Longevity Papers

Since the incidence of cardiovascular disease increases dramatically with age, it is crucial to understand the molecular mechanisms of heart damage in aging and how to reduce the damage caused by aging to the heart. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to mevalonate (MVA). Hmgcr not only affects cholesterol synthesis during the development process, but also regulates primordial germ cell migration and affects heart development. We investigated the expression and function of Hmgcr during cardiac development and aging. Changes during cardiac development may affect its entire life cycle. We used the Drosophila aging model to explore the expression changes of Hmgcr in the aging heart. The results showed that aging led to a significant decrease in the expression level of Hmgcr in cardiac tissue, accompanied by impaired cardiac function. Specific upregulation of cardiac Hmgcr expression can significantly improve aging-related cardiac dysfunction and extend lifespan. Interestingly, exercise can improve cardiac function and extend lifespan by upregulating Hmgcr expression levels in the aging heart. This finding provides a new theoretical basis for exercise to improve aging heart function and lifespan.

For diabetic patients, impaired wound healing is a serious complication, which characterized by prolonged inflammation, wound granulation tissue formation obstruction and impaired re-epithelialization. Accumulating evidence shows that senescent cells play a crucial role in the pathomechanism of diabetic wounds. In this study, we systematically evaluated the role of senescent cells in diabetic wound healing through diabetic mice (DM mice) model (including streptozotocin-induced type I DM mice model and db/db (type II DM) mice model, and actively assessed the therapeutic potential of ProcyanidinC1 (PCC1), the novel senolytic compound. We demonstrated that diabetic mice accumulated a significant number of senescent cells, primarily fibroblasts, in their normal skin and wound tissues. Local application of PCC1 selectively eliminated these senescent cells, leading to improved wound healing outcomes. By modulating the NF-κB signaling axis, PCC1 administration effectively downregulated senescence-associated secretory phenotype components, thereby ameliorating immune dysregulation in diabetic wounds. This therapeutic intervention concurrently revitalized the functional capacity of dermal fibroblasts and vascular endothelial cells, while stimulating coordinated matrix deposition and architectural remodeling of the extracellular compartment. Furthermore, PCC1 treatment enhanced epidermal barrier function after healing, a crucial aspect of wound repair which is often impaired in diabetes. And we also found that PCC1 would improve wound healing at type II diabetic mouse. Collectively, our findings elucidate the complex detrimental roles of senescent cells in diabetic wound repair and establish PCC1-mediated senolytic clearance as a promising therapeutic intervention.

Background: Telomere homeostasis is critical for normal cellular and organ function, and its dysregulation is implicated in aging and chronic diseases. Although telomere length (TL) is critical for normal telomere function, its functional status can also be altered by many other factors. The organization and protective status of telomere in failing human heart (FHH) remains incompletely understood. Methods: Using left ventricular tissues from patients with idiopathic dilated cardiomyopathy (IDC), ischemic heart disease (IHD), and non-failing heart (NFH), we performed a comprehensive analysis that included measurements of overall TL and 3\' overhang length in left ventricles and cardiomyocytes (CM), assessment of telomere-binding protein associations, and transcriptomic profiling through RNA sequencing. Results: Although TL varied among individuals, reduced median TL was observed only in IDC, while both IDC and IHD showed an increased frequency of very short telomeres, falling below the 5th percentile, in CMs. Strikingly, significant telomere 3\'-overhang attrition was detected in both disease groups and strongly correlated with elevated H2AX phosphorylated on serine 139 ({gamma}H2AX) in heart tissues, indicating DNA damage. This was accompanied by persistent activation of ataxia telangiectasia mutated (ATM) protein-mediated DNA damage responses and the formation of telomere dysfunction-induced foci (TIFs) in CMs from FHH. Concomitantly, the association of telomeres with the single-stranded telomere-binding protein, Protection of Telomeres 1 (POT1), and the double-stranded telomere-interacting protein, telomere repeat-binding factor 2 (TERF2), was markedly reduced, accompanied by an increase in association of {gamma}H2AX and ssDNA binding protein, RPA with telomeres in IDC and IHD relative to NFH, signifying telomere de-protection. Conclusions: CM telomere dysfunction, characterized by 3\' overhang attrition and de-protection, is a common feature in FHH, leading to persistent DNA damage response in telomeres. Better understanding of telomere biology throughout the progression of different heart diseases to heart failure will provide more effective prevention and treatment strategies.

Cognitive aging poses a major worldwide health concern. The association between basal metabolic rate (BMR) and cognition isn't well understood. This research examines sarcopenia's potential role as a mediator: linking BMR to cognitive function.

Cognitive decline with age is characterized by impairments in learning, sensory discrimination, and decision-making. While mammalian models have advanced understanding of the neural substrates of aging, their use in large-scale behavioral studies is limited. Invertebrate models, such as the house cricket (Acheta domesticus), offer short lifespans, high throughput, and conserved neurobiological pathways but remain underexplored in geroscience. We developed a dual behavioral paradigm integrating an olfactory discrimination Y-maze and an escape learning task requiring crickets to override innate odor preferences. Adult, mid-age, and geriatric crickets were tested for sensory discrimination, associative learning, and decision speed. Morphological traits, including antennal and femoral metrics, were quantified to evaluate their influence on cognitive outcomes. Data were analyzed using ANOVA, ANCOVA, and logistic regression models. Aging impaired olfactory preference and learning success, with geriatric crickets showing reduced task acquisition and memory retention. Mid-age individuals exhibited the slowest decision-making, suggesting an early onset shift in behavioral strategy. Morphological traits predicted aspects of sensory performance and physiological resilience, such as reduced weight loss in crickets with larger femoral dimensions but did not explain age-related cognitive deficits. Olfactory decline was particularly pronounced in males, mirroring sex differences observed in human cognitive aging. House crickets exhibit hallmark features of cognitive aging, including sensory decline, learning impairments, and reduced resilience, independent of morphological deterioration. These findings establish the house cricket as a scalable invertebrate model for dissecting conserved mechanisms of neural aging and testing interventions to promote cognitive health.

Episodic memory, the ability to recall past events, is particularly vulnerable to ageing. A decline in episodic memory performance is generally considered part of ageing. However, the episodic memory performance of superagers -defined as individuals aged 80+ years old with episodic memory of people 30 years younger- is superior to that typical of their chronological age. The aim of this study was to determine whether the discrepancy between the superager's episodic memory and chronological age is also evident in their brain age. A BrainAGE (Brain Age Gap Estimation) approach, a multidimensional computational neuroanatomical method that uses structural neuroimaging data to estimate biological brain age, was applied. The study population comprised 64 superagers (mean age = 81.9 ± 1.9) and 55 age-matched typical older adults (82.4 ± 1.9). Cross-sectional analyses revealed a negative BrainAGE score for superagers (mean = -0.95 ± 2.36) indicating a deceleration of the ageing process. By contrast, typical older adults showed an average score close to zero (0.05 ± 3.03) consistent with their chronological age. The BrainAGE score of superagers was found to be lower relative to typical older adults, and the progression over a 5-year follow-up period was slower in superagers, in keeping with their youthful memory ability. Therefore, superagers have a younger brain than those of typical older adults, suggesting that their ageing mechanisms may involve resistance to age-related brain structural changes. However, despite a 30-year gap in episodic memory, their BrainAGE score differed by only one year, indicating that factors beyond brain structure contribute to the superager phenotype.

