Longevity Papers

This study investigated the role of mitochondrial function in aortic aging. As the aorta ages, it becomes stiffer and less compliant, increasing the risk of aneurysmal disease, hypertension, and diastolic dysfunction. Given the role of mitochondrial dysfunction in non-age related aortopathies and as a hallmark of aging, we investigated its contribution to the aging aorta. Both male and female young (5-6 month) and aged (24-25 month) C57Bl/6J mice received mitochondrial-targeted peptide elamipretide (ELAM; SS-31) for 8 weeks. ELAM restored complex II-linked respiration in aged mice to values seen in young mice, while also improving relative phosphorylative flux. ELAM treatment also reduced inflammatory MMP9 expression and elastin breaks in aged mice. Bulk RNAseq analysis revealed that ELAM treatment significantly affected the aortic transcriptome in an age-dependent manner, reducing the expression of senescent and associated pro-inflammatory genes. Mitochondrial dysfunction thus drives aortic aging and is a potential therapeutic target for future study.

The geroscience hypothesis suggests that understanding underlying ageing mechanisms will enable us to delay aging and lessen age-related disability and diseases. While hallmarks of ageing list multiple contributing factors, role of mechanics has only been recently recognized and increasingly appreciated. Here, we use mouse models of ageing to investigate changes in mechanics of the proximal pulmonary artery, lung and right ventricle function in ageing. We found an age-related decline in the capacity to store energy and increased circumferential stiffness of the proximal pulmonary artery with age that associated with a reorientation of collagen towards the circumferential direction, decreased exercise ability, and decreased function of the lung and right ventricle. The observed compromised mechanics in proximal pulmonary artery is consistent across multiple mouse models of accelerated ageing. Further, transcriptional changes in proximal pulmonary artery indicate that aging is associated with senescence of perivascular macrophages, adventitial fibroblasts, and medial smooth muscle cells. Older pulmonary arteries increase expression of genes associated with ECM turnover (including genes in the TGF{beta} pathway) and increased intercellular signaling amongst perivascular macrophages, fibroblasts and smooth muscle cells. Our results provide promising biomarkers of ageing for diagnosis and potential pathways and molecular targets for targeting anti-ageing therapies.

Aging is associated with a decline in immune function termed immunosenescence, characterized by accumulation of senescent-like immune cells and chronic inflammation, known as inflammaging. While senescence-associated {beta}-galactosidase (SA-{beta}Gal) activity is a well established senescence marker, its functional significance and the precise cellular subsets affected within the T cell compartment remain unclear. Here, we identify and characterize a previously unrecognized subset of naive CD4 and CD8 T cells displaying high SA-{beta}Gal activity that significantly increases with age. Despite exhibiting hallmark features of senescence such as DNA damage, nuclear envelope disruption, loss of heterochromatin, and pronounced dysregulation of autophagy and lysosomal pathways, these SA-{beta}Gal-high naive T cells notably lack the canonical senescence marker p21CIP1 and retain robust proliferative capacity upon activation. Remarkably, naive CD4 SA-{beta}Gal-high T cells acquire cytotoxic properties including NK-like features, granzyme secretion, and the ability to induce paracrine DNA damage in endothelial cells. Mechanistically, we demonstrate that impaired autophagic flux contributes significantly to this phenotype. Our findings address critical knowledge gaps regarding the nature and functional plasticity of senescence-like states in naive T cells, highlighting a novel link between lysosomal-autophagic dysfunction, cellular stress adaptation, and inflammaging. Understanding this unique T cell population provides important insights into immune aging and offers potential targets to mitigate age-associated immune dysfunction and chronic inflammation.

Senescence is the gradual process of aging in tissues and cells, and a primary cause of aging-associated diseases. Among them, intestinal stem cells (ISCs) experience exhaustion during aging, leading to reduced regenerative capacity in the intestinal crypt, which impairs intestinal function and contributes to systemic health issues. Given the critical role ISCs play in maintaining intestinal homeostasis, preventing their senescence is essential for preserving intestinal function. Among the various strategies proposed to slow cellular senescence, regular exercise has emerged as one of the most well-known and widely accepted interventions. Here, we examined how exercise affects the small intestine in an aging mouse model. Using single-cell RNA sequencing, we found that signaling pathways and gene expression related to DNA replication and cell cycle progression were upregulated in ISCs. Additionally, genes promoting ribosome biogenesis showed increased expression in both ISCs and transit amplifying cells. Exercise also recovered Wnt signaling inhibition, potentially influencing ISC differentiation. Furthermore, exercise increased Reg3g expression in Paneth cells and improved gut barrier function, contrasting with findings from a diet-induced obese mouse model. This suggests that regular exercise helps inhibit the aging of ISCs in multiple ways, contributing to the maintenance of intestinal homeostasis.

