Longevity Papers

Given the well-established structural and functional changes in the aging brain, it is widely assumed that cognitive aging is primarily driven by robust group-level differences between young and older adults. However, our individual-level EEG functional connectivity analysis challenges this notion. We investigated the impact of cognitive training on functional brain connectivity using task-switching paradigms in 39 younger (18-25 years) and 40 older (60-75 years) women. Participants were randomly assigned to either a training group, which completed eight individualized one-hour cognitive training sessions, or a no-contact control group. EEG was recorded at both pre- and post-training sessions across three task-switching paradigms (trained and near-transfer versions). Unique functional connectivity of different sources of variation was examined by calculating how much variance was shared across stable traits (e.g., individual, age, and common factors), or dynamic states (e.g., task and training effects). Our results revealed that age accounted for only a modest proportion of variance, whereas self-similarity was a dominant factor - particularly in older adults. Similarly, group-level training effects were small but strongly modulated by individual neural profiles, suggesting person-specific trajectories. Participants recruited distinct neural networks across tasks, and even within the same task engaged unique, individual-specific network configurations, reflecting personalised brain adaptations to cognitive demands. Importantly, older adults displayed a shift from common to individual network patterns, consistent with increased neural specialization and compensatory mechanisms. These findings underscore the importance of moving beyond group-level contrasts toward models that capture the complexity of individual brain dynamics in cognitive aging and training responsiveness.

Sex differences in ageing and lifespan are widespread across taxa, yet their evolutionary causes remain debated. A leading hypothesis suggests these differences are adaptive and driven by sex-specific life-history trade-offs, but formal theoretical support is lacking. To address this, we developed a mathematical model to investigate how such trade-offs shape lifespan evolution in a monogamous mating system. In the model, individuals evolve to optimise a trade-off between reproduction and survival -- mediated by mating opportunities in males and offspring production in females. By systematically varying trade-off strengths, we show that either sex can evolve greater longevity, but male-biased longevity evolves under a broader set of conditions -- consistent with patterns in monogamous species. This asymmetry arises because female longevity is more constrained: the trade-off between offspring production and survival directly affects the fertility of both sexes. In contrast, the male trade-off for mating opportunities has a weaker indirect effect on female fertility, allowing selection to more readily favour longer male lifespans. We also show that extrinsic density-dependent mortality can disproportionately affect the intrinsically longer-living sex, and obscure the magnitude of this evolved difference. Together, our results provide new theoretical insights into the adaptive bases of sex-biased longevity and highlight the importance of life-history trade-offs in shaping lifespan evolution.

The hormone insulin-like growth factor 1 (IGF-1) is a key player in the insulin/IGF-1 signaling (IIS) pathway. Extensive biogerontological research demonstrates that this evolutionarily conserved nutrient-sensing pathway plays a causal role in the regulation of growth, reproduction and longevity under laboratory conditions. However, its potential role as a mediator of adaptive life-history variation in highly variable natural environments remains unclear. We measured IGF-1 concentrations in blood samples from approximately four-month-old wild Soay sheep lambs (n=669), collected over nine summers. We tested whether IGF-1 (i) was positively correlated with proxies of resource availability, (ii) was associated with morphological traits measured concurrently, and (iii) predicted subsequent fitness-related traits. Plasma IGF-1 concentrations were higher in males compared to females, and positively correlated with measures of resource availability in both sexes. IGF-1 was lower in years of high population density when per capita food availability was reduced; in twin lambs who have fewer available resources compared to singletons; and in lambs born to young and old mothers, who have poor maternal provisioning compared to mothers of intermediate age. Higher IGF-1 levels in summer were correlated with higher body mass, faster post-natal somatic growth and increased skeletal size, measured at the same time. These associations were independent of our proxies of resource availability. Lambs with higher summer IGF-1 were more likely to survive their first winter and reproduce the following spring. The association between IGF-1 and reproduction was independent of our resource availability proxies, whereas the association with first-winter survival was not. The association between summer IGF-1 and reproduction was mediated by positive associations with summer body mass. Our study reveals population-level phenotypic plasticity in circulating IGF-1, also finding IGF-1 to be positively associated with key morphological traits and positively predict fitness traits in early life. These findings highlight IGF-1 as a candidate physiological mechanism underpinning plastic responses to variation in food availability and influencing life-history traits in a wild mammal.

The regenerative response of retinal cells to injury and aging depends on the epigenomic plasticity that enables the dedifferentiation and neuronal differentiation capacities of Muller glial cells (MG). In mammals, this regenerative ability is extremely limited, and disruptions in epigenetic mechanisms, particularly those involving DNA methylation and demethylation, may underlie this restricted potential. To explore this possibility, we aimed to develop DNA methylation-targeting molecular tools to enhance the dedifferentiation and neurogenic capacity of primary MG cultures derived from mouse retina. Using CRISPR/dCas9-based gene regulation technology, we selectively and transiently inhibited Dnmt3a, a de novo DNA methyltransferase previously implicated in maintaining transcriptional repression. Our results show that Dnmt3a knockdown leads to sustained upregulation of pluripotency-associated genes, including Ascl1, Lin28, and Nestin, as measured by RT-qPCR and immunofluorescence. This epigenetic modulation also promoted increased cell proliferation and migration, both hallmarks of a regenerative response. Furthermore, Dnmt3a knockdown, either alone or in combination with neurogenic stimuli, induced MG to acquire neuronal-like morphologies and express the early neuronal marker {beta}III-tubulin. These findings suggest that Dnmt3a acts as a repressive regulator of MG plasticity, likely serving as an epigenetic barrier that counteracts injury-induced demethylation events. Overall, our study identifies Dnmt3a as a critical modulator of MG fate and highlights the potential of its targeted downregulation to facilitate reprogramming. By prolonging the transient progenitor-like state of MG, DNMT3a inhibition may serve as a complementary approach to unlock the neurogenic and regenerative potential of the mammalian retina, offering promising avenues for future therapeutic strategies.