Identifying interventions that reproducibly extend lifespan is a central aim in geroscience, with hopes of translating these findings to enhance the health and longevity of older adults. L-deprenyl, an FDA approved medication, has been investigated for its role in aging for over three decades. To evaluate the effect of L-deprenyl on lifespan in mammals we performed a random-effects meta-analysis on 22 rodent lifespan experiments. The results indicate L-deprenyl significantly increases average lifespan with moderate effect size (SMD = 0.6773, p = 0.0002). We identified no significant evidence of publication bias in the examined studies, but did observe substantial heterogeneity. Accounting for experimental factors revealed significant effects of dose (p = 0.0233) and age at initiation (p < 0.0001), with higher doses and older age associated with larger effects. Assessment of treatment effects by mean lifespan of controls suggests short-lived controls are not responsible for the observed effects. In addition to the meta-analysis, we reanalyzed a dog survival study by Ruehl et al. When accounting for age at enrollment and sex, the study no longer displayed a significant effect on survival, though power was limited by small sample size. Together, this analysis of 23 L-deprenyl lifespan experiments spans 27 years of research in 6 countries, 8 strains of rodents, 4 species, 6 doses, and 2 delivery methods, providing some of the most comprehensive data supporting the effect of a compound on lifespan in mammals. Future clinical studies examining L-deprenyls effects on health outcomes in older adults will be critical to determine the translatability of these findings.

Accurately quantifying oxidative DNA damage at the single-cell level remains a major challenge due to the limitations of conventional ensemble-based assays, which obscure cell to cell variability and lack molecular specificity. To address this, we developed a super-resolution imaging strategy that combines an 8-oxo-dG specific DNA aptamer with DNA-PAINT, enabling quantitative visualization of 8-oxo-dG lesions with ~22 nm spatial resolution in individual cells. Our approach reliably detects 8-oxo-dG clusters, distinguishes oxidative damage levels across cells, and exhibits superior specificity and labeling efficiency compared to antibody-based methods. Furthermore, it enables direct evaluation of the repair efficiency of hOGG1 and its catalytic mutants at the single-cell level, overcoming the confounding effects of variable transfection efficiency. This method also serves as a platform for assessing the effects of pharmacological modulators and antioxidants on DNA repair. Looking forward, this strategy can be extended to map other small molecular targets, such as epigenetically modified DNA or RNA bases, with single-cell precision.

Cortisol has been widely used as biomarker of stress and aging, but confounding effects and disruption of the hypothalamic-pituitary-adrenal axis can lead to misinterpretation of results based on a single measurement. A possible alternative is the co-measurement of cortisol and the adrenal hormone dehydroepiandrosterone-sulfate (DHEAS), a glucocorticoid antagonist that modulates the stress response. Using data from 969 individuals from the Midlife in the United States study, this study aimed to investigate the influence of age, sex, and self-identified biosocial group (SIBG) on DHEAS, cortisol, and the cortisol/DHEAS ratio, to test whether these hormones add predictive power to epigenetic age estimates, and to compare the performance of these three hormonal measures in predicting epigenetic age acceleration (EAA) using sex epigenetic clocks: Horvath, Horvath's skin & blood (Horvath2), Hannum, PhenoAge, GrimAge, and DunedinPACE. Our findings revealed that age, sex and SIBG significantly influenced all three hormonal measures. Controlling for these biodemographic factors, we found that the cortisol/DHEAS was the best predictor of epigenetic clocks. There was a significant and positive correlation between cortisol and Hannum epigenetic age, and between cortisol/DHEAS ratio in three out of the six clocks (Hannum, Horvath2, PhenoAge), but no significant associations between DHEAS and epigenetic age. The cortisol/DHEAS ratio also had a significant and positive correlation with Hannum EAA. DHEAS and cortisol were not significantly associated with EAA for any epigenetic clock. Our results reinforce the importance of co-measuring cortisol and DHEAS in studies investigating the effect of stress in aging processes.

Oxidative stress is a key driver of retinal pigment epithelium (RPE) damage and the development of age-related macular degeneration (AMD). Here, we demonstrate that the histone deacetylase (HDAC) inhibitors vorinostat and trichostatin A (TSA) elicit a coordinated cytoprotective response in RPE cells exposed to rotenone. Both compounds significantly reduced reactive oxygen species (ROS) levels, enhanced mitochondrial fusion, increased mitochondrial ATP production, and improved cell morphology and cell survival in the rotenone-treated cells. In addition, the compounds activated Nrf-2 as evidenced by Keap1 downregulation, increased p62/SQSTM1 expression, and induction of Nrf-2 targets, including heme oxygenase 1 (HO-1). Proteomic analysis of drug-treated cells revealed a significant enrichment of proteins involved in cytoskeletal organization and dynamics. Consistently, specific staining for actin filaments confirmed that vorinostat and TSA preserved cytoskeletal architecture and increased levels of the tight junction protein TJP3 in cells exposed to rotenone. Finally, inhibition of the vorinostat/TSA target HDAC6, or blockade of α-tubulin acetyltransferase, demonstrated that modulation of α-tubulin acetylation could influence ROS levels. Similarly, enhanced mitochondrial fusion by Mdivi-1 reduced ROS accumulation in the rotenone-treated cells. However, these last two interventions did not fully recapitulate the antioxidant effects observed with vorinostat or TSA. Our results identify a multifaceted protective mechanism triggered by HDAC inhibition in oxidatively stressed RPE cells and support the therapeutic repurposing of vorinostat in oxidative stress-driven RPE or retinal degeneration.

Socioeconomic status (SES) disadvantage shapes exposure to persistent infections and immune aging, but its life-course effects remain understudied. Early adulthood is a crucial period, as immune aging may begin before clinical signs appear.

Advances in single-cell sequencing have deepened our understanding of cellular identities. However, because they inherently capture only static snapshots, after which no further observations are possible, we cannot compare past and present profiles within the same cell. Thus, multi-time-point whole-genome profiling at single-cell resolution has been a long-standing goal. Here, we introduce the History Tracing-sequencing (HisTrac-seq) platform, which enzymatically labels genomic DNA adenine to bookmark gene regulatory statuses. This first enabled the profiling of transcriptomic and epigenetic states in the mouse brain over a period of two months. Furthermore, extending HisTrac-seq to single-cell multi-omics sequencing, we demonstrated the simultaneous mapping of past and present profiles of the same single cells. Analyzing over 93,000 cells, we discovered unexpected, drastic cell identity transitions on a large scale (identity jumps). This phenomenon was previously unobservable with current technologies and revealed a hidden layer of developmental plasticity. HisTrac-seq offers a powerful approach to temporal-multi-omics for disentangling dynamic biological processes involved in development, plasticity, aging, and disease progression.