Mitochondrial dysfunction caused by aging leads to decreased energy metabolism, resulting in functional decline and increased frailty in multiple tissues. Strategies for protecting and activating mitochondria under stressful conditions are required to suppress aging and age-related diseases. However, it is challenging to develop drugs capable of boosting mitochondrial respiration and compensating for the reduced intracellular adenosine triphosphate (ATP) levels. In this study, we developed a prodrug that stimulates the metabolism of intracellular adenine nucleotides (AXP: adenosine monophosphate (AMP), adenosine diphosphate (ADP), and ATP). It enhances AMP-activated protein kinase activity, fatty acid oxidation, oxidative stress resistance, and mitochondrial respiration, thereby increasing the intracellular ATP levels. Furthermore, this prodrug markedly extended the lifespan of

Ageing is the most important risk factor for many common human diseases, including cancer, diabetes, neurodegeneration and cardiovascular disease. Consequently, combating ageing itself has emerged as a rational strategy for addressing age-related multimorbidity. Over the past three decades, multiple genetic and pharmacologic interventions have led to substantial extension of lifespan and healthspan in model organisms. However, it is unclear whether these interventions target the causal mechanisms of ageing or downstream consequences. Ample evidence suggests that DNA damage to the somatic genome is a major causal mechanism of ageing, which compromises essential cellular functions such as transcription and replication, and leads to cellular senescence, apoptosis and mutations. Recently, new concepts have emerged to target the main consequences of DNA damage and enhance DNA repair capacities, thereby extending maintenance of the genome. Here, we review advances in this field and discuss approaches to pharmacologically mitigate the adverse effects of DNA damage to delay ageing, prevent mutation-driven cancer and mitigate age-related degenerative diseases.

Intervertebral disc degeneration (IDD) is a progressive and dynamic process in which the senescence-associated secretory phenotype (SASP) of nucleus pulposus cells (NPC) plays a significant role. While impaired chaperone-mediated autophagy (CMA) has been associated with inflammation and cellular senescence, its specific involvement in the self-perpetuating feedback loop of NPC senescence remains poorly understood. Through LAMP2A knockout in NPC, we identified a significant upregulation of DYRK1A, a core mediator of premature senescence in Down syndrome. Subsequent validation established DYRK1A as the critical driver of premature senescence in CMA-deficient NPC. Combinatorial transcription factor analysis revealed that under IL1B stimulation or CMA inhibition, elevated DYRK1A promoted FOXC1 phosphorylation and nuclear translocation, initiating transcriptional activation of cell cycle arrest. Intriguingly, CMA impairment concurrently enhanced glutamine metabolic flux in senescent NPC, thereby augmenting their survival fitness. Transcriptomic profiling demonstrated that CMA reactivation in senescent NPC facilitated fate transition from senescence to apoptosis, mediated by decreased glutamine flux via GLUL degradation. Therefore, CMA exerts protective effects against IDD by maintaining equilibrium between premature senescence and senolysis. This study elucidates CMA's regulatory role in SASP-mediated senescence amplification circuits, providing novel therapeutic insights for IDD and other age-related pathologies.

Extracellular matrix remodelling of cardiac tissue is a key contributor to age-related cardiovascular disease and dysfunction. Such remodelling is multifaceted including changes to the biochemical composition, architecture and mechanics, clouding our understanding of how and which extracellular matrix properties contribute to a dysfunctional state. Here we describe a decellularized extracellular matrix-synthetic hydrogel hybrid scaffold that independently confers two distinct matrix properties-ligand presentation and stiffness-to cultured cells in vitro, allowing for the identification of their specific roles in cardiac ageing. The hybrid scaffold maintains native matrix composition and organization of young or aged murine cardiac tissue, whereas its mechanical properties can be independently tuned to mimic young or aged tissue stiffness. Seeding these scaffolds with murine primary cardiac fibroblasts, we identify distinct age- and matrix-dependent mechanisms of cardiac fibroblast activation, matrix remodelling and senescence. Importantly, we show that the ligand presentation of a young extracellular matrix can outweigh the profibrotic stiffness cues typically present in an aged extracellular matrix in maintaining or driving cardiac fibroblast quiescence. Ultimately, these tunable scaffolds can enable the discovery of specific extracellular targets to prevent ageing dysfunction and promote rejuvenation.

