valuable insights into the biological mechanisms underlying human longevity and potential gerotherapeutic targets. We previously identified two linked missense variants in SIRT6 that are enriched in Ashkenazi Jewish centenarians. To investigate their functional impact in physiologically relevant cellular contexts, we generated human embryonic stem cells carrying these variants through precise genomic knock-in and differentiated them into somatic lineages. Functional characterization revealed that the centenarian variants endogenously elevated SIRT6 protein levels through weakened interaction with vimentin, and altered SIRT6 enzymatic activities including enhanced mono-ADP-ribosyl transferase activity and reduced deacetylase activity. These variants delayed replicative and progerin-induced cellular senescence, preserving genome stability through maintenance of DNA repair pathways and suppression of transposable element derepression. Moreover, pharmacologically mimicking the centenarian variants using SIRT6 activator Fucoidan-FV partially ameliorated premature aging-associated molecular defects in progeria fibroblasts. Together, our findings demonstrate that rare centenarian variants exert multifaceted effects on SIRT6 and enhance cellular resilience, providing insights for developing geroprotective therapies informed by genetic discoveries in exceptionally long-lived individuals.

Telomere homeostasis serves as a key regulatory mechanism linking aging and cancer. While telomere attrition imposes a proliferative barrier by inducing cellular senescence, abnormal telomere elongation circumvents this constraint, thereby granting malignant cells unlimited replicative capacity. This study systematically explores the causal relationship between telomere length and cancer risk, with the goal of elucidating the molecular pathways involved in telomere-driven tumorigenesis.

The testis, with the highest number of transcriptionally active genes among human tissues, offers a unique window into how aging affects complex gene regulation. Recent advancements in single-cell RNA sequencing have enabled multi-species studies of aging-related transcriptome changes in testes. However, a comprehensive aging-related cross-species platform for analyzing testicular single-cell transcriptomes remains absent. To address this gap, we developed Aging-TCA (Aging-related Testicular Cell Atlas, available at http://tca.xielab.tech/)—a comprehensive online platform containing aging-related testicular single cell and spatial transcriptome profiles from human, cynomolgus monkey, mouse, and zebrafish across 89 samples and over 460, 000 testicular cells, nuclei or spots. Aging-TCA provides versatile tools for temporal and spatial analyzing testicular aging, including aging-related testicular gene expression visualization, cell-cell communication comparisons, cell-trajectory analysis, gene regulatory network analysis, testicular cell type auto-identification, time-series analysis, and spatial transcriptome comparisons. In summary, we provide a novel platform Aging-TCA for advancing cross-species research into testicular aging, facilitating future investigations in this field.

Epigenetic modifications linked to biological aging, like DNA methylation (DNAm), may serve as biomarkers for future cardiometabolic disease risk. However, existing studies have focused on older adults, overlooking the early-life origins of cardiometabolic health.

Currently, little is understood about the genetic architecture underlying Genome-wide association study (GWAS)-related traits that influence the reproductive ageing of women. To address this knowledge gap, we estimated causal single nucleotide polymorphisms (SNPs) independent of variation in the reproductive of women via genomic structural equation modelling and multiple post-GWAS methodologies. This approach led to the identification of 99 genome-wide significant loci. Next, we employed various transcriptome-wide association methods to analyse highly correlated susceptibility gene signal loci and their associated regulatory elements in relation to a GWAS of reproductive ageing in women. These analyses were integrated at the tissue, cellular, and genomic element levels. Additionally, we evaluated the significant correlations between 1,200 identified susceptibility factors and the GWAS signals relevant to the reproductive ageing of women. The polygenic scores obtained through summary statistics were further used to clarify the risk evidence of different chromosomes based on structural equations and their relationship with the reproductive ageing of women. Through the analysis of a GWAS that did not directly measure phenotypes, our study provides for the first time a comprehensive characterization of the genetic structure of the reproductive ageing of women.

