Longevity Papers

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.

Epigenetic aging measures are novel molecular indicators of biological aging that predict age-related chronic disease. We examined whether several established indices of epigenetic aging mediated the association between life course socioeconomic status (SES) and decrements in kidney function across a decade. Biomarker data were from 252 non-Hispanic (NH) Black and white participants who had consented to genetic analyses in Wave 2 (2004-2009) and 3 (2014-2021) of the Midlife in the United States study (MIDUS). Life course SES included parental education, a proxy of early life SES, and a composite score of adult SES based on the highest education level, household income to poverty line ratio, health insurance coverage, perception of the availability of money to meet needs, and difficulty level paying monthly bills. We included five measures of epigenetic age accelerations (EAA), based on the residuals after each epigenetic clock was regressed on chronological age (Horvath, Horvath blood and skin, Hannum, PhenoAge, and GrimAge) and one measure of the pace of aging (DunedinPACE) obtained during MIDUS 2. Kidney function was based on serum creatinine-based estimated glomerular filtration rate (eGFR), calculated using the CKD-EPI formula (without race adjustment). We calculated absolute decrements in eGFR across 11 years between MIDUS waves 2 and 3. Analyses were adjusted for age, sex, and health-related covariates (currently smoking, obese, hypertension, and insulin resistance). Lower adult SES and accelerated epigenetic aging, especially accelerated GrimAge and faster DunedinPACE pace of aging, mediated the association between lower parental education and larger decrements in eGFR. Accelerated epigenetic aging is associated with larger decrements in kidney function across a decade and may be one of the critical explanatory pathways for the higher burden of chronic kidney disease (CKD) among lower SES individuals.

Mitochondria are the energy production centers in cells and have unique genetic information. Due to the irreplaceable function of mitochondria, mitochondrial dysfunction often leads to pathological changes. Mitochondrial dysfunction induces an imbalance between oxidation and antioxidation, mitochondrial DNA (mtDNA) damage, mitochondrial dynamics dysregulation, and changes in mitophagy. It results in oxidative stress due to excessive reactive oxygen species (ROS) generation, which contributes to cell damage and death. Mitochondrial dysfunction can also trigger inflammation through the activation of damage-associated molecular patterns (DAMPs), inflammasomes and inflammatory cells. Besides, mitochondrial alterations in the functional regulation, energy metabolism and genetic stability accompany the aging process, and there has been a lot of evidence suggesting that oxidative stress and inflammation, both of which are associated with mitochondrial dysfunction, are predisposing factors of aging. Therefore, this review hypothesizes that mitochondria serve as central hubs regulating oxidative stress, inflammation, and aging, and their dysfunction contributes to various diseases, including cancers, cardiovascular diseases, neurodegenerative disorders, metabolic diseases, sepsis, ocular pathologies, liver diseases, and autoimmune conditions. Moreover, we outline therapies aimed at various mitochondrial dysfunctions, highlighting their performance in animal models and human trials. Additionally, we focus on the limitations of mitochondrial therapy in clinical applications, and discuss potential future research directions for mitochondrial therapy.

Loss of protein homeostasis is a hallmark of cellular senescence, and ribosome pausing plays a crucial role in the collapse of proteostasis. However, our understanding of ribosome pausing in senescent cells remains limited. In this study, we utilized ribosome profiling and G-quadruplex RNA immunoprecipitation sequencing techniques to explore the impact of RNA G-quadruplex (rG4) on the translation efficiency in senescent cells. Our results revealed a reduction in the translation efficiency of rG4-rich genes in senescent cells and demonstrated rG4 structures within coding sequence (CDS) can impede translation both in vivo and in vitro. Moreover, we observed a significant increase in the abundance of rG4 structures in senescent cells, and the stabilization of the rG4 structures further exacerbated cellular senescence. Mechanistically, the RNA helicase DHX9 functions as a key regulator of rG4 abundance, and its reduced expression in senescent cells contributing to increased ribosome pausing. Additionally, we also observed an increased abundance of rG4, an imbalance in protein homeostasis, and reduced DHX9 expression in aged mice. In summary, our findings reveal a novel biological role for rG4 and DHX9 in the regulation of translation and proteostasis, which may have implications for delaying cellular senescence and the aging process.

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.