Longevity Papers

The incidence of stroke, heart failure, dementia, many cancers, coronary artery disease, and physical disability rise exponentially with age. Geroscience is a relatively new discipline that aims to define and modify aging-related biologic pathways, slow age-related disability, prevent age-related diseases, and increase disability-free survival.

Clonal hematopoiesis (CH) is defined as the age-associated expansion of hematopoietic stem and progenitor cells harboring somatic mutations, most frequently in epigenetic regulators such as DNMT3A, TET2, and ASXL1. Although CH was initially recognized as a precursor to hematological malignancies, accumulating evidence has led to its broad recognition as a relevant factor in various age-related nonmalignant diseases, particularly those with inflammatory components, such as cardiovascular disease, autoimmune disorders, and solid tumors. Notably, the increased overall mortality associated with CH is primarily driven by cardiovascular complications rather than hematological malignancies. Among CH-associated genes, ASXL1 mutations are distinguished by their strong associations with adverse clinical outcomes and pro-inflammatory signatures. However, compared to TET2 and DNMT3A, the molecular and pathological implications of ASXL1-mutated CH remain underexplored. Recent studies have expanded the disease spectrum of ASXL1 mutations beyond hematological malignancies, implicating them in clonal expansion and systemic inflammation. This review aims to summarize the current epidemiological and experimental insights into ASXL1-mutated CH, focusing on its potential contributions to inflammation-associated diseases. By integrating clinical observations and emerging mechanistic data, we highlight the urgent need for deeper investigation into ASXL1-driven CH and its systemic consequences beyond hematological transformation.

Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age. Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immune cells. Chronic inflammation contributes to a variety of age-related diseases, such as neurodegenerative disease, cancer, infectious disease, and autoimmune diseases. Although not fully understood, recent studies contribute greatly to uncovering the underlying mechanisms of immunosenescence at the molecular and cellular levels. Immunosenescence is associated with dysregulated signaling pathways (e.g., overactivation of the NF-κB signaling pathway and downregulation of the melatonin signaling pathway) and abnormal immune cell responses with functional alterations and phenotypic shifts. These advances remarkably promote the development of countermeasures against immunosenescence for the treatment of age-related diseases. Some anti-immunosenescence treatments have already shown promising results in clinical trials. In this review, we discuss the molecular and cellular mechanisms of immunosenescence and summarize the critical role of immunosenescence in the pathogenesis of age-related diseases. Potential interventions to mitigate immunosenescence, including reshaping immune organs, targeting different immune cells or signaling pathways, and nutritional and lifestyle interventions, are summarized. Some treatment strategies have already launched into clinical trials. This study aims to provide a systematic and comprehensive introduction to the basic and clinical research progress of immunosenescence, thus accelerating research on immunosenescence in related diseases and promoting the development of targeted therapy.

Older individuals are typically more susceptible to stroke, and age-related differences in brain plasticity significantly affect recovery and treatment responses following cerebral ischemia and traumatic brain injury. Extracellular vesicles (EVs) have emerged as promising diagnostic and therapeutic tools due to their role in intercellular communication and ability to cross the blood-brain barrier. While EVs hold potential in promoting brain repair, their efficacy is influenced by donor age-those derived from young stem cells exhibit more regenerative profiles, whereas aged donor EVs may carry senescence-related signals that impede recovery. Emerging therapies, including senolytics, exosome-based approaches, and immune modulation, aim to enhance post-stroke repair, yet a substantial translational gap persists, especially in adapting these strategies to the aged brain. Differences in immune responses, neurovascular integrity, and repair mechanisms between young and aged individuals further complicate therapeutic development. Incorporating aged animal models in preclinical research is thus essential for ensuring the relevance and safety of interventions in elderly patients. These findings underscore the need for age-tailored strategies that reflect the unique biological landscape of aging, paving the way for more effective treatments for stroke and related neurological conditions in older adults.

The desire to increase life expectancy, coupled with the decline in biological functions that occurs as we age, represents one of the most significant challenges facing our society. Age-related declines in biological functions contribute to frailty and morbidity, demanding innovative strategies to promote healthy aging. The circadian clock, which controls daily physiological processes, is intricately linked to aging and overall health. Circadian disruptions can lead to metabolic dysfunction, impaired immune responses, increased DNA damage, and elevated disease susceptibility. On the other hand, maintaining robust circadian rhythms through interventions such as regular sleep-wake patterns, time-restricted feeding, and physical activity may extend health span and longevity. The circadian clock affects various molecular pathways associated with aging, including the insulin/IGF, mTOR, and sirtuin signaling pathways. Enhancing circadian rhythms presents a promising avenue for mitigating age-related disorders and promoting healthy aging. This review highlights the potential of circadian clock-based interventions as a transformative strategy to improve the quality of life and extend the healthspan of aging individuals.

