Longevity Papers

Epigenetic clocks are powerful biomarkers of biological aging, however, their performance varies across studies and contexts. Current limitations include siloed datasets, inconsistent validation methods, and the absence of a standardized framework for systematic comparison. Here, we introduce TranslAGE: a publicly available online resource that addresses this gap by harmonizing 179 human blood DNA methylation datasets and precalculating a suite of 41 epigenetic biomarker scores for each of the >42,000 total samples. Users can explore these data through interactive dashboards that evaluate four fundamental performance domains: Stability, Treatment response, Associations, and Risk, collectively forming the STAR framework. Stability quantifies robustness to multiple types of technical and biological noise. Treatment response measures biomarker sensitivity to aging interventions and environmental exposures. Associations capture cross-sectional relationships with age, demographics, disease, and other phenotypes, and Risk assesses predictive power for future functional decline, morbidity and mortality. The STAR framework unifies these test metrics into a single composite scoring system that enables researchers to identify, benchmark, and validate biomarkers best suited to their scientific or clinical applications. TranslAGE will be continually updated, with rapid scaling by adding datasets, biomarkers, or analyses. By providing harmonized datasets, precomputed biomarker scores, and interactive data tools, TranslAGE establishes the first standardized, reproducible framework for benchmarking epigenetic aging biomarkers across populations, and accelerates the translation toward clinical use.

Cellular senescence is a fundamental driver of ageing and age-related diseases, characterized by irreversible growth arrest and profound epigenetic alterations. While long non-coding RNAs (lncRNAs) have emerged as key regulators of senescence, their potential for senescent cell rejuvenation remains unexplored. Here, we identify the ageing-associated lncRNA PURPL as an epigenetic regulator that controls cellular rejuvenation through H3K9me3-mediated transcriptional silencing. CRISPRi-mediated PURPL depletion produces striking rejuvenation effects, resulting in restored youthful cell morphology, as well as suppression of senescence markers such as p21 and SA-β-gal. Conversely, PURPL overexpression accelerates cellular senescence, recapitulating the transcriptional and phenotypic hallmarks of ageing. Mechanistically, nuclear-localized PURPL regulates H3K9me3 deposition at 411 genomic loci including SERPINE1 (PAI-1) and EGR1, which are key senescence drivers. PURPL-mediated H3K9me3 loss at these loci derepresses their transcription, establishing a pro-senescence gene expression program. These findings reveal that PURPL is an epigenetic modulator of senescence and highlight its potential as a therapeutic target for age-related pathologies.

Background: The American Heart Association's Life's Essential 8 (LE8) score was designed to quantify an individual's cardiovascular health (CVH). Previously we developed a novel biomarker (retinal BioAge) to estimate biological aging from a deep-learning analysis of retinal images. This study investigates the association between retinal BioAge and CVH, as quantified by LE8, and identifies the key health factors driving this relationship. Methods: This retrospective study included 4,887 participants (aged 40-70 years) from the UK Biobank. The retinal BioAgeGap (retinal BioAge minus chronological age) was calculated from retinal images. A CVH score was computed for each participant. Results: Participants in the highest CVH quartile were shown to have a negative retinal BioAgeGap while the lowest CVH quartile had a positive retinal BioAgeGap (-0.36 vs. +0.30 years; difference = -0.65 years, P<0.001). Ablation analysis identified blood pressure as the most significant driver of this association, accounting for 66.3% of the total change in effect size (??d?=0.11, P<0.001). Among individuals with high CVH scores, a negative retinal BioAge was no longer found among those with hypertension (?130/80mmHg) compared to those without (+0.08 vs -0.52 years, P<0.001). Conclusions: Better CVH is strongly associated with a "younger" retinal BioAge. Blood pressure was the predominant contributor to this association and an accelerated retinal BioAge was noted even in those individuals who had an otherwise favorable CVH score but were hypertensive. This study highlights retinal BioAge?s potential as a scalable, non-invasive tool for refining cardiovascular risk assessment.

This meta-analysis evaluated the effects of resistance training on insulin resistance, muscle function, and systemic inflammation in middle-aged and older adults (aged 50 years and older) with type 2 diabetes mellitus (T2DM). PubMed, Web of Science, Scopus, and Cochrane CENTRAL were systematically searched from their inception to May 20, 2025. Forty-three randomized controlled trials (n = 2012 (55.8 % women); mean age 57.8 ± 8.4 years; mean BMI 30.9 ± 3.8 kg/m

The aging process is characterized by a general decrease in physical functionality and poses the biggest risk factor for a variety of diseases such as cancer, cardiovascular diseases, and neurodegenerative disorders among others. Understanding the naturally evolved mechanisms that slow aging and rejuvenate an animal could reveal important concepts on how to prevent age-associated diseases and even revert aging. The C. elegans dauer stage is a robust and long-lived alternative developmental state that, after dauer exit, has a normal adult lifespan with fully retained fecundity. To understand how longevity during dauer and rejuvenation following dauer exit is mediated, we characterized the gene expression changes during dauer and upon exit. We assessed how biological age, as determined via BiT Age, a transcriptome aging clock, is affected during dauer and upon dauer exit. During the dauer stage, we measured a decelerated increase in age compared to the chronological age and an age reversal following dauer exit. Transcriptomic analyses revealed major metabolic shifts and enhanced biomolecular degradation that are reversed during exit. Moreover, we show that transcription-blocking lesions can induce lasting transcription stress in dauers that is rapidly resolved by transcription-coupled nucleotide excision repair during dauer exit. Our data provide new insights into the underlying mechanisms of naturally occurring age deceleration and rejuvenation.

Clonal haematopoiesis of indeterminate potential (CHIP) refers to the age-related expansion of haematopoietic stem cells bearing somatic mutations in the absence of overt haematological malignancy. Emerging evidence suggests that CHIP is not merely a marker of ageing, but an active driver of meta-inflammation, a chronic systemic inflammatory state arising from metabolic dysregulation. Indeed, several studies have linked CHIP with an increased risk of cardiovascular, renal and hepatic diseases, diseases which are known to be driven by inflammation. CHIP also appears to be associated with upstream metabolic precursors such as obesity and type 2 diabetes, suggesting its involvement across the cardiometabolic disease continuum. Importantly, this relationship may be bidirectional: systemic inflammation promotes CHIP expansion, while CHIP mutations further fuel inflammation. Thus, anti-inflammatory agents that mitigate CHIP-driven inflammation may have a future therapeutic role in cardiometabolic diseases. Furthermore, gene-based therapies offer exciting opportunities for precision approaches in CHIP. This review aims to synthesise emerging evidence that links CHIP with cardiovascular, renal and hepatic diseases, emphasising shared inflammatory pathways. Moreover, the review aims to highlight current knowledge gaps, including the need to establish causality between CHIP and cardiometabolic diseases. Furthermore, it emphasizes the need for future research in both human populations and pre-clinical models to elucidate the underlying mechanisms that could ultimately position CHIP at the forefront of cardiometabolic medicine.

We present a computational pipeline that links nuclear morphology to mRNA expression-based cell phenotypes under diverse biological conditions, including aging, disease progression, and drug response, using RNAscope imaging. The pipeline consists of three components: nuclear segmentation from RNAscope images, nuclear morphology identification, and downstream statistical analysis. Central to our approach is a novel unsupervised method, based on deep disentangled representation learning, which effectively captures diverse nuclear morphologies in large-scale datasets, as validated on synthetic benchmarks. We applied the full pipeline to RNAscope data targeting dopaminergic and glutamatergic neuron populations in the midbrains of mice and humans. Our analyses uncovered distinct nuclear morphology differences between dopaminergic and non-dopaminergic, as well as glutamatergic and non-glutamatergic neurons, in both species. Moreover, we identified a significant interaction between neurotransmitter identity and healthy aging in mice, reflected in systematic changes in nuclear morphology. These findings position nuclear morphology as a scalable and informative imaging-based readout of cell identity and physiological state.