The regeneration of human tissues is a great scientific challenge and a critical factor to achieve a long healthspan and prevent disabilities due to injury or disease. Materials chemistry can contribute to this goal with the development of bioactive supramolecular systems that can signal cells for regeneration. Recent work in our laboratory using in vivo models of spinal cord injury and cartilage regeneration has demonstrated that the motion of bioactive molecules in supramolecular scaffolds enhances receptor signaling. We report here on a novel molecular strategy to control supramolecular motion in filamentous assemblies using bone regeneration as a functional target. The supramolecular assemblies are composed of monomers that arrange, by design, with either parallel or antiparallel β-sheets, and some of them contain a terminal peptide sequence that binds BMP-2. We found that parallel β-sheet supramolecular assemblies promote greater osteogenic differentiation of progenitor cells in vitro relative to antiparallel assemblies, as well as superior quality of newly regenerated bone in a rat model of spinal fusion. Furthermore, these assemblies drastically reduce the dangerous supraphysiological dose of BMP-2 used clinically for spinal fusion. We attribute the enhanced bioactivity to the weaker nature of hydrogen bonds in parallel relative to antiparallel β-sheet assemblies, which in turn allows greater supramolecular motion and cell signaling of the growth factor-binding molecules.

Age-related bone defects cause disability and mortality in older individuals. During bone repair in older individuals, high oxidative stress and excessive inflammation in the senescent microenvironment (SME) lead to bone marrow mesenchymal stem cell (BMSC) senescence, thereby affecting bone regeneration. In this study, we prepared multifunctional magnesium (Mg) and cerium (Ce) ion-based metal-organic frameworks (MOFs) using a hydrothermal method and constructed a three-dimensional (3D) bioprinted scaffold to effectively scavenge reactive oxygen species (ROS) and sustainably release Mg

The global burden of neurologic disorders is rising, driven by aging populations and improved survival following acute neurologic events. As a result, more individuals are living with long-term disabilities from conditions such as stroke, dementia, and other neurodegenerative diseases. Despite significant advances in neurology, there remains an urgent need for a preventive approach to mitigate these trends. Growing evidence highlights the effectiveness of preventive strategies, including lifestyle modifications and risk factor management, in preserving brain health and reducing the risk of stroke, neurodegenerative conditions, and cognitive decline. Preventive neurology operates within a multilevel framework, ranging from direct patient-centered interventions to systemic policy actions requiring organizational and societal support. Neurologists are uniquely positioned as advocates for brain health, promoting preventive strategies in line with the American Academy of Neurology's Brain Health Initiative. This article explores how neurologists can drive change across individual, family, community, and policy levels by leveraging their clinical expertise, community engagement, and health policy influence. Sustainable progress in brain health will also require system-level changes that integrate preventive goals into the fabric of health care delivery, public health infrastructure, and policy frameworks. Special attention is given to underserved populations, who bear a disproportionate burden of neurologic diseases. Through targeted interventions, public health initiatives, and collaborative care models, preventive neurologists can shape brain health outcomes across the lifespan. Training neurologists with a preventive focus will integrate brain health promotion into standard neurology practice, complementing disease management. By addressing the root causes and risk factors of neurologic conditions, preventive neurology provides a pathway to improving quality of life while reducing the global health care burden.

The reactive oxygen species superoxide is generated by mitochondria during the process of producing energy. While superoxide can cause oxidative damage to the cell, we and others have shown that a mild increase in mitochondrial superoxide extends longevity in multiple model organisms. To elucidate the molecular mechanisms involved, we identified transcriptional changes in mitochondrial superoxide dismutase deletion mutants (sod-2 worms) using RNA sequencing. sod-2 mutants exhibit a number of changes in nuclear gene expression resulting from elevated mitochondrial superoxide suggesting that mitochondria-to-nucleus signaling is contributing to their longevity. Gene ontology enrichment analysis demonstrated that genes involved in innate immunity and cuticle formation are significantly upregulated in sod-2 worms. To identify kinases involved in this lifespan-extending pathway, we completed a targeted RNA interference screen to examine the contribution of 61 selected kinases to sod-2 longevity. From this screen, we found 25 kinases which are required for the long lifespan of sod-2 mutants including mak-2, which has an established role in a kinase signaling pathway involved in axon regeneration. Disruption of mak-2 specifically reduces sod-2 lifespan but not wild-type longevity and also decreases resistance to multiple exogenous stressors. In examining other genes that act with mak-2 in pathways controlling axon regeneration, we identified a SEK-3/PMK-3/MAK-2/CEBP-1 signaling pathway that is specifically required for sod-2 longevity but not wild-type lifespan. Combined these results suggest a novel role for kinases with established roles in axon regeneration in promoting longevity through a mitochondria-to-nucleus signaling pathway.