Cellular senescence, stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stressors, has been highlighted as one of the most important mechanisms involved in kidney diseases. It not only serves as a fundamental biological process promoting normal organogenesis and successful wound repair but also contributes to organ dysfunction, tissue fibrosis, and the generalized aging phenotype. Moreover, senescent cells exhibit reduced regenerative capacity, which impairs renal function recovery from injuries. Importantly, senescent cells are involved in immune regulation via secreting a diverse array of proinflammatory and profibrotic factors known as senescence-associated secretory phenotype (SASP) with autocrine, paracrine, and endocrine activities. Thus, eliminating detrimental senescent cells or inhibiting SASP production holds great promise for developing innovative therapeutic strategies for kidney diseases. In this review, we summarize the current knowledge of the intricate mechanisms and hallmarks of cellular senescence in kidney diseases and emphasize novel therapeutic targets, including epigenetic regulators, G protein-coupled receptors, and lysosome-related proteins. Particularly, we highlight the recently identified senotherapeutics, which provide new therapeutic strategies for treating kidney diseases.

In youth, energy deprivation primarily results from fasting. Because inconsistent nutrient availability is common for most organisms, natural selection has provided mechanisms that detect nutrient-deprived states, followed by adaptive responses that increase the likelihood of survival until nutrients are restored. Organisms respond to fasting first by oxidizing the cellular cytoplasm, then by activating redox-sensitive kinases - namely the c-Jun N-terminal kinases (henceforth collectively termed JNK) and AMP-activated protein kinase (AMPK) - and Foxo transcription factors (henceforth referred to collectively as Foxo). Together, JNK, AMPK and Foxo induce autophagy. This fasting response is beneficial because autophagy supplies substrates for metabolism that replace missing nutrients and enhances removal of damaged organelles such as mitochondria, which increases lifespan and enhances survival through the fast. Although this response is adaptive in the context of acute nutrient deprivation, it can have harmful consequences when activated chronically. Here, I propose that cells from old organisms are constitutively energy deprived because of lifetime accumulation of dysfunctional mitochondria. As a result, these cells reactivate the fasting response seen in youth. Hence, old organisms constitutively oxidize the cellular cytoplasm and activate JNK, AMPK, Foxo and, finally, autophagy. However, because energy deprivation in old age is driven by mitochondrial insufficiency rather than nutrient deprivation, this response fails to restore ATP production and becomes chronic and deleterious. I suggest that many age-related pathologies, such as oxidative stress, neurodegeneration and sarcopenia, result from aberrant activation of the fasting response.

Aging is an intrinsic biological decline marked by multidimensional alterations spanning molecular, cellular, tissue, and organ levels. One hallmark of aging is the progressive deterioration of immune function, a condition referred to as immunosenescence. This process often involves a persistent, mild, and non-infectious inflammatory state across the body, commonly described as inflammaging. The regulation of age-related immune and inflammatory processes is critically influenced by epigenetic mechanisms, such as alterations in DNA methylation patterns, histone modifications, chromatin structure reorganization, and the regulatory actions of non-coding RNAs. Recent research has increasingly focused on the regulatory roles of post-translational modifications (PTMs), including histone methylation, acetylation, ubiquitination, and O-GlcNAcylation, have been widely recognized as fundamental modulators of immunoinflammatory processes in aging. In this review, we provide a comprehensive overview of histone modification-mediated mechanisms involved in the regulation of immunosenescence. We further highlight their functional roles from the perspective of immune inflammation and explore potential therapeutic strategies targeting histone modifications to mitigate immunosenescence.

Metabolic changes can play a critical role in the structural and functional decline of the aging cardiovascular system. In this review, we examine how key metabolic pathways and regulatory mechanisms influence cardiovascular aging, highlighting recent studies into metabolic flexibility, mitochondrial function, nutrient sensing, and energy utilization in the aging heart. Potential metabolic-based interventions to mitigate cardiac aging are also discussed.

Physical activity (PA) and sedentary behavior (SB) are two key lifestyle factors with profound implications for bone health across the lifespan. While PA is recognized for its positive effects on bone mineral density (BMD) and fracture prevention, emerging evidence highlights the detrimental consequences of prolonged sedentary time, independent of PA levels. This review synthesizes current knowledge on the impact of PA and SB on bone health outcomes, focusing on BMD and fracture risk in children, adolescents, adults, and older populations. A selection of epidemiological studies, systematic reviews, and meta-analyses was analyzed to explore the associations between movement behaviors and bone health indicators across different life stages. Particular attention was given to studies objectively measuring SB and PA and to the substitution effects of sedentary time with light or moderate-to-vigorous PA. In children and adolescents, higher levels of SB are associated with lower BMD, particularly at weight-bearing sites, while participation in weight-bearing and impact-loading PA positively influences bone mass accrual. In adults and older individuals, regular PA, including moderate-to-vigorous intensity weight-bearing PA and resistance training activities, is consistently linked to greater BMD and reduced fracture risk. Conversely, high sedentary time is associated with lower BMD and increased fracture incidence, particularly among frail or pre-frail individuals. Importantly, replacing sedentary time with even light-intensity PA yields measurable benefits for bone health, particularly among older adults and postmenopausal women, and may contribute to a reduced risk of fractures, although evidence remains limited. Promoting PA while minimizing SB should be central to clinical practice and public health policies aimed at maximizing and preserving skeletal health and preventing osteoporotic fractures, across the lifespan. Early intervention, continuous promotion across life stages, and adherence to WHO guidelines offer an effective, evidence-based framework for lifelong bone health maintenance.

Aging population rates are significantly increasing and improved quality of life during aging is a top priority. The decline in skeletal muscle mass and strength is a major concern with aging, as it impairs the ability to perform activities of daily living and significantly diminishes quality of life. Effective strategies to counteract this decline are necessary for supporting longevity and enhancing quality of life in older adults.

Age-related vertigo and balance disorders can lead to falls, fractures, and prolonged confinement to bed. Loss of mobility and/or social interaction may cause cognitive decline and lower quality of life, resulting in significant social and economic burdens. Aging societies urgently need treatments for vestibular decline, as no cures exist, and current therapies only provide symptomatic relief. Oxidative stress contributes to age-related cochlear balance system damage, making antioxidants a potential treatment. Silicon-based agent (Si-agent) is an excellent antioxidant. When reacting with water, this agent produces hydrogen continuously, offering sustained antioxidant effects. Oral Si-agent has alleviated oxidative stress-related diseases in mouse models, such as ulcerative colitis and Parkinson's disease. This study evaluated Si-agent for age-related vestibular decline in mice. In balance beam tests, Si-agents-treated group showed less balance decline with age compared to untreated mice. However, vestibulo-ocular reflex (VOR) tests measuring semicircular canal and otolith organ function showed no significant differences. In linear VOR, no significant differences were observed at any frequency; however, a significant difference was found in the average slope of linear decline between 0.7 and 0.9 G. Structural damage to the inner ear's semicircular canals and otolith organs was also reduced in Si-agents-treated group. These findings suggest that Si- agent may help treat age-related in balance and motor decline.