Later life is characterized by the development of chronic inflammation, termed inflammaging, alongside changes in immune cell profiles, or immunosenescence. While these features contribute to health risk, they have also been interpreted as adaptive remodeling of the immune system in response to accumulating somatic damage. Here we consider a recently developed theoretical framework to understand these processes as interrelated: the Brain-Body Energy Conservation model of aging. This model views functional declines, such as immunosenescence, as part of an energy conserving response to the rising energy expenditure of inflammaging. This response promotes short term survival against somatic damage at the expense of future health risk. For example, naive T cells, which enhance defense against future infections, decline with age. We find evidence consistent with this model in the US Health and Retirement Study (HRS) and UK Biobank (UKB). TNFR1, a key marker of inflammaging, mediated 10% and 5% of the age-related declines in naive CD4T and CD8T cells respectively in the HRS (n = 8,261). Consistent with an impaired immune response to future infections, TNFR1 also mediated 16% of the age-related increased risk of hospitalization or death from COVID-19 in the UKB (n = 522 hospitalized or died, full sample n = 40,638). GDF15, which is produced in response to metabolic stress and has been found to induce immune tolerance in response to chronic inflammation, mediated 28% of the TNFR1-related COVID-19 health risk, as well as 38% of the age-related increased risk independent of TNFR1.

Genetic information in cells flows from DNA to RNA to proteins, which form molecular machines. During normal ageing, cell intrinsic and environmental factors alter this flow of information by damaging DNA in cells, including postmitotic neurons. Damage to DNA is associated with age-related neurodegenerative diseases such as Alzheimer's disease (AD). We previously reported an increase in DNA repair mechanisms in a fly model of AD. However, the causal mechanisms underlying somatic mutations in AD remain unclear. Here, we combine in silico methods from single-cell genomics of patients with AD with experimental validation in a Drosophila model of AD to elucidate the DNA repair processes in AD. We show that the levels of poly(ADP‒ribose) polymerase 1 (PARP1), which mediates multiple DNA damage repair pathways, are increased in the brains of patients with AD. We found that higher PARP1 levels in neurons from patients with AD are linked to increased disease risk and a greater burden of somatic mutations. Nucleotide imbalance can increase the frequency of somatic mutations upon activation of DNA repair processes. Using a fly model of AD, we identified a metabolic signature in AD animals characterised by decreased levels of phosphorylated nucleotides. Enhancing nucleotide metabolism via dietary supplementation or genetic manipulation protects against AD pathology in animals. Finally, Mendelian randomisation revealed that higher expression of human deoxyguanosine kinase (DGUOK) is linked to a lower risk of developing AD. Our results suggest that enhancing nucleotide metabolism could improve DNA repair and serve as an adjunct therapy to delay AD progression.

Presbycusis, or age-related hearing loss (ARHL), is a prevalent sensory disorder in the elderly, driven by genetic factors, oxidative stress, inflammation responses, and cellular senescence. Despite its significance, the molecular mechanisms underlying ARHL remain poorly defined. In this study, we employed bioinformatic analysis of public gene expression datasets to identify differentially expressed genes in ARHL. Protein-protein interaction network analysis further nominated LCN2 as a hub gene. Experimental validation in aging C57BL/6J mice and HEI-OC1 auditory cells revealed that elevated LCN2 expression promotes cellular senescence, while its knockdown delays this phenotype. Mechanistically, LCN2 drives senescence by activating the NF-κB signaling pathway, and its inhibition alleviates senescence induced by tert-butyl hydroperoxide (TBHP). Our findings establish LCN2 as a key pro-senescence factor in ARHL and demonstrate that it regulates auditory cell senescence through the NF-κB pathway, providing new mechanistic insights and revealing potential therapeutic targets for ARHL intervention.

Biological aging clocks across organ systems and tissues have advanced understanding of human aging and disease. In this study, we expand this framework to develop seven magnetic resonance imaging-based multi-organ biological age gaps (MRIBAGs), including the brain, heart, liver, adipose tissue, spleen, kidney and pancreas. Using data from 313,645 individuals curated by the MULTI Consortium, we link the seven MRIBAGs to 2,923 plasma proteins, 327 metabolites and 6,477,810 common genetic variants. Genome-wide associations identify 53 MRIBAG-locus pairs (P < 5 × 10

Frailty is a major health concern associated with aging and has been linked to gut microbiome composition, especially in elderly individuals needing care. People with HIV (PWH) present high risk of early-onset frailty. This study examines the relationship between frailty and the gut microbiome, with an emphasis on sex-based differences in PWH. Data were drawn from 268 participants in the New Orleans Alcohol Use in HIV (NOAH) Study, including 16S microbiome sequencing from stool samples, cytokine levels, viral load, and T cell counts. Frailty was assessed using phenotypic frailty index (PFI) and a 58-item deficit index (DI-58). Fourteen taxa were significantly linked to both PFI and DI-58. Among females, butyrate-producing genera (e.g., Eubacterium ventriosum and Butyricimonas) were inversely associated with frailty, while genera such as Paraprevotella and Romboutsia showed positive associations. In males, Prevotella and Erysipelotrichaceae UCG-003 were inversely associated, whereas Christensenellaceae R-7, Clostridium sensu stricto, and others were positively associated with frailty. Fifteen genera were also linked to circulating cytokine levels (IL-1β, IL-17A, IL-2, IFN-γ). We identified three community state types (CSTs) with unique bacterial structures. Community state analysis identified CST 2, characterized by lower diversity and more pathobionts, to be highly predictive of increased frailty. These findings underscore the relevance of sex-specific differences in the gut microbiota relations with frailty, supporting tailored interventions for frailty in PWH.

Osteoarthritis (OA) is the most common age-induced degenerative joint disease associated with synovial inflammation, subchondral bone remodeling, and cartilage degradation. One of the significant emerging causes of OA progression is senescent cell accumulation within the joint compartment during lifespan. Currently, there are no therapeutic approaches nor stratification tools that rely on the senescence burden in OA. In this study, we identified the b-series ganglioside 3 (GD3) as new senescent cell surface marker associated with OA. Joint RNA sequencing analysis revealed an increase expression of the GD3 synthase, ST8SIA1 in cartilage, synovial tissue, and subchondral bone marrow from OA patients compared to healthy donors. Moreover, we revealed a strong correlative association between the expression of ST8SIA1 and GD3 production with senescence hallmarks in an in vitro-induced 3D organotypic OA cartilage model but also with cartilage histological grading scores in human and preclinical murine OA joints. Anti-GD3 cell sorting showed that GD3-positive human OA chondrocytes or human OA synoviocytes are enriched in senescence and SASP markers compared to GD3-negative counterparts confirming that GD3 is a cell surface marker linked to the senescence stage. Intra-articular anti-GD3 antibody delivery in experimental OA model reduced local expression of senescence and OA markers in association with a protection against OA-induced subchondral bone remodeling. Our research demonstrates a compelling linkage between ST8SIA1 gene, GD3, and senescence in OA pathology, revealing knowledge and perspectives for a better understanding and anti-senescence treatment of OA pathogenesis.