Sex differences in lifespan are pervasive in nature and in humans, yet the contribution of sex chromosomes to DNA methylation-linked aging remains incompletely defined. We leveraged human sex chromosome aneuploidies to test whether X and Y chromosome dosage influences epigenetic aging, quantified with DNA methylation (DNAm) clocks. In whole blood from individuals with karyotypes 46,XX (female) and 46,XY, 47,XXY, 47,XYY (male), we measured epigenetic age and age acceleration using a first-generation clock (Skin & Blood) and two next-generation clocks (GrimAge and DunedinPACE), and examined the components underlying GrimAge. Next-generation clocks indicated lower epigenetic age acceleration and a slower pace of aging in 47,XXY versus 46,XY. In GrimAge, a weighted sum of DNAm surrogates, higher DNAmLeptin (negatively weighted) and lower DNAmPACKYRS (positively weighted smoking proxy) in 47,XXY jointly reduced GrimAge in comparison to 46,XY. DunedinPACE also indicated a slower pace of aging in 47,XXY. In contrast, the first-generation Skin & Blood clock indicated higher age acceleration in 47,XXY and 47,XYY than in 46,XY. Enrichment analyses of autosomal EWAS loci highlighted immune pathways and karyotype-specific signatures, for example, metabolic/cancer-related processes in 47,XXY and renal/amino acid transport processes in 47,XYY. Overall, X chromosome gain in 47,XXY was associated with lower GrimAge and slower DunedinPACE, whereas the Skin & Blood clock diverged, suggesting that DNAm clocks capture partially distinct biological domains of aging differentially perturbed by sex-chromosome dosage. These findings motivate larger, age-spanning studies with direct phenotyping to define mechanisms.

Lysosomes are essential for neuronal homeostasis, providing degradation and recycling functions necessary to support neurons' complex operations and long lifespans. However, the regulation of lysosomal degradative capacity in healthy neurons is poorly understood. Here, we investigate the role of HLH-30, the sole Caenorhabditis elegans homolog of Transcription Factor EB (TFEB), a master regulator of lysosome biogenesis and autophagy that is thought to predominantly function in the context of starvation or stress. We demonstrate that HLH-30 is dispensable for neuronal development but acts cell-intrinsically to expand lysosomal degradative capacity during early adulthood. Loss of HLH-30 leads to lysosomal dysfunction and delayed turnover of synaptic vesicle proteins from the synapse. Notably, we show that basal HLH-30 activity is sufficient to expand neuronal lysosomal capacity without nuclear enrichment, in contrast to the nuclear translocation associated with starvation- and stress-induced activation of TFEB and HLH-30. Furthermore, we show that neuronal lysosomal function declines with age in wild-type animals, and this corresponds to a decrease in basal HLH-30-mediated transcription. We further demonstrate that basal HLH-30 activity is crucial for neuron maintenance: lysosomal dysfunction due to inadequate HLH-30 activity leads to dendrite degeneration and aberrant outgrowths. In summary, our study establishes a critical role for HLH-30/TFEB in promoting lysosomal capacity to preserve neuronal homeostasis and structural integrity of mature neurons in vivo.

Immunosenescence increases susceptibility to infectious diseases like tuberculosis (TB) in older subjects ([≥]60 years) and may impact containment of Mycobacterium tuberculosis (Mtb) during therapeutic intervention. A deeper understanding of cellular and molecular changes with age could inform new strategies to improve therapeutic outcomes. Here, we monitored the immunopathology, frequency and functionality of immune cells across extreme age groups of C57BL/6 mice following low aerosol dose infection (100-120 cfu) with Mtb H37Rv and treatment with rifampicin and isoniazid (RIF-INH). Up to 6 weeks of infection, tissue (lung, spleen and liver) mycobacterial load in old (17-19 months; M) and aged (31M) C57BL/6 mice was similar compared to young (2-4M) mice. However, at two weeks post-treatment, older mice showed a slower rate of Mtb clearance in the lungs. Old Mtb-infected mice had higher splenic T-follicular cytotoxic (TFC)-like cells and proteomic analysis of flow-sorted CD4+CD44+ T cells revealed deregulated mitochondrial proteins (4-hydroxy-2-oxoglutarate aldolase, aspartate aminotransferase and prostaglandin E synthase), pointing to impaired mitochondrial function. Collectively, these findings suggest that age-associated immune alterations may impair immunometabolic processes contributing to delayed Mtb clearance. These results highlight the potential importance of targeting immunometabolic dysfunction to improve TB treatment outcomes in older populations and reduce morbidity. SummaryThe elderly population is particularly susceptible to tuberculosis (TB), making it crucial to understand the cellular and molecular mechanisms contributing to the decline in immune responses with age. Evaluating the immunopathology, frequency and functionality of immune cells and Mtb-specific antibody responses across different age groups is essential for developing adjunct therapies for geriatric TB patients.

