Longevity Papers

AMPK (AMP-activated protein kinase) is a crucial signaling protein found in essentially all eukaryotic organisms and acts as an energy sensor. When activated by metabolic stress, AMPK phosphorylates a variety of molecular targets, altering enzyme activity and gene expression to regulate cellular responses. In general, in response to low intracellular ATP levels (high ADP:ATP ratio), AMPK triggers the activation of energy-producing pathways while simultaneously inhibiting energy-consuming processes. Recent studies have established a connection between molecular pathways involved in sensing energy and potential for extending longevity. AMPK indirect activator compounds have shown a potential strategy to obtain an anti-aging biological activity. This study explores the conformational changes and transient druggable binding pockets over the 1 μs trajectory of molecular dynamics simulations to comprehend the behavior of main domains and allosteric drug and metabolite (ADaM) site. The described conformations of the apo-ADaM site suggest an important influence of specific residues on the cavity volume variations. A clustering set of representative AMPK conformations allowed to identify the more favorable binding site volume and shape at the protein apo form, including the carbohydrate-binding module (CBM) region which exhibited a stable movement near the ADaM site of the alpha-subunit. The identification of gamma-subunit transient druggable binding pocket CBS3 during the microscale time trajectory simulations also offers valuable insights into structure-based AMP-mimetic drug design for AMPK activation.

The glymphatic system facilitates efficient waste clearance in the brain through the movement of cerebrospinal fluid (CSF) along perivascular spaces. Animal studies have demonstrated that glymphatic efficiency declines with age, but evidence for such decline in humans is limited. We hypothesized that reduced glymphatic efficiency in older adults may be related to age-related worsening of sleep quality, potentially contributing to cognitive impairment.

Type I collagen is the main structural protein of vertebrates and forms molecular trimers from the COL1A1 and COL1A2 gene products; pro-alpha-1(I) and pro-alpha-2(I)), during biosynthesis. The amino acid sequence of the C-propeptide of collagen, which is removed before collagen fibril formation, initially drives heterotrimerisation and calcium ions are required for trimers to form. The homotrimeric form is associated with age-related diseases including cancer, fibrosis, musculoskeletal and cardiovascular conditions but circumstances under which the abnormal homotrimer may form were poorly understood. Here we used molecular dynamics simulations of the C-propeptide protein structure, to show that intra- and intra-chain hydrogen bonding is affected by the loss of calcium and that chains become destablised, particularly at the interfaces of each chain. Loss of calcium resulted in an increased distances between cysteine residues that form inter-chain disulphide bonds, predicting an inability for disulphides to form in the absence of calcium. Pulling simulations and modeling calcium dissociation from monomers showed that calcium ions were more strongly bound to the alpha-1(I) than the alpha-2(I) chain. However, pulling a single alpha chain from the heterotrimer or homotrimer demonstrated that the alpha-2(I) chain had a higher affinity to trimers than a third alpha-1(I) chain. Hence although heterotrimerisation is normally favoured, in reduced calcium conditions the homotrimer can form by sequestering available calcium to the alpha-1(I) chains. This study provides a molecular explanation for a calcium-based mechanism driving heterotrimerisation versus homotrimerisation of type I collagen.

Ceruloplasmin (CP) is a multi-copper ferroxidase mainly synthesized by liver, secreted into the peripheral blood, playing a critical role in regulating the iron homeostasis. In the central nervous system (CNS), the CP expressed by astrocytes plays an important role in the transportation of iron from the blood across the blood-brain barrier (BBB) into the brain. Our previous study showed that conditional knockout of astrocytic CP with Cre-LoxP system (Cp

Ageing-related DNA methylome and proteome changes and machine-learned ageing clock models have been described previously; however, there is a dearth of ageing clock prediction models based on human blood transcript information. Applying various machine learning algorithms is expected to aid in the development of age prediction models. Using blood transcriptome data from healthy subjects ranging in age from 21 to 90 in the 10 K Immunomes repository, we evaluated differentially regulated transcripts, assessed enriched gene ontology, pathway and disease ontology analysis to characterize biological functions associated with the genes associated with age. Furthermore, we constructed and compared age prediction models developed by applying the Least Absolute Shrinkage and Selection Operator (LASSO), Elastic Net (EN), eXtreme Gradient Boosting (XGBoost) and Light Gradient-Boosting Machine (LightGBM) algorithms. Compared to LASSO (7 genes) and EN (9 genes) regularized regression, XGBoost (142 genes) and LightGBM (149 genes) Gradient Boosted Decision Tree methods performed better in this dataset (training set r = 0.836 (LASSO), 0.837 (EN), 1.000 (XGBoost) and 0.995 (LightGBM); test set: r = 0.883 (LASSO), 0.876 (EN), 0.931 (XGBoost) and 0.915 (LightGBM); external validation set: r = 0.535 (LASSO), 0.534 (EN), 0.591 (XGBoost) and 0.645 (LightGBM)). Blood transcriptome-based age prediction models may provide a simple method to monitor biological ageing, and provide additional molecular insight. Future studies to externally validate these models in various diverse large populations and molecular studies to elucidate the underlying mechanisms by which the gene expression levels may be related to ageing phenotypes would be advantageous.

Emerging evidence has highlighted that olfactory dysfunction, a common feature of aging, is increasingly linked to cognitive decline in older adults. However, research on the underlying mechanism, particularly the role of nasal microbiome, remains limited. In this study, we investigated the associations between olfactory function, the nasal microbiome, and cognition among 510 older adults with an average age of 77.9 years. Olfactory function was assessed using the brief Chinese Smell Identification Test, and cognitive assessments were conducted via the Mini-Mental State Examination and the Revised Hasegawa Dementia Scale. Nasal microbiome profiles were generated through 16S RNA gene sequencing. We observed that olfactory dysfunction (i.e., hyposmia) was associated with a higher richness of nasal bacteria, and such observation was replicated in an external dataset. A total of 18 nasal bacterial genera were identified to be associated with olfactory function, with eight genera such as Acidovorax and Morganella being enriched in the hyposmic group. A composite microbial index of nasal olfactory function significantly improved the reclassification accuracy of traditional risk model in distinguishing hyposmic from normosmic participants (P = 0.008). Furthermore, participants with a nasal biotype dominated by Corynebacterium had a lower prevalence of mild cognitive impairment compared to those dominated by Dolosigranulum or Moraxella. Our findings suggested that the nasal microbiome may play a role in the association of olfactory function with cognition in older adults, providing new insights into the microbial mechanisms underlying hyposmia and cognitive decline.

To systematically understand age-induced molecular changes, we performed spatial transcriptomics of young, middle-aged, and old mouse brains and identified seven transcriptionally distinct regions. All regions exhibited age-associated upregulation of inflammatory mRNAs and downregulation of mRNAs related to synaptic function. Notably, aging white matter fiber tracts showed the most prominent changes with pronounced effects in females. The inflammatory signatures indicated major ongoing events: microglia activation, astrogliosis, complement activation, and myeloid cell infiltration. Immunofluorescence and quantitative MRI analyses confirmed physical interaction of activated microglia with fiber tracts and concomitant reduction of myelin in old mice. In silico analyses identified potential transcription factors influencing these changes. Our study provides a resourceful dataset of spatially resolved transcriptomic features in the naturally aging murine brain encompassing three age groups and both sexes. The results link previous disjointed findings and provide a comprehensive overview of brain aging identifying fiber tracts as a focal point of inflammation.

Long-term exercise is recognized as one of the most effective means of maintaining health after aging, but the relationship between moderate exercise and health in the older population is often overlooked.