Hutchinson Gilford progeria syndrome (HGPS) is a fatal premature aging disorder caused by pathogenic farnesylated lamin A variants that disrupt nuclear architecture and DNA repair. Current therapies, including farnesyltransferase inhibitors, provide only modest survival benefits and lack molecular specificity, while mutation-specific genome-editing strategies cannot address atypical laminopathies. Here, we develop Farnesylation Amino acid Targeted Editing (FATE), a mutation-agnostic base-editing platform that selectively disrupts the LMNA farnesylation motif without affecting other farnesylated proteins. Using isogenic human pluripotent stem cell derived neuromuscular organoids (NMOs), we reveal muscle-specific progerin accumulation that sequesters 53BP1 and abolishes DNA damage foci formation. FATE eliminates perinuclear progerin, restores 53BP1 mobility, reconstitutes DNA repair foci, and normalizes heterochromatin architecture. Importantly, transient delivery of FATE mRNA conjugated with lipid nanoparticles to HGPS NMOs achieves efficient base editing and phenotypic rescue. These findings establish FATE as a mutation-independent therapeutic strategy targeting a fundamental pathogenic mechanism in HGPS and provide a proof-of-concept for RNA-based in situ genome editing in progeroid disease.

Individuals diagnosed with Alzheimer\'s disease (AD) are at an increased risk of bone fractures. Conversely, a diagnosis of osteoporosis in women is the earliest known predictor for AD. However, mechanisms responsible for the coupled decline in cognitive and skeletal health remain unclear. Proteomic analysis of cortical bone from aged mice revealed neurological disease-associated proteins that are highly enriched in aged mouse bones, including apolipoprotein E (Apoe) and amyloid precursor protein. Further, Apoe localized specifically to bone-embedded osteocytes with expression twice as high in aged female bone as in young or male counterparts. In humans, APOE allele variants carry differing AD risk with age. To investigate APOE allelic roles in bone, we utilized a humanized APOE knock-in mouse model that expresses either the protective APOE2, the neutral APOE3, or the AD risk factor APOE4, and analyzed bone and hippocampus from the same mice. APOE4 exerted strong sex-specific effects on the bone transcriptome and proteome, relative to APOE2 or APOE3. Interestingly, the APOE4-associated perturbation in the female bone proteome was more pronounced than the corresponding alterations observed in the hippocampus. APOE4 protein causes bone fragility in females, but not males, even without changes in cortical bone structure. These bone quality deficits arose from suppression of osteocyte perilacunocanalicular remodeling. We find that APOE4 is a new molecular culprit capable of disrupting osteocyte maintenance of bone quality as early as midlife in a manner that disproportionately affects females. These findings highlight osteocytes as potential targets for early diagnosis of age-related cognitive impairment, and treatment for bone fragility, in females.

Aging is a major risk factor for neurodegenerative diseases, yet the underlying mechanisms linking aging to neurodegeneration remain incompletely understood. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in sensing mislocalized cytoplasmic DNA, triggering innate immune responses such as type I interferon (IFN-I) and NF-κB signaling, and promoting senescence-associated secretory phenotypes (SASP). In the aging central nervous system (CNS), cellular senescence is accompanied by mitochondrial DNA (mtDNA) leakage, nuclear DNA damage, and other changes that may aberrantly activate the cGAS-STING pathway. This activation drives neuroinflammation, potentially increasing susceptibility to neurodegenerative diseases or exacerbating pre-existing pathology. Conversely, neurodegenerative disease-related processes-such as pathological protein aggregation-can further stimulate cGAS-STING signaling, amplifying inflammatory cascades and accelerating cellular senescence. This review explores the molecular mechanisms linking cGAS-STING activation to neurodegeneration and discusses potential therapeutic strategies targeting this pathway.

Biological aging exhibits significant heterogeneity across individuals, and a precise evaluation at scale is urgently needed. Here, we developed a PCAge, based on common clinical, physiological, and laboratory indices routinely collected in primary healthcare, in the CHARLS. PCAge demonstrated strong correlations with chronological age (r = 0.86-0.88, P < 0.001) and robust performance in the prediction of mortality (C-index = 0.798) over a 10-year follow-up. Biologically older individuals (PCAge > chronological age) suffered from substantially higher risk of age-related diseases, including cardiovascular disease (HR = 1.30, P < 0.001), heart disease (HR = 1.35, P = 0.003), stroke (HR = 2.38, P < 0.001), hypertension (HR = 1.28, P = 0.007), and diabetes (HR = 1.51, P < 0.001). Furthermore, the generalizability of PCAge was validated in the South China Cohort (SCC, n = 68,920). Biologically older individuals were more likely to have hypertension, diabetes, cardiovascular disease, and respiratory diseases. Being female (proportion ratios [PR] = 1.94, P < 0.001), lower education attainment (PR = 1.18, P < 0.001), higher income (PR = 1.47, P < 0.001), and unfavorable lifestyles (PR = 1.41, P < 0.001) were associated with a higher probability of having accelerated aging. PCAge identified aging trajectories up to a decade before clinical disease onset, offering a cost-effective tool for population-level aging surveillance. Our findings underscore the potential of PCAge as a highly accessible tool for the evaluation of aging status, especially in resource-limited areas.

Brain-age prediction from neuroimaging data provides a proxy of biological aging, yet most models rely on structural magnetic resonance imaging (MRI), a modality that captures macroanatomy but offers limited biological specificity. We tested whether integrating molecular-enriched functional connectivity (FC), from resting-state functional MRI (rs-fMRI) data, improves brain-age prediction and biological explainability. We analyzed MRI data of 2,120 healthy adults (1,243/877 F/M; 18 -90 years) from three public datasets. Molecular-enriched connectivity maps were derived with Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) using receptor-density templates for the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporter systems. Support vector regression models were applied to predict chronological age from molecular-enriched FC, structural morphometry, or both combined. The effect of multi-site variability was mitigated via ComBat harmonization with and without Empirical Bayes pooling. We additionally conducted a common-parcellation analysis to assess the impact of differing parcellations between modalities. Single-transporter molecular-enriched FC explained up to 51% of age variance. The most predictive transporter varied by dataset, with DAT dominating in the harmonized and common-parcellation settings. Combining the three molecular-enriched maps consistently improved prediction over any single map and increased explained variance up to 64%. In the merged multi-site cohort using a common parcellation, augmenting structural information with transporter-enriched FC reduced mean absolute error (MAE) from 6.02 to 5.81 years, supporting complementarity of the two modalities. In contrast, when different parcellations were applied, incorporating molecular-enriched FC into brain age prediction resulted in a 2% higher MAE compared to structural morphometry alone, suggesting that parcellation mismatch may obscure the functional contributions. In conclusion, molecular-enriched FC is a feasible and biologically informative extension to brain-age modeling, enhancing prediction and interpretability with respect to neurotransmitter systems.

Marine ecosystems harbor a remarkable diversity of bioactive compounds with unique chemical structures and potent pharmacological activities. These marine-derived metabolites have gained increasing attention as promising therapeutic agents for metabolic disorders, particularly diabetes and aging-related diseases. This review highlights the emerging roles of marine-sourced Sirtuin 1 (SIRT1) and Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) activators in modulating glucose and lipid metabolism, enhancing antioxidant defense mechanisms, and ameliorating cellular senescence. We summarize the mechanistic pathways by which key marine compounds-such as fucoxanthin, bromophenols, and coral-derived steroids-modulate SIRT1 and NRF2 signaling, potentially providing synergistic effects superior to those of terrestrial or synthetic analogues. The review also addresses the challenges in pharmaceutical formulation and sustainable production, emphasizing the need for advanced biotechnological strategies and innovative delivery systems. While preclinical evidence is compelling, clinical translation remains limited by issues related to bioavailability, safety, and sustainable production. Future research should focus on clinical trials, improved formulations, and sustainable production platforms to unlock the therapeutic potential of marine natural products for diabetes and aging-related metabolic disorders.