Microglia are resident immune cells of the central nervous system (CNS) and critical regulators of neural homeostasis, mediating immune surveillance, synaptic remodeling, debris clearance, and inflammatory signaling. Emerging evidence highlights the extracellular matrix (ECM) as important to microglial behavior in both physiological and pathological contexts. The CNS ECM is a dynamic and bioactive scaffold composed of three primary compartments: interstitial matrix, basement membranes at neurovascular and neuroepithelial interfaces, and perineuronal nets (PNNs). Each compartment exhibits distinct molecular architectures, ranging from fibrillar collagens and glycoproteins in basement membranes to chondroitin sulfate proteoglycans and hyaluronan-rich structures in PNNs. In this review we examine how microglia engage with and reshape the ECM to dynamically respond to disruptions in homeostasis with aging and disease. We discuss the concept of the microglial-ECM "interactome", which may represent a molecular interface through which microglia sense, modify, and respond to their extracellular environment. This interactome enables microglia to enact fine-scale ECM remodeling during routine surveillance, as well as large-scale alterations under pathological conditions to help preserve function and motility. In aging and disease, dysregulation of the microglial-ECM interactome is characterized by aberrant mechanotransduction, elevated proteinase activity, remodeling of the ECM, and sustained pro-inflammatory cytokine release. These pathological changes compromise ECM integrity, challenge microglial activity, and contribute to progressive neurovascular and synaptic dysfunction. Deciphering the molecular mechanisms underpinning microglial-ECM interactions is essential for understanding region-specific vulnerability in neurodegeneration and may reveal new therapeutic targets for preserving ECM structure and countering CNS disorders.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) can reverse senescence after acute kidney injury (AKI) via maintaining mitochondrial homeostasis. Copper accumulation and STAT3 nuclear translocation promote senescence, but their mitochondrial localization in response to MSCs remains unclear.

Methylation of the Opg promoter inhibits hepatic OPG expression in obese mice. Hepatic OPG regulates glucose metabolism and insulin sensitivity in obese mice. OPG regulates glucose metabolism through interaction with mammalian target of rapamycin complex 1 (Raptor). Opg deficiency in mice reduces age-related metabolic dysfunction.

The Target of Rapamycin, TOR, is a conserved signalling pathway with characterised chemical inhibitors such as rapamycin and torin1. Bi-steric third-generation inhibitors, such as rapalink-1 have been developed, however, their effects on organismal gene expression and lifespan have not been characterised. Here, we demonstrate that rapalink-1 affects fission yeast spatial and temporal growth and prolongs chronological lifespan with a distinct TORC1 selectivity profile. Endosome and vesicle-mediated transport and homeostasis processes related to autophagy render cells resistant to rapalink-1. Our study reveals TOR-regulated genes with unknown roles in ageing, including all fission yeast agmatinases, the enzymes that convert agmatine to putrescine and urea. Through genome-wide screens, we identify sensitive and resistant mutants to agmatine and putrescine. Genetic interactome assays for the agmatinase agm1 and further cell and molecular analyses demonstrate that impairing the agmatinergic branch of arginine catabolism results in TOR activity levels that are beneficial for growth but detrimental for chronological ageing. Our study reveals the anti-ageing action of agmatinases within a metabolic circuit that regulates TOR activity, protein translation levels and lifespan.