Biological evolution continuously refines the design of species, resulting in highly optimised organisms over hundreds of millennia. Intuitively, we expect that random changes-evolution's primary mechanism-are more likely to be harmful than beneficial, leading to widespread detrimental effects in evolving species. The Evolvable Soma Theory of Ageing (ESTA) suggests that ageing is the cumulative result of these harmful effects, which predominantly cause bodily damage, while a few may lead to beneficial adaptations that evolution can exploit. While standard evolutionary ageing theories view aging as a consequence of limited evolutionary pressure, ESTA posits that ageing is essentially evolution in action. In this study, we gather evidence supporting this theory through computer simulations. We conduct experiments using a platform where genes are linked to onset values that determine when they are expressed. Three scenarios are tested: one with single-point fitness evaluation, constant mutation rate and fixed gene onsets; one with single-point fitness evaluation, onset-dependent mutation rate and fixed gene onsets; and one with spread fitness evaluation, onset-dependent mutation rate and evolvable gene onsets. The last scenario, which embodies the evolvable soma hypothesis, demonstrates superior performance in both algorithmic efficiency and biological plausibility compared to the others.

Telomere length (TL) is a marker of cellular aging associated with risk for age-related diseases and is known to be influenced by various factors, including oxidative stress and inflammation, in the contexts of stress and aging. The physiological demands of pregnancy may impact maternal TL, though research in this area is sparse. We tested oxidative stress and explored inflammation as predictors of maternal TL in a sample of women with normative pregnancies.

The general association between longevity and energy metabolism has been well-documented for some time, yet the specific metabolic processes that regulate longevity remain largely unexplored. In contrast to the common active swimming daphnids (e.g., Daphnia sinensis), Simocephalus vetulus is notable for being sedentary and having a lower metabolic rate, yet it has a longer lifespan than D. sinensis. In this study, metabolomic analysis and drug validation experiments are employed to demonstrate that the lower pyruvate dehydrogenase (PDH) activity reduces the locomotor performance of S. vetulus and to identify PDH activity as a regulator of the lifespan of daphnids. Inhibition of PDH activity in daphnids by CPI-613 attenuates its ATP supply and locomotor performance but significantly induces longevity. The study also determines that the invertebrate neurotransmitter octopamine and temperature have a significant impact on PDH activity and modulate daphnids lifespan. And when the effects of temperature and octopamine on PDH activity are counteracted by inhibitors or agonists, the impact on lifespan becomes ineffective. These results support an important role for PDH in lifespan regulation and locomotor performance in daphnids and provide insights into the metabolic regulation of lifespan.

Accumulation of cytosolic DNA has emerged as a hallmark of aging, inducing sterile inflammation. STING (Stimulator of Interferon Genes) protein translates the sensing of cytosolic DNA by cGAS (cyclic-GMP-AMP synthase) into an inflammatory response. However, the molecular mechanisms whereby cytosolic DNA-induced cGAS-STING pathway leads to aging remain poorly understood. We show that STING does not follow the canonical pathway of activation in human fibroblasts passaged (aging) in culture, senescent fibroblasts, or progeria fibroblasts (from Hutchinson Gilford Progeria Syndrome patients). Despite cytosolic DNA buildup, features of the canonical cGAS-STING pathway like increased cGAMP production, STING phosphorylation, and STING trafficking to perinuclear compartment are not observed in progeria/senescent/aging fibroblasts. Instead, STING localizes at endoplasmic reticulum, nuclear envelope, and chromatin. Despite the non-conventional STING behavior, aging/senescent/progeria cells activate inflammatory programs such as the senescence-associated secretory phenotype (SASP) and the interferon (IFN) response, in a cGAS and STING-dependent manner, revealing a non-canonical pathway in aging. Importantly, progeria/aging/senescent cells are hindered in their ability to activate the canonical cGAS-STING pathway with synthetic DNA, compared to young cells. This deficiency is rescued by activating vitamin D receptor signaling, unveiling new mechanisms regulating the cGAS-STING pathway in aging. Significantly, in HGPS, inhibition of the non-canonical cGAS-STING pathway ameliorates cellular hallmarks of aging, reduces tissue degeneration, and extends the lifespan of progeria mice. Our study reveals that a new feature of aging is the progressively reduced ability to activate the canonical cGAS-STING pathway in response to cytosolic DNA, triggering instead a non-canonical pathway that drives senescence/aging phenotypes.

The possibility of reversing the adverse impacts of aging could significantly reduce age-related diseases and improve quality of life in older populations. Here we report that the sexual lineage of the planarian Schmidtea mediterranea exhibits physiological decline within 18 months of birth, including altered tissue architecture, impaired fertility and motility, and increased oxidative stress. Single-cell profiling of young and older planarian heads uncovered loss of neurons and muscle, increase of glia, and revealed minimal changes in somatic pluripotent stem cells, along with molecular signatures of aging across tissues. Remarkably, amputation followed by regeneration of lost tissues in older planarians led to reversal of these age-associated changes in tissues both proximal and distal to the injury at physiological, cellular and molecular levels. Our work suggests mechanisms of rejuvenation in both new and old tissues concurring with planarian regeneration, which may provide valuable insights for antiaging interventions.

Skeletal muscles of the mammalian trunk and limbs comprise myofibers that express four types of myosin heavy-chain (MyHC) isoforms, each with distinct contractile and metabolic properties. Despite histochemical and immunohistochemical staining to identify myofiber types, all myofiber types cannot be identified simultaneously in vivo. In this study, we generated a novel knock-in mouse model, termed "MusColor," that enables the simultaneous identification of individual MyHC isoforms through the expression of four fluorescent proteins. The identification of fibre types by fluorescent expression in MusColor mice was consistent with that achieved by immunostaining and had higher sensitivity. By studying the aging-associated changes in myofiber types using the MusColor mice, we were able to identify changes in hybrid myofibers that simultaneously express multiple MyHCs. Furthermore, by culturing satellite cells isolated from MusColor mice and treatment of thyroid hormone or rapamycin, changes in myofiber type and metabolic function could be analysed in living cells. The MusColor mouse proved useful for elucidating the mechanisms of muscle fibre changes caused by diseases such as sarcopenia, neuromuscular and metabolic diseases, as well as by exercise and nutritional environments.

Abnormal α-Klotho (KL) levels play an essential role in the pathogenesis of aging-related lung diseases. However, the correlation between circulating KL levels and aging-related lung diseases has not been determined. This study aimed to determine whether circulating KL levels causally affect aging-related lung diseases using Mendelian randomization (MR).

Due to the paucity of longitudinal DNA methylation data (DNAm), especially among Hispanic/Latino adults, the association between changes in epigenetic clocks over time and cognitive aging phenotypes has not been investigated. This longitudinal study included 2671 Hispanic/Latino adults (57 years; 66% women) with blood DNAm data and neurocognitive function assessed at two visits approximately 7 years apart. We evaluated the associations of 5 epigenetic clocks and their between-visit change with multiple measures of cognitive aging that included a global cognitive function score at each visit, between-visit change in global cognitive function score, MCI diagnosis, and presence of significant cognitive decline at visit 2 (V2). There were significant associations between greater acceleration for all clocks and lower global cognitive function at each visit. The strongest associations were observed for GrimAge and DunedinPACE. Similar results were observed for domain-specific cognitive function at each visit and MCI diagnosis at V2. There was a significant association of decline in global cognitive function with increase in age acceleration between the two visits for PhenoAge and GrimAge. Between-visit increase in age acceleration for these two clocks was also associated with a greater risk of MCI diagnosis and presence of significant cognitive decline at V2. Epigenetic aging is associated with lower global and domain-specific cognitive function, greater cognitive decline, and greater risk of MCI in Hispanic/Latino adults. Longitudinal assessment of change in age acceleration for second-generation clocks, GrimAge and PhenoAge may provide additional value in predicting cognitive aging beyond a single time point assessment.

