Longevity Papers

Macrophages are pleiotropic immune cells essential for maintaining tissue homeostasis and modulating immune responses. Their inherent plasticity enables polarization into distinct functional phenotypes: M1 (pro-inflammatory) and M2 (anti-inflammatory), which critically influence the progression of various diseases, including cancer. Cellular senescence, a state characterized by irreversible cell cycle arrest and the secretion of pro-inflammatory factors (SASP), substantially contributes to aging and disease pathogenesis. The interaction between macrophages and senescent cells is complex: macrophages contribute to tissue integrity by clearing senescent cells to prevent tissue dysfunction, while senescent cells can alter macrophage function, influencing inflammation and cancer development. This review examines the dual roles of macrophages in cellular senescence and cancer, focusing on their capacity to both protect against and promote tumor progression. It examines how macrophages recognize and phagocytose senescent cells, the impact of macrophage dysfunction on senescence-associated pathologies, and the role of tumor-associated macrophages (TAMs) in shaping the tumor microenvironment. Key concepts to be addressed include macrophage plasticity, SASP-mediated modulation of macrophage function, and the dual role of macrophages in cancer, where they can either suppress tumor growth or promote progression via angiogenesis, immune evasion, and metastasis. The mutual interplay between macrophages and senescent cells highlights the therapeutic potential of targeting this interaction for managing age-related diseases and cancer.

Cognitive aging, a pivotal domain at the intersection of neuroscience and psychology, exhibits a strong association with neurodegenerative disorders; however, its comprehensive underlying mechanisms remain incompletely elucidated. This review aims to provide a thorough synthesis of recent advancements in the investigation of cognitive aging in the brain, highlighting multidimensional assessment techniques, neurobiological foundations, molecular regulatory pathways, systemic changes, environmental-gene interactions, and intervention strategies. Evidence suggests that cognitive aging is marked not only by widespread neuronal loss but also by subtle modifications within neural networks, protein homeostasis, mitochondrial functionality, and epigenetic regulation. The integration of various technological methodologies has shed light on the continuum that exists between cognitive aging and neurodegenerative disorders. Concurrently, multidimensional intervention strategies are being proposed; however, current research frameworks face challenges due to limitations in biomarker systems, indicating a need for a paradigm shift. Future investigations should leverage emerging technologies to develop more precise regulatory frameworks and personalized intervention strategies aimed at addressing the global challenges associated with aging, thereby enhancing the prevention and treatment of related pathologies.

Aging is a natural phenomenon characterized by the loss of normal morphology and physiological functioning of the body, causing wrinkles on the skin, loss of hair, and compromised immune systems. Peptide therapies have emerged as a promising approach in aging studies because of their excellent tolerability, low immunogenicity, and high specificity. Computational methods can significantly expedite wet lab-based anti-aging peptide discovery by predicting potential candidates with high specificity and efficacy. We propose AAGP, an anti-aging peptide predictor based on diverse physicochemical and compositional features. Two datasets were constructed, both shared anti-aging peptides as positives, with the first using antimicrobial peptides as negatives and the second using random peptides as negatives. Peptides were encoded using 4,305 features, followed by adaptive feature selection with a heuristic algorithm on both datasets. Nine machine learning models were used for cross-validation and independent tests. AAGP achieves reasonably accurate prediction performance, with MCCs of 0.692 and 0.580 and AUCs of 0.963 and 0.808 on the two independent test datasets, respectively. Our feature importance analysis shows that physicochemical features are more crucial for the first dataset, whereas compositional features hold greater importance for the second. The source code of AAGP is available at https://github.com/saptawtf/AAGP .

Cognitive frailty, defined by the coexistence of physical frailty and mild cognitive impairment, can be reversed through targeted interventions. This meta-analysis evaluated the efficacy of physical activity interventions on cognitive function and well-being in older adults with frailty.

Aging brain undergoes a structural decline over lifespan accompanied by changes in neurotransmitter levels, leading to altered functional markers. Past studies have reported human resting state brain display a remarkable preservation of coordination among neural assemblies stemming from an underlying neurocomputational principles along aging trajectories, however, the true nature of which remains unknown. Here, we identify the computational mechanisms with which neurotransmitters, such as altered GABA and glutamate concentrations, can preserve functional integration across lifespan aging, despite structural decline. We employ multiscale, biophysically grounded modeling, constrained by the empirically derived anatomical connectome of the human brain, where the neurotransmitter concentrations can be free parameters that are algorithmically adjusted to maintain regional homeostasis and optimal working point. The two estimated neurotransmitters can maintain critical firing rates in the brain region and mimic age-associated functional connectivity patterns, consistent with empirical observations. We identified invariant GABA and reduced glutamate as the principle computational mechanism that can explain the topological variation of functional connectivity along lifespan, validated using graph-theoretic metrics. The results are subsequently replicated on three distinct datasets. Thus, the study offers an operational framework that integrates brain network dynamics at macroscopic and molecular scales, to gain insight into age-associated neural disorders.

Circadian freerunning periods change across the lifespan, yet most computational models do not reproduce these shifts without assuming additional mechanisms. Although the maturation and later deterioration of the suprachiasmatic nucleus (SCN) shape behavioral and humoral rhythms, the underlying driver of period change is more general. We show that it arises from an inherent property of a positively skewed frequency distribution, which naturally follows from a symmetric Gaussian distribution of intrinsic periods. Using a Kuramoto framework with a time-dependent coupling strength and age-related widening of period variability, we map the geometry of synchronization and macroscopic period and trace a developmental trajectory across this surface. Strong coupling in early adulthood pulls the synchronized period below the mean, matching data from C57BL/6 mice, whereas declining coupling and greater heterogeneity in late life lengthen the period and reduce amplitude. The same mechanism explains the negative correlation between amplitude and macroscopic period when period variability is high. This "circadian geometry" reveals that age-dependent variations in the macroscopic period are sufficiently explained by coupling and the width of the period distribution, and provides a parsimonious framework applicable to the SCN and other oscillator populations for understanding long-term changes in circadian dynamics during development and aging.