Alzheimer's disease (AD) is the most prevalent form of dementia with incompletely understood pathogenesis. A major gap arises from the lack of proteomics tools capable of characterizing alternative splicing (AS)-derived proteoforms and their contributions to neurodegeneration. We developed a novel bioinformatics pipeline, TMTCrunch, tailored for rigorous quantitative meta-analysis of big proteomics data at the splice-proteoform level. TMTCrunch characterizes each proteoform by unique peptides, assessing similarity to canonical peptides and unique peptide coverage, employing SMD-based quantitation, and predicting proteoform-specific alterations of protein-protein interactions (PPIs) and novel post-translational modifications (PTMs) on spliced peptides. Applying TMTCrunch to 420 brain samples, we constructed the first atlas of splicing translatomes in AD, reproducibly identifying 870 noncanonical proteoforms. Differential analysis suggests splicing affecting proteoforms implicated in cytoskeletal regulation (e.g., MAPT, CLU, DPYSL3, ACTN2, SORBS1, FHL1), glutamatergic transmission (GRIA3), pre-mRNA splicing regulation (ARL6IP4), potassium channel modulation (DPP6), and cAMP signaling (PDE4D). Our analysis predicts disruption of PPIs within the Rho GTPase and EGFR signaling pathways and PTMs (deamidation, oxidation, phosphorylation) within AS regions, regardless of disease state. This approach implicates specific proteoforms in neurodegeneration: DPP6 (P42658-2), GRIA3 (P42263-2), the three-repeat isoforms of tau (3R-MAPT), and ASPH (Q12797-7). This study provides new insights into linking splicing to neurodegeneration.

The cardiovascular system exhibits circadian rhythmicity, responding to central and peripheral clocks. Sexual dimorphism and aging independently influence circadian rhythms and cardiac electrical activity, which the autonomic nervous system regulates. However, the extent to which sex and aging affect autonomic dynamics remains unclear. This study investigates their role in circadian cardiac autonomic activity in healthy subjects. Data from 51 males and 51 females with 24-hour Holter recordings were analyzed. Circadian patterns of Heart Rate Variability parameters, indicators of autonomic function, were assessed using fast Fourier transformation with 5-minute Blackman-Harris windows on artifact-free recordings. Fractal, multifractal, visual, and information methods were applied to evaluate parasympathetic and sympathetic influences. We calculated the means and standard deviation for all numeric variables. We found temporal fluctuations across the time domain and frequency parameters. Six of the eight nonlinear HRV parameters significantly fluctuated. Among the 17 fluctuating parameters analyzed, nine circadian indicators (MESOR, amplitude, and acrophase) showed significant differences between sexes, with women exhibiting higher vagal oscillatory activity. Aging diminished fluctuations across all parameters and was associated with chronodisruption of cardiac autonomic markers. These findings highlight neurohumoral differences as key modulators of cardiac autonomic dynamics. The interaction effect of sex and age impacts the circadian rhythmicity of cardiac electric activity, as reflected by the HRV analysis. Our results have implications for personalized diagnostics, treatment timing, risk prediction, and biomarkers, highlighting the need for age-and sex-specific approaches in precision medicine and chronomedicine.