Dysfunction of muscle satellite cells is linked to diabetic myopathy. The mechanisms vitiating muscle satellite cell proliferative activity in diabetes are not well understood. Here, we show that AS160, a key cytosolic Rab-GTPase activating protein (RabGAP) in insulin signaling, is a moonlighting protein regulating muscle satellite cell proliferation as a transcriptional co-factor. Deletion of AS160, but not its GAP-inactive mutation, impairs muscle satellite cell proliferation and consequent muscle regeneration, and exacerbates age-related sarcopenia. Mechanistically, Thr

Aging is the most important risk factor for multiple pathologies including cardiovascular, neoplastic, metabolic and neurodegenerative diseases. Potential geroprotective strategies involve lifestyle-related, nutritional and pharmacological interventions. Recently, chalcones, a subgroup of secondary plant metabolites, have gained attention. 4,4'-dimethoxychalcone was the first chalcone to be shown to mediate geroprotection and lifespan extension across different species. Several other chalcones also exert anti-aging effects at the cellular and organismal levels. Defined mechanistic routes that are causally involved in these protective effects have been delineated. Here, we summarize current evidence supporting the potential of 4,4'-dimethoxychalcone and other chalcones as geroprotective agents.

Aging imposes a significant socioeconomic and healthcare burden worldwide, while effective therapy is still lacking. Impaired brain drainage and excessive accumulation of metabolites and toxins such as advanced glycation end products (AGEs) are characteristics of aging that contribute to the development of neurological disorders. Recent discoveries have highlighted the role of meningeal lymphatic vessels (MLVs) in the clearance of toxic metabolites, cells, tumors, and viruses from the brain, positioning them as significant targets for the treatment of various brain diseases. In this study, we demonstrate that noninvasive 1275-nm photobiomodulation (PBM) effectively improves brain drainage and promotes lymphatic clearance of AGEs in a D-galactose-induced aging model (AM) in male mice, while being safe due to its minimal thermal effects. These improvements are associated with nitric oxide release-mediated dilation of MLVs. PBM can also effectively ameliorate redox imbalance, neuroinflammation, and neuronal damage, as well as improve spatial learning ability and short-term recognition memory in AM mice. These findings introduce a promising and easily accessible strategy for nonpharmacological phototherapy of meningeal brain drainage and neurological decline in individuals with aging and aging-related neurodegenerative diseases, offering high potential for rapid implementation into routine clinical practice.

Chaperone-mediated autophagy (CMA) declines in ageing and neurodegenerative diseases. Loss of CMA in neurons leads to neurodegeneration and behavioural changes in mice but the role of CMA in neuronal physiology is largely unknown. Here we show that CMA deficiency causes neuronal hyperactivity, increased seizure susceptibility and disrupted calcium homeostasis. Pre-synaptic neurotransmitter release and NMDA receptor-mediated transmission were enhanced in CMA-deficient females, whereas males exhibited elevated post-synaptic AMPA-receptor activity. Comparative quantitative proteomics revealed sexual dimorphism in the synaptic proteins degraded by CMA, with preferential remodelling of the pre-synaptic proteome in females and the post-synaptic proteome in males. We demonstrate that genetic or pharmacological CMA activation in old mice and an Alzheimer's disease mouse model restores synaptic protein levels, reduces neuronal hyperexcitability and seizure susceptibility, and normalizes neurotransmission. Our findings unveil a role for CMA in regulating neuronal excitability and highlight this pathway as a potential target for mitigating age-related neuronal decline.

Diet is a major environmental factor influencing the human gut microbiome. However, the effects of specific foods and dietary patterns on microbial composition, diversity, and function is not fully understood, limiting progress toward personalized dietary strategies. Leveraging 10,064 participants from the Human Phenotype Project with app-based diet logs and shotgun metagenomics, we predicted diet-microbiome associations at species-level resolution. Diet significantly predicted microbial diversity (Richness r=0.24, Shannon index r=0.22), the relative abundance of 664 of 724 species tested (91.5%, FDR<0.05), and 313 of 320 functional pathways (97.8%, FDR<0.05). Feature attribution identified distinct food-microbe links, including coffee with Lawsonibacter asaccharolyticus (r=0.41), yogurt with Streptococcus thermophilus (r=0.38), and milk with Bifidobacterium species (r=0.31-0.35). In parallel, broader dietary patterns, especially those related to the degree of food processing, emerged as predictors of microbial diversity and composition. Longitudinal analyses on test set data showed that models remained predictive over two and four years (R2=0.73-0.79), with significant associations between observed and predicted changes in 115 and 92 species, respectively. Finally, we developed an exploratory analysis for suggesting personalized dietary interventions with predicted microbiome shift effects that are associated with improvements in key clinical biomarkers such as triglycerides. Overall, our findings establish diet as a key modulator of microbiome composition, diversity, and function, and highlight its potential for guiding personalized interventions.

Defects in the faithful expression of the human mitochondrial genome underlies disease states, from rare inherited disorders to common pathologies and the aging process itself. The ensuing decrease in the capacity for oxidative phosphorylation alone cannot account for the phenotype complexity associated with disease. Here, we address how aberrations in mitochondrial nascent chain synthesis per se exert a decline in cell fitness using a classic model of mitochondrial induced premature aging. We identify how intrinsic errors during mitochondrial nascent chain synthesis destabilize organelle gene expression, triggering intracellular stress responses that rewire cellular metabolism and cytokine secretion. Further, we show how these mechanisms extend to pathogenic variants associated with inherited human disorders. Together, our findings reveal how aberrations in mitochondrial protein synthesis can sensitize a cell to metabolic challenges associated with disease and pathogen infection independent of oxidative phosphorylation.

Mammalian female reproductive span is thought to be limited by a fixed \"ovarian reserve\" determined at birth. With age, a dwindling ovarian reserve leads to infertility, culminating in menopause in humans. In addition to infertility, accumulating evidence has shown that age-related ovarian functional decline contributes to multisystem aging and frailty, making post-menopausal women most susceptible to an array of chronic diseases. However, due to limited tissue accessibility and lack of reliable research models, molecular drivers of ovarian aging remain poorly understood. A key barrier in the field has been the limited establishment and benchmarking of preclinical models faithfully recapitulating human ovarian biology. To address this, we curated publicly available single-cell/nucleus ovarian RNA-seq datasets from human, macaque, mouse, and goat, and processed them using a consistent and stringent pipeline. Datasets were then annotated in a harmonized fashion across studies in order to conduct a robust, integrative, cross-species analysis of ovarian aging with single cell resolution. We systematically evaluated cell-type composition, global transcriptional perturbations, gene-level changes, pathway and network features, and drug-response alignments. Across analyses, granulosa and theca cells emerged as the cell-types most affected by aging. We observed limited but promising consistencies across species, including granulosa-specific signature genes (FSHR and OSGIN2) and cell type-linked pathways, with extracellular matrix/adhesion programs in granulosa and ribosomal/mitochondrial programs in theca cells. These convergences suggest that cross-species modeling likely capture core aspects of ovarian aging. Together, our meta-analysis approach may help refine model selection, generate testable hypotheses, and cautiously inform preclinical and translational work in ovarian aging.