Axenic dietary restriction (ADR) represents a powerful and unique DR regimen for C. elegans as it robustly extends lifespan independently of well-known key genes associated with DR, such as those of insulin/IGF-1 signaling, skn-1, and pha-4. Here, we analyze C. elegans survival in a dilution series of axenic medium to explore the dependency of lifespan extension on nutrient availability. We find a non-linear relationship between lifespan and axenic nutrient levels with a four-fold axenic dilution yielding peak longevity. Notably, lifespan extension at specific dilutions permits maintenance of reproductive potential and survivability after bacterial reintroduction, indicating a partial reliance on adult reproductive diapause mechanisms. Genetic analyses found the involvement of AMPK/aak-2, sir-2.1, and cbp-1 in mediating lifespan extension across the axenic dilution spectrum, the essential role of daf-16 and hlh-30 under severe nutrient scarcity, and the specific contribution of bli-4 to standard ADR longevity. These findings elucidate that C. elegans lifespan extension under different levels of nutrient restriction is governed by overlapping yet distinct genetic pathways.

The advanced maternal age is strongly correlated with a notable decline in oocyte quality, yet definitive and effective strategies to enhance it remain incompletely identified. In this study, we reported that near-infrared light, administered in vitro, efficaciously improves the quality of post-ovulatory aging (POA) and reproductive aged oocytes by recovering mitochondrial activity. Near-infrared light has the capacity to ameliorate abnormalities in mitochondrial membrane potential, optimize mitochondrial distribution, augment ATP synthesis, and modulate the expression of mitochondrial-related genes. It can consequently enhance the quality of oocytes by reducing the reactive oxygen species (ROS) level, improving the abnormal distribution of spindles and maintaining the fertilization ability. Moreover, transcriptome analysis also shows that the beneficial effect of near-infrared light on POA and reproductive aged oocytes is mediated by restoration of mitochondrial function. Collectively, our data reveal that the near-infrared light treatment, especially of 810 nm or 950 nm with a cumulative dosage of 1.5 J*cm-2, is a feasible approach to protect oocytes from POA and reproductive aged deterioration, contributing to the improvement of reproductive outcomes of aged women and assisted reproductive technology.

Background Senescence identification is rendered challenging due to a lack of universally available biomarkers. This represents a bottleneck in efforts to develop pro-senescence therapeutics - agents designed to induce the arrest of cellular proliferation associated with a senescence response in cancer cells for therapeutic gain. This is particularly true in contexts such as basal-like breast cancer (BLBC), which often express high levels of widely reported senescence hallmarks, which has led to the designation of these subtypes as senescence marker positive (Sen-Mark+). Unfortunately, these are often cancers with the most limited treatment options, where novel pro-senescence compounds would be of potential clinical utility. Results To address these challenges, we have developed SAMP-Score, a machine learning classification tool for identifying senescence induction in Sen-Mark+ cancers. This technique builds upon our previous observation that senescent cells develop distinct senescence-associated morphological profiles (SAMPs), which can be assessed readily in traditionally challenging contexts for senescence identification, including high-throughput screens. Conclusions Through application of SAMP-Score, we have identified QM5928, a novel pro-senescence compound, that is able to induce senescence in a variety of Sen-Mark+ cancers and has potential utility as a tool molecule to explore the mechanisms and pathways through which senescence induction occurs in these cells.