Obesity and aging synergistically reinforce neuroinflammation and disruption of homeostatic mechanisms, triggering pathological behaviors such as increased anxiety. Cannabidiol (CBD) has been reported to exert anxiolytic, anti-inflammatory, and neuroprotective effects, supporting the hypothesis that it may attenuate the detrimental consequences of obesity, even in aged animals. To test this hypothesis, 18-month-old male Wistar rats were divided into four experimental groups: control + vehicle (CT + vehicle), CT + CBD, cafeteria diet + vehicle (CAF + vehicle) and CAF + CBD. The animals were fed their diets for 8 weeks. Oral treatment with CBD (15 mg/kg/day) or vehicle began in the 9th week and continued until the end of the experiment, concurrently with the ongoing diet. We found that the CAF increased anxiety-like behaviors in the open field and elevated plus maze tests, while CBD mitigated these behaviors in the open field. Obesogenic diet also increased circulating levels of lipopolysaccharide, which were reduced by CBD. In the prefrontal cortex, CAF increased levels of interleukin 6 (IL-6), which were decreased by CBD. Additionally, CBD reduced the expression of tumor necrosis factor-α (TNF-α) and toll-like receptor 4 (TLR4). CAF feeding also caused a reduction in the main endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA). In the prefrontal cortex, CAF increased transcripts of cannabinoid receptor 1 (CB1) and reduced those of cannabinoid receptor 2 (CB2) and serotonin receptor 5-hydroxytryptamine receptor 1A (HTR1A). Moreover, levels of triggering receptor expressed on myeloid cells 2 (TREM2) were reduced by the diet. These findings support the notion that obesity, through its metabolic and inflammatory consequences, exacerbates neuroinflammation and contributes to the dysregulation of the endocannabinoid system in aged animals. Notably, CBD demonstrated the ability to attenuate inflammatory markers and improve anxiety-like behavior, suggesting its potential as a therapeutic strategy to counteract obesity-induced neurobiological alterations in aging.

Oxidative stress plays a critical role in age-related pathophysiology, and postmenopausal women are particularly vulnerable due to hormonal and metabolic changes. Although dietary quality has been implicated in modulating oxidative balance, few studies have explored whether obesity mediates this relationship in this population, representing a novel perspective in dietary-oxidative research.

Structurally similar oxysterols such as 7α-hydroxycholesterol, 7β-hydroxycholesterol, and 7-ketocholesterol; 5,6α- and 5,6β-epoxycholesterol; and 24(R/S)-hydroxy cholesterol, 25-hydroxy cholesterol, and 27-hydroxycholesterol are traditionally difficult to resolve using reversed-phase liquid chromatography (RPLC). We present a simple yet highly optimized method for the simultaneous quantification of eight oxysterols using RPLC coupled with mass spectrometry (MS) without derivatization. Optimal separation of most oxysterols was achieved at a lower column temperature (25°C), with specific combinations of stationary and mobile phases enhancing resolution, particularly for isomeric pairs such as 7α-/7β-OHC, 5,6α-/5,6β-EC, 24 R/S-OHC, and 25-OHC. Although certain analytes (e.g., 24S-OHC and 27-OHC) remained challenging to separate due to similar retention behavior, they were distinguishable by their unique MRM transitions. We applied this method to investigate oxysterol changes in a longitudinal mouse study comparing a normal diet to a high-fat diet. Liver and brain samples were analyzed, revealing distinct distribution patterns between the two organs. Notably, 24(S)-hydroxycholesterol levels, a signature cholesterol metabolite exclusively produced in the brain, increased with age independent of diet. In contrast, 5,6α-epoxycholesterol production in the liver was influenced by both age and dietary factors. Our method provides a robust tool for studying oxysterol variation and its implications in aging and diet, offering new insights into cholesterol-derived lipid regulation across different physiological conditions.

Physical activity benefits health, whereas physical inactivity increases the risk of age-related conditions and adverse health outcomes. Kyotango City in Japan is known for its residents' longevity, and many centenarians live there. This study investigated the physical activity associations with physical function and body composition in older adults living in this area.

Epigenetic age acceleration (EAA) predicts morbidity and mortality in the general population, but its prognostic utility in people with HIV (PWH) on suppressive antiretroviral therapy remains unclear.

Given resveratrol's (RES) potential as an anti-aging agent, this study explored its ability to inhibit the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome through the miR-217/SIRT1 axis in senescent endothelial cells. Male C57BL/6 mice were administered a customized regular diet supplemented with 0.04 % RES for 64 consecutive weeks. Subsequently, the effects of RES on senescent human umbilical vein endothelial cells (HUVECs) induced by H