Evidence indicates that exposure to environmental chemicals may be related to frailty; however, most existing research has focused on single-exposure scenarios. This study aims to systematically evaluate the relationships between multiple environmental toxin exposures and frailty using a comprehensive exposure group approach and to investigate potential mechanisms mediated by systemic inflammation. Data from 2354 participants in the 2013-2016 National Health and Nutrition Examination Survey (NHANES) were analyzed. Environmental toxins were categorized into 10 groups, encompassing 61 substances. Frailty was assessed using a 36-item Frailty Index (FI). We applied an exposure‑wide association study (ExWAS; to screen for individual toxin-frailty associations) and deletion/substitution/addition (DSA; to identify key exposures in multi‑exposure contexts) models, and used Bayesian kernel machine regression (BKMR; to evaluate joint relationships and potential interactions among selected exposures). The role of systemic inflammation was evaluated through mediation analysis. Of the 2354 adults analyzed, 657 (27.9 %) were classified as frailty. ExWAS and DSA models identified total nicotine equivalent-2, tungsten, cobalt, tin, and N-acetyl-S-(2-carboxyethyl)-L-cysteine as significant exposures associated with frailty. BKMR analysis revealed a positive correlation between key exposures and frailty. Mediation analysis indicated that systemic inflammation mediated 2.5-14.6 % of these associations. To our knowledge, this is the first comprehensive study to report associations between three categories of five environmental toxins and frailty in U.S. adults, with inflammation potentially serving as a partial mediator. These findings are critical for identifying hazardous environmental chemicals and developing targeted strategies to promote healthy aging.

Mitochondrial dysfunction driven by calcium overload is a hallmark of cardiac hypertrophy, yet the role of Sirtuin-3 (Sirt3) in regulating this process remains incompletely defined. Specifically, the mechanism by which CD38-mediated NAD depletion links Sirt3 deficiency to mitochondrial calcium dysregulation remains incompletely elucidated. Therefore, 12 week-old Sirt3-deficient mice were used as cardiac hypertrophy model. The morphological changes of cardiac muscle fibers and the ultra-structure changes of mitochondria were detected by hematoxylin and eosin (HE) staining and transmission electron microscopy (TEM). Then, multi-omics approach was used to analyze the differently expressed genes and different metabolites. Key genes and metabolites were scrutinized through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, in vitro studies examining the effects of Sirt3 knockdown on H9C2 cells, including intracelluler and mitochondrial reactive oxygen species (ROS) and calcium, and mitochondrial membrane potential (MMP). Western blot and qPCR were used to verify the differently expressed genes. The hearts of Sirt3-deficient mice increased myofiber thickness, and altered mitochondrial morphology. Sirt3 deficiency induced mitochondrial dysfunction was promoted by an inhibition of the translation of oxidative phosphorylation (OXPHOS) complex subunits. Multi-omics profiling implicated CD38 as a major NAD consumer and linked the metabolites of CD38 to cAMP signaling pathways. Furthermore, in vitro studies examining H9C2 Sirt3 knockdown showed an increase in intracellular and mitochondrial ROS levels, a decrease in MMP, and promoted MCU expression and mitochondrial calcium overload. However, CD38 inhibitors effectively attenuated Sirt3 knockdown-induced elevations in intracellular and mitochondrial ROS levels, dissipation of mitochondrial membrane potential, and mitochondrial calcium overload, thereby restoring mitochondrial function. In summary, the Sirt3-CD38 axis induces mitochondrial dysfunction in hypertrophied heart by regulating mitochondrial calcium overload. These findings will aid in providing new ideas for the prevention and treatment of age-related cardiac hypertrophy.

Aging is a major, yet unmodifiable, cardiovascular risk factor and is associated with vascular alterations, increased cardiac fibrosis, and inflammation, all of which contribute to impaired cardiac function. However, the microenvironment inciting age-related alterations within the multicellular architecture of the cardiac tissue is unknown.

Aging is a highly complex and heterogeneous process that progresses at different rates across individuals, making biological age (BA) a more accurate indicator of physiological decline than chronological age. While previous studies have built aging clocks using single-omics data, they often fail to capture the full molecular complexity of human aging. In this work, we leveraged the Human Phenotype Project, a large-scale cohort of 12,000 adults aged 30--70 years, with extensive longitudinal profiling that includes clinical, behavioral, environmental, and multi-omics datasets -- spanning transcriptomics, lipidomics, metabolomics, and the microbiome. By employing advanced machine learning frameworks capable of modeling nonlinear biological dynamics, we developed and rigorously validated a multi-omics aging clock that robustly predicts diverse health outcomes and future disease risk. Unsupervised clustering of the integrated molecular profiles from multi-omics uncovered distinct biological subtypes of aging, revealing striking heterogeneity in aging trajectories and pinpointing pathway-specific alterations associated with different aging patterns. These findings demonstrate the power of multi-omics integration to decode the molecular landscape of aging and lay the groundwork for personalized healthspan monitoring and precision strategies to prevent age-related diseases.

Cellular senescence is a stable state of cell-cycle arrest characterized by extensive remodeling of the secretome, known as the senescence-associated secretory phenotype (SASP). The SASP profoundly influences tissue microenvironments and contributes to chronic inflammation and age-related diseases. While previous studies have characterized the SASP using bottom-up proteomics, intact proteoforms' diversity and structural complexity remain poorly understood. In this study, we apply quantitative top-down mass spectrometry to profile the intact proteoform composition of the SASP in senescent human fibroblasts, alongside quiescent and proliferating controls. This approach enables direct identification of intact proteoforms with post-translational modifications (PTMs), sequence variants, and isoforms, offering deep insight into the proteomic landscape of senescence. We identify a rich repertoire of previously uncharacterized proteoforms, including variants of HMGA2 with N-terminal acetylation and multiple phosphorylation states (di-, tri-, and tetra-phosphorylated), implicating them as potential senescence biomarkers. Our findings underscore the functional complexity of the SASP and the value of proteoform-level resolution in understanding cellular senescence. This work establishes a robust top-down proteomics strategy for SASP analysis and highlights novel molecular targets for therapeutic strategies aimed at mitigating age-related pathologies.

DNA methylation based aging biomarkers, or epigenetic clocks, are increasingly used to estimate biological age and predict health outcomes. Their translational utility, however, depends not only on predictive accuracy but also on reliability, the ability to provide consistent results across technical replicates and repeated biological measures. Here, we leveraged the TranslAGE platform to comprehensively evaluate the technical and biological reliability of 18 Epigenetic clocks, including chronological predictors, mortality predictors, pace-of-aging measures, reliable variants, and newer explainable clocks. Technical reliability was quantified across four independent datasets. For standard replicate assays on EPIC and 450K arrays, nearly all clocks achieved excellent technical reproducibility. However, some clocks showed dramatic drops in technical reliability based on differences in slide position and DNA extraction protocol. PC-based clocks, especially PCGrimAge and SystemsAge remained technically reliable in all cases. In contrast, biological reliability, measured across repeated samples collected within hours, before and after meals, under acute stress, across environmental exposures, and over days, was markedly lower, with most clocks showing only moderate stability. PCGrimAge was the only clock with good ICC > 0.75 for biological reliability. Importantly, technical reproducibility did not predict biological reliability; clocks that were technically robust often proved biologically unreliable. We further demonstrated that reliability directly constrains downstream applications. Clocks with higher ICCs produced more stable prognostic associations with cognitive decline and more consistent responsiveness to a vegan diet intervention, whereas unreliable clocks yielded highly variable or spurious effects. Together, these findings reveal that technical reliability is not enough: biological reliability remains a critical limitation for many DNA methylation clocks that constrains their utility, and our work provides a roadmap for prioritising next-generation clocks most suited for clinical translation.