Comparative genomic data can be used to look for substitutions in coding sequences that are associated with the variation of a particular phenotypic trait. A few statistical methods have been proposed to do so for phenotypes represented by discrete values. For continuous traits, no such statistical approach has been proposed, and researchers have resorted to sensible but uncharacterized criteria. Here, we investigate a phylogenetic model for coding sequences where amino acid preferences at a site are given by a continuous function of a quantitative trait. This function is inferred from the amino acids and the trait values in extant species and requires inferred point estimates of ancestral values of the trait at internal nodes. For detecting sites whose evolution is associated with this trait, we use a significance test against the hypothesis that amino acid preference does not depend on the trait. This procedure is compared to simpler strategies on simulated alignments. It displays an increased recall for low false positive rates, which is of special importance for performing whole-genome scans. This comes however at a much higher computational cost, and we suggest using a simple test to filter promising candidate sites. We then revisit a dataset of alignments for 62 species of mammals, using longevity as a phenotypic trait. We apply our method to three protein families that have previously been proposed to display sites associated with variation in lifespan in mammals. Using a graphical representation extracted from the detailed phylogenetic analysis of candidate sites, we suggest that the evidence for this in the sequence data alone is weak. The proposed method has been added to our Pelican software. It is available at https://gitlab.in2p3.fr/phoogle/pelican and can now be used with both discrete and continuous phenotypes to search for sites associated with phenotypic variation, on data sets with thousands of alignments.

Although tea polyphenols have antiaging potential, the molecular interplay between black tea components and cellular longevity remains unclear. This study has pioneered a dual approach combining

Aging is a dynamic process characterized by complex molecular changes, including shifts in lipid metabolism. To systematically define lipidome dynamics with age and identify sex-specific lipidomic signatures, we performed targeted lipidomic profiling of plasma samples from 1030 adults aged 50-98 years, analyzing 543 lipid species across all lipid classes using high-throughput mass spectrometry and assessing the circulating fatty acid composition by gas chromatography. Our results reveal age-related lipidomic shifts, with ceramides and ether-linked phospholipids most affected. We identified three aging crests (55-60, 65-70, 75-80 years), with the 65-70 years crest dominant in men and the 75-80 years crest in women. Lipid enrichment analyses highlight acylcarnitines, sphingolipids and ether-linked phospholipids as key contributors, with functional indices indicating compositional shifts in lipid species. These findings suggest an impairment of lipid functional categories, including loss of dynamic properties, alterations in bioenergetics, antioxidant defense, cellular identity, and signaling platforms. This study underscores the non-linear nature of lipid metabolism in aging and provides a foundation for identifying biomarkers and interventions to promote healthy aging.

As the aging population continues to grow, falls among older adults have become a significant public health concern worldwide. Data-driven approaches for effective fall risk prediction, which integrate standard functional tests with 3D skeleton data from depth sensors, are gaining increasing attention. However, the complex physiological and functional interactions among skeletal keypoints during ambulation pose challenges for multidimensional feature extraction in most predictive models. In this study, we developed a novel approach based on preprocessed 3D skeleton data, named Multivariate SpatialTemporal Gated Transformer (MSTG-Transformer). This approach consists of three main stages. First, gait cycle sequences are constructed to sophisticatedly depict the movement patterns of subjects, amplifying the distinctions between groups. Then, spatial and topological features are extracted via convolutional modules, and a dual-stream encoder block is employed to encode the features of 3D skeleton data across both time steps and time channels. Finally, a voting scheme is used to determine fall risk by integrating the classification results of individual gait cycle segments. Validation experiments on a real-world dataset demonstrate that our proposed approach outperforms classical methods, achieving a superior prediction accuracy of 0.9510 ± 0.0240. Additionally, our study highlights the crucial role of potential interactions between skeletal keypoints in accurately predicting fall risk.

Signaling pathways and transcriptional regulation during cellular senescence have been investigated; however, energy metabolism is one of the understudied areas. Senescent cells secrete pro-inflammatory cytokines and release proteins and RNAs via exosomes that contribute to organismal aging. Although senescent fibroblasts in solid organs are in a low oxygen environment, these fibroblasts have more active glucose metabolism and consume more oxygen than proliferating ones. A critical gap in our knowledge is how senescent fibroblasts facilitate glucose metabolism and organismal aging by creating a distinct microenvironment. Our high throughput profiling of mRNAs and proteins from Human Diploid Fibroblasts (HDFs) revealed that the expression of pyruvate metabolic enzymes is inhibited by the anti-senescent RNA-binding protein (RBP) AUF1 (AU-binding Factor 1). Our studies revealed that AUF1 promotes the decay of mRNAs encoding two enzymes: PGAM1 (phosphoglycerate mutase 1), a glycolytic enzyme involved in the pyruvate synthetic pathway, and PDP2 (Pyruvate Dehydrogenase Phosphatase 2), which activates Pyruvate Dehydrogenase. We also demonstrated that AUF1 is phosphorylated by a Serine/Threonine kinase, MST1 (Mammalian Ste20-like kinase 1; encoded by STK4), resulting in the inactivation of AUF1, which leads to target mRNA stabilization and senescence. Overexpression of PGAM1 and PDP2 predicts an acceleration of pyruvate production and subsequent citrate metabolism, leading to cellular senescence and aging. Thus, our studies revealed regulatory mechanisms of glycolysis-driven cellular senescence by AUF1-mediated decay of