Poor circadian health is increasingly recognized as a determinant of aging and chronic diseases, yet longitudinal evidence in free-living populations remains limited. Most prior studies have been restricted to cross-sectional designs or short 7-day monitoring, precluding insight into long-term aging dynamics. To address this gap, we analyzed multi-year consumer wearable data linked with electronic health records from the All of Us Research Program to evaluate circadian rest-activity rhythms as longitudinal predictors of biological aging. Among 2,222 participants (median age 60.6 years, 68.5% female) contributing 8,447 person-years of Fitbit activity data with annual biological age estimates (PhenoAge), we performed high-dimensional digital phenotyping integrating functional data analysis with conventional rhythm metrics. Higher rhythm intensity reduced the odds of accelerated aging by 26-46%, greater regularity lowered the odds by 9-13%, whereas delayed acrophase increased the odds by 22%. Sex-stratified analyses revealed universal protection from rhythm intensity in both sexes, but stronger timing- and regularity-related vulnerabilities to accelerated aging in females (12-18% higher odds). In contrast, males exhibited a biphasic instability phenotype, characterized by early-morning surges and late-evening rebounds, uniquely linked to accelerated aging. This study provides the first large-scale longitudinal evidence establishing circadian rest-activity rhythms derived from consumer wearables as digital biomarkers of aging trajectories. With the growing scalability and ubiquity of consumer devices, our findings pave the way toward scalable aging risk assessment, targeted interventions, and advancing digital precision medicine to promote healthy longevity at the population level.

Age-related tissue changes lead to reduced oxygen delivery to photoreceptors and the retinal pigment epithelium (RPE), and contribute to the pathology of age-related macular degeneration (AMD). The implication of hypoxia-inducible factors (HIFs) in this process makes them good candidates as therapeutic targets for AMD. We developed a multiplex dual-acting therapy utilizing the shRNAmir system, delivered by a single AAV, that reduces mRNA levels of Hif1a in photoreceptors and Hif2a in the RPE. This RNA interference-based strategy demonstrated a strong therapeutic effect, potently preserving photoreceptors and the RPE in two models of pseudo- and true hypoxia up to 61 weeks post-injection. The efficacy of our dual-acting virus proved superior to single-acting viruses targeting only Hif1a in photoreceptors or Hif2a in the RPE. By targeting a common, conserved disease pathway, this gene-agnostic RNAi therapy shows significant potential to protect tissues from chronic hypoxic insults in complex diseases such as AMD.

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders influenced by environmental factors and characterised by a dysregulated immune response. DNA methylation (DNAm) a key epigenetic mechanism plays a role in the etiology of complex diseases like IBD. Epigenetic clocks which estimate biological aging through DNAm patterns have also been linked to various health states, including IBD. Previously, we profiled DNA methylation in peripheral blood from adult IBD patients and controls using the Illumina 450K microarray (n = 184). We now expand this dataset with 8-year clinical follow-up data, including disease progression and treatment response. Additionally, we generate second and third-generation epigenetic clock measures in this cohort to investigate if IBD patients exhibit epigenetic age acceleration compared to healthy controls. We identified one CpG site (cg03583111) significantly differentially methylated in IBD patients with long-term clinical recurrence (after the first year of study) compared to non-recurrence (no treatment escalation after 8 years). We assessed DNAm aging signatures in IBD patients versus controls, finding evidence of significant epigenetic age acceleration, as measured by three epigenetic clocks (GrimAge, GrimAge2, and DunedinPACE), in IBD patients compared to controls. These associations were replicated in two independent IBD cohorts: adult (GSE87648, n = 377) and paediatric (GSE112611, n = 238). Moreover, we observed higher age acceleration (GrimAge, U = 669, p = 0.003) and a faster pace of aging (DunedinPACE, t = 3.233, p = 0.002) in patients with active UC compared to inactive disease, but not for CD. These findings suggest that blood-based DNAm signatures could serve as biomarkers for detecting, monitoring, and classifying IBD.