This narrative review investigates how urolithins produced by the gut microbiota can regulate transcription factors (such as NRF2, NF-kB, and PPAR-γ) associated with senescence, inflammation, and imbalanced redox status. It also discusses the potential benefits of urolithins for patients with chronic diseases, including cardiovascular disease, cancer, diabetes, obesity, and chronic kidney disease.

Aging is associated with a reduction in skeletal muscle fiber size and number, leading to a decline in physical function and structural integrity-a condition known as sarcopenia. This syndrome is further characterized by elevated levels of inflammatory mediators that promote skeletal muscle catabolism and reduce anabolic signaling.Androgens are involved in various biological processes, including the maintenance, homeostasis and trophism of skeletal muscle mass. The decline in androgen levels contributes, indeed, to androgen deficiency in aging people. Such clinical syndrome exacerbates the muscle loss and fosters sarcopenia progression. Nevertheless, the mechanism(s) by which the reduction in androgen levels influences sarcopenia risk and progression remains debated and the therapeutic benefits of androgen-based interventions are still unclear. Given the significant societal and economic impacts of sarcopenia, investigating the androgen/androgen receptor axis in skeletal muscle function is essential to enhance treatment efficacy and reduce healthcare costs.This review summarizes current knowledge on the role of male hormones and their-dependent signaling pathways in sarcopenia. We also highlight the cellular and molecular features of this condition and discuss the mechanisms by which androgens preserve the muscle homeostasis. The pros and cons of clinical strategies and emerging therapies aimed at mitigating muscle degeneration and aging-related decline are also presented.

Collagens are widely studied proteins given their implications in the skin extracellular matrix and pathological conditions such as fibrosis. Type V collagen is a member of the fibrillar collagens, and three different polypeptide chains, α1, α2 and α3 form isoforms through associations. The third chain, α3, of type V collagen was initially identified in the placenta, but after decades, it remains poorly characterized. The aim of this study is to investigate the expression and localization of the α3 chain of type V collagen in the skin and its evolution during skin aging. The identification of α3(V) collagen as a target of retinoic acid and its interaction with matrix metalloproteinase-9 (MMP-9) was investigated.

In previous studies we reported the S-glutathionylation at Cys residues (C76 and C221) of the α5 subunit of the 20S catalytic unit of the yeast proteasome, later mutated to Ser residues. Notably, the strain with the α5-C76S mutation exhibited a reduced chronological life span when grown in glucose as the carbon source. In the present study, we aimed to explore the interplay between mitochondria and the proteasome, considering the α5-C76S-mutated strain as a model of proteasomal impairment. For this purpose, we focused on the growth of the C76S strain in glycerol/ethanol as the carbon source. C76S strain exhibited poor growth and morphological alterations under these conditions, while the proteasomal activity was significantly decreased. We observed decreased activity of the 30S and 26S complexes in the C76S strain, which were accompanied by increased pool of poly-ubiquitinylated proteins. Regarding mitochondrial function, O

In recent years medical science and research are increasingly directed towards a holistic approach that considers health as global well-being rather than solely as the absence of disease. In this framework, lifestyle interventions and, in particular, physical exercise, are of crucial importance in prevention and treatment. Therefore, the purpose of this study is to describe this mutual interplay between physical behaviours, sarcopenia, and frailty, as well as to illustrate the role of structured exercise training in aging and disease.

Background: Aging is associated with significant changes in the immune system, leading to increased susceptibility to infections, reduced vaccine efficacy, and a higher risk of autoimmune diseases. However, the molecular mechanisms driving these immunological alterations remain incompletely understood. In this study, we performed differential gene expression analysis (DGEA) to identify genes implicated in immune aging and explored their functional significance through enrichment analysis. Methods: Using publicly available transcriptomic data from aged versus young individuals, we conducted DGEA to identify significantly dysregulated genes. Functional enrichment analyses, including Gene Ontology (GO) and Reactome pathway analysis, were performed to uncover biological processes and pathways enriched in the differentially expressed genes. We specifically focused on ERAP2, a gene found to be differentially expressed in aging, and examined its expression across various tissues. Additionally, we reviewed existing literature to assess ERAP2s role in antigen presentation and immune regulation. Results: Our analysis revealed significant enrichment of pathways related to antigen processing and presentation, peptide metabolism, and immune system regulation. ERAP2, an aminopeptidase involved in trimming peptides for MHC class I presentation, was highly associated with these processes. Interestingly, no direct KEGG pathway annotation was found for ERAP2, suggesting a potential gap in functional characterization. However, Reactome analysis confirmed its involvement in class I MHC-mediated antigen processing and immune system pathways, aligning with its known immunological role. The expression analysis across multiple tissues showed ERAP2 to be widely expressed in immune-related tissues, further supporting its relevance. Conclusion: Our findings highlight the potentially underexplored role of ERAP2 in immune aging. The lack of KEGG pathway annotation suggests that its function in aging and immune modulation may not be fully characterized, presenting an opportunity for further research. Given its role in antigen presentation, ERAP2 may represent a critical factor in the declining immune function observed in aging individuals. Further experimental validation is required to establish its mechanistic involvement and potential as a therapeutic target for age-related immune dysfunction.

Telomere biology disorders (TBD) are genetic diseases caused by defective telomere maintenance. TBD patients often develop bone marrow failure and have an increased risk of myeloid neoplasms. To better understand the factors underlying hematopoietic outcomes in TBD, we comprehensively evaluated acquired genetic alterations in hematopoietic cells from 166 pediatric and adult TBD patients. 47.6% of patients (28.8% of children, 56.1% of adults) had clonal hematopoiesis. Recurrent somatic alterations involved telomere maintenance genes (7.6%), spliceosome genes (10.4%, mainly U2AF1 p.S34), and chromosomal alterations (20.2%), including 1q gain (5.9%). Somatic variants affecting the DNA damage response (DDR) were identified in 21.5% of patients, including 20 presumed loss-of-function variants in ATM. Using multimodal approaches, including single-cell sequencing, assays of ATM activation, telomere dysfunction-induced foci analysis, and cell growth assays, we demonstrate telomere dysfunction-induced activation of ATM-dependent DDR pathway with increased senescence and apoptosis in TBD patient cells. Pharmacologic ATM inhibition, modeling the effects of somatic ATM variants, selectively improved TBD cell fitness by allowing cells to bypass DDR-mediated senescence without detectably inducing chromosomal instability. Our results indicate that ATM-dependent DDR induced by telomere dysfunction is a key contributor to TBD pathogenesis and suggest dampening hyperactive ATM-dependent DDR as a potential therapeutic intervention.

A core facet of the National Institute on Aging's mission is to identify pharmacological interventions that can promote human healthy aging and long life. As part of the comprehensive effort toward that goal, the NIA Division of Biology of Aging established the Caenorhabditis Intervention Testing Program (CITP) in 2013. The C. elegans model (with an ~ 21 day lifespan) has led the field in dissection of longevity genetics and offers features that allow for relatively rapid testing and for the potential elaboration of biological mechanisms engaged by candidate geroprotectants. CITP builds on this foundation by utilizing a genetically diverse set of intervention test strains so that "subjects" represent genetic diversity akin to that that between mouse and humans. Another distinctive aspect of the CITP is a dedicated focus on reproducibility of longevity outcomes as labs at three independent test sites confirm positive outcomes. The overall goal of the Caenorhabditis Intervention Testing Program (CITP) is to identify robust and reproducible pro-longevity interventions affecting genetically diverse cohorts in the Caenorhabditis genus. A strong Data Collection Center supports data collection and dissemination. Pharmacological interventions tested by CITP can be nominated by the general public, directed by in-house screens, or supported by published scientific literature. As of December 2024, CITP tested > 75 compounds and conducted > 725,000 animal assays over 891 trials. We identified 12 compounds that confer a ≥ 20% increase in median lifespan to reproducibly and robustly extend lifespan across multiple strains and labs. Five of these interventions have pro-longevity impact reported in the mouse literature (most CITP positive interventions are not tested yet in mouse). As part of the celebration of the 50th Anniversary of the NIA, we review the development history and accomplishments of the CITP program, and we comment on translation and the promise of advancing understanding of fundamental aging biology that includes the pharmacological intervention/health interface.