Caloric restriction (CR) extends lifespan, yet the convergent immunometabolic mechanism of healthspan remains unclear. Using longitudinal plasma proteomics analyses in humans achieving 14% CR for 2 years, we identified that inhibition of the complement pathway is linked to lower inflammaging. The protein C3a (and its cleaved form) was significantly lowered by CR, thus reducing inflammation emanating from three canonical complement pathways. Interestingly, circulating C3a levels are increased during aging in mice, with visceral adipose tissue macrophages as the predominant source. In macrophages, C3a signaling via ERK elevated inflammatory cytokine production, suggesting the existence of an autocrine loop that promotes inflammaging. Notably, long-lived FGF21-overexpressing mice and PLA2G7-deficient mice exhibited lower C3a in aging. Specific small molecule-mediated systemic C3 inhibition reduced inflammaging, improved metabolic homeostasis, and enhanced healthspan of aged mice. Collectively, our findings reveal that complement C3 deactivation is a metabolically regulated inflammaging checkpoint that can be harnessed to extend healthspan.

Unintentional weight loss (UWL) is related to mortality and mobility limitation. Here, we aimed to develop a metabolite-based score for UWL and evaluate its prediction performance and explanation value for UWL-related health outcomes. Participants from the Health, Aging and Body Composition (Health ABC) study with available metabolomics and valid follow-ups were included (N = 2286). First, in the derivation group (N = 1200), 27 of the 77 metabolites associated with incident UWL (> 3% annual UWL vs. weight stable) were selected by LASSO-logistic regression. The UWL metabolite score was calculated as a weighted sum of these 27 standardized metabolites, with higher scores indicating greater UWL risk. We then examined the standardized UWL metabolite score against all-cause mortality and incident mobility limitation using Cox regression. Overall, older adults with a one-SD higher UWL metabolite score had higher risks for mortality (1.44 [1.36, 1.52]) and mobility limitation (1.23 [1.15, 1.32]). The score also improved mortality prediction beyond traditional risk factors. Similar results were observed in the hold-out test group (n = 1086). Furthermore, this score explained 28% of the UWL-mortality relationship and 22% of the UWL-mobility limitation relationship beyond lifestyle and medical history, respectively. The score also predicted higher mortality and mobility limitation among those with intentional weight loss and weight gain, demonstrating a good Out-Of-Distribution generalizability. This metabolomic characterization of UWL is predictive of key aging outcomes in the Health ABC participants and captures a substantial portion of the mortality and mobility limitation risks related to unintentional weight loss, further validating the importance of these metabolite signatures.

Members of the AT-HOOK MOTIF NUCLEAR LOCALIZED (AHL) gene family have been shown to play important roles in plant development. In Arabidopsis thaliana, one member of this family, AHL15, induces somatic embryogenesis and extends plant longevity when overexpressed - the latter through strong repression of several ageing-related developmental transitions. However, its direct target genes and the mechanisms by which it regulates their expression have remained elusive to date. In this study we identified the genome-wide DNA binding sites of AHL15, and show that AHL15 binds throughout the genome at AT-rich sequences near the transcription start- and end sites in regions depleted of epigenetic marks. We show that induction of AHL15 activity causes strong and rapid changes in transcription, with the majority of the differentially expressed genes being downregulated but without directly affecting chromatin accessibility, resulting in developmental defects. In addition, AHL15 binding to regions near the transcription start and end sites was enhanced at genes that were differentially expressed upon AHL15 induction, and was especially strong near the transcription start site of upregulated genes and near the transcription end site of downregulated genes. Finally, we show that AHL15 shares binding sites with the chromatin architectural protein GH1-HMGA2/HON5, which was previously shown to alter transcription by disrupting gene loop formation. Together, our findings suggest that AHL15 affects the expression of its target genes by regulating the 3D organization rather than the accessibility of chromatin.