An aging population necessitates strategies for extending healthy lifespan, with physical frailty as a key obstacle. Social activity participation is a potential intervention. However, previous studies examining the association between social activity participation and physical frailty have predominantly employed cross-sectional designs with single-wave surveys or longitudinal designs with two-wave surveys, and studies using multi-wave longitudinal designs are limited. Few studies have systematically evaluated the classification of physical frailty in subsequent follow-up assessments while considering temporal variations in social activity participation. Therefore, we studied the effect of temporal variations in social activity on subsequent physical frailty classifications using a three-wave survey. We found that sustained non-participation in sports-based activities significantly increased the risk of Pre-Frailty or Frailty at follow-up compared to sustained participation. Similarly, transitioning from participation to non-participation in culture-based activities increased this risk. These results suggest that maintaining participation in sports activities and avoiding cessation of cultural activities are crucial for preventing frailty. Individuals who consistently avoided sports or stopped cultural activities were more likely to be classified as pre-frail or frail in subsequent assessments.

Prenatal exposure genocide-related to trauma has been previously associated with increased morbidity. Whether the prenatal exposure to genocide and rape also impacts various aspects of biological regulation, including patterns of DNA methylation, remains unknown. The purpose of this study was to evaluate whether prenatal exposure to genocide-related trauma, including conception through rape, is associated with accelerated epigenetic aging, a molecular indicator of biological aging.

Successful postural control depends on the integration of visual, vestibular, and proprioceptive inputs. With age, postural control degrades, leading to impaired balance and greater fall risk. Understanding how this integration changes over the lifespan is invaluable for designing more effective interventions that enable healthy postural control in older age. Earlier studies measured visual dependence using perceptual tasks or spontaneous sway comparisons across visual conditions. This study evaluates how visual dependence differs between younger and older adults within the postural control mechanism using a Central Sensorimotor Integration (CSMI) test. Eighty healthy adults (n=40, 60-87 years, n=40, 21-52 years) were exposed to small pseudorandom visual scene movements implemented in virtual reality while standing on a compliant surface. Sway responses were measured using virtual reality trackers and interpreted using an established frequency domain balance control model. Model parameters included visual weight, proportional and derivative feedback gains, time delay, and torque feedback gain. Test-retest reliability was assessed in a subgroup (n = 40) and showed excellent intra-class correlation coefficients for visual weight, proportional and derivative feedback gains (ICC = 0.89-0.96), and lower ICCs for time delay (ICC = 0.59) and torque parameters (ICC = 0.39). The main difference between age groups was visual dependence, with older adults relying 40% on vision, compared to 33% for the younger group (p = 0.042). No significant group differences were found in other model parameters. Our results provide direct evidence of an increase in visual contribution to posture control with age.

Activation of hepatic stellate cells (HSCs) represents a central pathological event in liver fibrogenesis, and targeted clearance of activated HSCs is considered to be a promising therapeutic strategy. However, our understanding of the underlying molecular mechanisms is limited. Here, we report that Oroxylin A (OA) inhibited the activation of HSCs by inhibiting the dual roles of Sirtuin 7 (SIRT7). Single-cell transcriptome sequencing analysis and bioinformatics analysis were employed to identify critical pathways, followed by validation through molecular assays including Western blotting, immunofluorescence, and co-immunoprecipitation. In human samples, animal models, and primary cultures, the translational relevance of molecular discoveries was heightened. OA binds to the Gln299 and Asp305 residues of SIRT7, triggering a dual regulatory program in hepatic fibrosis. OA suppresses SIRT7, triggering succinylation-dependent proteasomal degradation of protein arginine methyltransferase 5 (PRMT5). This cascade attenuated symmetric dimethylation of cyclic GMP-AMP synthase (cGAS), thereby activating the cGAS-stimulator of interferon genes (STING) signaling and promoting HSC senescence. Concurrently, OA-elicited SIRT7 inhibition promotes externalized calreticulin (ecto-CRT) expression, thereby enhancing natural killer (NK) cell recognition and targeted elimination of activated HSCs. However, enzymatically dead mutant SIRT7 (H187Y) also suppressed ecto-CRT expression promoted by OA, showing that it is independent of its desuccinylase activity. Our findings reveal a dual regulatory mechanism whereby SIRT7 inhibition by OA coordinates PRMT5 degradation-mediated cellular senescence and ecto-CRT-dependent NK cell immune clearance of HSCs. This work establishes SIRT7 as a pivotal therapeutic target and provides mechanistic insights for developing antifibrotic strategies.

The rising prevalence of individuals reporting extreme stress has major public health implications as it increases vulnerability to accelerated premature biological aging, thus increasing risk of chronic disease. To examine the impact of stress on premature biological aging, we assessed the association between exposure to increased stress, quantified by the Perceived Stress Scale, and odds of high allostatic load (AL). To illuminate previously unexplored socio-contextual factors, we controlled for self-reported individual and neighborhood social determinants of health that included discrimination, loneliness, food insecurity, neighborhood disorder, and neighborhood social cohesion. We utilized a cross-sectional design to examine the association between perceived stress and AL among 7,415 participants ages 18-65 in the All of Us Research Program, who enrolled from 2017-2022. We used logistic regression to evaluate the association between stress and high AL, controlling for sociodemographic factors and self-reported social determinants of health. Participants who were younger, receiving Medicaid, or Hispanic had increased prevalence of high stress. High stress was associated with elevated odds of high AL in age and sex-adjusted models (OR=2.18, 95%CI = 1.78, 2.66, high stress vs. low), an association which remained significant after adjusting for social determinants of health (OR=1.29, 95%CI = 1.01, 1.65). Using restricted cubic splines, high stress was significantly associated with increased odds of high AL, even after controlling for upstream individual and neighborhood-level determinants of health. While individuals living below the medium poverty-to-income ratio demonstrated little appreciable association between high stress and increased odds of high allostatic load, those living above the median poverty-to-income ratio reporting increased stress appeared to have increased odds of high allostatic load. Through addressing the upstream factors causing undue burdens of stress, which particularly affect marginalized communities and younger generations, we can begin to address premature biological aging and the comorbid conditions it accompanies.