Resident tissue macrophages (RTMs) are essential for tissue homeostasis. Their diverse functions, from monitoring interstitial fluids to clearing cellular debris, are accompanied by characteristic morphological changes that reflect their functional status. While current knowledge of macrophage behaviour comes primarily from in vitro studies, their dynamic behavior in vivo is fundamentally different, necessitating a more physiologically relevant approach to their understanding. In this study, we employed intravital imaging to generate dynamic data from peritoneal RTMs in mice under various conditions and developed a comprehensive image processing pipeline to quantify RTM morphodynamics over time, defining human-interpretable cell size and shape features. These features allowed for the quantitative and qualitative differentiation of cell populations in various functional states, including pro- and anti-inflammatory activation and endosomal dysfunction. The study revealed that under steady-state conditions, RTMs exhibit a wide range of morphodynamical phenotypes, constituting a naive morphospace of behavioral motifs. Upon challenge, morphodynamic patterns changed uniformly at the population level but predominantly within the constraints of this naive morphospace. Notably, aged animals displayed a markedly shifted naive morphospace, indicating drastically different behavioral patterns compared to their young counterparts. The developed method also proved valuable in optimizing explanted tissue setups, bringing RTM behavior closer to the physiological native state. Our versatile approach thus provides novel insights into the dynamic behavior of bona fide macrophages in vivo, enabling the distinction between physiological and pathological cell states and the assessment of functional tissue age on a population level.

Recent pre-clinical evidence suggests that the tryptophan metabolite 3-hydroxyanthranilic acid (3-HAA) and the related enzyme activity along the kynurenine metabolic pathway (KP) are associated with lifespan extension. We aimed to translate these findings into humans and expose exercise training as a potential non-pharmacological intervention to modulate this metabolic hub.

Alterations in the composition and function of the intestinal microbiota have been observed in organismal aging across a broad spectrum of animal phyla. Recent findings, which have been derived mostly in simple animal models, have even established a causal relationship between age-related microbial shifts and lifespan, suggesting microbiota-directed interventions as a potential tool to decelerate aging processes. To test whether a life-long microbiome rejuvenation strategy could delay or even prevent aging in non-ruminant mammals, we performed recurrent fecal microbial transfer (FMT) in mice throughout life. Transfer material was either derived from 8-week-old mice (young microbiome, yMB) or from animals of the same age as the recipients (isochronic microbiome, iMB) as control. Motor coordination and strength were analyzed by rotarod and grip strength tests, intestinal barrier function by serum LAL assay, transcriptional responses by single-cell RNA sequencing, and fecal microbial community properties by 16S rRNA gene profiling and metagenomics.

Retrotransposable elements (RTEs) are interspersed repetitive sequences that represent a large portion of eukaryotic genomes. Ancestral expansions of RTEs directly contributed to the shaping of these genomes and to the evolution of different species, particularly mammals. RTE activity is tightly regulated by different epigenetic mechanisms but this control becomes compromised as cells age and RTEs are reactivated. This dysregulation of RTEs leads to perturbation of cell function and organ and organismal homeostasis, which drives ageing and age-related disease. Environmental stress is associated with both ageing-related characteristics and the epigenetic mechanisms that control RTE activity, with accumulating evidence indicating that RTE reactivation mediates the effects of environmental stressors on ageing onset and progression. A better understanding of how RTEs are reactivated and their subsequent biological roles may help the development of therapies against ageing-related phenotypes and diseases.

This study aimed to investigate the relationship between total antioxidant capacity (TAC) and phenotypic age acceleration (PhenoAgeAccel), a measure of accelerated biological aging, using data from the National Health and Nutrition Examination Survey (NHANES). Data from the 2003-2010 NHANES surveys, encompassing 16,395 participants, were analyzed. Principal component analysis (PCA) was used to reduce data dimensionality. Multivariate logistic regression models were employed to evaluate the association between TAC and antioxidant vitamins (α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein-zeaxanthin, vitamin A, vitamin C, vitamin E) with PhenoAgeAccel, adjusting for demographic, lifestyle, and clinical factors. Smoothed curve fitting and threshold effects analysis were conducted to explore the nonlinear relationship between log-transformed TAC and PhenoAgeAccel. Subgroup analyses were performed to assess potential effect modifiers based on age, gender, race, education, smoking, alcohol use, diabetes, hypertension, and hyperlipidemia. The weak correlations between the original variables prevent PCA from effectively capturing the primary variability within the data. Higher TAC was significantly inversely associated with PhenoAgeAccel in both unadjusted and adjusted models. Participants in the second tertile (T2) of TAC exhibited 11% lower odds of PhenoAgeAccel compared to those in the first tertile (T1) (OR = 0.89, 95% CI: 0.81-0.98, P = 0.0176). Intake of several antioxidant vitamins, including α-carotene, β-carotene, lutein-zeaxanthin, vitamin A, vitamin C, and vitamin E, was also inversely associated with the odds of PhenoAgeAccel. A nonlinear relationship between log-transformed TAC and PhenoAgeAccel was observed, with a significant protective effect within a specific range of TAC. Subgroup analyses revealed no significant effect modification by most factors, except for gender, smoking, and alcohol consumption. TAC is closely associated with PhenoAgeAccel. A nonlinear relationship was observed, with higher TAC exhibiting significant protective effects within a specific range, particularly among males, smokers, and alcohol consumer. These findings underscore the potential value of TAC in mitigating the aging process.

Background: Aging is a major, yet unmodifiable risk factor for cardiovascular diseases, leading to vascular alterations, increased cardiac fibrosis, and inflammation, all of which contribute to impaired cardiac function. However, the microenvironment inciting age-related alterations withing the multicellular architecture of the cardiac tissue is unknown. Methods: We investigated local microenvironments in aged mice hearts applying an integrative approach combining single-nucleus RNA sequencing and spatial transcriptomics in 12-week-old and 18-month-old mice. We defined distinct cardiac niches and studied changes in their cellular composition and functional characteristics. Results: Integration of spatial transcriptomics data across young and aged hearts allowed us to identify 11 cardiac niches, which were characterized by distinct cellular composition and functional signatures. Aging did not alter the overall proportions of cardiac niches but leads to distinct regional changes, particularly in the left ventricle. Whereas cardiomyocyte-enriched niches show disrupted circadian clock gene expression, vascular niches showed major changes in pro-inflammatory and pro-fibrotic signatures and altered cellular composition. We particularly identified larger vessel-associated cellular niches as key hotspots for activated fibroblasts and macrophages in aged hearts, with interactions of both cell types through the C3:C3ar1 axis. These niches were also enriched in senescence cells exhibiting high expression of immune evasion mechanisms that may impair senescent cell clearance. Conclusion: Our findings indicate that the microenvironment around the vasculature is particularly susceptible to age-related changes and serves as a primary site for inflammation-driven aging, so called \"inflammaging\". This study provides new insights into how aging reshapes cardiac cellular architecture, highlighting vessel-associated niches as potential therapeutic targets for age-related cardiac dysfunction.