Gravity, the force that structures the cosmos, also shapes human physiology. It influences skeletal, muscular, cardiovascular, respiratory, and neurological systems, sustaining balance, blood circulation, and functional capacity. Unlike other senses, the brain lacks a dedicated gravity-sensing region and instead relies on a distributed vestibular network-graviception-to interpret gravitational cues. On Earth, gravity-driven blood pooling in the legs triggers compensatory responses that preserve cerebral perfusion. In microgravity, these mechanisms are altered, leading to fluid shifts toward the head, visual disturbances, cerebral changes, and increased thrombosis risk. Prolonged spaceflight induces muscle atrophy, bone demineralization, cardiovascular deconditioning, and orthostatic intolerance upon return to Earth. Whether these changes represent "adaptation" or "deconditioning" remains debated, but the outcomes resemble the physiological decline of frailty and aging. Earth-based analogs, including bed rest, dry immersion, and parabolic flights, reproduce many of these effects, linking gravitational unloading to postural instability, orthostatic hypotension, falls, and fractures. Such complications often fuel a vicious cycle of immobility and functional decline, central to both chronic illness and geriatric care. Viewing spaceflight as a model of accelerated aging offers new opportunities for clinical innovation. Research in altered gravity environments provides insights into countermeasures that preserve muscle mass, cardiovascular stability, and postural control. Strategies such as targeted exercise, optimized fluid management, and even hypergravity interventions may not only safeguard astronaut health but also translate into novel therapies for older adults. By bridging space medicine and aging research, these approaches can help mitigate frailty, reduce healthcare burdens, and enhance quality of life.

The mitochondrial genomic homeostasis is essential for the function of the oxidative phosphorylation system and cellular homeostasis. Mitochondrial DNA is particularly susceptible to aging-related oxidative stress due to the lack of a histone coat. Disturbances in mitochondrial DNA may contribute to functional decline during the aging process and in neurodegenerative diseases, leading to further impairment of mitochondrial DNA and initiating a vicious cycle. To date, it remains unclear how disturbed mitochondrial DNA is involved in the etiology of pathological aging and neurodegenerative diseases. The purpose of this review is to clarify the crucial roles of mitochondrial DNA homeostasis in the pathogenesis of neurodegenerative diseases. Mitochondrial DNA is distributed within nucleoids and is then transcribed into polycistronic mitochondrial DNA molecules within the mitochondrial granule region. Within the ultrastructure of the mitochondrial nucleoid and granule, a group of essential mitochondrial proteins involved in DNA replication, DNA transcription, RNA translation, RNA surveillance, and RNA degradation plays a crucial role in maintaining mitochondrial structure, genome integrity, and mitochondrial DNA processing. The uniparentally inherited mitochondrial DNA undergoes heritable polyploid variations, which include homoplasmy and heteroplasmy. Accumulating mitochondrial DNA alterations, such as deletions, point mutations, and methylations, occur during the pathogenic processes of neurodegenerative diseases. The increased mitochondrial DNA alterations can be propagated by the rise of deleterious heteroplasmy in neurodegenerative diseases, ultimately resulting in impairment to the oxidative phosphorylation system, biogenesis defects, and cellular metabolic dysfunction. Therefore, developing appropriate gene editing tools to rectify aberrant alterations in mitochondrial DNA and targeting the key proteins involved in maintaining mitochondrial DNA homeostasis can be considered promising therapeutic strategies for neurodegenerative diseases. Although therapeutic strategies targeting mitochondrial DNA in diseases show great potential, challenges related to efficacy and safety require a better understanding of the mechanisms underlying mitochondrial DNA alterations in aging and neurodegenerative diseases.

The influence of physical activity (PA) and sedentary behavior (SB) on survival to late age with intact mobility is unclear. This study investigated associations between accelerometer-measured daily PA, SB, and survival to age 90 birthyear with and without intact mobility in the Women's Health Accelerometry Collaboration (WHAC).