Reproductive aging is characterized by the progressive decline of reproductive function, with broad implications for overall health and longevity. Environmental factors, including assisted reproductive technologies (ART), can accelerate reproductive aging by promoting premature ovarian failure in females. In vitro fertilization (IVF), though widely used and generally considered safe, is associated with lasting effects on offspring health. Using a mouse model that closely approximates human IVF, we demonstrate that IVF accelerates reproductive aging in female offspring by inducing premature ovarian failure. IVF-conceived females exhibit altered ovarian function, disrupted endocrine profiles, and transcriptomic and epigenetic changes consistent with premature reproductive decline. These findings reveal long-term consequences of IVF on female reproductive health and highlight the need to understand how early-life interventions influence reproductive longevity.

With an aging global population, cognitive decline in older adults presents significant healthcare challenges. Emerging evidence suggests that physical activity can support cognitive health by promoting plasticity, functional reorganization, and structural adaptation of the brain. In the FIT4BRAIN study, we examined the effects of multi-component physical activity on cognitive and brain health. Here, we report the results on one of the secondary outcomes, namely changes in brain age (BrainAGE), which estimates the difference between chronological and predicted brain age based on structural MRI data, and changes in brain structure, assessed through voxel-based morphometry (VBM). Ninety-two healthy older adults were randomized into a multi-component physical activity group, performing aerobic, coordination, and balance exercises, or an active control group engaging in non-aerobic relaxation exercises and educational content (physical activity group (PAG): 36 participants; active control group (CON): 33 participants). Of these, 69 participants underwent MRI assessment and were included in the present analyses. BrainAGE analyses revealed a greater decrease in the physical activity group compared to the control group, indicating a beneficial effect of physical activity on brain aging. Subgroup analyses based on baseline cardiorespiratory fitness (CRF) further revealed that participants with lower CRF showed greater benefits, consistent with VBM findings of structural changes in the same subgroup. These results underscore BrainAGE as a sensitive biomarker for intervention outcomes and suggest that stratification by baseline fitness level may help identify differences in the benefits of physical activity on brain health.

The maintenance of a stable genome requires constant repair. Congenital DNA repair defects lead to cancer susceptibility and progeroid (premature aging-like) syndromes. Even with intact repair, DNA lesions accumulate in aging organisms, leading to replication and transcription stress and age-dependent somatic mutations. These, in turn, can compromise cellular function and elevate cancer risk. DNA damage response (DDR) mechanisms can lead to cellular death and senescence, and targeting the DDR has emerged as therapeutic strategy not only in cancer but also to protect from age-associated phenotypes. Inhibiting DNA repair can promote cancer cell death. Eliminating senescent cells may alleviate proinflammatory consequences on their tissue environment. Moreover, strategies to limit DNA damage and augment repair in normal cells are in active development. Here, we review emerging concepts for targeting genome maintenance mechanisms to lower cancer risk and lengthen healthy lifespan by extending the integrity and functionality of somatic genomes.

The emerging perception that the mammalian dermis encloses fibroblasts with differing functional identities has profound implications for understanding a wide range of genetic pathological states, including aging. MDPL syndrome (mandibular hypoplasia, deafness, progeroid characteristics, and lipodystrophy; MIM #615381) is an extremely rare, genetic progeroid disorder. Patients reported variants in the POLD1 gene (NM_002691.3), encoding for the evolutionarily conserved catalytic subunit of DNA polymerase delta (Polδ). The protein is a critical enzyme reliable for synthesizing nascent DNA strands in the eukaryotic genome. Importantly, Polδ also serves to repair DNA lesions due to mutagen exposure. As the natural history of MDPL still remains poorly known, we have performed RNA sequencing analyses on human dermal fibroblasts (HDFs) of two MDPL patients, heterozygotes for p.Ser605del, compared to WT HDFs. The bioinformatic analyses identify differentially expressed transcripts related to the extracellular matrix of connective tissue and transduction signal markers. Successively, we shed light on the capacity of MDPL cells to respond to and repair DNA damage by comparing transcript levels between X-irradiated MDPL HDFs and non-irradiated ones. Importantly, the results allowed us to identify specific downregulated molecular traits in irradiated MDPL HDFs, including those genes closely involved in the mechanisms of DNA replication and repair. These data were further validated at the functional level, choosing four pivotal proteins (CDC6 (Cell Division Cycle 6), CLSPN (Claspin), XRCC3 (X-Ray Repair Cross Complementing 3), RAD51 (DNA repair protein RAD51 homolog 1)) involved in interconnected pathways ensuring genomic stability. This work provides critical insights into the pathogenesis and the regulatory mechanisms of MDPL syndrome and related diseases, paving the way for future therapeutic interventions. KEY MESSAGES: We identified a molecular signature in MDPL human dermal fibroblasts by transcriptomic profiling. We identified specific markers linked to the extracellular matrix of connective tissue and transduction signal markers. We ascertained in irradiated MDPL human dermal fibroblasts specific downregulated molecular traits, involved in the mechanisms of DNA replication and repair. We validated at functional and biochemical level specific those proteins involved in pathways ensuring genomic stability. The markers identified could be targeted for therapeutic intervention in MDPL syndrome and aging-related diseases.

The human somatic genome evolves throughout our lifespan, producing mosaic individuals comprising clones harboring different mutations across tissues. While clonal expansions in the hematopoietic system have been extensively characterized and reported to be nearly ubiquitous, clonal mosaicism (CM) has more recently also been described across multiple solid tissues. However, outstanding questions remain about the parameters and processes of human somatic evolution in non-cancerous solid human tissues, including when clones arise, how they evolve over time, and what mechanisms lead to their expansion. Questions of timing and clonal dynamics can be addressed through phylogenetic reconstruction, which serves as a \'temporal microscope\', while uncovering the mechanisms of expansion necessitates simultaneous phenotypic profiling. To address this gap, here we develop Single-cell Miniaturized Automated Reverse Transcription and Primary Template-directed Amplification (SMART-PTA) for joint single-cell whole-genome and whole-transcriptome sequencing for large scale and cost-efficient interrogation of solid tissue CM. We established a workflow that generates hundreds of matched single-cell whole genome and transcriptome libraries within a week. We profiled phenotypically normal esophagus tissue from four aged donors\' and used somatic variants to build high-resolution single-cell lineages from >2,700 cells with accompanying transcriptomic information, reconstructing >70 years of somatic evolution. T cell expansions identified from T cell receptor (TCR) sequences validated the clonal structure of the single-nucleotide variant (SNV)-based phylogenies and phylogenetic cross-correlation analysis showed that epithelial cells had higher degrees of shared ancestry by spatial location compared to immune cells. Mapping mutation signatures to the phylogenetic tree revealed the emergence of tobacco/alcohol exposure-related signatures later in life, consistent with the donors\' exposure histories. We identified variants in driver genes that were previously reported in the phenotypically normal esophagus, detecting clonal expansions harboring mutations in genes including TP53 and FAT1. We mapped the evolution of clones with both monoallelic as well as biallelic TP53 loss, including a clone associated with high expression of cell cycling genes and higher chromosome instability. Leveraging the matched transcriptome data, we uncovered cell type biases in mutant clones, with a higher proportion of TP53 or FAT1-mutant cells in an earlier basal epithelial cell state compared to wild-type cells. We further observed copy-neutral loss of heterozygosity (CNLOH) events on chromosome 9q that spanned the NOTCH1 locus in up to ~35% of epithelial cells. Mapping CNLOH events to the phylogenetic tree revealed a striking pattern in which CNLOH was separately acquired many times, reflecting convergent evolution. Cells with CNLOH events were biased towards the earlier basal epithelial state, suggestive of a selective advantage that leads to prevalent recurrence of chr9q CNLOH. Together, we demonstrate that SMART-PTA is an efficient, scalable approach for single-cell whole-genome and whole-transcriptome profiling to build phenotypically annotated single-cell phylogenies with enough throughput and power for application to normal tissue somatic evolution. Moreover, we reconstruct the evolutionary history of the esophageal epithelium at high scale and resolution, providing a window into the dynamics and processes that shape clonal expansions in phenotypically normal tissues throughout a lifespan.