The evolution of menopause, grandmothering and long lifespan represent key events in the evolution of human life history. Demographic studies have amply demonstated inclusive fitness benefits from grandmaternal care, but the hormonal bases of such care, and how it evolved in relation to other reproductive and demographic traits, have yet to be addressed in detail. We propose and evaluate a novel hypothesis for the coevolution and adaptive covariation of life history, physiology, and behavior among women in this context. The hypothesis centers on relatively low testosterone, which promotes: (1) earlier, higher fertility and fecundity, (2) earlier cessation of ovarian activity (leading to earlier grandmothering), and (3) enhanced alloparental care. The hypothesis can help to explain among-female variation in grandmaternal care, and potential trajectories for the concerted evolution of grandmothering, prolonged human lifespan, and associated life history traits. A suite of convergent evidence supports the hypothesis, and it makes new predictions that are straightforward to test.

Intervertebral disc degeneration (IDD) is a major cause of chronic low back pain, the mechanism of which is still unclear. Inflammation-induced extracellular matrix metabolism (ECM) dysregulation in the nucleus pulposus (NP) and NP cell senescence are known to be the key causes of IDD. However, few drugs can reliably alleviate ECM dysregulation and NP cell senescence. Muscone, as the key natural component of musk, is a widely applied antiapoptotic and anti-inflammatory drug. We found Muscone exerts protective effects by inhibiting the expression of ECM catabolism-related genes, cell apoptosis, the cell senescence and senescence-associated secretory phenotype (SASP) in NP cells, which is the key cellular phenotype associated with IDD. We have also shown that muscone can increase the expression of ECM anabolism-related genes and the proliferation of NP cells during inflammation. High-throughput RNA sequencing indicated that muscone protects NP cells mainly by altering the phosphorylation and expression of p53. Further validation confirmed both in vivo and in vitro that muscone could regulate ECM-related genes, cell apoptosis, cell senescence and the SASP by inhibiting p53. In summary, our findings show that muscone protects against the degeneration of nucleus pulposus cells by inhibiting p53 signaling and thus may have therapeutic value for IDD.

Oxidative stress and hypoxia lead to dysfunction of retinal pigment epithelium (RPE) cells and are hallmarks of diseases such as age-related macular degeneration (AMD), the most common blinding disease in the elderly population. We have previously shown that a combination of these two risk factors, i.e. hypoxidative stress, exacerbates RPE cell death by ferroptosis. Hypoxia leads to stabilization of hypoxia-inducible factors (HIFs), key regulators of cellular adaptation to hypoxic conditions. In the present study, we have therefore investigated the roles of HIF-1 and HIF-2 in RPE cell death in a human RPE cell line under hypoxidative stress. For this purpose, we conducted siRNA-mediated knockdowns of the α-subunits of HIF-1 and HIF-2. We found that especially iron metabolism, in particular the expression of transferrin receptor 1 (TFR1) was affected by HIF-1α silencing, resulting in decreased intracellular iron levels and ferroptosis susceptibility. We also found that heme oxygenase 1 (HO-1) contributed to cell death by hypoxidative stress. In addition, we also observed that cell metabolism was improved by HIF-1α silencing under hypoxia, most likely contributing to the protective effect. Furthermore, we identified an FDA-approved small molecule inhibitor, Vorinostat, to downregulate HIF-1α, TFR1, and HO-1 and improve cell metabolism, which eventually resulted in a full rescue of RPE cells from hypoxidative stress-induced cell death. In conclusion, this study highlights the importance of considering targeted HIF inhibition as a promising approach to protect RPE cells from degeneration.

Vascular aging is considered now to be the first factor of multiorgan aging in what is called "the vascular theory of aging". Clinical understanding of vascular aging has long been limited to arterial hypertension and arterial stiffness. The effects of age on arterial mechanical properties have always been difficult to interpret for reasons linked to the non-linear behaviour of the stiffness/pressure function and the complex interactions between vascular cells and the matrix. Even new methodologies for decoding aging at the single-cell level are equally difficult to interpret. This objectives of this review are: (i) to introduce new computational approaches in biomechanics and mechanobiology; (ii) to revisit the role of oxidative stress and cellular senescence; (iii) to summarize some of the main molecular, cellular and mechanistic contributions to vascular aging; (iv) to present the latest human studies of accelerated arterial aging with particular reference to cognitive impairment and functional decline; (v) to propose some future directions for research related to vascular aging.

Previous research suggests that centenarians reach exceptional ages primarily by avoiding major diseases rather than surviving them. However, how they manage multiple conditions over the life course remains less understood. Examining the accumulation and distribution of diseases across lifespan can provide insights into mechanisms underlying their resilience.

The aging population worldwide necessitates the development of novel therapeutics that enhance the quality of life by preventing and treating age-related diseases. In this review, we first discuss the advantages of a dual-purpose target identification strategy for aging and age-related diseases, with assessment of the hallmarks of aging as an approach to identify such dual-purpose targets. Resulting from a convergence of aging research with machine learning (ML) and other artificial intelligence (AI) models, aging clocks were initially developed as aging biomarkers, but its value in identifying therapeutic targets is also increasingly recognized. Building on recently published aging clocks, we reestablish a significant proportion of known drug targets by identifying clock-associated genes, highlighting the potential of these clocks for target identification. Lastly, we discuss other applications of aging clocks in drug development such as population stratification and disease and treatment monitoring. With the growing availability of multi-omics data and rapid advancements in ML and AI, we anticipate accelerated progress in aging clock research, paving the way for innovative treatments to meet the healthcare needs of a global aging population.

The immune system comprises multiple cell lineages and subsets maintained in tissues throughout the lifespan, with unknown effects of tissue and age on immune cell function. Here we comprehensively profiled RNA and surface protein expression of over 1.25 million immune cells from blood and lymphoid and mucosal tissues from 24 organ donors aged 20-75 years. We annotated major lineages (T cells, B cells, innate lymphoid cells and myeloid cells) and corresponding subsets using a multimodal classifier and probabilistic modeling for comparison across tissue sites and age. We identified dominant site-specific effects on immune cell composition and function across lineages; age-associated effects were manifested by site and lineage for macrophages in mucosal sites, B cells in lymphoid organs, and circulating T cells and natural killer cells across blood and tissues. Our results reveal tissue-specific signatures of immune homeostasis throughout the body, from which to define immune pathologies across the human lifespan.