Age-related cognitive decline occurs, in part, due to diminishing white matter integrity. Higher cardiorespiratory fitness (CRF) is associated with better cognitive performance, but the neurobiological mechanisms underlying this association remain uncertain. Previous magnetic resonance imaging (MRI) studies have suggested that CRF-related changes in white matter microstructure might prevent or slow age-related cognitive decline, but have been limited by small sample sizes and methodological limitations. Specifically, most prior studies used tensor-based diffusion-weighted MRI metrics, which are insensitive to complex white matter architectures, including crossing fibers.

Numerous studies carried out in the last 30-40 years have strongly demonstrated that the endocannabinoid system exerts important modulatory functions in the central nervous system (CNS). These neuromodulatory functions encompass the whole life of animals, with specific activities during neurodevelopment (prenatal, postnatal and adolescent periods), adulthood and possibly senescence too. However, this is the life stage less investigated in relation with the endocannabinoid system to date. In the aged brain, the activity of this system appears to be altered, which contributes to subtle impairments that typically occur during ageing in learning and memory, motor behaviour, social behaviour and other neurobiological functions. Some of the changes in endocannabinoid activity may represent a process to attenuate ageing-related impairment in the brain function, which is consistent with its role as a pro-homeostatic system. An important observation is that these alterations become extreme when normal brain ageing acquires pathological characteristics, as happens in chronic neurodegenerative disorders. This includes the cannabinoid type-1 (CB

Successful aging (SA) is important for the increasing population aging. The role of handgrip strength(HGS) asymmetry and weakness in successful aging requires further clarification. This study aimed to elucidate the association of HGS asymmetry and weakness with successful aging in older adults.

Major Depressive Disorder is a major contributor to aging-related health burdens. Preventing and managing depression symptoms are suggested strategies to reduce these burdens. However, the cooccurrence of depression and aging-related disease/disability could arise from reverse causation (i.e. aging-->depression) or confounding by a common cause (aging<-->depression). We investigated the connection between depression and biological aging, a root cause of aging-related health decline, using US Health and Retirement Study (HRS) data and a genetic design to address potential confounding. We tested associations among polygenic scores measuring genetic risk for depression, longitudinal measurements of depression symptoms, and a measurement of biological aging in 3,806 White and 1,207 Black HRS participants. Results showed that participants with higher depression polygenic scores and more depression symptoms were biologically older than those of the same chronological age with lower genetic risk and fewer symptoms. However, depression symptoms mediated only a fraction of the association between genetic risk and biological aging. Findings suggest that the link between depression and aging burden may not be fully addressable through depression treatment in later life. Further research is needed to determine whether our findings reflect the accumulated effects of depressive symptoms earlier in life or some other pathway linking genetic risk for depression with accelerated biological aging.

Sarcopenia causes muscle loss and functional decline in older adults, yet the lower limb muscle activation patterns of sarcopenic patients during functional activities remain unclear. This study aims to investigate the differences in muscle activation between sarcopenic and healthy older adults during functional activities and to explore task-specific compensatory neuromuscular strategies. Eight sarcopenic patients and eight age-matched healthy older adults performed the standardized six-meter walk test (6MWT) and five times sit-to-stand test (5STS) with surface electromyography (EMG) used to record activity from eight muscles of the dominant leg. Sarcopenic individuals exhibited lower walking speed (p = 0.005) and shorter stride length (p < 0.001) in 6MWT, as well as longer completion time (p < 0.001) in 5STS. Significant differences in muscle activation (p < 0.05) included: increased proximal muscle activation with decreased distal activation in both tasks; elevated antagonist co-activation during critical movement transitions; and task-specific EMG variability patterns with increased EMG variability during walking but decreased variability during sit-to-stand activities. Sarcopenic individuals demonstrate distinct muscle activation patterns compared to normally aging individuals. Rehabilitation for sarcopenia may benefit from incorporating ankle-strengthening exercises, functional coordination training, and task-specific neuromuscular control strategies with traditional strength-focused approaches.

Robust evidence supports optimism as an asset for good physical and emotional health in aging populations, but its role in cognitive aging remains understudied. This study evaluated whether higher optimism levels would be prospectively associated with higher initial levels and slower decline in cognitive functioning over 26 years in a community-dwelling cohort of aging men.

Accurate and convenient assessment of individual aging is crucial for identifying health risks and preventing aging-related diseases. Nonetheless, current aging proxies often face challenges such as methodological limitations, weak associations with adverse outcomes and limited generalizability. Here we propose a framework that leverages large language models (LLMs) to estimate individual overall and organ-specific aging using only health examination reports. We validated this approach across six population-based cohorts, encompassing over 10 million participants and demonstrated effectiveness and reliability. Our results showed that the LLM-predicted overall age achieved a concordance index (C-index) of 0.757 (95% CI 0.752-0.761) for all-cause mortality, significantly outperforming other aging proxies such as telomere length, frailty index, eight epigenetic ages and four machine-learning models predictions. The overall age gap was strongly associated with multiple aging-related phenotypes and health outcomes, showing a hazard ratio of 1.055 (95% CI 1.050-1.060) for all-cause mortality. For organ-specific aging, LLM-predicted ages and age gaps also demonstrated superior performance in predicting corresponding organ-specific diseases compared to machine-learning models. Additionally, we examined the dynamic aging assessment capability of LLMs and applied age gaps to identify proteomic biomarkers associated with accelerated aging and to develop risk prediction models of 270 diseases. Interpretability analyses were also conducted to explore the decision-making process of LLMs. In conclusion, our LLM-based aging assessment framework offers a precise, reliable and cost-effective approach for estimating overall and organ-specific aging. It has potential for personalized aging assessment and health management in large-scale general populations.