The ageing global population is experiencing an increased prevalence of cerebrovascular diseases, such as stroke and dementia. This highlights a need for understanding the pathophysiological mechanisms of age-related cerebrovascular alterations, alongside benefits of interventions such as physical activity. Therefore, our aims were to: (1) examine the impact of ageing and exercise training on cerebrovascular function and (2) to characterize age- and exercise training-related changes in the hippocampus transcriptome. Young and old male rats were randomized to a sedentary condition or exercise training for 10 weeks. In the first protocol, cerebral arteries were isolated to test vasomotor reactivity, quantify gene/protein expression and assess nitric oxide production. In the second protocol, anhedonia was assessed and hippocampal tissue collected for RNA-sequencing. Bioinformatic analyses (i.e. protein-protein interaction mapping) were performed. Ageing impaired endothelium-dependent vasoreactivity in the posterior communicating artery (PCoA), with a shift from endothelial nitric oxide synthase (NOS)- to neuronal NOS-mediated vasorelaxation, as well as alterations in oxidative stress production. In support, PCoA superoxide-mediated vasoreactivity and neuronal NOS-mediated production of NO decreased with age. Exercise enhanced vasodilatation in young rats, but the results suggested reduced cerebrovascular plasticity in older animals. In the second protocol, exercise training attenuated the age-related increase in anhedonia behaviour. Hippocampal RNA-sequencing revealed altered inflammatory and oxidative stress pathways with ageing that were mitigated by exercise training. Our findings underscore the complex interplay between vascular/neuronal factors in the ageing brain. Furthermore, these findings highlight the therapeutic potential of exercise in mitigating the adverse effects of ageing on cerebral health. KEY POINTS: Ageing is associated with increased risks of cerebrovascular disease and neurocognitive decline. Little is known about the underlying mechanisms involved in this process, limiting our ability to design appropriate interventions. Ageing is associated with alterations in cerebrovascular function, including possible changes in the mechanisms underlying vasomotor reactivity. Hippocampal RNA-seq revealed age-related alterations in neuronal, vascular, immune and oxidative-stress related signalling pathways. Exercise training may have mitigated many of these age-related changes, suggesting that enhancing physical activity may be a feasible means to preserve cerebral health in older individuals.

Skin firmness and elasticity are largely determined by the dermal extracellular matrix, particularly the elastin fiber network. Age-related degradation of elastin alters its architecture, contributing to diminished skin resilience. However, the quantitative relationship between elastin fiber geometry and macroscopic skin firmness remains incompletely understood. In this study, we developed a novel computational framework integrating realistic 3D elastin fiber geometries-extracted from confocal microscopy images of human abdominal skin samples (Caucasian females, aged 38-78 years)-into a finite element (FE) model of the dermal matrix. The elastin networks were explicitly represented as beam elements within the FE domain. Unconfined compression simulations were conducted to evaluate skin's elastic resistance force and correlate it with quantified geometric parameters of the elastin networks. The results revealed a significant age-dependent decline in skin firmness, strongly associated with reductions in fiber diameter, fiber count, volume fraction, network connectivity (as indicated by increased fragmentation and reduced maximum cluster size), and the proportion of vertically oriented fibers. Among these, fiber count and maximum cluster size were the most important predictors of skin firmness. This study provides quantitative, mechanistic insights into how specific architectural alterations in elastin fibers directly impact the mechanical properties of aging skin. These findings emphasize the critical role of elastin network integrity and structural organization in maintaining skin function and offer a compelling rationale for therapeutic or cosmetic strategies aimed at preserving or restoring the elastin framework to maintain skin firmness.

Muscle wasting leads to reduced activities of daily living, an increased number of care-dependent individuals, and increased mortality. However, the metabolomic adaptations underlying muscle wasting remain poorly understood. Here, by comparing physiological, genetically induced, pathological, and age-related muscle atrophy, we identify the metabolites modulated by muscle atrophic stimuli, which we term "atrometabolites." Integrated metabolomics reveal that dysfunctional polyamine synthesis is a common feature of muscle atrophy. Mechanistically, we identify that adenosylmethionine decarboxylase 1 (Amd1) and Amd2 are important for maintaining polyamine metabolism and that downregulation of Amd1 and Amd2 is a trigger of myotube atrophy. Using skeletal muscle-specific FoxO triple-knockout mice, we find that FoxOs are required for immobilization-induced metabolomic remodeling and identify FoxO-dependent atrometabolites. This study comprehensively elucidates the molecular basis of muscle metabolomic adaptation and provides the datasets that will lead to the discovery of mechanisms underlying tissue adaptation to maintain homeostasis.