Cellular senescence has been strongly linked to aging and age-related diseases. It is well established that the phenotype of senescent cells is highly heterogeneous and influenced by their cell type and senescence-inducing stimulus. Recent single-cell RNA-sequencing studies identified heterogeneity within senescent cell populations. However, proof of functional differences between such subpopulations is lacking. To identify functionally distinct senescent cell subpopulations, we employed high-content image analysis to measure senescence marker expression in primary human endothelial cells and fibroblasts. We found that G2-arrested senescent cells feature higher senescence marker expression than G1-arrested senescent cells. To investigate functional differences, we compared IL-6 secretion and response to ABT263 senolytic treatment in G1 and G2 senescent cells. We determined that G2-arrested senescent cells secrete more IL-6 and are more sensitive to ABT263 than G1-arrested cells. We hypothesize that cell cycle dependent DNA content is a key contributor to the heterogeneity within senescent cell populations. This study demonstrates the existence of functionally distinct senescent subpopulations even in culture. This data provides the first evidence of selective cell response to senolytic treatment among senescent cell subpopulations. Overall, this study emphasizes the importance of considering the senescent cell heterogeneity in the development of future senolytic therapies.

An age-related decline in mitochondrial function is a multi-factorial hallmark of aging, driven partly by increased lipid hydroperoxide levels that impair mitochondrial respiration in skeletal muscle, leading to atrophy. Although pharmacological and genetic manipulations to counteract increased lipid hydroperoxide levels represent a promising strategy to treat sarcopenia, the mechanisms driving such phenotypes remain understudied. Peroxiredoxin 6 (Prdx6) is a multifunctional enzyme that contributes to peroxidized membrane repair via its phospholipid hydroperoxidase and phospholipase A

Under predation risk, prey face tradeoffs between foraging, reproduction, and predator avoidance. These tradeoffs can affect life history traits, such as growth, reproduction, and lifespan. By increasing the risk of death, predators can cause prey to prioritize current reproduction at the expense of future reproduction, resulting in earlier reproduction, less growth, and reduced lifespan. Alternatively, predators can cause prey to invest energy in defensive morphology or growth at the expense of reproduction, resulting in reduced or delayed reproduction, larger size, and longer lifespan. Finally, responding to predators can be costly to prey. For example, the energetic cost from reduced foraging can potentially reduce growth, reproduction, and lifespan. Exposing prey to predation risk at different parts of the lifespan can disentangle these potential mechanisms. In this experiment, we tested how the timing of predation cues affects the life history of a freshwater snail pond snail (Physa acuta). We exposed the snails to predation cues in early life (post-hatching to 39 days old), late life (39 to 78 days old), or both and measured how predation exposure early and late in life affected growth, age at first reproduction, total reproduction, and life expectancy. We found that exposure to predation during early life led to a delay in first reproduction, lower life expectancy, and lower fecundity, regardless of cue removal later in life. Exposure to predation cues in late life had no effect on growth, life expectancy, or reproduction. These results suggest a developmental window in which predation risk affects life history traits and suggest a potential cost to prey responding to predators early in life.

Stress urinary incontinence commonly arises with aging or following prostatectomy, yet its underlying mechanisms remain unclear. To address this, we investigated the role of metabolic pathways-particularly the tricarboxylic acid (TCA) cycle-in the differentiation of human external urethral sphincter myoblasts. Immortalized sphincter cells (US2-KD) were induced to differentiate over 192 h. Metabolomic profiling using gas chromatography-mass spectrometry, along with pathway enrichment analysis, identified key metabolic changes. Inhibition of mitochondrial pyruvate transport with UK5099 markedly suppressed TCA cycle metabolites, including citrate, α-ketoglutarate, fumarate, and malate. This inhibition also significantly reduced MYH7 expression and intracellular adenosine triphosphate levels throughout the differentiation period. These results demonstrate that the TCA cycle plays a critical role in both energy metabolism and the differentiation of urethral sphincter myoblasts. This study is the first to suggest that impaired TCA cycle activity may contribute to the pathogenesis of Stress urinary incontinence and represents a potential therapeutic target. Our findings offer new insight into age-related metabolic decline associated with Stress urinary incontinence and support the development of therapies that combine metabolic modulation with regenerative approaches.

Microplastics, particularly polystyrene (PS), are ubiquitous environmental contaminants and concerns about their potential detrimental effects on human health are increasing. Emerging evidence suggests that microplastics may disrupt the gut microbiota, a critical ecosystem involved in regulating host metabolism, immunity, and aging processes. However, the specific effects of PS on the gut microbiota composition and its potential role in modulating aging are yet to be fully elucidated. In this study, we aimed to investigate the effects of PS exposure on gut microbiota dysbiosis and its potential role in the acceleration of aging. Gut microbiota composition was assessed using 16S rDNA sequencing, while fecal metabolites were analyzed using gas chromatography-mass spectrometry. Exposure to PS resulted in a significant reduction in the abundance of beneficial microbiota, including

Low dose rapamycin therapy has been proposed as a longevity candidate in healthy aging adults. We present a review of the evidence for low dose rapamycin and rapalog therapies in healthy human adults and model the findings of one cohort study using the PhenoAge model. Despite the preclinical evidence supporting the use of sirolimus to enhance mean and maximal lifespan, the data in humans have yet to establish that rapamycin, or its analogues, is a proven seno-therapeutic that can delay aging in healthy older adults. Rapamycin and rapalogs warrant further study with larger cohorts to better establish their contribution to human aging.

Aging increases the risk of developing fibrotic diseases by hampering tissue regeneration after injury. Using longitudinal single-cell RNA-seq and spatial transcriptomics, here we compare the transcriptome of bleomycin (BLM) -induced fibrotic lungs of young and aged male mice, at 3 time points corresponding to the peak of fibrosis, regeneration, and resolution. We find that lung injury shifts the transcriptomic profiles of three pulmonary capillary endothelial cells (PCEC) subpopulations. The associated signatures are linked to pro-angiogenic signaling with strong Lrg1 expression and do not progress similarly throughout the resolution process between young and old animals. Moreover, part of this set of resolution-associated markers is also detected in PCEC from samples of patients with idiopathic pulmonary fibrosis. Finally, we find that aging also alters the transcriptome of PCEC, which displays typical pro-fibrotic and pro-inflammatory features. We propose that age-associated alterations in specific PCEC subpopulations may interfere with the process of lung progenitor differentiation, thus contributing to the persistent fibrotic process typical of human pathology.