Gut microbiota (GM) is implicated in aging biology, yet its dual regulatory role in the distinct yet interconnected processes of lifespan extension and aging remains poorly understood. This study employed genetic approaches to identify GM taxa exerting causal effects on longevity and aging and assess the mediation role of cerebrospinal fluid (CSF) proteins. We leveraged summary statistics of the GM taxa (207 taxa, 7738 participants from the Dutch Microbiome Project), the CSF proteins (7008 aptamers, 3506 participants), and the longevity and aging phenotypes (UK Biobank, Longevity Genomics, and Edinburgh DataShare) from the largest genome-wide association studies so far. We performed bidirectional Mendelian randomization (MR) to explore causal relationships between GM and longevity and aging and two mediation analyses, the two-step MR and the multivariable MR (MVMR), to discover potential mediating proteins. Nine taxa exhibited causal associations with longevity-related phenotypes, such as the Bacteroides vulgatus and Blautia. Three taxa demonstrated causal associations with aging-related phenotypes, such as Streptococcus. Among them, Streptococcus was causally associated with aging (β = 0.3310, P = 0.0019) and lifespan-shortening (β =  - 0.0247, P = 0.0184), while Bacteroides vulgatus associated with aging (β = 0.3884, P = 0.0204) and lifespan-promoting (β = 0.0354, P = 0.0198). Mediation MR analysis found that CSF protein CD28 mediated the causal effects of Streptococcus on longevity (mediation proportion 11.7%, P = 0.0394). These findings establish genetic links between GM, CSF proteins, and longevity and aging-related outcomes, advancing gut-brain axis understanding while offering insights for future mechanistic exploration and clinical investigation.

Ageing significantly impacts lung function and increases susceptibility to chronic lung diseases. The lung is a complex organ with multiple cell types that undergo cellular age-related perturbations or hallmarks. As knowledge of ageing mechanisms has progressed, we have a better understanding how intracellular adaptations impact cellular crosstalk and integrate to increase the susceptibility to age-related diseases in the lung. Herein, we discuss the prospects of exhaustion of lung progenitor cells, disrupted lung cell plasticity, perturbation in fibroblasts, impaired adaptive immune responses and alterations in lung microenvironment in the promotion of ageing and age-related lung diseases. Additionally, the ageing process trajectory of the lung depends on a combination of biological, genetic, metabolic, biomechanical and sociobehavioural factors that range from protective phenotypes to accelerated ageing phenotypes. We propose the concept of AgEnOmics, which expands the temporal dimension of lung ageing by distinguishing between chronological ageing and accelerated lung ageing phenotypes. Based on this concept, we define biomarkers of biological ageing that will help to define accelerated ageing and early interventions in biological ageing-related lung diseases.

Immune aging is associated with decreased vaccine responses, but biomarkers for vaccine responsiveness remain unidentified. We analyzed immunotypes describing pre-vaccination immune cell profiles and their associations with triple vaccine responsiveness to influenza, pneumococcal, and SARS-CoV-2 vaccines in adults aged 25-78 years. Additionally, we developed an innovative measure, immune entropy, to quantify cumulative perturbations in the immune cell subset network. Specific immunotypes were associated with either weak or robust triple vaccine responsiveness. In addition, immune entropy was inversely related to vaccine responsiveness regardless of age. In a validation cohort of older adults, higher immune entropy was also associated with a lower antibody response to the BNT162b2 vaccine. A separate cohort of kidney transplant recipients, typically exhibiting diminished vaccine responses, demonstrated significantly increased immune entropy compared to healthy counterparts. Our findings suggest immunotypes and immune entropy as potential indicators to identify individuals at risk for suboptimal vaccine responses, potentially guiding personalized vaccination strategies.

There has been increasing attention to differences in function along the hippocampal long axis, with the posterior hippocampus proposed to be well suited to representing fine-grained details and the anterior hippocampus having coarser representations. Whether long axis functional specialization persists into older age is not well understood, despite known age-related declines in the level of detail in memories. In this study, we used a large database of resting state fMRI data (n =322 humans of both sexes included) from across the adult lifespan (ages 18-88) to determine the degree of functional differentiation across the hippocampal posterior-anterior axis. Our first approach was to measure the similarity among signals within hippocampal subregions. We found that signals within the most posterior hippocampal subregion became more similar to one another in older age, but this effect did not relate to memory performance. As a second approach, we measured functional connectivity between hippocampal subregions and the rest of the brain. The functional connectivity profiles of the posterior and anterior hippocampal subregions became more distinct from one another with increasing age, driven by relative stability in anterior hippocampal functional connectivity but more significant age-related differences in posterior subregions of the hippocampus. Stronger connectivity between the anterior hippocampus and several cortical regions was associated with better memory performance in older adults, suggesting that maintenance of anterior hippocampal connectivity may help preserve episodic memory among high performing older adults.