In our society, the aging of the population is a major concern of public health. Recently we have identified a new snoRNA (jouvence) in Drosophila, and showed that its deletion (F4) reduces lifespan, while its overexpression increases it. F4 deleted flies also present neurodegenerative lesions and a deregulation of metabolic parameters as triglycerides and sterol. However, a deeper characterization of this genomic locus has revealed the presence of two other snoRNAs. Here, we have characterized at the whole organismal level, the role of each them. First, we show that each snoRNAs are expressed in the epithelium of the gut (enterocytes), and in the fat body. Second, in F4 deletion, the re-expression of each snoRNA in the enterocytes or in the fat body is sufficient to improve lifespan, and protect against neurodegeneration in old flies. In addition, depending of the snoRNAs, it rescues the expression of specific deregulated genes within the epithelium of the gut, involved in lipids and sterol metabolism. Consequently, these two metabolic parameters are also rescued, establishing a relationship between the lesions of the brain, the metabolic disorders, the lifespan, and each snoRNAs respectively. Finally, histological stainings as Nile Red and BODIPY C11-581/591 have revealed that the neurodegenerative lesions are due to an increase of free sterol within the brain, and lipid peroxydation in the pericerebral fat body. Altogether, these results point-out a causal relationship between the epithelium of the gut and the neurodegenerative lesions through the metabolic parameters, indicating a gut-brain axis.

Resolving the molecular basis for heterogeneous aging in the human brain requires integrating its diverse molecular layers, including the transcriptional, epigenetic, and proteomic states. To provide such a view, we applied a tensor decomposition framework to jointly analyze single-nucleus RNA-seq, DNA methylation, histone acetylation, and proteomic data from 276 postmortem human dorsolateral prefrontal cortex samples from the ROSMAP aging cohort. Our analysis revealed two dominant themes defined by components with strong multi-omic coherence. First, we identified a robust immunometabolic axis characterized by microglial activation, suppression of PI3K-Akt-mTOR signaling, and epigenetic signatures suggesting the repurposing of developmental transcription factors. Second our analysis resolved the effect of sex into a mosaic of distinct, cell-type-specific molecular programs within glia. These included male-biased mitochondrial programs in microglia, a shift toward precursor-like states in the female oligodendrocyte lineage, and bidirectional epigenetic remodeling in astrocytes. This work provides a high-resolution atlas of glial aging, demonstrating that broad risk factors manifest as complex, cell-specific vulnerabilities; a critical insight for developing targeted therapeutic strategies.

Trajectories of age-related neurocognitive decline are not uniform, and are impacted by numerous environmental and physiological factors. Earlier life phases set the stage for later life neurocognitive function, with midlife marking a critical transition characterized by increasing variability in cognitive, affective, and physiological functioning. Despite its importance, this turbulent period remains underrepresented in open neuroimaging and phenotypic data resources. To address this gap, the Nathan Kline Institute - Rockland Sample (NKI-RS) initiative created the 'Mapping Interindividual Variation in the Aging Connectome' (MIVAC) substudy, an openly shared, multimodal dataset designed to map brain aging trajectories beginning in midlife and assess the influence of modifiable factors such as cardiorespiratory fitness. This longitudinal investigation includes 348 community-ascertained participants aged 38 to 71 years at baseline. Data collection incorporated deep phenotyping across cognitive, behavioral, medical, and cardiorespiratory fitness domains, along with multimodal neuroimaging (resting-state fMRI, diffusion MRI, morphometric MRI, and arterial spin labeling) and biospecimen collection. The protocol harmonizes with prior NKI-RS substudies while incorporating age-specific considerations for cognitive and neural aging. The full dataset is openly available.

As the global population ages, understanding the mechanisms underlying age-related diseases becomes increasingly important. Inflammaging, a state of chronic inflammation and immune dysregulation, is a key feature of aging. Macrophages, as master regulators of inflammation, are critical to this process. However, the effects of natural aging on alveolar macrophages (AMs) in the lungs remain poorly understood. In this study, we evaluated AM biology in older compared with young rhesus macaques. We compared cytokine profiles in plasma and bronchoalveolar lavage (BAL) fluid between young and aged macaques and performed single-cell RNA sequencing (scRNA-seq) to characterize age-related transcriptional and functional changes in AMs. Compared to young animals, AMs from aged animals exhibited similar cytokine inflammaging profile observed in the plasma of elderly humans. However, the general decrease of chemokine levels in BAL fluid relative to plasma suggest BAL may not reflect AM status in the lung tissues of rhesus macaques. scRNA-seq data corroborated plasma inflammaging findings, revealing increased inflammatory cytokine responses in AMs from older macaques. The consistent elevation of macrophage migration inhibitory factor (MIF) across plasma, AMs, and BAL fluid marks it as a promising biomarker and potential therapeutic target for age-associated inflammation. scRNA-seq further identified genes and pathways linked to macrophage senescence and turnover, suggesting potential targets for therapeutic intervention. Overall, our findings highlight the essential role of tissue-resident macrophages in pulmonary aging and underscores the need to further investigate their role in age-associated lung disease.

The endoplasmic reticulum (ER) stress-response is an adaptive cellular mechanism activated by an accumulation of unfolded proteins within the ER. Although recent evidence shows that the ER stress-response is activated in aged tissues, and therefore ER stress is considered a candidate driver of aging, the spatiotemporal regulation and roles of the ER stress-response during aging remain unclear. To address this research gap, we introduced an Ire1-Xbp1s ER stress-response pathway-sensitive reporter into the ultra-short-lived vertebrate Nothobranchius furzeri that allows for the analysis of its aging processes within a short period of time. Using this reporter in N. furzeri, we confirmed the previously reported age-dependent activation of ER stress in various tissues and identified an unexpected role of the Ire1-Xbp1s ER stress-response pathway in regulating epidermal tissue homeostasis and aging. The Ire1-Xbp1s ER stress-response pathway is active in the young epidermal basal layer but declines with aging. Photo-isolation chemistry-based spatial transcriptomics and functional assays revealed that the Ire1-Xbp1s pathway maintains young epidermal cell proliferation by activating the cell cycle regulator Vcp, whereas the age-dependent decline in glucose metabolism reduces Ire1-Xbp1s activity, consequently downregulating cell proliferation. Collectively, our study elucidates a previously unidentified role of the ER stress-response in skin aging, which can offer insights into therapeutic targets for promoting healthy skin.

Aging is a progressive and complex process of physiological changes that accumulate over time and end up undermining organismal performance. In many cases, this leads to the development of age-related diseases. Therefore, the identification of the exact mechanisms connecting aging to disease will be critical for the advancement of biomedical research in the field. Recently, a growing number of reports have linked ferroptosis, a form of non-apoptotic regulated cell death, to numerous age-related human pathologies. Although key molecular events associated with ferroptosis have been consistently observed with aging in various tissues, the interaction between ferroptosis and aging remains mostly unexplored. In this review, we investigate this interplay by examining reported findings from three different perspectives: (1) the manifestation of ferroptosis with age; (2) the acceleration of aging when ferroptosis is experimentally enhanced; and (3) the potential to slow, stop, or reverse aging through ferroptosis-targeted therapeutic interventions. Based on this analysis, we hypothesize that, although ferroptosis is defined as a cell death pathway, ferroptosis-related processes can operate at a chronic, sublethal level during aging. Importantly, the persistence of this stress might increase the susceptibility of organisms to age-associated diseases by undermining fundamental cellular functions that are critical to their healthspan, even in the absence of overt cell death. The implications for the design and development of new treatments for a broad range of age-related diseases where ferroptosis-related stress could play a central role is discussed.