Senescent foamy macrophages are key drivers of atherosclerosis and plaque instability. N

Over the past 12 years, a significant body of evidence derived from extensive research has underscored the pivotal involvement of ferroptosis in the mechanisms underlying aging. Despite the growing body of literature on this topic, there remains a paucity of analytical and descriptive studies that explore its trajectory, key research directions, current trends, primary focal points, and future outlooks. This research endeavors to provide an exhaustive overview of the advancements in understanding the relationship between ferroptosis and aging over the past 12 years. The dataset utilized in this study was extracted from the Web of Science, encompassing records from January 1, 2012, through June 19, 2024. We conducted comprehensive bibliometric and visual analyses using advanced analytical tools. The results highlight China's dominant contribution, which accounts for 48.52 % of total publications, positioning it as a key player in this research area. Leading institutions, including Columbia University, Southern Medical University, and the Salk Institute for Biological Studies, demonstrate high research productivity. Pamela Maher and Gu Wei are identified as the most prolific researchers in this field. Free Radical Biology and Medicine is the leading journal, publishing the most articles in this field. This study identifies mitochondrial diseases, arrhythmias, Parkinson's disease, hepatocellular carcinoma, and iron-refractory iron deficiency anemia as the key diseases investigated in this field. This bibliometric evaluation offers critical perspectives for both experienced scholars and early-career researchers, enabling the identification of novel ideas and advancements within this domain.

Aging is a key risk factor for many diseases, including cancer, and a better understanding of its underlying molecular mechanisms may help to prevent, delay, or treat age-related pathologies. Epigenetic alterations such as DNA methylation (DNAme) changes are a hallmark of aging and form the basis of so-called epigenetic clocks, yet their functional relevance and directionality in different organs during disease development is often unclear.

Rebuilding muscle through the power of mRNA binding protein therapeutics.

Finland's national vitamin D fortification policy has significantly improved the population's vitamin D sufficiency. This study investigates the association between serum vitamin D concentration and muscle health, considering the impact of menopause and aging in Finnish cohorts.

Aging is a predominant risk factor for heart disease. Aging heart reveals low-grade chronic inflammation, cell apoptosis, cardiac fibrosis, and increased vulnerability to ischemic injury. The underlying molecular mechanisms responsible for the cardiac aging phenotype and its susceptibility to injury are far from being fully understood. Although previous literature reports a role of the mitochondrial enzyme arginase-II (Arg-II) in development of heart failure, contradictory results are reported and no systematic analysis of cellular expression and localization of Arg-II in the heart has been performed. Whether and how Arg-II participates in cardiac aging are still unknown. In this study, we demonstrate, to our surprise, that Arg-II is not expressed in cardiomyocytes from aged mice and human patients, but upregulated in non-myocytes of the aging heart, including macrophages, fibroblasts, endothelial cells. Mice with genetic deficiency of arg-ii (arg-ii-/-) are protected from age-associated cardiac inflammation, myocyte apoptosis, interstitial and perivascular fibrosis, endothelial-mesenchymal transition (EndMT), and susceptibility to ischemic injury. Further experiments show that Arg-II mediates IL-1beta release from macrophages of old mice, contributing to the above-described cardiac aging phenotype. In addition, Arg-II enhances mitochondrial reactive oxygen species (mtROS) and activates cardiac fibroblasts that is inhibited by inhibition of mtROS. Thus, our study demonstrates a non-cell-autonomous effect of Arg-II on cardiomyocytes, fibroblasts, and endothelial cells mediated by IL-1b from aging macrophages as well as a cell-autonomous effect of Arg-II through mtROS in fibroblasts contributing to cardiac aging phenotype.

There is a close connection between aging and osteoarthritis (OA), but the specific mechanisms are still unclear. This study aims to explore the potential connections and molecular mechanisms between OA and aging through multi-omics and genetics methods. Integrating single-cell RNA sequencing (scRNA-seq), bulk RNA-seq data, Mendelian randomization (MR), colocalization analysis, and cell function analysis, this study explores the correlation between OA and aging. Furthermore, it investigates the potential causal relationship between key marker genes and OA. Integrating and analyzing scRNA-seq data from OA, aging, and control groups revealed a significant increase in the proportion of the classical monocyte core subgroup. Differential expression analysis yielded 77 marker genes, and further MR analysis identified four key marker genes (DUSP6, CSTA, CD300E, and GPX1) as causally related to OA, which was confirmed in an independent validation cohort. Reverse MR and Steiger filtering indicated no evidence of reverse causality. DUSP6- and CSTA-classical monocytes may interact with other cell subgroups through the MIF-(CD74 + CD44) signaling pathway. This study revealed the heterogeneity of monocyte subgroups in OA and aging patients, identifying key marker genes with a causal relationship to OA through an integrated multi-omics approach, providing potential molecular targets for the diagnosis and treatment of OA from an aging perspective.

While some prior studies have identified an association between exposure to fine air borne particulate matter (PM2.5) and indices of aging, the extent of these associations and their underlying mechanisms are uncertain. In this study we exposed male C57BL/6J mice to filtered air and concentrated ambient PM2.5 (CAP) and assessed two common hallmarks of aging, telomere shortening and a senescent phenotype. Of the cell types examined, peripheral blood mononuclear cells (PBMNCs), endothelial progenitor cells (EPCs), and bone marrow-derived c-kit+ cells, all three demonstrated shortened telomeres when isolated from CAP-exposed mice as compared with cells derived from filtered air controls. We found that telomere attrition in PBMNCs and EPCs was mitigated in those CAP-exposed mice receiving water supplemented with the antioxidant, carnosine and was reversible in PBMNCs, but not EPCs, when CAP-exposed mice were allowed to recover in normal air conditions. Telomere attrition in these cell types appeared to result from the attenuated catalytic activity of telomerase reverse transcriptase (Tert). PBMNCs and EPCs obtained from CAP-exposed mice also displayed increased β-galactosidase activity and expression of genes characteristic of the senescence-activated secretory phenotype. Of PBMNC subtypes, the increase of β-galactosidase activity was greatest in CD8+ T-cells. Our results suggest that the pro-aging effects of PM2.5 impacts multiple cell types, including bone marrow stem cells, and that telomere attrition resulted from attenuated Tert activity. The aging and senescence of multiple cell types, including bone marrow stem cells, may underlie the diverse pathological outcomes of PM2.5 exposure.

Aging of the fetal membranes participates in labor onset. However, the underlying mechanism is poorly understood. Here, we identify that the classical secretory protein S100 calcium-binding protein A9 (S100A9), upon de-phosphorylation at Thr 113, translocates to the nuclei of amnion fibroblasts of the human fetal membranes, where S100A9 causes heterochromatin erosion via segregation of heterochromatin maintenance proteins, resulting in Long Interspersed Nuclear Element-1 (LINE1) de-repression at parturition. Increased LINE1 retrotransposition further activates the type I interferon response via the cGAS-STING pathway, thereby leading to amnion fibroblast senescence with consequent increased secretion of components associated with senescence-associated secretory phenotype. Mouse studies show that intra-amniotic injection of vector specifically expressing S100A9 in the nucleus induces preterm birth along with LINE1 de-repression and increased cellular senescence in the fetal membranes, which is blocked by inhibition of LINE1 reverse-transcription. Together, these findings highlight that nuclear-translocated S100A9 acts as a heterochromatin disruptor to de-repress LINE1 which subsequently triggers amnion fibroblast senescence at parturition.