The eye is a recognised source of biomarkers for cardiovascular and neurodegenerative disease risk. Here, we characterise the breadth of these associations and identify biological axes that may mediate them. Using UK Biobank data, we developed a multi-omic analysis pipeline integrating physiological, radiomic, metabolomic, and genomic information. We trained adversarial autoencoders (Ret-AAE) to represent optical coherence tomography (OCT) images and colour fundus photographs as 256-dimensional embeddings. Ret-AAE derived embeddings were associated with a range of cardiovascular and neurodegenerative diseases, including ischaemic heart disease, cerebrovascular disease, Parkinsons disease, and dementia. Examining associations across diverse omics datasets, we provide evidence linking ophthalmic imaging features to neurological and cardiovascular anatomy and function, lipid metabolism, and gene sets associated with neurodegenerative pathology. Collectively, our findings demonstrate that ophthalmic features reflect complex, multisystem biological processes, and reinforce the role of the eye as a composite indicator of systemic health.

Skeletal muscle adaptation to contractile activity is modulated by redox signalling, primarily through reactive oxygen species (ROS) such as hydrogen peroxide (H

Cardiovascular aging is a key contributor to cardiovascular diseases (CVDs). As individuals age, the frequency and severity of cardiovascular events rise, establishing CVDs as a primary cause of death in older adults. Therefore, the development and exploration of drugs or bioactive molecules that can effectively prevent cardiovascular aging and related diseases are urgently needed. This study evaluated the effects of salidroside, a key component of Rhodiola rosea extract, on cardiomyocyte senescence. We established an in vitro cardiomyocyte senescence model using D-gal/H

Autophagic decline accompanies age and causes a deterioration in proteostasis, rendering neuronal demise. Rab27 functions as a vesicle regulator for macroautophagic/autophagic degradation and exocytosis. Loss of

Frailty is an age-related syndrome characterized by an increased vulnerability to adverse health outcomes in the face of stressors. By deriving a blood-based proteomic signature for frailty, the current study aimed to enhance the understanding of frailty biology and created a person-specific predictor for the risk of frailty and other adverse age-related health outcomes. A 25-protein signature (proteomic frailty index [pFI]) predictive of the cumulative frailty index (FI) in the LonGenity cohort was derived using a penalized regression method. The pFI was significantly correlated with the FI at baseline (Pearson r = 0.58) and showed significant associations with age-related chronic conditions, incident mortality, and clinical measures. In an independent cohort of 5195 participants in the Atherosclerosis Risk in Communities study, pFI was successfully validated with measured FI (r = 0.61, p < 0.001) and was associated with physical frailty at baseline (p < 0.001). The pFI was significantly associated with physical, clinical, and cognitive measures, as well as incident mortality (HR [95% CI] = 1.13 [1.12-1.14]) and dementia (HR [95% CI] = 1.07 [1.05-1.09]) after accounting for demographic factors. The pFI was further validated against FI (r = 0.45, p < 0.001) in a second independent study in 654 participants from the Baltimore Longitudinal Study of Aging. In conclusion, we identified and validated a 25-protein signature as an index of frailty that also captures overall well-being, health, and risk for key age-related diseases.

Age-related reductions in skeletal muscle insulin responsiveness promote metabolic dysregulation and contribute to an elevated probability of type 2 diabetes onset. The malfunction of nutrient-responsive signaling routes, specifically AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR), constitutes a central component of this biological process. The integrated activity of these kinases in controlling energy dynamics, protein formation, and glucose processing is fundamental to ensure metabolic homeostasis in skeletal muscle tissue. Through its modulation of AMPK and mTOR pathways, exercise helps reinstate signaling equilibrium and supports better insulin efficacy in aging skeletal muscle. This review explores the molecular mechanisms by which different forms of exercise-endurance, resistance, and combined training-modulate the AMPK/mTOR axis in aging muscle. This analysis focuses on exercise-induced AMPK signaling as a catalyst for mitochondrial development, enhanced glucose processing, and intensified fatty acid breakdown, while also temporally coordinating mTOR activity to support muscle maintenance without exacerbating insulin resistance. By integrating insights from aging biology, exercise physiology, and molecular metabolism, this review highlights the therapeutic potential of targeting AMPK/mTOR signaling through physical activity to combat insulin resistance in the elderly.

In recent years, the intensifying global aging trend has made anti-aging research a critical area of scientific interest, with dietary interventions playing an essential role. Among dietary components, food-derived microRNAs (miRNAs), emerging as biologically active nutrients, have attracted increasing attention. Accumulating evidence indicates that dietary miRNAs may exert anti-aging effects by modulating gene expression and influencing key signaling pathways related to antioxidant defense, inflammation resolution, and metabolic homeostasis. Notably, recent studies have demonstrated the potential cross-species transfer of dietary miRNAs, highlighting their biological availability and functional relevance in mammalian systems. This review systematically summarizes current advances regarding the anti-aging potential of miRNAs derived from plant-, animal- and microbe-based foods, discusses underlying molecular mechanisms, and critically evaluates their realistic potential and limitations in dietary anti-aging strategies. Finally, we highlight open questions and propose future directions to harness dietary miRNAs as viable nutritional interventions for promoting healthy aging.