After stroke, microglia and hematogenous macrophages, together referred to as MΦ, clear dead cells and cellular debris in the infarcted brain through phagocytosis as an essential part of the recovery process. However, the phagocytic capability of MΦ declines with age. Furthermore, aged MΦ become overactivated in response to stroke, enhancing secondary brain injury. In this study, we demonstrated that by reversing the age-related dysfunctions in MΦ through activating the retinoid x receptor (RXR), the recovery after stroke in the aged brain could be improved. Using RNA sequencing, we compared the transcriptomes between MΦ isolated from the brains of young and aged male mice. We observed higher levels of pro-inflammatory genes and lower levels of phagocytosis-facilitating genes (

The mitochondrial transcription factor A (TFAM) is essential for mitochondrial genome maintenance. It binds to mitochondrial DNA (mtDNA) and determines the abundance, packaging and stability of the mitochondrial genome. Because its function is tightly associated with mtDNA, TFAM has a protective role in mitochondrial diseases and supportive studies demonstrate reversal of disease phenotypes by TFAM overexpression. In addition, TFAM deficiency has been shown to cause release of mtDNA into the cytosol and activation of the cGAS/STING innate immune response pathway. As such, TFAM presents as a unique target for therapeutic intervention, but limited efforts for activators have been reported. Herein we disclose novel TFAM small molecule modulators with sub-micromolar activity. Our results demonstrate that these compounds result in increase of TFAM protein levels and mtDNA copy number. This results in inhibition of a mtDNA stress-mediated inflammatory response by preventing mtDNA escape into the cytosol. Furthermore, we see beneficial effects in cellular disease models in which boosting TFAM activity has been advanced as a disease modifying strategy including improved energetics in MELAS cybrid cells and a decrease of fibrotic markers in Systemic Sclerosis (SSc) fibroblasts. These results highlight the therapeutic potential of using small molecule TFAM activators in indications characterized by mitochondrial dysfunction.

Based on the observation of silicon content decrease in the muscles and serum with aging, this study proposes a silicate bioactive material based therapy for treating sarcopenia. Two therapeutic strategies were designed. One utilizes calcium silicate (CS) hydrogel for localized intramuscular treatment, and the other employs CS solution for systemic treatment through Intravenous injection. Both treatments restore silicon levels in the muscles and serum of aging mice, and show therapeutic effects on sarcopenia. Specifically, the CS hydrogel demonstrates more pronounced short-term efficacy in promoting local muscle regeneration, while the CS solution exhibits superior outcomes in modulating the overall condition of aging mice. The fundamental mechanism of the CS treatments on sarcopenia may involve the direct regulation of the SIRTs signaling pathway by silicate ions released from CS, as well as the indirect regulation of SIRTs pathway via the suppression of Sarcolipin (SLN) overexpression by silicate ions. Specifically, silicate ions directly upregulate SIRT1 expression in macrophages and on one side promote NF-kB deacetylation to inhibit M1 polarization, and on the other side facilitate STAT3 deacetylation to inhibit M2 polarization, ultimately reducing the expression of inflammatory factors (TNF-α, IL-6) and fibrotic factors (IL-10, TGF-β). Meanwhile, silicate ions directly upregulate SIRT3 in myoblasts, leading to the promotion of STAT3 dephosphorylation, inhibits mitochondrial reactive oxygen species (ROS) secretion, and enhances the expression of MyoD, MyoG, and Myosin, and accelerates myogenic differentiation. This bioactive CS based therapy provides a new approach for combating sarcopenia.

Zearalenone (ZEN), a ubiquitous mycotoxin contaminating cereals and feed, is best known for reproductive toxicity. It remains unclear whether chronic, low-level exposure contributes to aging and mitochondrial decline. Here, we combine network toxicology, molecular docking, transcriptomics and zebrafish (Danio rerio) models to address this question. In silico analyses identified 30 high-confidence ZEN targets linked to aging or mitochondrial biology; AKT1, MAPK3, TP53 and NFKB1 emerged as the central hubs. Docking predicted strong binding affinities (-6.2 to -8.3 kcal/mol) and 100 ns molecular-dynamics simulations confirmed stable complex formation. Translating these predictions to a living system, we exposed zebrafish larvae to 2 μM ZEN. Within 72 h this produced overt developmental toxicity (delayed hatching, bradycardia, skeletal malformations) and sarcopenia-like muscle degeneration. Transmission-electron microscopy revealed disorganised sarcomeres; immunostaining showed reduced myosin heavy-chain expression. Oxidative stress (DCF fluorescence) rose markedly, while ATP-synthase transcripts were down-regulated. Locomotor assays at 96 h revealed a selective loss of high-speed swimming bouts. RNA-seq corroborated dysregulation of MAPK, PI3K-AKT and apoptosis pathways; longevity-linked genes (igf1, sirt1, nfkb2) were significantly downregulated. Collectively, our work provides the first integrated evidence that ZEN exposure accelerates organismal aging through mitochondrial dysfunction and suggests that tighter mycotoxin surveillance is warranted as populations grow older.

Close social ties are known to increase survival, reduce chronic diseases, and promote healthful eating. Little research has explored whether adverse changes in these relationships lead to less healthful eating in older adults, with attention to gender differences.

Ageing plays a critical role in the deterioration of artery function and structure, and clearly represents the first cardiovascular (CV) risk factor in men but also in women. Coronary and cerebral arteries are particularly prone to atheroma, and the tissues they perfuse are particularly vulnerable to ischaemia. In both sexes, the age-related decrease in sex hormones (menopause and andropause) has deleterious effects on CV health. The extent to which hormonal supplementation can limit the CV risks increased by ageing remains controversial. The Women Health Initiative study, the main clinical intervention designed to evaluate the benefit/risk ratio of hormone treatment after menopause, revealed in 2002 an unexpected increase in CV events in aged women (>70 years) given estrogens plus a peculiar synthetic progestin medroxyprogesterone acetate, whereas estrogens alone were not harmful but even protective in younger women (<60 years). This pointed out the double problem of the progestin (now natural progesterone is preferred) and of the age. The clinical situation is not yet clear for testosterone and CV disease in men. Related to these questions, we will analyse and summarize: (i) the importance of the doses and concentrations of estrogens and testosterone, both in humans and in experimental models, allowing to define relevant/physiological or pharmacological actions of sex hormones in respect to their medical modulations in practice; (ii) the main clinical studies conducted with estrogens or androgens, in terms of CV protection and the impact of age on these effects; (iii) the mechanisms underlying these actions; (iv) the gender-affirming hormone therapy, as these sex hormones are the cornerstone of gender transition care management.