BackgroundParkinson's disease (PD) is one of the most widespread neurodegenerative diseases that affect the central nervous system (CNS) in elderly individuals. As of right now, there is no recognized cure for this illness. Parkinson's disease is not developing because of new medications. Bioactive phytochemicals are a natural alternative that can help older persons postpone age-related cognitive diseases.PurposeCurrently, FDA-licensed medicines for Parkinson's disease only provide symptomatic relief. This study attempts to establish whether nicotine, an alkaloid found naturally in nightshade plants, especially tobacco, may diminish parkinsonism in a model of Caenorhabditis elegans disease.MethodsThis study analyzes the antioxidant and restorative mitochondrial dysfunction potential of nicotine and its related neuroprotective benefits by utilizing models of Caenorhabditis worm strains that are different from the wild type. We examined the effects of nicotine on oxidative stress tolerance and associated regulatory pathways using a model of Caenorhabditis worms.ResultsOur results showed that wild-type C. elegans treated with nicotine had higher survival rates during oxidative stress caused by Juglone than those treated with the control. Nicotine decreased intracellular reactive oxygen species levels in C. elegans. In addition, nicotine increased levels of SOD, CAT, and MDA as well as the expression of genes related to stress response, including gst-4, hsf-6, and hsf-1, and mitochondrial function genes, including mev-1, isp-1, and cox-4. Finally, our molecular analysis indicates that the anti-oxidative effects of nicotine are mediated via skin-1 modulation. After Paraquat was administered, nicotine therapy also resulted in higher levels of ATP and MMP.ConclusionOur research clarifies the various mechanisms of action and communication pathways that underlie nicotine's antioxidant activity in vivo, offering a solid pharmacological foundation for its potential therapeutic use in neurodegeneration.

Aging involves the alteration of the central nervous system myelin, which is produced by oligodendrocytes. These cells originate from oligodendrocyte precursor [neural/glial antigen 2 (NG2)] cells, which are influenced by neuroinflammatory processes. Neuroinflammatory activity contributes to accelerated aging in individuals with mental illnesses such as major depressive disorder (MDD). This study was conducted to better understand the anti- and pro-neuroinflammatory changes associated with NG2 cells in aging individuals with MDD. Human postmortem dorsolateral prefrontal cortex samples were obtained from adults with MDD and normal controls (NCs) of different ages. Western blotting was performed to measure the protein levels of the oligodendrocyte progenitor cell marker NG2, the inflammatory markers interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), hepatocyte growth factor (HGF), and the anti-inflammatory neuronal viability marker B-cell lymphoma 2 (Bcl-2). Age-related changes in these markers were examined by simple linear regression. In NCs, the levels of NG2 and HGF increased linearly with age (

Age-Related Macular Degeneration (AMD) is one of the leading causes of irreversible vision loss worldwide, characterized by the degeneration of the retinal pigment epithelium (RPE) and photoreceptor cells, resulting in progressive loss of central vision. RPE cells are highly specialized and essential for retinal function, and their malfunction due to genetic, environmental, or age-related factors contributes significantly to AMD pathogenesis. Ultraviolet A (UVA) radiation is recognized as a major causative factor, as it induces the accumulation of reactive oxygen species (ROS) in RPE cells, ultimately contributing to the development of AMD. On the other hand, acemannan, a D-isomer mucopolysaccharide derived from Aloe vera pulp, is known for its antioxidant and anti-inflammatory properties. In this study, we extracted a highly purified Aloe-derived polysaccharide fraction enriched in acemannan, designated Aloe polysaccharide J2 (ACJ2), to investigate its protective effects against UVA-induced RPE damage. The results showed that post-treatment with ACJ2 significantly reduced UVA-induced cell death by lowering mitochondrial ROS levels, suppressing phosphorylation of mitogen-activated protein kinases (MAPKs), including p38 MAPK, extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK), and downregulating proinflammatory mediators including tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and inducible nitric oxide synthase (iNOS). Furthermore, ACJ2 enhanced heme oxygenase-1 (HO-1) expression and mitochondrial DNA levels, and inhibited p62/sequestosome-1 (p62) consumption and microtubule-associated protein 1 light chain 3 (LC3)-I/II conversion, thereby reducing autophagic flux. These findings demonstrate that ACJ2 mitigates UVA-induced damage and restores disrupted autophagy in RPE cells, supporting its potential as a therapeutic candidate for AMD.