Atherosclerosis (AS) poses a substantial risk to human health, leading to serious cardiovascular and cerebrovascular incidents, such as myocardial infarction, coronary heart disease, and ischemic shock. The treatment and control of AS are challenging because of its complex pathogenesis and multiple risk factors. Notably, changes in the estrogen levels and aging are associated with the formation and progression of AS because of their involvement in lipid metabolism, inflammatory responses, coagulation and fibrinolytic systems. Emerging evidence suggests that estrogen modulates vascular senescence pathways, whereas aging exacerbates endothelial dysfunction induced by estrogen deficiency, thereby establishing a bidirectional pathogenic loop. However, the precise interplay between estrogen and aging in AS pathogenesis remains uncertain, particularly regarding whether their effects are synergistic or sequential, and how sex-specific aging trajectories influence this relationship. In this review, In this review, we provide a comprehensive analysis of the interplay among estrogen, aging, and AS, thereby laying the foundation for developing novel therapeutic approaches to AS management. We propose the integration of targeted aging interventions, such as the elimination of senescent cells or the inhibition of senescence-associated secretory phenotype (SASP), with refined estrogen replacement strategies that account for therapeutic timing, receptor subtype specificity, and aging-related vascular microenvironment changes. Future research should prioritize longitudinal studies to delineate estrogen-aging interactions during the menopausal transition, develop tissue-selective estrogen analogs, and design combinatorial therapies targeting hormonal deficits and cellular senescence. This dual-pathway strategy may overcome limitations of conventional estrogen replacement therapies while addressing the root causes of age-exacerbated AS pathogenesis.

Animal oogenesis utilizes features shared among diverse phylogenetic groups, whose functional roles in promoting progeny development have remained unclear. However, germ cells not only produce the next generation, they also maintain long term species integrity by fully restoring acquired damage that deviates from genomic specifications and by controlling parasitic elements that pose a multi-generational threat. Here we discuss how oogenesis "rejuvenates" the germline to sustain the effective immortality needed for species to survive, adapt and evolve. We argue that animal oocytes actively rebuild critical cellular components including organelles during meiosis, usually within an ancient syncytial format, the germline cyst, that enhances renewal mechanisms long inherent to meiosis in single-celled eukaryotes. The Balbiani body accumulates rejuvenated materials and connects them with germ cell inducers relatively early in oogenesis, to ensure genome-quality constituents are inherited by germ cells of the next generation. This strategy explains the existence of germ plasm and why the GV-Bb axis presages the embryo's animal-vegetal axis in diverse species. The advent of a more powerful rejuvenation system may have enabled the evolution of animals.

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.

Senile osteoporosis progression is closely related to the decreased osteogenic differentiation capacity of senescent bone marrow stromal stem cells (BMSCs). This study demonstrated that the Traf6-mediated Nrf2/Nlrp3 signaling axis significantly influences inflammatory senescence progression in BMSCs, and targeting Traf6 can effectively alleviate bone loss caused by inflammatory senescence. High-throughput sequencing revealed that primary BMSCs from 18Ms mice were differentially enriched in anti-inflammatory, antioxidant, and immune-related biological processes compared to those from young mice, with significant differences in the protein expression of Traf6, Nrf2, and Nlrp3-related pathways, indicating potential crosstalk. In vitro experiments using western blotting and immunofluorescence confirmed high levels of intracellular inflammation, oxidative stress, and elevated expression of Traf6, Nrf2, and Nlrp3 inflammatory vesicles in senescent BMSCs. We used lentiviral transfection to knockdown Traf6 and intervention with Nrf2 agonists and inhibitors, and we verified the regulation of the expression of Nrf2/Nlrp3 inflammatory vesicles by Traf6 and its effect on inflammatory senescence progression in BMSCs. We performed in vivo experiments involving targeted Traf6 knockdown in bone tissue, morphological analysis of the femur by micro-computed tomography and immunohistochemistry, measurement of serum MDA and bone metabolism-related indices using ELISA, and calcein labeling to observe the calcium salt deposition rate. These experiments confirmed that the Traf6-mediated Nrf2/Nlrp3 signaling axis significantly influences the inflammatory senescence of BMSCs. Targeting Traf6 effectively alleviates bone loss caused by inflammatory senescence, presenting a potential method for preventing and controlling senile osteoporosis.

Cells must constantly adapt their metabolism to the availability of nutrients and signals from their environment. Under conditions of limited nutrients, cells need to reprogram their metabolism to rely on internal stores of glucose and lipid metabolites. From the emergence of eukaryotes to the mitochondria as the central source of ATP to hundreds of other metabolites required for cellular homeostasis, survival, and proliferation, cells had to evolve sensors to detect even modest changes in mitochondrial function in order to safeguard cellular integrity and prevent energetic catastrophe. Homologs of AMP-activated protein kinase (AMPK) are found in all eukaryotic species and serve as an ancient sensor of conditions of low cellular energy. Here we explore advances in how AMPK modulates core processes underpinning the mitochondrial life cycle and how it serves to restore mitochondrial health in parallel with other beneficial metabolic adaptations.

Δ133p53α is a naturally occurring isoform of the tumor suppressor protein p53. Δ133p53α functions as a physiological dominant-negative inhibitor of the full-length p53 protein (commonly referred to as p53). Δ133p53α preferentially inhibits p53-mediated cellular senescence, while it does not inhibit, or may even promote, p53-mediated DNA repair. Owing to this selective inhibitory activity that preserves genome stability, Δ133p53α represents a promising target for enhancement in the prevention and treatment of diseases associated with increased senescence of normal cells. These diseases include Alzheimer's and other neurodegenerative diseases, premature aging diseases such as Hutchinson-Gilford progeria syndrome (HGPS), and idiopathic pulmonary fibrosis (IPF). Current cell-based therapies, which are limited by increased cellular senescence, may also benefit from Δ133p53α-mediated improvements. As an initial application of Δ133p53α in improving therapeutic cells, we here introduce Δ133p53α-armored chimeric antigen receptor (CAR)-T cells. Based on our previous and ongoing studies using various types of senescent human cells in vitro, we also discuss the importance of further exploring the therapeutic potentials of Δ133p53α, with particular focus on HGPS and IPF. The development of mouse models facilitates in vivo evaluation of the therapeutic effects of Δ133p53α, potentially leading to future clinical applications.