Aging is characterized by a gradual decline of cellular and physiological functions over time and an increased risk of different diseases. RNA therapeutics constitute an emerging approach to target the molecular mechanisms of aging and age-related diseases via rational design and have several advantages over traditional drug therapies, including high specificity, low toxicity and the potential for rapid development and production. Here, we discuss the latest developments in RNA therapeutics designed to promote healthy aging, including RNA activation, messenger RNA therapy, RNA interference, antisense oligonucleotides, aptamers and CRISPR-Cas-mediated RNA editing. We also review the latest preclinical and clinical studies of RNA technology for treating age-related diseases, including neurodegenerative, cardiovascular and musculoskeletal diseases. Finally, we discuss the challenges of RNA technology aimed at supporting healthy aging. We anticipate that the fusion of RNA therapeutics and aging biology will have an important effect on the development of new medicines and maximization of their efficacy.

Retinal age has emerged as a promising biomarker of aging, offering a non-invasive and accessible assessment tool. We developed a deep learning model to estimate retinal age with enhanced accuracy, leveraging retinal images from diverse populations. Our approach integrates self-supervised learning to capture chronological information from both snapshot and sequential images, alongside a progressive label distribution learning module to model biological aging variability. Trained and validated on healthy cohorts (34,433 participants from the UK Biobank and three Chinese cohorts), the model achieved a mean absolute error of 2.79 years, surpassing previous methods. When applied to broader populations, analysis of the retinal age gap-the difference between retina-predicted and chronological age-revealed associations with increased risks of all-cause mortality and multiple age-related diseases. These findings highlight the potential of retinal age as a reliable biomarker for predicting survival and aging outcomes, supporting targeted risk management and precision health interventions.

Dogs serve as ideal research subjects for aging studies. In this study, 9 aging-related cell populations are identified through single-cell RNA sequencing of dogs of different ages. Additionally, 9 CD8+ T cell senescence-specific markers conserved across species are identified. Furthermore, multi-omics technology is employed to characterize 17 transcriptional and protein markers, along with 5 metabolic markers, associated with stem cell aging. Penitrem A and UDP-N-acetylglucosamine are further validated as two consistent metabolic markers of both individual and cellular senescence. A customized metabolic assessment system and blood-based assessment framework specifically for aging dogs are developed. Notably, it is demonstrated that mesenchymal stem cells, particularly those overexpressing NMNAT1, can delay or reverse aging in dogs. This study sheds light on the mysteries of aging from multiple perspectives and provides a broad target for future research efforts aimed at uncovering the complexity of this fundamental biological process.

Early vascular aging plays a central role in chronic kidney disease (CKD), but its molecular causes remain unclear. Somatic mutations accumulate in various cells with age, yet their functional contribution to aging tissues is not well understood. Here we found progerin, the protein responsible for the premature aging disease Hutchinson-Gilford progeria syndrome, steadily recurring in vascular smooth muscle cells of patients with CKD. Notably, the most common progeria-causing mutation, LMNA c.1824C>T, was identified as a somatic mutation in CKD arteries. Clusters of proliferative progerin-expressing cells in CKD arteries and in vivo lineage-tracing in mice revealed clonal expansion capacity of mutant cells. Mosaic progerin expression contributed to genomic damage, endoplasmic reticulum stress and senescence in CKD arteries and resulted in vascular aging phenotypes in vivo. These findings suggest that certain somatic mutations may be clonally expanded in the arterial wall, contributing to the disease-related functional decline of the tissue.

Skin aging is a complex biological process driven by intrinsic and extrinsic factors, leading to a progressive structural and functional decline. The balance between extracellular matrix (ECM) degradation and synthesis is critical for maintaining skin homeostasis, with collagen loss and reduced cell proliferation contributing to age-related deterioration. Serpin Family A Member 3 (SERPINA3), a serine protease inhibitor, has been implicated in inflammation and tissue remodeling. However, its role in skin aging remains largely unexplored. In this study, we examined the expression and function of SERPINA3 in human skin cells. RNA-seq analysis revealed that SERPINA3 expression is significantly downregulated in aged human dermal fibroblasts and was further diminished under oxidative stress. Functional assays demonstrated that SERPINA3 promotes cell proliferation, accelerates wound healing, and activates key signaling pathways such as ERK and AKT. These findings suggest that SERPINA3 may serve as a protective factor against skin aging by supporting ECM integrity and enhancing cellular regeneration. These results provide novel insights into the molecular functions of SERPINA3 and highlight its potential as a therapeutic target for age-related skin deterioration.