Follicular (F) and germinal center (GC) immune dynamics are crucial in generating pathogen-specific antibodies with high affinity and neutralizing activity capable of combating infections. GCs are populated by highly differentiated CD4 T-cell and B-cell populations with unique phenotypes, functions, and molecular signatures. Aging, which is associated with a state of "immunosenescence," is characterized by compromised B-cell responses to infections and reduced vaccine efficacy, pointing to altered GC immunoreactivity and function. Therefore, there is a need for novel, improved approaches to strengthen antibody responses in these individuals and mitigate morbidity and mortality. Despite the importance of mouse models, studies focusing on human F/GC immune dynamics are of great interest. Furthermore, studying these dynamics in various human diseases could provide important insights into the cellular and molecular mechanisms that regulate GC development under different local microenvironmental conditions. The development and application of cutting-edge methodologies allowing for the comprehensive analysis of relevant cell types and a better understanding of the spatial organization of the immune system in these anatomical sites are essential to delineate the impact of molecular targets and pathways that could be used in designing

Collagen, the most abundant structural protein in animals, plays a crucial role in maintaining skin integrity, elasticity, and strength. Type I collagen, which predominates in the skin, is particularly vulnerable to environmental stressors, such as solar radiation. Prolonged sun exposure accelerates collagen degradation, driving skin aging and impairing tissue functionality. However, the molecular mechanisms governing these intricate processes remain unclear. In this study, we employed bovine Type I collagen as a model system to investigate the molecular alterations induced by solar radiation, focusing on changes in structure, morphology, and fibrillogenesis potential. Collagen samples were irradiated using a solar simulator that mimics the full solar spectrum to ensure standardized conditions. Structural changes at different levels, were analyzed using a multi-technique approach combining classical spectroscopies, fluorescence lifetime imaging microscopy, and scattering-type scanning near-field optical microscopy (s-SNOM). This multimodal approach enabled both sensitive detection of molecular alterations and spatial mapping of local heterogeneities within collagen fibers. Results indicate partial destabilization of the triple-helical structure and a loss of cross-links and telopeptides, consistent with molecular misalignment. FLIM imaging on samples stained with Anilinonaphthalene-1-sulfonic acid (ANS), a gold standard fluorescent dye for the study of protein conformational transition highlighted increased sample heterogeneity and a reduction in hydrophobic regions, pointing to structural disruption which could be also related to the loss of self-assembly capabilities of collagen molecules.

Mitochondrial reactive oxygen species (mtROS) regulate cellular signaling pathways, but also cause oxidative stress when de-regulated during aging and pathological conditions such as neurodegenerative diseases. The dynamic redistribution of proteins between cellular compartments is a common mechanism to control their stability and biological activities. By targeting the BirA∗ biotin ligase to the outer mitochondrial membrane in HEK293 cells, we identified proteins whose labeling increased or decreased in response to treatment with menadione, consistent with a dynamic change in their mitochondrial localization in response to increased mtROS production. These proteins represent potential candidates for future studies of mitochondrial oxidative stress signaling. A subset of glycolytic enzymes was found in this screen and confirmed, by mitochondrial fractionation and imaging, to increase localization to mitochondria in response to menadione, despite no change in their overall abundance. Submitochondrial fractionation studies are consistent with import of a pool of these enzymes to the mitochondrial intermembrane space. Localization of glycolytic enzymes to mitochondria was also increased in cells grown under hypoxia or that express a mitochondria-targeted d-amino-acid oxidase (conditions that induce increased mtROS production), and inhibited basally under normal growth conditions by the mitochondrial antioxidant MnTBAP. Finally, primary Alzheimer's disease fibroblasts also had glycolytic enzymes associated with mitochondria that was reduced by antioxidants, consistent with increased mtROS altering their relative distribution between the cytoplasm and mitochondria. We speculate that the increased mitochondrial localization of glycolytic enzymes is an adaptive response to mtROS that alters glucose flux toward the antioxidant pentose phosphate pathway, creates distinct regulatory pools of mitochondrial metabolites or new metabolic circuits, and/or provides cytoprotection or other adaptive responses via moonlighting functions unrelated to their enzymatic activity.

Aging is increasingly understood not as the passive accumulation of molecular damage, but as the cumulative cost of unresolved physiological adaptation under bioenergetic constraint. This review introduces Exposure-Related Malnutrition (ERM) as a mechanistically grounded and clinically actionable phenotype of early maladaptation. ERM arises from sustained metabolic strain during chronic stress exposure and manifests not through overt weight loss or nutrient deficiency, but through subtle, multisystem declines in physical, cognitive, and regenerative capacity. These include fatigue, impaired recovery, cognitive slowing, immune dysregulation, chronic pain, anabolic resistance, and reproductive decline-features often missed by classical malnutrition criteria. We propose a unifying framework-Respond → Adapt → Resolve-to model the trajectory of stress response and resolution, emphasizing the critical role of bioenergetic availability in shaping divergent outcomes. When metabolic substrates are insufficient, resolution fails and the system defaults to a trade-off state, prioritizing immediate survival over long-term maintenance. ERM represents this inflection point: a reversible, energy-constrained condition that precedes frailty and chronic disease. We review interconnected mechanisms-including neuroendocrine activation, immune reprogramming, skeletal muscle catabolism, translational suppression, and mitochondrial distress-that create a self-perpetuating loop of maladaptive adaptation. We map ERM onto key hallmarks of aging, propose a multidimensional staging model, and outline clinical strategies to detect and reverse ERM using dynamic biomarkers, functional assessments, and circadian-aligned lifestyle interventions. By reframing aging as a failure of adaptive resolution, this framework offers a novel lens to extend healthspan-via early detection of metabolic compromise and restoration of resilience before functional decline becomes irreversible.

Vascular endothelial cell (VEC) dysfunction is a key contributor to vascular diseases. Oxidative stress-induced ferroptosis accelerates VEC aging and injury, while protective autophagy mitigates this damage by clearing damaged organelles and reducing oxidative stress. GABARAPL2, a critical autophagy-related protein, and ACSL3, a regulator of lipid metabolism and ferroptosis, are emerging as interconnected mediators of cellular protection. However, their precise roles in oxidative stress-induced VEC aging and injury remain unclear. This study aimed to investigate how GABARAPL2 and ACSL3 regulate autophagy and ferroptosis to protect VECs. Human umbilical vein endothelial cells (HUVECs) were treated with hydrogen peroxide to establish a cellular oxidative stress model. Gene expression was analyzed through Western blot and immunofluorescence, while cell viability, apoptosis, reactive oxygen species (ROS), Fe

Cytoskeleton-Associated Protein 4 (CKAP4) is a multifunctional protein implicated in diverse cellular processes, including cytoskeletal organization, signal transduction, and extracellular matrix remodeling. Recent studies have highlighted the dual role of CKAP4 in regulating cell growth and aging. On one hand, CKAP4 can promote cell proliferation and survival by activating signaling pathways such as PI3K/Akt, thereby delaying cellular senescence under physiological conditions. On the other hand, under chronic stress or pathological stimuli, CKAP4 may induce cell cycle arrest and accelerate aging by interacting with ligands such as antiproliferative factor (APF) and Dickkopf-1 (DKK1), leading to the upregulation of cell cycle inhibitors and the suppression of autophagy. Moreover, CKAP4 has emerged as a key mediator linking extracellular matrix remodeling to inflammatory responses, which are closely associated with age-related diseases. This review comprehensively summarizes the current understanding of CKAP4's molecular mechanisms in cell longevity and aging, discusses its involvement in inflammation and tissue homeostasis, and explores its potential as a therapeutic target for aging-related disorders.