Geroscience explores aging at the cellular level. We developed a lay-friendly science communication intervention (MitoFit) that addresses healthy aging through mitochondrial fitness. The intervention aims to promote physical activity by educating aging adults about optimizing mitochondrial function to promote healthy aging and prevention of chronic disease. We conducted focus groups to gauge older adults' responses to the video component of the intervention and the effect on their uptake of the intervention.

A plethora of senolytic compounds and technologies have been identified. However, the efficacy of these treatments in eliminating senescent cells and the suppression of chronic inflammation remains to be substantiated in vivo. Here, we employ single-cell RNA sequencing and find the selective elimination of highly inflammatory fibroblasts, endothelial cells in the lung, and proximal tubule cells in the kidney from the GLS1 inhibitor BPTES-treated aged mice. The eliminated fibroblasts share typical phenotypes with in vitro human senescent cells. These cells predominantly express Dpp4 (CD26) and Cadm3, showing activated IFN signaling and lysosomal membrane damage. Cells eliminated by BPTES in lungs exhibit transcriptomes similar to those eliminated in p16-DTR mice, where DTR expression is limited in p16-expressing cells. BPTES treatment results in the T cell population shift from cytotoxic to a protective state, suggesting the suppression of age-related chronic inflammation. CellChat analysis revealed that multiple cytokine signals are transmitted from inflammatory fibroblasts and proximal tubular cells to immune cells in lungs and kidneys. These results provide evidence that GLS1 inhibitor functions as a bona fide senolytic drug to eliminate inflammatory cells, including a subset of senescent cells, and suppresses age-related chronic inflammation.

This study is the first to investigate the anti-aging effects of the newly synthesized compound, 3,4,5-tri-feruloylquinic acid (TFQA), in vivo using the senescence-accelerated mouse prone 8 (SAMP8) model, through integrated whole-transcriptomic and biochemical analyses. Oral administration of TFQA (1 mg/kg body weight) for 37 days led to significant cognitive improvements, as demonstrated by enhanced performance in the Morris water maze (MWM) test, including reduced escape latency and increased time spent in the target zone, target crossings, distance traveled, and swimming speed. Gene Ontology (GO) analysis of hippocampal microarray data revealed that TFQA upregulated genes associated with neurotransmitter and synaptic functions, while downregulating inflammatory pathways. Protein-protein interaction (PPI) analysis indicated that neurotrophin signaling was a critical upstream regulator in TFQA-treated mice. Further biochemical validation showed elevated levels of neurotransmitters (serotonin, noradrenaline, and dopamine) in the brain. Additionally, mRNA expression of tumor necrosis factor (Tnf), an inflammatory cytokine, was significantly reduced in the brain. Examination of the neurotrophins involved in neurotrophin signaling revealed that TFQA most prominently regulated brain-derived neurotrophic factor (Bdnf) co-expressed genes, which was validated by increased Bdnf expression in both the brain and serum of SAMP8 mice. Bioluminescence imaging demonstrated that a single oral dose of TFQA significantly increased BDNF expression in the brains of BDNF-IRES-AkaLuc mice. Binding studies showed that TFQA has a strong affinity for the tyrosine receptor kinase B (TrkB) receptor. In summary, TFQA holds potential as a neuroprotective agent, mitigating learning and memory deficits in aging mice via neurotrophin signaling, particularly through BDNF upregulation.

Cellular aging is a multifaceted, complex process. Many genes and factors have been identified that regulate cellular aging. However, how these genes and factors interact with one another and how these interactions drive the aging processes in single cells remain largely unclear. Recently, computational systems biology has demonstrated its potential to empower aging research by providing quantitative descriptions and explanations of complex aging phenotypes, mechanistic insights into the emergent dynamic properties of regulatory networks, and testable predictions that can guide the design of new experiments and interventional strategies. In general, current complex systems approaches can be categorized into two types: (1) network maps that depict the topologies of large-scale molecular networks without detailed characterization of the dynamics of individual components and (2) dynamical models that describe the temporal behavior in a particular set of interacting factors. In this review, we discuss examples that showcase the application of these approaches to cellular aging, with a specific focus on the progress in quantifying and modeling the replicative aging of budding yeast

Thin endometrium (TE) is generally recognized as a contributing factor to reduced pregnancy rates and adverse perinatal outcomes, yet the pathogenesis of the disease remains elusive. We conducted an analysis and validation of the single-cell RNA sequencing (scRNA-seq) data pertaining to TE and demonstrated that insulin-like growth factor binding protein 2 (IGFBP2) expression is down-regulated, resulting in the senescence of endometrial epithelial cells. In both human primary endometrial epithelial cells and the Ishikawa cell line (a well-established endometrial-derived epithelial cell), the introduction of recombinant human IGFBP2 protein effectively alleviates hydrogen peroxide (H2O2)-induced cellular senescence. Notably, it demonstrates superior performance compared to the well-known anti-aging agent Dasatinib in specific aspects. Specifically, transfecting IGFBP2 protein siRNAs promotes cyclin dependent kinase inhibitor 1A (P21) accumulation through the phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway by regulating phosphatase and tensin homolog deleted on chromosome ten (PTEN) activity. Furthermore, administering IGFBP2 protein or Dasatinib to TE mouse models, which was established by endometrial curettage combined with H2O2 instillation, restored endometrial thickness by inhibiting senescence. Our findings demonstrate that down-regulation of IGFBP2 protein plays a pivotal role in mediating the senescence of endometrial epithelial cells in TE. This offers novel insights into elucidating the pathogenesis of TE and identifying potential new therapeutic targets.