Laboratory-raised mice live approximately seven times longer and healthier lives compared to their wild counterparts, due to a standardized healthy diet and limited exposure to environmental stressors. Aging is associated with increased inflammation and microbial dysbiosis. Collectively, these influence microbiota evolution and may contribute to the enrichment in pathobiont frequency observed in old age. Alternatively, this increase could stem from a decline in colonization resistance, creating favorable conditions for pathobiont invasion. Here, we sought to test whether aging in healthy, controlled conditions, could prevent the selection of age-associated pathobionts. We have followed the adaptive evolution of a commensal strain of

Biological aging is a critical risk factor of age-related diseases, but its impact on diabetic individuals remains unclear. This study aimed to examine the associations of biological aging with the incident cardiovascular diseases (CVDs) and life expectancy loss in diabetic individuals.

A human's ability to transfer oxygen from the environment to skeletal muscle and conversely remove carbon dioxide from skeletal muscle back to the environment during physical exertion is a critical representation of healthy longevity and functional capacity. Cardiorespiratory fitness (CRF) is the accepted construct for the assessment of oxygen consumption (VO

Neuroimaging studies have shown that aging alters the brain mechanisms underlying attentional control, even when behavioral performance is equivalent between younger and older adults. Instead of attributing these changes to compensatory mechanisms, we investigated whether age-related neuromodulatory changes in the locus coeruleus-noradrenaline (LC-NA) system are underlying these effects. To test whether aging leads to LC-NA system hyperactivity, we combined two methodological approaches: an oculomotor visual search task to assess eye movements and the threat of unpredictable electric shock paradigm to induce sustained arousal. Using pupillometry, we found that arousal reduced evoked pupil responses in both age groups, demonstrating the expected pattern of lower phasic noradrenergic activity under arousal. Young adults made significantly more first fixations to the physically salient distractor under threat of shock compared to baseline conditions, unlike in older adults with no effect. This modulation of attentional priority was only observable immediately following shock delivery and dissipated over time. Additionally, we found moderate evidence supporting the null hypothesis that arousal does not modulate the speed of attention processing in either age group. These results suggest that arousal selectively modulates attentional priority maps in the early visual cortex but does not influence broader interactions across higher order attentional networks. While first fixation measures revealed age-related differences consistent with the hypothesis of LC-NA system hyperactivity in aging, pupillometry and processing speed measures showed age-equivalent effects. Together, these findings highlight the potential for age-related changes in the LC-NA system to modulate mechanisms of attentional control and demonstrate the utility of eye movement measures as a promising tool to track changes across the adult lifespan. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Mitochondrial dysfunction is a hallmark of aging and many age-related neurodegenerative diseases. Mild cognitive impairment (MCI) refers to a clinical condition characterized by noticeable cognitive decline that exceeds normal age-related changes but does not significantly interfere with daily functioning. MCI is often considered an early stage of neurodegenerative conditions, including Alzheimer's disease. We therefore investigated the relationship between mitochondrial function in peripheral blood cells and cognitive performance in individuals with amnestic (aMCI) and nonamnestic mild cognitive impairment (naMCI). Control groups consisted of young (YC) and older adults (OC) who were physically and mentally healthy. Cross-sectional observational study involving 90 participants, including young adults, cognitively healthy older adults, and individuals with MCI. Mitochondrial function was determined in cryopreserved PBMCs. Cognitive status was assessed using the German version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery. ATP levels in cryopreserved PBMC isolated from individuals with aMCI were significantly lower than those of OC and YC. Endogenous respiration varied significantly between groups, with the MCI group exhibiting the lowest respiration. Linear regression analyses with ATP as a predictor for cognitive performance showed a significant positive relationship between ATP levels and both immediate recall and fluency. The regression coefficients indicated a moderate positive correlation between ATP levels and performance in both tests. This suggests that higher ATP levels are associated with improved cognitive performance. Our data suggest that mitochondrial dysfunction in PBMC is associated with MCI and correlates with cognitive impairment. Subjects who performed poorly on neuropsychological tests also exhibited lower ATP levels. Given that PBMC are easily accessible, they offer valuable insights into the bioenergetic status of individuals at increased risk for dementia. The study (PEM-MCI) has been retrospectively registered at the German Register of Clinical Trials (DRKS) DRKS00036017 (registered on 30.01.2025).

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.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by irreversible airflow limitation, primarily due to cigarette smoke (CS) exposure. Emerging research underscores the pivotal role of cellular senescence in the pathogenesis of COPD. The arylsulfatase family, known for its involvement in various age-related diseases, has yet to be investigated in the context of COPD. This study investigated the role of the arylsulfatase family, particularly ARSK, in COPD pathogenesis. Bioinformatics analysis and clinical validation revealed significantly reduced ARSK expression in COPD patients' lungs, especially in airway epithelium. ARSK overexpression alleviated CS-induced epithelial cellular senescence and improved mitophagy and mitochondrial function, while ARSK knockdown had an opposite effect. In vivo, Arsk-AAV administration relieved lung senescence and impaired lung function upon CS exposure, whereas airway-specific Arsk knockout aggravated these effects. Mechanistically, ARSK interacted with Parkin (PRKN) to regulate the phosphorylation of PRKN at serine 65 and subsequent mitophagy, thus attenuating cellular senescence. Additionally, the androgen receptor (AR) was identified as a transcription factor binding to the ARSK promoter, modulating its expression. These findings highlight the protective role of ARSK against epithelial cellular senescence, offering a potential therapeutic target for COPD.