Sirtuins are a class of NAD-dependent histone deacetylases that regulate important biological pathways in prokaryotes and eukaryotes. This enzyme family comprises seven members, named SIRT1 to SIRT7. Among them, Sirtuin 6 (SIRT6) is a human sirtuin that deacetylates histones and plays a key role in DNA repair, telomere maintenance, carbohydrate and lipid metabolism, and lifespan. SIRT6\'s structure consists of a zinc finger domain, a Rossmann fold domain containing the NAD+ binding site, and disordered N-terminal and C-terminal (CTD) extensions. The specific role of the CTD on SIRT6 interaction with nucleosomes for histone deacetylation remains unclear. Here, we resort to extended molecular dynamics simulations to uncover the dynamical behavior of the full-length SIRT6 bound to a nucleosome core particle. Our simulations reveal that the CTD preferentially interacts with DNA at the entry/exit near the enzyme\'s docking site, exhibiting a variety of different binding modes. In specific cases, the CTD participates to the promotion of DNA unwrapping and promotes H3K27 accessibility to SIRT6\'s active site, suggesting a pivotal role of this domain for H3K27 deacetylation. This work provides new structural insights into the binding process of the full-length SIRT6 to a nucleosome core particle, shedding light on the conformational behavior and functional role of its CTD. It constitutes an important step towards the understanding of SIRT6 deacetylation mechanisms and specificity.

Frailty, a significant predictor of adverse health outcomes, has become a focal point of research, particularly with the advent of artificial intelligence (AI) technologies. This study aimed to provide a comprehensive bibliometric analysis of research trends in AI and frailty to map conceptual developments, collaborations, and emerging themes in the field.

Fibrosis-related disorders represent an increasing medical and economic burden on a worldwide scale, accounting for one-third of all disease-related deaths with limited therapeutic options. As central mediators in fibrosis development, myofibroblasts have been gaining increasing attention in the last 20 years as potential targets for fibrosis attenuation and reversal. While various aspects of myofibroblast physiology have been proposed as treatment targets, many of these approaches have shown limited long-term efficacy so far. However, ongoing research is uncovering new potential strategies for targeting myofibroblast activity, offering hope for more effective treatments in the future. The circadian molecular clock is a feature of almost every cell in the human body that dictates the rhythmic nature of various aspects of human physiology and behavior in response to changes in the surrounding environment. The dysregulation of these rhythms with aging is considered to be one of the underlying reasons behind the development of multiple aging-related chronic disorders, with fibrotic tissue scarring being a common pathological complication among the majority of them. Myofibroblast dysregulation due to skewed circadian clockwork might significantly contribute to fibrotic scar persistence. In the current review, we highlight the role of the circadian clock in the context of myofibroblast activation and deactivation and examine its dysregulation as a driver of fibrogenesis.

Dysmotility of the gastrointestinal (GI) tract is commonly seen in elderly individuals, where it causes significant morbidity and can lead to more severe conditions, including sarcopenia and frailty. Although the precise mechanisms underlying aging-related GI dysmotility are not fully understood, neuronal loss or degeneration in the enteric nervous system (ENS) may be involved. Aged garlic extract (AGE) has been shown to have several beneficial effects in the GI tract; however, it is not known whether AGE can improve GI motility in older animals. The aim of the present study was to examine the effects of AGE on the ENS and gut motility in older mice and elucidate potential mechanisms of action. An AGE-formulated diet was given to 18-month-old female mice for 2 weeks. Organ bath studies and cell culture demonstrated that AGE: i) Altered gut contractile activity; ii) enhanced viability of ENS cells; and iii) exhibited neuroprotective effects on the ENS via reduction in oxidative stress. These findings suggest that AGE could be used to develop novel dietary therapeutics for aging-related GI dysmotility by targeting the associated loss and damage of the ENS.

The aim of this study was to determine whether oxidative stress-induced premature senescence in mouse auditory cell line HEI-OC1 cells in vitro is associated with NLRP3 inflammasome activation and pyroptosis, and whether melatonin has a protective effect. HEI-OC1 cells were exposed to different concentrations of hydrogen peroxide (H

Spermidine (SPD) is an organic compound known for its powerful antioxidant stress and anti-aging properties, and whether SPD has the ability to reduce bone mass in elderly iron overload rats is unknown. The study aimed to assess SPD's impact on iron overload-induced bone loss in elderly rats. In our aged rat model, we found that iron overload negatively influences bone metabolism and remodeling, resulting in decreased bone mineral density and increased bone loss. However, SPD treatment effectively alleviated these harmful effects, as shown by reduced serum levels of MDA and increased SOD and GSH levels. Additionally, SPD-treated rats exhibited enhanced bone mass and higher expression of OC, BMP2, SIRT1, and SOD2 in their bones. Moreover, SPD restored the imbalance in bone metabolism by counteracting the inhibition of osteogenic differentiation and promoting osteoclast differentiation induced by iron overload in MC3T3-E1 and RAW264.7 cells affected by EX527. In summary, our findings suggest that SPD's antioxidant properties may exert anti-osteoporosis effects through activation of the SIRT1/SOD2 signaling pathway.

The common occurrence of cognitive decline is one of the most significant manifestations of aging in the brain, with the hippocampus - critical for learning and memory - being one of the first regions to exhibit functional deterioration. BGLAP/OCN/osteocalcin (bone gamma-carboxyglutamate protein), a pro-youth systemic factor produced by the bone, improves age-related cognitive decline by boosting hippocampal neuronal autophagy. However, the mechanism by which hippocampal neurons detect BGLAP/OCN in the systemic milieu and adapt their downstream response was previously unknown. We determined that BGLAP/OCN modulates core primary cilia (PC) proteins, suggesting that this "extracellular antenna" may play a role in mediating BGLAP/OCN's anti-aging effects. Furthermore, selective downregulation of core PC proteins in the hippocampus impairs learning and memory by reducing neuronal macroautophagy/autophagy. In contrast, restoring core PC protein levels in the hippocampus of aged mice improved this phenotype and was necessary for the induction of autophagy machinery by BGLAP/OCN. Together, these findings reveal a novel mechanism through which pro-youth systemic factors, like BGLAP/OCN, can regulate neuronal autophagy and foster cognitive resilience during aging.

Aging is a complex and systematic biological process that involves multiple genes and biological pathways across different tissues. While existing studies focus on tissue-specific aging factors, the inter-tissue interplay between molecular pathways during aging remains insufficiently explored. To bridge this gap, we propose a novel computational framework to identify the effect of aging on the coordinated patterns of gene-expression across multiple tissues. Our framework includes (1) an adjusted multi-tissue weighted gene co-expression network analysis, (2) differential network connectivity analysis between age groups and (3) machine learning models, XGBoost and Random Forest (RF) fed by gene expression levels and lower-dimensional pathway score space, to identify unique key inter-tissue genes and biological pathways for classifying aging. We applied our approach to three representative tissues: Adipose-Subcutaneous, Muscle-Skeletal and Brain-Cortex. The RF model demonstrated the best performance in predicting age group (AUC < 88%) highlighting key genes involved in inter-tissue coordination processes in aging. We also identified the inter-tissue involvement of lipid metabolism, immune system, and cell communication pathways during aging and detected distinct aging pathways manifested between tissues. The proposed framework highlights the importance of inter-tissue coordination processes underlying aging and provides valuable insights into aging mechanisms which can further assist in the development of therapeutic strategies promoting healthy aging.