Trained immunity (TRIM) is the process through which the innate immune system undergoes memory-like epigenetic and metabolic reprogramming following an earlier infectious challenge. Trained immunity can be induced, in a similar fashion to microbial structures, by various endogenous compounds: oxidized low-density lipoproteins, lipoprotein(a), glucose and uric acid, and monosodium urate. Lipids, glucose, and protein metabolic dysfunction have the potential to perpetuate a proinflammatory feedback loop through the induction of maladaptive trained immunity programs, as shown in cardiovascular diseases, diabetes, and hyperuricemia. Molecular mechanisms leading to TRIM are susceptible to homeostatic disruptions of advanced age, and maladaptive TRIM may be the link between immune aging and age-associated pathologies. The present review discusses the current knowledge on metabolic pathways in adaptive and maladaptive trained immunity and its deleterious consequences of inappropriate activation during aging. Finally, we discuss how several dietary patterns modulate immunometabolism and influence trained immunity in aging.

Aging is associated with alterations in immune cell function, contributing to age-related diseases and frailty. As peripheral blood mononuclear cells (PBMCs) are key drivers of the immune response, we investigated their transcriptome using RNA-sequencing before and immediately after a single bout of high-intensity knee-extension exercise in young (Young; n=7, 23 ± 4 years) and older individuals (Old; n=8, 65 ± 7 years). We used bioinformatics analyses to identify the biological processes and pathways that may be altered with age and in response to acute exercise. At baseline, 665 genes differed between Young and Old with notable differences in pathways involved in DNA Damage/Telomere Stress Induced Senescence, NAD Signaling Pathway, and Oxidative Stress Induced Senescence. After the exercise bout, 53 genes were differentially expressed in Young, while 1,026 genes changed in Old. In Young, the enriched processes and predicted pathways were linked to natural killer cells, while in Old these pathways were associated with cell signaling immune responses. Lastly, 26 genes exhibited similar responses to exercise between groups, enriching the biological process of natural killer cell-mediated immunity regulation. Our findings indicate that PBMC gene expression and the response to acute exercise are altered with aging, where exercise induced more pronounced PBMC transcriptomic adaptations in the Old. Additionally, while aging is associated with increased expression of genes linked to cellular dysfunction and suppressed immune function, acute exercise attenuated these age-related differences by downregulating the genes related to those pathways. Finally, acute exercise activated similar immune related pathways in both age groups.

Understanding the role of genetic risk and lifestyles on life expectancy (LE) without cardiovascular disease (CVD) and total LE may help optimize healthy aging strategies after taking genetic background into account.

The Tsimane and Moseten of the Bolivian Amazon are highly physically active and exhibit low rates of cognitive impairment and brain atrophy.

Metabolites produced by gut microbes have been linked to the pathophysiology of several disorders, including cardiovascular disease (CVD), such as atherosclerosis, hypertension, heart failure, and myocardial infarction. Trimethylamine-N-oxide (TMAO) is a primary diet-induced metabolite generated by the gut microbiota. TMAO is involved in dysregulation of bile acid and cholesterol metabolism, which promotes oxidative stress, inflammation, and endothelial dysfunction leading to vascular damages. Aging is usually associated with cardio-metabolic diseases, and the increasing evidence reveals that TMAO is linked with an increased risk of CVD in elderly. However, the exact relationship between plasma TMAO levels, the risk of CVD, and aging remains unclear. In this review, we explore the three-dimensional relationship between TMAO, aging, and CVD. Moreover, we discussed the new therapies used to reduce TMAO levels in aging and CVD.

As populations age, identifying the neurobiological basis of cognitive resilience is critical for delaying or preventing Alzheimers disease (AD). While most older adults experience memory decline, a subset known as superagers (SA) maintains youthful memory into late life, offering a unique window into protective mechanisms against neurodegeneration. Here, we identified a functional connectivity (FC) signature, termed Alzheimer\'s-resilient connectome (ARC), that robustly differentiates SA from age-matched patients with AD. Using resting-state fMRI in a discovery cohort (N = 290), we identified ARC derived from machine learning classifiers that distinguished SA from AD with high accuracy (AUC = 0.85), and validated the replicability of the ARC in an independent replication cohort (N = 143). ARC involved prefrontal, temporal and insular networks and was strongly associated with brain age. When applied to cognitively unimpaired (CU) adults (discovery cohort: N = 818 and replication cohort: N = 497), ARC-based subtyping revealed SA-like and AD-like subgroups with similar baseline cognitive performance but markedly divergent longitudinal trajectories. SA-like CU individuals showed slower cognitive decline, reduced amyloid-{beta} accumulation, and lower risk of conversion to mild cognitive impairment and AD, reinforcing the ARC signature as a potential early indicator of resilience. Genome-wide association analysis identified CLYBL and FRMD6 as novel genetic modulators associated with these divergent aging phenotypes. Together, our findings position ARC as a sensitive and generalizable biomarker of resilience, enabling early risk stratification and precision prevention for AD.