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

Arterial biomechanical indicators have long been recognized as fundamental contributors to the physiology and pathology of cardiovascular systems. Probing multiple biomechanical parameters of arteries simultaneously throughout the cardiac cycle is highly important but remains challenging. Here, we report a method to quantify arterial anisotropic stiffness, arterial wall stresses, and local blood pressure in a single measurement. With programmed ultrasound excitation and imaging, arterial axial and circumferential guided waves were simultaneously induced and measured in the longitudinal view. Then, a mechanical model was proposed to quantitatively predict the correlation of arterial guided waves with arterial biomechanical parameters. Our experimental design and biomechanical model enable an elastography method to assess temporal variations in blood pressure, bidirectional stiffness, and mechanical stresses in arterial walls. In vivo experiments were performed on healthy young, normotensive older, and hypertensive older volunteers. The results demonstrate that our method can find applications in understanding aging of cardiovascular system and diagnosis of cardiovascular diseases.

Vitamin D plays a crucial role in various aspects of human body, including aging, but chronological age may not accurately reflect the true biological aging status. Recently, PhenoAge has been developed to estimate an individual's biological age based on different biological and clinical measures. Therefore, we investigated the relationship between 25(OH)D serum levels and biological aging calculated by PhenoAge Acceleration (PhenoAgeAccel) using data from the 2007-2016 National Health and Nutrition Examination Survey (NHANES). 25(OH)D serum levels were negatively associated with PhenoAgeAccel (β = -0.04 standard deviation [SD]; 95% confidence interval [CI]: -0.08 to 0.00). This negative association was dose-dependent in females (β = -0.07 SD; 95% CI: -0.12 to 0.01), but not in males. Generalized additive models further revealed gender-specific non-linear patterns: a U-shape pattern in males but an L-shaped pattern in females. Using segmented regression to confirm inflection points, we observed that 25(OH)D serum levels were linked to reduced PhenoAgeAccel at levels below 38.2 nmol/L (15.3 ng/mL) in males (β = -0.013 SD; 95% CI: -0.025 to -0.002) and 62.5 nmol/L (25.0 ng/mL) in females (β = -0.007 SD; 95% CI: -0.01 to -0.004,). However, 25(OH)D serum levels above 125 nmol/L showed no association with PhenoAgeAccel in females (β = -0.001 SD; 95% CI: -0.005-0.002), while in males, elevated levels (>91.6 nmol/L) were associated with increased PhenoAgeAccel (β = 0.005 SD; 95% CI: 0.002-0.008). Our findings indicate that vitamin D insufficiency has an inverse link with accelerated biological aging, and high levels of vitamin D in males accelerated biological aging as well, offering valuable insights into the relationship between vitamin D and biological aging.

Population aging is rapidly emerging as a global concern, with the proportion of older individuals rising steadily. In India, this demographic shift carries significant socioeconomic consequences, often pushing older people into financial insecurity and extending their participation in the workforce beyond retirement age. While studies from developed countries have shown a positive impact of continued engagement in later life on the mental health of older individuals, the present study aims to examine whether this relationship holds in the Indian context, where older individuals often continue working out of financial necessity rather than personal passion or motivation. Using nationally representative data from the Longitudinal Ageing Study in India, the study finds that working beyond retirement age is associated with a reduced risk of depression and poor cognitive functioning among older individuals. These findings are consistent across both logistic regression and propensity score matching analyses. The matched analysis shows that older working people have a 4.0 percentage point lower likelihood of poor cognitive functioning and a 3.5 percentage point lower likelihood of experiencing depression (both P < 0.001) compared to their matched non-working counterparts. This highlights the positive role of later-life engagement in supporting mental health. The study also emphasizes the need to create age-inclusive work environments, provide opportunities for skill development, and adapt job roles to suit physical capacities, enabling older people to remain productive and mentally engaged.

Aging is a risk factor for the development of chronic diseases; however, it is heterogeneous. Measuring aging in midlife, commonly done using laboratory markers and statistical methods for estimation of biological age (BA), cannot directly inform behavioral intervention goals aiming to promote healthier aging. The Midlife Aging and Performance Study (MAPS) examined the association between an extended, inclusive assessment of physical capacity (PC), as a behavioral marker of aging, and BA, estimated using the Klemera-Doubal method from 11 laboratory and physiological biomarkers, in 112 individuals aged 42-46 (47% women). PC was comprehensively measured by a battery covering five domains: muscle strength, endurance, balance, agility and flexibility. Better performance in strength, endurance, balance, and flexibility domains was correlated with younger BA (Pearson's r 0.33-0.49, p < 0.001). A lower composite PC score based on all five domains was significantly associated with an accelerated aging state in which BA was greater than chronological age. In a logistic regression, a composite PC score had an odds ratio of 0.40 (95% CI 0.25-0.64), demonstrating each incremental rise in PC corresponds with a 60% odds reduction of being in an accelerated aging state. The proposed PC battery could be used as a functional behavioral assessment for aging state, relevant for population wide risk-screening assessments, communicating intervention goals, and as a means to evaluate temporal changes in health, independent of laboratory tests.

Although the global interest in plant-based diets is rising due to their environmental and health benefits, little is known about how plant-based diets and their quality relate to health aging. This study examined the associations of three plant-based diet indices with healthy aging in a community-based cohort of 6817 middle-aged and older adults.

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.

Cellular senescence plays a crucial role in the progression of various diseases, and targeting senescence is a potential therapeutic strategy for osteoarthritis (OA). However, the complex biomechanical environment surrounding chondrocytes significantly affects their senescence process. Currently, few biomaterials are available that have the ability to modulate stresses and counteract chondrocyte senescence. In this study, we used cationic liposomes as the core of the crosslinked structure of the hydrogel network through imine bonding to construct a high-mobility network hydrogel microsphere system (Res@Lipo@HMs). The deformability of liposomes endowed mobility to the crosslinked structure of the hydrogel network. This system not only enhanced joint lubrication through a rolling mechanism but also distributed mechanical stress on chondrocytes by increasing the elastic deformation capacity of the microspheres. Moreover, this approach delayed chondrocyte senescence, improved chondrocyte physiological function, and slowed down OA progression by enhancing mitochondrial function and inhibiting senescence pathways. This study offers new insights into antisenescence strategies for chondrocyte therapy.