Neurodegenerative diseases are linked with dysregulation of the integrated stress response (ISR), which coordinates cellular homeostasis during and after stress events. Cellular stress can arise from several sources, but there is significant disagreement about which stress might contribute to aging and neurodegeneration. Here, we leverage directed transdifferentiation of human fibroblasts into aged neurons to determine the source of ISR activation. We demonstrate that increased accumulation of cytoplasmic double-stranded RNA (dsRNA) activates the eIF2 kinase PKR, which in turn triggers the ISR in aged neurons and leads to sequestration of dsRNA in stress granules. Aged neurons accumulate endogenous mitochondria-derived dsRNA that directly binds to PKR. This mitochondrial dsRNA leaks through damaged mitochondrial membranes and forms cytoplasmic foci in aged neurons. Finally, we demonstrate that PKR inhibition leads to the cessation of stress, resumption of cellular translation, and restoration of RNA-binding protein expression. Together, our results identify a source of RNA stress that destabilizes aged neurons and may contribute to neurodegeneration.

Frailty is a multifaceted clinical state associated with accelerated aging and adverse health outcomes. Informed etiological models of frailty hold promise for producing widespread health improvements across the aging population. Frailty is currently measured using aggregate scores, which obscure etiological pathways that are only relevant to subcomponents of frailty. Here we perform a multivariate genome-wide association study of the latent genetic architecture between 30 frailty deficits, which identifies 408 genomic risk loci. Our model includes a general factor of genetic overlap across all deficits, plus six new factors indexing a shared genetic signal across specific groups of deficits. We demonstrate the added clinical and etiological value of the six factors, including predicting frailty in external datasets, highlighting divergent genetic correlations with clinically relevant outcomes and uncovering unique underlying biology linked to aging. We show that nuanced models of frailty are key to understanding its causes and how it relates to worse health.

Osteoporosis, which is characterized by reduced bone mass and structurally compromised bone tissue, along with aberrant levels of reactive oxygen species (ROS) and inflammation, has been a pressing clinical challenge. A large accumulation of ROS and pro-inflammatory factors can result in mitochondrial dysfunction and progressive cellular senescence, impeding efficacious regeneration of bone defects. Herein, in this work, a ROS-responsive hydrogel system containing HA-PBA coated Ce-ZOL nanocomposites (GHCZ) for excessive ROS scavenging and reversal of cellular senescence to accelerate bone regeneration in osteoporosis was designed and presented. The GHCZ hydrogel system allows for the sustained release of HA-PBA coated Ce-ZOL nanoparticles, which may scavenge the extracellular and intracellular ROS of BMSCs and macrophages through their prominent enzyme-like catalytic effect. Moreover, the GHCZ hydrogel system transforms the polarization phenotype of macrophages into anti-inflammation M2 type and inhibits pro-inflammatory cytokines. Meanwhile, it could reverse the senescence of BMSCs and apparently elevate their pro-osteogenic capacity through safeguarding mitochondrial function and reprograming the metabolic processes, ultimately promoting the healing of bone defects. Based on

Vascular ageing often accompanies inflammation, contributing to the onset of local or systemic vascular diseases. Nevertheless, limited research focuses on pivotal factors triggering chronic vascular inflammation and associated pathological changes. This study aimed to investigate the role of methyltransferase-like protein 14 (METTL14) in inflammation in the pathogenesis of vascular ageing.

Senescent cells (SnCs) have typical changes in multiple features, such as increased cellular and nuclear size, morphofunctional alterations in organelles, and high secretory activity. The literature generally groups cellular changes and the non-proliferative character of SnCs into the autonomous senescent phenotype. In contrast, the influence of molecules and extracellular vesicles secreted by SnCs characterizes their non-autonomous phenotype. Unlike the detailed characterization of the structure of SnCs, the discussion regarding SnC states, which are characterized by the comprehensive integration of multiple features a cell harbors in a given moment, is still incipient. This review discusses the possible SnC states (SenStates) and their influence in pathophysiological contexts. We also discuss the main mechanisms and molecular players involved in the establishment and dynamics of these states, such as transcription factors, epigenetic marks, chromatin structure, and others. Finally, we discuss the biological relevance and potential clinical applications of SenStates, as well as open questions in the field.