The progressive loss of cerebral white matter during aging contributes to cognitive decline, but whether reduced blood flow is a cause or a consequence remains debatable. Using deep multi-photon imaging in mice, we examined microvascular networks perfusing myelinated tissues in cortical layer 6 and the corpus callosum. We identified sparse, wide-reaching venules, termed principal cortical venules, which exclusively drain deep tissues and resemble the vasculature at the human cortex and U-fiber interface. Aging led to selective constriction and rarefaction of capillaries in deep branches of principal cortical venules. This resulted in mild hypoperfusion that was associated with microgliosis, astrogliosis and demyelination in deep tissues, but not the upper cortex. Induction of comparable hypoperfusion in adult mice using carotid artery stenosis triggered a similar tissue pathology specific to layer 6 and the corpus callosum. Thus, impaired capillary-venous drainage is a contributor to hypoperfusion and a potential therapeutic target for preserving blood flow to white matter during aging.

Proteostasis, or protein homeostasis, is a tightly regulated network of cellular pathways essential for maintaining proper protein folding, trafficking, and degradation. Neurons are particularly vulnerable to proteostasis collapse due to their post-mitotic and long-lived nature and thus represent a unique cell type to understand the dynamics of proteostasis throughout development, maturation, and aging. Here, we utilized a dual-species co-culture model of human excitatory neurons and mouse glia to investigate cell type-specific, age-related changes in the proteostasis network using data-independent acquisition (DIA) LC-MS/MS proteomics. We quantified branch-specific unfolded protein response (UPR) activation by monitoring curated effector proteins downstream of the ATF6, IRE1/XBP1s, and PERK pathways, enabling a comprehensive, unbiased evaluation of UPR dynamics during neuronal aging. Species-specific analysis revealed that aging neurons largely preserved proteostasis, although they showed some signs of collapse, primarily in ER-to-Golgi transport mechanisms. However, these changes were accompanied by upregulation of proteostasis-related machinery and activation of the ATF6 branch, as well as maintenance of the XBP1s and PERK branches of the UPR with age. In contrast, glia exhibited broad downregulation of proteostasis factors and UPR components, independent of neuronal presence. Furthermore, we quantified stimulus-specific modulation of select UPR branches in aged neurons exposed to pharmacologic ER stressors. These findings highlight distinct, cell-type-specific stress adaptations during aging and provide a valuable proteomic resource for dissecting proteostasis and UPR regulation in the aging brain.

Alzheimer's disease (AD), a global health crisis exacerbated by aging populations, demands innovative therapeutic strategies. Curcumin, a natural compound with anti-aging and anti-inflammatory properties, holds promise for AD treatment but is hindered by poor bioavailability. Here, we developed curcumin-loaded nanovesicles (NV-CUR) derived from brain-homing B16 melanoma cells to overcome these limitations. NV-CUR enhanced the solubility, stability, and blood‒brain barrier (BBB) penetration of curcumin, enabling systemic delivery in aged 3 × Tg AD mice. Our 3R strategy for removing senescent cells, remodeling the neuroinflammatory microenvironment, and repairing neuronal damage was comprehensively validated. NV-CUR effectively cleared p16

Background: Decline in cognitive abilities in old age is highly heterogenous, while most show decline, however a small subset called SuperAgers can reach late life with cognitive functioning comparable to those decades younger. We aimed to categorise the potential lifestyle factors that may be responsible for SuperAger status in old age. Methods: SuperAgers were identified in the UK Whitehall II cohort (n = 2701, 25.88% female) as participants 65 years or older at phase 12 who scored above the sex specific mean on a test of verbal memory of participants at phase 5 and who scored within one standard deviation above the mean on a test of fluency at phase 12. Generalised structural equation models for each sex were used to measure the association between lifestyle factors and being a SuperAger. Results: The prevalence of SuperAger status was higher in women (48.07%) than men (40.00%), with SuperAgers exhibiting higher education level and lower age. Higher social engagement increased the odds of being a SuperAger in women (odds ratio [OR] = 0.02, p = 0.009), with lower biomedical dementia risk increasing the odds in men (OR = 0.87, p = 0.034), all other factors were insignificant. Conclusion: While some factors were significant, the results presented are inconsistent with existing literature and future research should examine the role of lifestyle factors across the lifespan and the potential influence of genetic risk factors to better understand what may contribute towards SuperAger status.

Cerebral small vessel disease (cSVD) is the most common cause of vascular cognitive impairment and dementia (VCID) and highly associated with Alzheimer's disease pathogenesis. There is an urgent need to establish relevant animal models for cSVD. As aging is the strongest risk factor for these diseases, cerebrovascular senescence is implicated in cSVD pathogenesis. We investigated how AAV-based expression of senescence marker CDKN2A/p16

Life course adversity has been linked to various health outcomes, but the interrelationship between adversity, Life's Essential 8 (LE8), and premature mortality remains unclear. We aimed to examine the associations of childhood and adulthood adversity with premature mortality and life expectancy, and whether LE8 modifies these associations.

Food restriction is a common environmental stressor, and it can have beneficial effects such as increased longevity when applied to non-reproducing adults. At the molecular level, food restriction can have beneficial effects through increased DNA repair, reduced DNA damage and longer telomeres, but a lack of food may also hinder the ability to utilize carotenoids, or antioxidants obtained from diet. When food restriction overlaps with a period of high energetic demand, such as during offspring provisioning, a combination of the two may instigate reproductive trade-offs. In this study, adult zebra finches (Taeniopygia guttata castanotis) were exposed to either ad libitum (control) or 40% restricted (food-restricted) diet while raising their young. Blood samples and beak pictures of parents were taken when birds were paired (before treatment), when their offspring fledged (~13 days on treatment), and when their offspring reached nutritional independence (~40 days on treatment). DNA was extracted from red blood cells to quantify telomere length and DNA damage, RNA was extracted from whole blood to quantify expression of DNA repair genes, and beak pictures were used to quantify beak color as a measure of carotenoids. We found that while provisioning their offspring, food-restricted birds increased the length of their telomeres, while controls did not alter telomere length. However, there was no effect of food restriction on DNA damage, gene expression of Pot1, Neil3, Aptx, or Hspa2, or beak color, and DNA damage and telomere length were not significantly associated with each other. The results of this study suggest that food-restricted parents provisioning offspring are behaviorally calorically restricting themselves and promoting genomic maintenance. Furthermore, the lack of significance in DNA damage and repair under food restriction suggests the relationship between telomeres, oxidative stress, repair mechanisms, and morphometric indicators of antioxidants under food restriction is complex and requires further exploration.