Aging is a major risk factor for neurodegenerative diseases, yet the role of senescent microglia in age-related cognitive dysfunction remains incompletely understood. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been extensively studied for their significant potential in anti-aging. In this study, we demonstrated that hUC-MSCs ameliorate age-related cognitive decline and downregulate senescence-associated markers in the aged hippocampus. Furthermore, co-culture experiments showed that senescent microglia exacerbate neuronal senescence and neuroinflammation, while also suppressing the apoptosis of senescent neurons. These findings suggested that senescent microglia contribute to age-related cognitive decline by exacerbating neuronal damage and impairing senescent neurons' clearance. We also elucidated a novel mechanism by which hUC-MSCs alleviate age-related cognitive decline by targeting senescent microglia. Specifically, we showed that hUC-MSCs reduce senescence-associated markers, decrease lipid droplet accumulation, and restore phagocytic function in senescent microglia through the inhibition of the NF-κB-SREBP1 pathway. This pathway modulation attenuates neuronal damage and promotes the apoptosis of senescent neurons, facilitating the clearance of damaged neurons. These findings highlight the therapeutic potential of hUC-MSCs in age-related neurodegenerative disorders.

Immune cell metabolism is increasingly recognized as an important regulator of immune function, but its role in age-related immune dysfunction, chronic inflammation, and cardiometabolic complications in humans remains incompletely understood. This study investigated the impact of aging on monocyte metabolic and functional signatures in a healthy elderly population. We aimed to leverage these immunometabolic signatures to identify healthy elderly individuals with reduced immune cell fitness and, therefore, potentially at a higher risk for age-related complications. We characterized lactate and cytokine secretion, phagocytic capacity, and glycolytic and oxidative metabolic responses in monocytes from 103 elderly individuals and included 52 young adults as a reference group with healthy immune responses. We observed strong similarities in monocyte functional and metabolic signatures between young adults and elderly individuals. However, monocytes from the elderly secreted significantly more cytokines and displayed more ATP-linked respiration and a reduced proton leak compared to young adults. These significant differences were driven by a subgroup within the elderly population characterized by higher monocyte lactate secretion compared to the remainder of the elderly and young adults and were therefore classified as "immune-unfit". The immune-unfit elderly exhibited "hyperactive" monocytes, evidenced by significantly higher metabolic and functional signatures. Interestingly, compared to immune-fit individuals, immune-unfit elderly individuals had significantly elevated levels of circulating vascular endothelial growth factor and low-density lipoprotein cholesterol. Hence, we propose lactate secretion from monocytes as a parameter to classify "immune-unfit" elderly individuals with divergent immunometabolic properties of monocytes that could reflect increased susceptibility to age-related cardiometabolic complications. Trial Registration: NCT05940337.

Induced pluripotent stem cells (iPSCs) derived from patients with premature aging disorders are widely regarded as a foundation for both the study of fundamental aging mechanisms and preclinical testing of anti-aging therapies. The most well-studied is Hutchinson-Gilford progeria syndrome (HGPS), which is caused by a lamin A gene mutation. Comparing the progeroid phenotype in cell models of distinct premature aging syndromes is critical for identifying early and common aging hallmarks. In this study, using a non-integrative episomal approach we reprogrammed iPSCs from cells of a patient suffering from Wiedemann-Rautenstrauch Syndrome (WRS), which is caused by bi-allelic pathogenic mutations of the RNA polymerase III subunit A gene (POLR3A). In parallel, an iPSC line with the classic HGPS caused by a lamin A mutation was obtained. HGPS and WRS patient fibroblasts showed similar signs of cellular aging; however, unlike HGPS, the causal link between the premature aging phenotype and WRS driving mutations is unclear. RNA polymerase III is required for the transcription of small nuclear RNAs and being a target of TORC1 (Target of Rapamycin kinase Complex 1), it plays a role in longevity and aging in model organisms. Whereas lamin A is downregulated in iPSCs, allowing for regeneration of HGPS iPSCs, we found that POLR3A is upregulated during reprogramming. Enhanced expression of mutant POLR3A in WRS iPSCs led to nucleolus abnormalities and telomerase RNA component (TERC) sequestration in the nucleoli in WRS iPSCs. WRS iPSCs may be an important model for developing new therapeutic approaches affecting premature aging of stem cells.

Postoperative Cognitive Dysfunction (POCD), a key phenotype within the broader spectrum of Postoperative Neurocognitive Disorders (PND), represents a significant neurological complication, predominantly affecting elderly individuals and resulting in cognitive impairment and diminished quality of life. The Sigma-1 receptor (Sigma-1R), a critical modulator of cellular stress endowed with neuroprotective properties, has emerged as a potential therapeutic target. This investigation aimed to elucidate the role of Sigma-1R in age-related susceptibility to POCD and to assess the therapeutic efficacy of the Sigma-1R agonist, PRE-084. Employing an exploratory laparotomy mouse model of POCD, we evaluated age-dependent variations in hippocampal Sigma-1R expression, its specific cellular localization, and the effects of PRE-084 administration on cognitive performance and associated molecular pathways in aged mice. Our findings revealed significantly lower basal hippocampal Sigma-1R levels in aged mice compared to their adult counterparts. Subsequent to surgical intervention, adult mice demonstrated a robust upregulation of Sigma-1R, which correlated with preserved cognitive function. In contrast, aged mice exhibited a blunted Sigma-1R response (a non-significant trend towards an increase), correlating with more pronounced cognitive deficits. Immunohistochemical analysis confirmed predominant Sigma-1R expression within hippocampal neurons. Post-surgical administration of PRE-084 to aged mice resulted in a substantial amelioration of cognitive function, as assessed by the Morris water maze. These salutary effects were associated with an attenuation of endoplasmic reticulum (ER) stress, evidenced by reduced levels of BIP and p-eIF2α, mitigation of neuroinflammation, indicated by decreased microglial and astrocytic activation, inhibition of NF-κB activation, and promotion of CREB phosphorylation. In conclusion, this study underscores the pivotal role of a differential Sigma-1R response to surgical stress in the pathogenesis of age-related POCD. PRE-084 demonstrates promise as a therapeutic agent, exerting neuroprotection by alleviating neuronal ER stress, which in turn curtails secondary neuroinflammation and recalibrates critical NF-κB and CREB signaling pathways.

A decrease in osteoblast number and bone formation are seminal contributors to age-related osteoporosis. However, the aging-associated molecular mechanisms that impact osteoblast precursors, osteoblasts, osteocytes, and other bone mesenchymal cell types remain unclear. We performed single-cell RNA-sequencing of mesenchymal cells present at the endosteum and periosteum of young and old C57BL/6 mice of both sexes. Osteoblast precursors and osteoblasts from female endosteum exhibited the greatest changes with aging. Transcriptional changes revealed decreased matrix protein production and autophagy, as well as increased senescence, phosphorylation, and hypoxia. Because deficient macroautophagy in osteoblast lineage cells decreases bone formation, we contrasted the transcriptional changes caused by autophagy inactivation in Atg7