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.

The expression levels of telomerase exhibit regulatory heterogeneity across different cell types and various biological stages of cell development. The expression of telomerase is dynamically regulated across cell types and developmental stages, with its activity predominantly determined by the abundance of its catalytic subunit, telomerase reverse transcriptase (TERT). Telomerase levels are typically high in the pluripotent embryonic stem cells, germline cells, and cancer cells, and silenced in the terminally differentiated cells. Minimal telomerase activity is present in the stem and progenitor cells of highly proliferative tissues, although preventing telomere shortening is beyond common sense in the field of biology and cannot be achieved, eventually leading to replicative senescence. While telomerase silencing in somatic cells and adult stem cells acts as a barrier to tumorigenesis by limiting their lifespan, the eventual exhaustion of stem cell pools leads to tissue dysfunction and aging. Telomerase reactivation via telomerase overexpression represents a potential strategy to reverse stem cell aging and rejuvenate aged or dysfunctional tissues. In this review, we discuss the dynamics of telomere (length, activity, and expression level) in pluripotent and adult stem cells as well as their impact on aging. Notably, we have summarized the recent evidence in the application of mesenchymal stem cells immortalized through exogenous telomerase expression in regenerative medicine.

Frailty has been linked to adverse health outcomes, but its relationship with stroke remains insufficiently understood in general populations. In this study, we examined the association between frailty and stroke using two nationally representative cohorts: the U.S. National Health and Nutrition Examination Survey (NHANES) and the China Health and Retirement Longitudinal Study (CHARLS). Frailty was assessed using a multidimensional frailty index, analyzed both continuously and by category. Weighted logistic regression and restricted cubic spline models were applied. We found that higher frailty index scores were associated with greater odds of stroke in both populations, independent of demographic and clinical risk factors. The association appeared remained consistent in multiple sensitivity and subgroup analyses. Each 0.1-unit increase in the frailty index was associated with a 2.90-fold and 1.78-fold higher odds of stroke in NHANES and CHARLS, respectively. While CHARLS provides prospective evidence supporting the temporal relationship between frailty and stroke, the cross-sectional nature of NHANES limits causal inference. Overall, these findings suggest that frailty may be a useful marker for identifying individuals at higher risk of stroke. Further research is needed to validate its predictive utility and to explore whether modifying frailty can help reduce stroke incidence, particularly in aging populations.

Aging poses one of the greatest biomedical challenges of our time, with rising rates of frailty, sarcopenia, and cognitive decline globally. Preserving muscle and brain health is central to maintaining independence and quality of life in aging populations. This commentary explores how hibernation research, rooted in comparative physiology, offers unprecedented opportunities for drug discovery and therapeutic innovation. Hibernating animals exhibit remarkable abilities to regulate metabolism, protect the brain and muscles from atrophy, and prevent cellular damage under extreme conditions. These adaptations could inform new strategies for muscle preservation during inactivity, neuroprotection, and targeted temperature management, as well as critical needs in aging, neurocritical care, and space medicine. The bidirectional relationship between muscle and brain health underscores the potential for hibernation-inspired therapies to address both sarcopenia and cognitive decline. Applying these insights to space medicine and critical care settings could lead to groundbreaking solutions for unmet medical needs. Just as GLP-1 agonists emerged from the study of Gila monster venom, focusing on nature's extreme survivors may reveal overlooked molecular targets for drug development. By harnessing these adaptations, we can advance biomimicry in medical research and inspire sustainable solutions for healthy aging, critical care, and space exploration-offering new hope for patients, clinicians, and policymakers.

The effects of calorie restriction (CR) on age-related epigenetic modifications have recently been exposed, yet there is a road ahead in explaining the effects of CR on the epigenetic regulations. Although the exact mechanism(s) underlying the beneficial effects of CR on healthy brain aging is still unclear, increasing evidence suggests that epigenetic modifications are promising regulators that may be involved in this phenomenon. Here, we assessed the long-term effects of two different types of CR on DNA methylation levels of nutrient and aging related Igf1r, Adipor1, and Foxo1 genes in aging mice brains. Mice underwent different types of CR-application for up to 72 weeks: Ad-libitum (AL), chronic CR (CCR, 15% CR), and intermittent CR (ICR) alternating one week 60% CR (ICR-R) with three weeks AL feeding (ICR-RF) cyclically. DNA methylation levels were analyzed by pyrosequencing. Expressions of mRNA levels were measured by RT-PCR. Pyrosequencing results revealed that the methylation levels of CpG1 in Igf1r and CpG2-5-68 in Foxo1 were significantly changed by age in different dietary groups. Average DNA methylation levels were similar in calorie-restricted groups for all genes of interest. The gene expression level of only Igf1r was correlated with the average DNA methylation. In addition, there was a significant negative correlation between CpG5 methylation and Igf1r expression. These findings report that CR may exert its preventive effects on the regulation of nutrient sensing and aging related genes, Igf1r, Adipor1, and Foxo1, by modulating the methylation levels of specific CpG sites rather than altering overall methylation levels.

Carnosol, a diterpene derived from rosemary, has recently emerged as a potential strategy to counteract skeletal muscle loss associated with aging, during diseases or sedentary lifestyle. It may protect skeletal muscle cells from inflammation, oxidative damage, and atrophy through multiple mechanisms. Here, to investigate the structure-activity relationship of carnosol, both natural and synthetic derivatives were evaluated for their ability to reduce oxidative damages and to enhance skeletal muscle hypertrophy and function. The natural analogues rosmanol and isorosmanol were selected for their conserved hydroxyl groups at positions C-11 and C-12, while differing in the B-ring moiety. In parallel, dimethylcarnosol and dimethylisorosmanol, featuring methoxy substitutions at C-11 and C-12, were used to assess the functional importance of these hydroxyl groups. In two oxidative damage assays, carnosol, rosmanol, and isorosmanol showed similar antioxidant activity, reducing lipid peroxidation accumulation in post-mortem mouse skeletal muscle tissue and phosphorylation of H2AX, a DNA damage marker, in human skeletal muscle cells. Carnosol and isorosmanol, but not rosmanol, promoted myotube hypertrophy and suppressed the E3 ubiquitine ligase MuRF1 in human skeletal muscle cells, while methoxylated derivatives lacked both antioxidant and hypertrophic effects. The functional efficacy of selected compounds was further evaluated in zebrafish larvae. Carnosol improved locomotion, increased slow myosin heavy chain positive fibers, and downregulated E3 ubiquitin ligases. Isorosmanol also enhanced locomotor performance, whereas its methoxylated analogue showed no effect. The obtained results highlighted the role of specific structural elements, conserved hydroxyl groups at C-11/C-12 and a 20,7-lactone moiety, in mediating the muscle-protective effects of carnosol analogues.