Fatty acids are involved in disease risk and aging processes. In the US National Health and Nutrition Examination Survey (1999-2002), we tested for associations of total, saturated (SFA), monounsaturated (MUFA), polyunsaturated (PUFA), and subtypes of dietary fatty acids with DNA methylation-based aging biomarkers, adjusting for age, BMI, total energy intake, and sociodemographic and behavioral factors (N=2,260). Higher SFA and MUFA were associated with greater GrimAge2, an aging biomarker of mortality; PUFA was associated with lower Horvath1, Hannum, and PhenoAge (p<0.05). Omega-3 and the PUFA:SFA ratio were negatively associated with Horvath1, Hannum, Vidal-Bralo, and PhenoAge. Notably, a one-unit increase in PUFA:SFA was associated with 1.05 years lower PhenoAge (95% CI=-1.87, -0.22). There were consistent trends of positive associations of SFA subtypes and negative associations of PUFA subtypes with epigenetic aging; associations of MUFA subtypes varied. Future studies, including randomized controlled trials, are needed to investigate causality and downstream clinical outcomes.

Age-related differences in white matter structure are increasingly understood as nonlinear, regionally specific, and behaviorally relevant. Using whole-brain fixel-based analysis (FBA), we examined how recognition memory speed relates to micro- and macrostructural white matter properties across a sample spanning young to middle adulthood. Slower response times were associated with higher fiber density (FD) in left frontoparietal tracts, nonlinear increases in fiber cross-section (log(FC)) in the anterior corpus callosum, and elevated combined fiber density and cross-section (FDC) in posterior callosal and cingulum pathways. These associations were most pronounced among individuals in the later decades of this age range, suggesting that white matter morphology reflects both extended maturation and emerging age-related decline. In a separate, hypothesis-driven analysis, we applied deterministic tractography to reconstruct the fornix and extracted mean fractional anisotropy (FA) along its length. Greater fornix FA and younger age together explained 34% of the variance in retrieval speed. These findings highlight regionally distinct structural contributions to memory performance and support lifespan models emphasizing individual variability and neuroplasticity in white matter development. This integrative approach underscores the value of combining whole-brain and tract-specific analyses to advance our understanding of white matter contributions to cognitive aging.

Observational studies have shown that physical activity and sedentary behavior are associated with aging. However, whether these associations underlie causal effects remains unknown. Thus, this study aimed to assess the genetic correlation and causal relationships between genetically predicted physical activity, sedentary behavior, and aging.

In postmenopausal women, estrogen deficiency can exacerbate inflammation associated with aging, increasing the risk of neuroinflammatory disorders. Although physical activity (PA) may reduce this risk, it may not be feasible for all patients. Metformin, an anti-diabetic drug, has been proposed as an exercise mimetic due to its ability to reduce systemic inflammation. We investigated whether the voluntary wheel running (VWR) or metformin treatment (MF) impacts neuroinflammation of female mice following ovariectomy. Middle-aged (A) and young adult (Y) mice underwent ovariectomy (OVX) or sham operation (SHAM), and had access to VWR or MF in their drinking water for six weeks. A sedentary control group received water without metformin. The frontal cortex and serum samples were collected for further evaluation using western blot, RT-qPCR, and ELISA methods. Ovariectomy reduced running activity in both age groups. A decrease in NLRP3 expression was observed in middle-aged mice following PA. The NF-κB p-p65/p65 ratio increased in OVX/MF_Y mice compared to SHAM/MF_Y mice. Our results indicate a modulatory effect of running and metformin on neuroinflammation with varying effects that seem age-related and ovarian status-dependent. The responsiveness to PA and MF in the frontal cortex of adult mice could be mainly associated with the NF-κB p65 signal.

Transposable elements (TEs) constitute a significant portion of the nuclear genome, but their influence on and ability to manage their activity during tissue regeneration remain largely unknown. Here, we revealed that LINE1, the most abundant TE, responds to cardiomyocyte injury and is overexpressed in a myocardial infarction (MI) model. We developed selectin binding peptide (SBP)-engineered extracellular vesicles (EVs) with targeted functions, which are loaded with LINE1 antisense oligonucleotide (ASO). The engineered EVs display targeted accumulation in injured hearts and protect against myocardial senescence by inhibiting the cGAS-STING-TBK1-IRF3 pathway and suppressing the expression of senescence-associated secretory phenotype (SASP) factors. Our data revealed that LINE1 retrotransposon activation is triggered by cardiomyocyte injury in the MI model. We also propose a strategy to reduce cardiomyocyte senescence post-myocardial infarction by modulating LINE1 activity.

As the innermost lining of blood vessels, endothelial cells (ECs) regulate blood flow, maintain vascular tone, and limit inflammation for vessel health. EC-derived nitric oxide (NO), synthesized by endothelial nitric oxide synthase (eNOS), is a vasodilator essential for improving blood flow and vascular homeostasis. The RhoA/ROCK pathway regulates eNOS levels, where overactivation decreases eNOS expression and downstream NO production. As such, RhoA/ROCK hyperactivity and increased pMLC have been identified as major contributors to age-associated vasoconstriction and hypertension. Intriguingly, recent studies identify Sun1, a key component of the linker of nucleoskeleton and cytoskeleton (LINC) complex, as a major regulator of RhoA/ROCK activity. Moreover, endothelial aging deteriorates nuclear pore complexes (NPCs) (i.e. nucleoporin [Nup93]) and impairs nucleocytoplasmic transport, thereby insinuating a role for nuclear envelope components in vessel homeostasis. Here, we show that targeted loss of endothelial Nup93 in adult mice significantly reduces eNOS expression and NO bioavailability for consequent defects in NO-dependent vasodilatory responses. In vitro knockdown of Nup93 in primary human ECs also decreases both eNOS expression and NO production. Mechanistically, we find that loss of Nup93 significantly reduces endothelial Sun1 levels for a concomitant increase in RhoA activity. Indeed, restoring Sun1 protein levels in Nup93-deficient ECs mitigates RhoA activity to rescue both eNOS expression and NO production. Taken together, we demonstrate endothelial Nup93, through Sun1 stabilization, as a novel regulator of eNOS-NO signaling and vessel reactivity, contributing to the growing importance of nuclear membrane components in EC and vascular biology.