With advancing age, the decline in intestinal stem cell (ISC) function can lead to a series of degenerative changes in the intestinal epithelium, a critical factor that increases the risk of intestinal diseases in the elderly. Consequently, there is an urgent imperative to devise effective dietary intervention strategies that target the alterations in senescent ISCs to alleviate senescence-related intestinal dysfunction. The 28-month-old naturally aging mouse model was utilized to discover that the primary factor contributing to the compromised barrier function and digestive absorption of the small intestine was a decrease in both the number and regenerative capacity of ISCs. The underlying mechanism involves the degeneration of mitochondrial function in ISCs, resulting in insufficient energy supply and decreased metabolic capacity. Additionally, our findings indicate that fasting-refeeding can influence the mitochondrial metabolism of ISCs, and that alternate day fasting (ADF) can facilitate the restoration of both the quantity and regenerative capabilities of ISCs, thereby exhibiting a notable antiaging effect on the small intestine. In conclusion, this study provides new insights into the potential beneficial role of ADF in ameliorating intestinal aging, thereby establishing a foundation for future investigations into dietary interventions aimed at addressing age-related intestinal dysfunction.

With the aging population, postmenopausal osteoporosis (PMOP), clinically manifested by reduced bone density, weakened skeletal strength, and compromised skeletal microstructure, has become the most prevalent type. The decline in estrogen levels fosters oxidative stress and osteoclastogenesis, which significantly enhance the activity of osteoclasts. Current treatments prefer to adopt relevant strategies to inactivate osteoclasts but come with unavoidable side effects. In our study, Catharanthine Tartrate (CAT), a derivative of the alkaloid catharanthine found in Catharanthus roseus, promised to be an effective therapy for PMOP. CAT inhibited RANKL-induced osteoclast differentiation and bone resorption in vitro. Moreover, CAT inhibited osteoclast activity by enhancing the ubiquitination-mediated proteasomal degradation of HIF-1α, which reduced oxidative stress and subsequently suppressed osteoclast activity. The inhibitory effects of CAT on osteoclast function and oxidative stress were reversed by DMOG, a known inhibitor of HIF-1α degradation. Next, an in vivo mouse experiment using the Ovariectomized (OVX) model to induce osteoporosis indicated that CAT enhanced bone mass density, bone structure, and bone remodeling. Our findings revealed that CAT inhibits PMOP through facilitating HIF-1α ubiquitination and degradation, suggesting a promising therapeutic approach for this disorder.

The gut microbiome changes with age and has been proposed to mediate the benefit of lifespan-extending interventions such as dietary restriction. However, the causes and consequences of microbiome ageing and the potential of such interventions remain unclear. Here we analysed 2,997 metagenomes collected longitudinally from 913 deeply phenotyped, genetically diverse mice to investigate interactions between the microbiome, ageing, dietary restriction (caloric restriction and fasting), host genetics and a range of health parameters. Among the numerous age-associated microbiome changes that we find in this cohort, increased microbiome uniqueness is the most consistent parameter across a second longitudinal mouse experiment that we performed on inbred mice and a compendium of 4,101 human metagenomes. Furthermore, cohousing experiments show that age-associated microbiome changes may be caused by an accumulation of stochastic environmental exposures (neutral theory) rather than by the influence of an ageing host (selection theory). Unexpectedly, the majority of taxonomic and functional microbiome features show small but significant heritability, and the amount of variation explained by host genetics is similar to ageing and dietary restriction. We also find that more intense dietary interventions lead to larger microbiome changes and that dietary restriction does not rejuvenate the microbiome. Lastly, we find that the microbiome is associated with multiple health parameters, including body composition, immune components and frailty, but not lifespan. Overall, this study sheds light on the factors influencing microbiome ageing and aspects of host physiology modulated by the microbiome.

Aging is closely associated with cardiovascular diseases, the leading cause of mortality worldwide. Mitochondrial dysfunction is a hallmark of cardiovascular aging because it generates most of the heart\'s ATP at the cristae, specialized sub-compartments where OXPHOS takes place. In this study, we used multiple-scale electron microscopy approaches to evaluate age-related mitochondrial and cristae ultrastructural alterations in human and mouse hearts. We found that aged patients\' hearts displayed reduced cristae density as seen by TEM, even before any significant decline in the expression of cristae-shaping proteins. Similarly, a multi-scale approach that included SBF-SEM and TEM showed that in aged mice\'s hearts cristae undergo ultrastructural remodeling processes, resulting in a decrease in cristae density and width. Electron tomography suggests an apparent decline in cristae connectivity, and an increase in fenestration size. These changes were linked to Opa1 downregulation, accompanied by reduced OXPHOS maximal respiration, but unrelated to alterations in the levels of OXPHOS core subunits and ATP synthase assembly. Altogether, this indicates that alterations in cristae structure alone are sufficient to impair oxidative metabolism, which highlights its potential as an early signal of cardiac aging, even before noticeable changes in mitochondrial morphology occur.

Reproductive aging is an increasing health concern affecting family planning and overall well-being. While extensively studied in females, the mechanisms driving male reproductive aging remain largely unexamined. Here we found that mammalian Sirtuin 7 (SIRT7) sustains spermatogenesis in an age-dependent manner through the control of histone 3 lysine 36 acetylation (H3K36ac). SIRT7 deficiency in mice resulted in increased levels of H3K36ac in spermatogonia and spermatocytes. In a germ cell line, SIRT7 deficiency disrupted nucleosome stability and increased vulnerability to genotoxic stress. Importantly, undifferentiated spermatogonia, which are required for continuous sperm production, decreased prematurely in Sirt7-/- mice and showed genome damage accumulation. These changes were concurrent with age-dependent defects in homologous chromosome synapsis and partial meiotic arrest. Taken together, our results indicate that SIRT7 connects H3K36ac epigenetic regulation to long-term genome stability in male germ cells, ensuring steady-state spermatogenesis during the lengthy male reproductive lifespan.

To determine the feasibility and preliminary effects of a home-based 12-week high-intensity functional strength training (HIFST) intervention for community-dwelling older adults (≥55 years) experiencing preclinical mobility limitations after a slip, trip, or fall.

Professional drivers represent an ideal cohort for investigating the effects of solar radiation on skin due to their unique, asymmetric exposure to sun, a consequence of vehicle window orientations. Consequently, one side of the face is naturally subjected to more solar radiation, resulting in uneven sunlight exposure. This scenario supports a paired experimental design for precise within-individual comparisons, crucial for assessing sun exposure's impact on skin health, including signs of aging. Leveraging this approach, our study reveals sun-induced overexpression of proteins linked to photoaging through paired proteomic analysis, providing novel insights into the skin's adaptive responses to chronic solar exposure. Initially, our research focused on a dataset from ten male professional drivers, identifying a set upregulated proteins in sun-exposed skin compared to the less exposed side of the face. To validate these findings, we extended our investigation to a new cohort of seven female bus drivers. Our motivation in switching genders and utilizing different mass spectrometry equipment and sample preparation techniques was for assessing the robustness of our initial findings, encompassing not just sex differences but also methodological variations, and also for understanding the broader implications of our results for photodermatology. To enable this detailed analysis, we developed specialized software that allows precise paired proteomic analysis, significantly enhancing the robustness and clarity of our findings. Our results shortlisted keratins, S100A14, and F-box proteins-by remaining consistently overexpressed in sun-exposed skin-and hemoglobin subunit beta as downregulated across both cohorts. Our findings underscore the potential of proteomic techniques in advancing our understanding of the molecular dynamics of photoaging and highlight the value of selecting cohorts with specific exposure characteristics.