The limited doubling capacity of human cells, known as replicative senescence or cellular senescence, is a major factor in cellular aging. This process is triggered by telomere erosion, which activates a p53-mediated DNA damage response (DDR) that halts cell proliferation. p53, a transcriptional regulator, responds to DNA damage by increasing the expression of the cyclin-dependent kinase inhibitor p21. p21 then arrests cells at specific stages of the cell cycle. Additionally, p53 upregulates serpinB2 (also known as plasminogen activator inhibitor-2, PAI-2), which stabilizes p21 in senescent cells. This study reveals that serpinB2 upregulation activates transglutaminase 2 (TGM2), which selectively deamidates multiple glutamine residues on p21, stabilizing the protein and halting cell proliferation in senescent cells. Moreover, inhibiting TGM2-mediated deamidation accelerates p21 degradation, delaying the onset of senescence. Notably, pharmacological inhibition of TGM2 improves aging phenotypes in an accelerated aging model of chronic kidney disease (CKD). These findings provide crucial insights into the role of TGM2-mediated enzymatic deamidation in senescence and its potential relevance to age-associated conditions.

Telomere shortening occurs in multiple tissues throughout aging. When telomeres become critically short, they trigger DNA-damage responses and p53 stabilization, leading to apoptosis or replicative senescence. In vitro, cells with short telomeres activate the cGAS-STING innate immune pathway resulting in type-I interferon-based inflammation and senescence. However, the consequences of these events for the organism are not yet understood. Here, we show that sting is responsible for premature aging of telomerase-deficient zebrafish. We generated sting-/- tert-/- double-mutant animals and observed a thorough rescue of tert-/- phenotypes. At the cellular level, lack of cGAS-STING in tert mutants resulted in reduced senescence, increased cell proliferation, and decreased inflammation despite similarly short telomeres. Critically, absence of sting function resulted in dampening of the DNA damage response and reduced p53 levels. At the organism level, sting-/- tert-/- zebrafish regained fertility, showed delayed cachexia, and decreased cancer incidence, resulting in increased healthspan and lifespan of telomerase mutant animals.

Exercise induces neural and muscular adaptations, improving muscle mass and function in older adults. We investigated its impact on gait neuromuscular control in young and older adults, classified as more active (young: n = 15, 5185 ± 1471 MET-min/week; old: n = 14, 6481 ± 4846 MET-min/week) or less active (young: n = 14, 1265 ± 965 MET-min/week; old: n = 14, 1473 ± 859 MET-min/week). Isometric maximal voluntary torques were assessed for proximal (knee) and distal (ankle) extensors, and muscle mechanical properties of these muscles were assessed using Myoton. Gait was analysed using ground reaction forces, motion capture, and electromyography. Less active older adults exhibited shorter steps, higher mechanical cost, and greater collision at heel strike. These differences were linked to altered neuromuscular control, wider activation of lumbar and sacral motor pools, different activation timing, and reduced muscle-tendon stiffness. Our findings highlight that physical activity preserves neuromuscular control, muscle mechanical properties, and gait efficiency, mitigating age-related decline.

Aging is a major risk factor for insulin resistance and type 2 diabetes, driven in part by declining pancreatic beta cell function. While calorie restriction (CR) initiated early in life improves metabolic health and preserves beta cell function, its impact when initiated later in life remains unclear. We implemented a two-month, 20% CR intervention in 72-week-old male mice and assessed in vivo glucose homeostasis and beta cell function using meal tolerance tests, single cell RNA-sequencing, and confocal microscopy. We found that old mice exposed to CR have significantly improved glucose tolerance due to higher insulin sensitivity, which drives a two-fold reduction in glucose-stimulated beta cell insulin secretion. At the molecular level, CR enhanced beta cell proteostasis by downregulating ER stress pathways. Remarkably, CR reprogrammed the alpha cell transcriptome to suppress antigen presentation pathways and cytokine signaling pathways, including major histocompatibility complex class I (MHC-I) signaling. These transcriptional changes correlated with profound reduction in the density of adaptive immune cells in aging islets, including a near-complete loss of cytotoxic CD8+ T cells due to weakened intercellular communication between antigen-presenting cells with T and B lymphocytes. Importantly, aging human alpha cells from non-diabetic donors display similar proinflammatory phenotypes, including higher expression of MHC-I antigens that correlates with higher density of Cd8+ cells in aging human pancreases. Together, these findings demonstrate that CR remodels aging alpha and beta cell structure-function to modulate immune cell interactions in aging pancreases to mitigate age-related immune activation and islet inflammation.