Pancreatic β-cells are essential for maintaining endocrine function, and their age-related decline is strongly associated with insulin resistance and an increased risk of developing diabetes. By integrating cross-species bioinformatics analyses (single-cell RNA-seq data from young and aged cynomolgus macaques and microarray data from young and old mouse pancreatic β-cells), we identified mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum (ER) stress-related gene, as a key regulator of β-cell aging. Using a d-galactose (D-gal)-induced aging mouse model (400 mg/kg/day for 10 weeks) and H

Chronic periodontitis (CP) is one of the most prevalent local inflammatory disorders and is associated with various systemic diseases. However, the relationship between local CP pathogenesis and systemic metabolic responses is not fully elucidated. In this study, we show that CP causes systemic inflammation, leading to apoptotic resistance and senescent cell accumulation, which are crucial for maintaining local inflammation in a CP mouse model. Eliminating senescent cells through systemic senolytic therapy ameliorate local CP pathological changes. Proteomic analysis reveals that CP patient plasma extracellular vesicles show upregulation of immune response-related proteins and downregulation of metabolic and apoptosis-related proteins, among which pyruvate kinase M2 (PKM2) was significantly reduced. Moreover, CP mice show reduced circulating apoptotic vesicles (apoVs), particularly those carrying PKM2. Systemic administration of PKM2

Alzheimer's disease (AD), a neurodegenerative disease, has been linked to cellular senescence. Elimination of senescent cells through pharmacological and genetic could enhance memory performance of patient with AD. Despite extensive research, its complexity remains a significant challenge, leaving us without an effective remedy so far. In this study, by utilizing adeno-associated virus, we successfully suppressed the expression of Plau in mice with AD, providing further evidence for its significant contribution to the initiation and progression of this neurodegenerative disorder. Mechanistically, the activation of Cox-2 expression by Plau leads to the induction of senescence in neuronal cells. By specifically targeting the Plau in senescent cells, vilazodone, a novel inhibitor of Plau, can effectively trigger autophagy in these senescence cells and thereby eliminate them from the system. Additional in vivo studies demonstrated the potential of vilazodone to enhance cognitive function and memory in mice with AD, suggesting its therapeutic efficacy for treating AD. The results indicate that focusing on Plau may offer a hopeful approach for treating AD. Additionally, exploring the ability to inhibit Plau and alter the structure of vilazodone could provide valuable knowledge for developing drugs aimed at targeting Plau in AD-related conditions.

The relationship between physical activity and hippocampal volume is important; however, most studies have used questionnaires to measure physical activity. We aimed to determine whether maintaining high levels of daily physical activity measured by an accelerometer reduces hippocampal atrophy in community-dwelling adults.

Frailty is a complex ageing-related trait with a growing evidence base for genetic influence. While a single polygenic score (PGS) for frailty has shown predictive value, few studies have examined the joint effect of multiple genetic risks. This study used a multi-polygenic score (MPS) approach to evaluate the combined and relative contributions of 26 PGSs to frailty, measured via the Frailty Index (FI), in two UK cohorts aged 65 and older: the English Longitudinal Study of Ageing (ELSA) and the Lothian Birth Cohort 1936 (LBC1936). Using elastic net regression with repeated cross-validation, we identified chronic pain and depressive symptoms PGSs as the strongest risk predictors of cross-sectional frailty status, while educational attainment, parental longevity, and rheumatoid arthritis PGSs were protective. Compared to single PGS models, MPS models provided improved prediction of frailty levels, explaining up to 4.7% of variance in frailty status - an improvement over the best single PGS (2.5%). To assess whether PGSs also predicted longitudinal frailty progression, we applied generalized additive mixed models (GAMMs) to model age-related trajectories. In ELSA, five PGSs (chronic pain, depressive symptoms, rheumatoid arthritis, educational attainment, and parental death) significantly interacted with age, influencing the rate of frailty change. In LBC1936, consistent though weaker effects were observed for chronic pain and education PGSs. These findings show that polygenic liability shapes both frailty levels and trajectories in later life. Our results support the use of multi-trait genomic models to improve risk prediction and understanding of frailty's complex aetiology.

Dietary restriction is one of the most effective and reproducible dietary interventions known to regulate aging and increase the healthy lifespan in various model organisms, ranging from the unicellular yeast to worms, flies, rodents, and primates. This study examined the effects of short-term fasting during early life (STFEL) on longevity in the phytoseiid predatory mite Amblydromalus limonicus, hypothesizing that STFEL-especially at the facultative feeding larval stage-would extend lifespan. Experimental mites were divided into a control group with no fasting and four treatment groups subjected to 1-day fasting at the start in different developmental stages: Larval (T1), protonymph (T2), deutonymph (T3), and adult (T4). Results demonstrate that STFEL could significantly extends lifespan, with the most pronounced effects observed when fasting occurred at the start of the larval stage compared to other periods. These findings highlight the adaptive role of facultative feeding larvae and provide a foundation for developing physiological enhancement strategies in biocontrol applications.