Aging is associated with alternative splicing (AS) defects that have broad implications on aging-associated disorders. However, which drug(s) can rescue age-related AS defects and extend lifespan has not been systematically explored. We performed large-scale compound screening in C. elegans using a dual-fluorescent splicing reporter system. Among the top hits, doxifluridine, a fluoropyrimidine derivative, rescues age-associated AS defects and extends lifespan. Combining bacterial DNA sequencing, proteomics, metabolomics and the three-way screen system, we further revealed that bacterial ribonucleotide metabolism plays an essential role in doxifluridine conversion and efficacy. Furthermore, doxifluridine increases production of bacterial metabolites, such as linoleic acid and agmatine, to prolong host lifespan. Together, our results identify doxifluridine as a potent lead compound for rescuing aging-associated AS defects and extending lifespan, and elucidate drug's functions through complex interplay among drug, bacteria and host.

Splenic T cells are pivotal to the immune system, yet their function deteriorates with age. To elucidate the specific aspects of T cell biology affected by aging, we conducted a comprehensive multi-time point single-cell RNA sequencing study, complemented by single-cell Assay for Transposase Accessible Chromatin (ATAC) sequencing and single-cell T cell repertoire (TCR) sequencing on splenic T cells from mice across 10 different age groups. This map of age-related changes in the distribution of T cell lineages and functional states reveals broad changes in T cell function and composition, including a prominent enrichment of Gzmk+ T cells in aged mice, encompassing both CD4+ and CD8+ T cell subsets. Notably, there is a marked decrease in TCR diversity across specific T cell populations in aged mice. We identified key pathways that may underlie the perturbation of T cell functions with aging, supporting cytotoxic T cell clonal expansion with age. This study provides insights into the aging process of splenic T cells and also highlights potential targets for therapeutic intervention to enhance immune function in the elderly. The dataset should serve as a resource for further research into age-related immune dysfunction and for identifying potential therapeutic strategies.

Recent studies have indicated the potential of transcutaneous auricular vagus nerve stimulation (taVNS) as an intervention for cognitive decline. In this study, we systematically analyzed the effects of taVNS on cognitive enhancement from the perspective of brain networks, by combining functional near-infrared spectroscopy (fNIRS) signal analysis with virtual brain simulations. Behavioral experiments with older adults demonstrated that participants with low baseline performance experienced significant improvements in working memory performance following taVNS, while those with high baseline performance tended to decline. This pattern was closely associated with functional connectivity (FC) in the prefrontal cortex (PFC) concurrently measured during the behavioral tasks, i.e., task performance correlated with FC in the PFC, particularly in the medial PFC (mPFC). Moreover, the changes in performance due to taVNS, which varied based on baseline performance, exhibited a notable alignment with the FC changes in the mPFC. These findings were further explored through virtual brain simulations. The simulation results demonstrated that the brain's functional state could vary depending on the network coupling parameter-capable of reflecting loss of structural brain connectivity associated with aging-and that the modulation effects induced by taVNS may also differ based on those functional states. Current results indicate that the efficacy of taVNS interventions for cognitive enhancement may vary according to the pre-intervention structural and functional states of individual brains. Therefore, the development of personalized optimization strategies for taVNS intervention is crucial, and digital brain research holds significant promise in advancing this field.

Resveratrol, a natural polyphenol compound, possesses anti-aging, antitumor, and vascular protective properties. These attributes are believed to stem from its influence on Sirtuin 1 (Sirt1), a member of the human Sirtuin family and a nicotinamide adenine dinucleotide-dependent histone deacetylase.

Late adulthood is accompanied by declines in manual motor performance and reduced neuroplasticity, which can influence the effects of motor practice and learning. Corticomotoneuronal (CM) connectivity can be targeted non-invasively through individualized paired corticospinal-motoneuronal stimulation (PCMS) to prime ballistic motor learning in young adults. However, the priming effects of PCMS on motor output and ballistic motor learning in older adults remain unexplored. Part one of this study investigates ballistic motor performance and learning in young (20-30 years) and older (65-75 years) adults as within-session changes in peak acceleration of rapid index finger flexions and delayed retention 1 week later. The results demonstrate that older adults display lower maximal acceleration compared to young adults and smaller improvements with practice, indicating inferior learning and low levels of delayed retention. Part two of the study investigates the effects of PCMS on motor learning and corticospinal excitability in older adults. Corticospinal excitability was assessed throughout the experiment by recording motor evoked potentials from the first dorsal interosseous. PCMS increased subsequent ballistic learning and corticospinal excitability after practice compared to SHAM. Importantly, combined PCMS and motor practice also enhanced long-term retention, and performance remained enhanced 7 days later. This means that PCMS effectively reinstated the otherwise absent long-term learning in older adults. We demonstrate that PCMS primes experience-dependent plasticity accompanying motor learning resulting in long-term benefits on motor performance in older adults. These findings highlight the potential of PCMS to enhance the effects of motor practice and benefit functional abilities in older adults. KEY POINTS: Late adulthood is associated with reduced activation of spinal motoneurons during vigorous movements, resulting in slower and less precise movements. Older adults (aged 65-75 years) display lower ballistic motor performance compared to younger adults (aged 20-30 years); furthermore, older adults exhibit smaller improvements during practice, and lower retention. A single session of paired corticospinal-motoneuronal stimulation (PCMS) increases corticospinal excitability and primes within-session ballistic motor learning in older adults. A single session of PCMS improves long-term retention following ballistic motor learning. We provide proof-of-principle that PCMS represents a potential strategy to enhance the effects of motor practice and counteract age-related decline in motor function.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, mitochondrial dysfunction, and neuroinflammation. This study evaluates the therapeutic potential of DDQ, a small molecule in the humanized Abeta knockin (hAbKI) mice that represents late-onset AD. Our findings demonstrate that DDQ treatment significantly improves cognitive performance as assessed through behavioral tests, including the rotarod, open field, Y-maze, and Morris water maze, compared to untreated hAbKI mice. At the molecular level, DDQ promoted mitochondrial biogenesis, as evidenced by enhanced expression of key proteins like PGC1α, NRF1, and TFAM. Additionally, DDQ treatment facilitated mitophagy, as indicated by elevated levels of PINK1 and Parkin, and reduced neuroinflammation, reflected by decreased Iba1 and GFAP levels. Transmission electron microscopy analysis revealed a marked improvement in mitochondrial morphology, with increased mitochondrial length and reduced mitochondrial numbers in DDQ-treated mice. Furthermore, DDQ treatment led to an increase in mitophagic vacuoles, suggesting that it effectively removes dysfunctional mitochondria. Taken together, for the first time, our study results support the potential of DDQ as a promising neuroprotective agent for late-onset AD, addressing mitochondrial dysfunction, neuroinflammation, and cognitive decline. Our study focused on developing small molecules that modulate mitophagy, mitochondrial dynamics and neuroinflammatory pathways for aging, AD and other neurodegenerative disorders.

Age-related deterioration in muscle volume, intramuscular fat content and muscle function can be modulated by physical activity. We explored whether Masters athletes, as examples of highly physically active people into old age, could prevent these age-related muscle deteriorations. Four groups of 43 men were examined: young athletes (20-35 years, n = 10), Masters athletes (60-75 years, n = 10) and two age-matched control groups (old: n = 11, young: n = 12). Volumes and fat fractions of 17 different hip and leg muscles were determined using magnetic resonance imaging. In the soleus muscle extra- and intramyocellular lipids were measured using 1H-MR-spectroscopy. Finally volumes of glutei, quadriceps and triceps surae muscles were cumulated and compared to peak jumping power. In both age groups the sum of glutei, quadriceps and triceps surae muscles showed larger volumes in athletes (young: 5758 ± 1139 ml, old: 5285 ± 895 ml) compared to the corresponding control groups (young: 4781 ± 833 ml, old: 4379 ± 612 ml) (p < 0.001). Fat fraction varied between 1.5% and 12.5%