Abstract Background and Aims The sodium-dependent multivitamin transporter, encoded by SLC5A6, mediates cellular uptake of the vitamins, biotin and pantothenic acid, both of which are essential cofactors for energy metabolism. Here, we report two families with SLC5A6 mutations presenting with early-onset dilated cardiomyopathy (DCM). To investigate the link between vitamin deficiency and DCM, we generated a novel cardiac-specific Slc5a6 knockout (Slc5a6cKO) mouse model and tested the therapeutic potential of vitamin supplementation. Methods Cardiac function in Slc5a6cKO mice was assessed by cardiac magnetic resonance imaging and ECG measurements. Histological, biochemical, and proteomic analyses were conducted to identify structural and metabolic changes. The impact of dietary biotin and pantothenic acid supplementation on disease progression was evaluated. Results Slc5a6cKO mice developed progressive cardiac dysfunction, manifesting as DCM with cardiac dilation, cardiomyocyte hypertrophy, fibrosis, impaired Coenzyme A synthesis, and metabolic imbalance, culminating in premature death by 26 weeks. Proteomic analysis revealed early mitochondrial metabolic disruption and extracellular matrix protein upregulation at 8 weeks, preceding overt cardiac dysfunction. Strikingly, vitamin supplementation from preconception onwards, prevented the cardiac phenotype, preserving cardiac structure, function, morphology and survival. This parallels the clinical outcome in one patient who received early vitamin treatment, compared to another who required a heart transplant following delayed vitamin treatment. Conclusions This study establishes a direct link between SLC5A6-mediated vitamin transport, mitochondrial function, and cardiac health. It highlights how vitamin deficiency contributes to DCM pathogenesis and supports early vitamin supplementation as a potential therapeutic strategy for metabolic cardiomyopathies.

The transient upregulation of cellular senescence within wound tissues has been demonstrated to be an important biological process facilitating efficient tissue repair. Dysregulation of this transient wound-induced senescence-like response can result in impaired healing outcomes. Given the established age-related decline in tissue regenerative capacity, we hypothesized that alterations in this senescence response contribute to the delayed healing of cutaneous wounds in aged individuals. Our investigation demonstrated a significant delay in the closure of full-thickness dorsal skin wounds in aged mice compared to their young counterparts. Analysis of the wound microenvironment revealed a transient upregulation of senescence-associated markers (p16, p21, senescence-associated {beta}-galactosidase) and senescence-associated secretory phenotype factors in the wound tissue of young mice, a response that was markedly attenuated in aged mice. Single-cell RNA sequencing analysis of all cells isolated from day 6 wounds identified a distinct population of p16+/p21+/Ki67- senescent fibroblasts in young mice, characterized by a transcriptional signature indicative of pro-healing extracellular matrix production, a finding corroborated in human wound tissue from young donors. Crucially, in aged wounds, we observed a lower quantity of these senescent cells, a deficit compounded by a qualitative, age-dependent shift in their function, moving away from beneficial extracellular matrix remodeling towards a more detrimental pro-inflammatory state, which ultimately can contribute to the delayed wound healing.

Epigenetic drift, which is gradual age-related changes in DNA methylation patterns, plays a significant role in aging and age-related diseases. However, the relationship between exercise, epigenetics, and aging, and the molecular mechanisms underlying their interactions are poorly understood. Here, we investigated the relationship between cardiorespiratory fitness (CRF), epigenetic aging, and promoter methylation of individual genes across multiple organs in selectively bred low- and high-capacity runner (LCR and HCR) aged rats. Epigenetic clocks, trained on available rat blood-derived reduced representation bisulfite sequencing data, did not reflect differences in CRF between LCR and HCR rats across all four organs. However, we observed organ-specific differences in global mean DNA methylation and mean methylation entropy between LCR and HCR rats, and the direction of these differences was the opposite compared to the age-related changes in the rat blood. Notably, the soleus muscle exhibited the most pronounced differences in promoter methylation due to CRF. We also identified seven genes whose promoter methylation was consistently influenced by CRF in all four organs. Moreover, we found that age acceleration of the soleus muscle was significantly higher compared to the heart and the hippocampus, and significantly lower compared to the large intestine. Finally, we found that the age acceleration was not consistent across organs. Our data suggest that CRF associates with epigenetic aging in an organ-specific and organ-common manner. Our findings provide important insights into the biology of aging and emphasize the need to validate rejuvenation strategies in the context of the organ-specific nature of epigenetic aging.