The degradation of cellular components through autophagy is essential for longevity and healthy aging. However, autophagy function decreases with aging, contributing to age-related diseases. In this study, we characterized a small-molecule activator of autophagy called

High pulse wave velocity (PWV), a measure of increased arterial stiffness, is a risk factor for cerebrovascular disease. PWV can be estimated (ePWV) from age and blood pressure (BP). Elevated ePWV is associated with cerebral small-vessel disease, cognitive decline, and dementia risk in middle-aged and older adults. We examined data from the Midlife in the United States (MIDUS) Neuroscience Project to examine the association of ePWV with brain white matter microstructure. BP was measured in 132 middle-aged adults (mean age 53+/- 10 years, n = 77 women, n = 38 Black/African American) between 2004 and 2009 and used to calculate ePWV. Diffusion-weighted imaging (DWI) data were acquired between 2017 and 2022 and used to estimate: global white matter fractional anisotropy; axial, radial, and mean diffusivity and kurtosis; neurite density index; and orientation dispersion index. High ePWV was associated with: lower fractional anisotropy; axial, radial, and mean kurtosis; and neurite density index. High ePWV was also associated with higher axial, radial, and mean diffusivity, and orientation dispersion index. Except for axial diffusivity/kurtosis and orientation dispersion, all associations between high ePWV and white matter microstructure remained after adjusting for exogenous controls (sex and race), education, the constituent components of ePWV (age and blood pressure), and the time lag between BP and DWI measures. In conclusion, high ePWV in middle-aged adults is prospectively associated with compromised brain white matter microstructure more than a decade later. ePWV may be a useful metric of vascular aging that can be applied to the study of brain aging.

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.

Recent developments in healthcare and scientific research have shifted the perception of ageing from a period of decline to recognising its potential for sustained functional ability, well-being, and societal contributions. In light of this perspective, a multidisciplinary panel of experts from five European countries conducted a narrative review of the literature. It convened for a one-day consensus meeting to identify key barriers, facilitators, and research priorities related to healthy ageing. Thus, this paper aims to (1) define the concept of positive ageing, (2) discuss barriers and facilitators to healthy ageing, (3) examine the role of healthcare professionals in maintaining and improving intrinsic capacity, and (4) propose a research agenda to address gaps in healthy ageing. The panel identified 70 barriers and 64 facilitators, structured within the WHO's ICOPE framework, related to intrinsic capacity. Twenty-six interventions across five domains-locomotor, sensory, psychological, cognitive capacities, and vitality- were proposed, aimed at both frail and robust individuals, focusing on social integration, psychological well-being, physiological resilience, deficit management, and disorder prevention. The panel also outlined a research agenda emphasising AI-driven ageing support, improved communication strategies, early frailty detection, and the development of locally adapted guidelines and infrastructure for healthy and positive ageing. This framework emphasizes the importance of early-life interventions and advocates for a preventive, holistic, and multidisciplinary approach to aging. In conclusion, the MIPAG's fosters a proactive mindset and early interventions throughout life to prevent the decline and optimise intrinsic capacity.

The Systemic Immune-Inflammation Index (SII), a marker of systemic inflammation, has been linked to various age-related diseases, but its association with Epigenetic Age Acceleration (EAA) remains underexplored. This study aimed to investigate the SII and EAA relationship. We analysed data from 1,915 participants from the National Health and Nutrition Examination Survey (NHANES). SII was calculated as platelet count × (neutrophil count/lymphocyte count). EAA was defined as HorvathAccel, HannumAccel, Skin&BloodAccel, PhenoAgeAccel, GrimAge2Accel, and DunedinPoAm. These metrics were derived utilizing the residual method. Multivariate linear regression, smooth curve fitting, threshold effect analyses, and subgroup analyses were employed to assess the relationship between the SII and EAA. Higher SII levels were significantly associated with HannumAccel, PhenoAgeAccel, GrimAge2Accel, and DunedinPoAm. Threshold effect analyses revealed non-linear relationships, with inflection points at SII values of 24.200, 12.553, 7.766, and 10.133, respectively. Subgroup analyses identified sex, age, poverty-to-income ratio, and marital status as significant effect modifiers. The elevated SII was associated with accelerated epigenetic ageing.

Ganoderma lucidum (G. lucidum), a revered medicinal mushroom in traditional Chinese medicine (TCM), has been historically documented for its anti-aging properties and nephroprotective effects. Nevertheless, its mechanism of action through gut microbiota modulation to attenuate renal and systemic aging remains incompletely understood.

Gut microbial stability typically decreases with physiological aging. This decline may vary between sexes and can potentially be mitigated by adopting a healthy lifestyle. Microbial guilds, defined as functionally coherent groups of bacteria, may serve as meaningful ecological indicators of aging. This study included 2944 participants aged 51-89 years from the Shanghai Men's and Women's Health Studies. Using 16S rRNA gene sequencing and a guild-based approach, we evaluated the associations between gut microbiota and age in 1353 relatively healthy individuals. We found that women demonstrated a decline in the Chao1 index, an increase in Pielou evenness, and a remarkable shift in Bray-Curtis distance, whereas men exhibited an increase in Bray-Curtis uniqueness. Of the 45 age-related guilds identified, 16 (8 in men and 10 in women) were considered potential aging biomarkers (p