Objectives: The gut microbiome plays a critical role in metabolism, immunity, and aging. While endurance training has been shown to beneficially modulate the microbiome, the effects of resistance training remain less clear, with some studies reporting minimal changes. This project aims to investigate whether structured resistance training elicits significant changes in gut microbiome composition and diversity in sedentary, healthy adults. Methods: 150 participants completed an 8-week supervised resistance training program. Session-level training data, including weights and repetitions, were recorded alongside metrics like load and compliance. Fecal samples were collected throughout the study period at designated timepoints for 16S rRNA gene amplicon sequencing to assess microbiome composition and for metabolomics analyses to evaluate microbial metabolic activity. Results: No differences in microbial diversity were observed, and there were no significant changes in microbial community composition or fecal metabolomics across all participants post-training. However, within-individual microbial community changes significantly correlated with strength improvement, and significantly stronger shifts in beta diversity were observed in participants with high average strength gains compared to those with smaller gains. In these high responders, differential abundance analysis revealed time-dependent microbial changes, with more taxa enriched or depleted by week 8 of training. Notably, Faecalibacterium and Roseburia hominis - both associated with a healthier, anti-inflammatory microbiome - were significantly enriched. Many differentially abundant taxa belonged to the Lachnospiraceae family. Conclusion: Resistance training drives significant, time-dependent gut microbiome changes, particularly in those demonstrating greater improvements in strength. These shifts mirror endurance training effects and may reflect improved overall health.

Biological age estimation, derived from physiological signatures such as brain activity, is emerging as a valuable biomarker for health and well-being. Discrepancies between biological and chronological age have been linked to multiple physical, mental, and cognitive health outcomes. However, current approaches primarily focus on MRI-based measurements, which are costly, challenging to obtain, and contraindicated for certain populations. This study explores polysomnographic (PSG) sleep signals, which capture activity from multiple physiological systems, as an accessible alternative for biological age prediction. Sleep serves as an ideal platform for age prediction due to its standardized data collection protocols, abundant public data resources, and the presence of well-documented age-related changes in sleep architecture. Additionally, the proliferation of consumer sleep monitoring tools offers potential for widespread application and longitudinal analysis. We trained transformer-based neural network models on over 10,000 nights of PSG data and performed rigorous internal and external validation. Our best models achieved age predictions with an absolute error of 5-10 years from just a single physiological time series input and were especially accurate with respect to certain stages of sleep (specifically, N2). Electroencephalography (EEG) signals were essential for capturing sleep architecture changes that correlate with age, while electrocardiogram (ECG) signals, although less accurate overall, tended to overestimate age in association with health conditions such as elevated blood pressure, higher body mass index, and sleep apnea. Despite strong performance, generalization beyond the training dataset remains a challenge (age prediction errors increase between internal validation and external data by at least 3 to 5 years). These findings show that noninvasive sleep-derived electrophysiological signals, particularly EEG, can rival MRI-based age prediction models in accuracy-while offering lower cost, greater accessibility, and broader applicability.

A strong regenerative capacity is a hallmark of youth. From the tadpole's tail to the mammalian brain, young animals of many species can repair or regrow damaged tissues more effectively than older animals. Here, we take a broad perspective on ageing, inclusive of the transition from the developmental processes of embryogenesis through maturation to adulthood, as well as the processes that occur as an animal reaches the end of its lifespan. In some cases, the loss of regenerative capacity occurs once development is complete, and in others it occurs in the latter part of the animal's life. Regardless, the loss of regenerative capacity is caused by a failure to activate genes required for successful regeneration. This, in part, can be attributed to restructuring of the epigenome.

Aging is marked by a decline in physiological functions and an increased susceptibility to neurodegenerative disorders. As the aging population rapidly expands, optimizing dietary nutrients has become a crucial strategy for promoting healthy aging. Bioactive compounds, abundant in dietary sources, offer a promising solution to reduce the risks of age-related diseases. Focusing on Caenorhabditis elegans (C. elegans) models and clinical research, this review synthesizes recent advances in understanding the anti-aging effects and mechanistic insights of dietary bioactive compounds, such as fisetin, quercetin, epicatechin, nobiletin, naringenin, nomilin, resveratrol, ergothioneine, coumarin, sesamin and oleic acid. By exploring the metabolic similarities between C. elegans and humans, we propose C. elegans model serves as a pioneer for discovering dietary anti-aging compounds, which enables high-throughput screening. This up-to-date summary of the anti-aging effect of dietary bioactive compounds has demonstrated powerful potential for promoting healthy aging in the human population. Future research should focus on elucidating the bioavailability, metabolic interactions, and synergistic effects of these bioactive compounds to facilitate their translation into effective dietary interventions.

Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD), but much less is known about the key cell types and pathways driving senescence mechanisms in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed single-cell RNA-seq data from the ROSMAP and SEA-AD cohorts to uncover cell type-specific senescence pathologies. In ROSMAP snRNA-seq data (982,384 nuclei from postmortem prefrontal cortex), microglia emerged as central contributors to AD-associated senescence phenotypes among non-neuronal cells. Homeostatic, inflammatory, phagocytic, lipid-processing, and neuronal-surveillance microglial states were associated with AD-related senescence in both ROSMAP (152,459 microglia nuclei from six brain regions) and SEA-AD (82,486 microglia nuclei) via integrative analysis. We assessed top senescence-associated bioprocesses and demonstrated that senescent microglia exhibit altered cholesterol-related processes and dysregulated cholesterol metabolism. We identified three gene co-expression modules representing cholesterol-related senescence signatures in postmortem brains. To validate these findings, we applied these signatures to snRNA-seq data from iPSC-derived microglia（iMGs) exposed to myelin, Aβ, apoptotic neurons, and synaptosomes. Treatment with AD-related substrates altered cholesterol-associated senescence signatures in iMGs. This study provides the first human evidence that dysregulated cholesterol metabolism in microglia drives cellular senescence in AD. Targeting cholesterol pathways in senescent microglia is an attractive strategy to attenuate AD progression.

Physical fitness, particularly cardiorespiratory fitness (CRF) and muscle strength, is associated with reduced disease risk. However, its combined association with biological aging in promoting healthy longevity remains unanswered. We investigated whether cardiorespiratory fitness (CRF) and muscle strength could modify the prospective associations between accelerated biological aging and premature termination of healthy longevity.

Bone matrix is a multiscale composite material mainly composed of collagen, crystalline apatite mineral, water, and a small amount of non-collagenous proteins. Nested within bone matrix, mechanosensitive osteocytes orchestrate bone adaptation to mechanical loading, which is affected by the ultrastructural composition and mechanical properties of the osteocyte-surrounding bone matrix. In this review, we shed light on the impact of ageing-related modifications in ultrastructural composition of bone matrix on the mechanosensitivity of osteocytes.

Aging is a natural process that involves various physiological changes, including increased susceptibility to diseases. With aging, the immune system weakens, and the body becomes more vulnerable to infections and inflammation. Moreover, conditions such as sarcopenia, osteoporosis, and non-communicable chronic diseases (hypertension, type 2 diabetes mellitus, and obesity) are more common among older adults. However, diet can play a fundamental role in maintaining health and preventing various pathologies. Fermented dairy products, which are rich in high-quality proteins and bioactive peptides, can serve as valuable allies in healthy aging. These peptides, released during fermentation, ripening, or digestion, exhibit several beneficial activities, including antihypertensive, antioxidant, immunomodulatory, and antidiabetic effects, with the potential to improve the quality of life in older adults. This review aims to present the benefits of consuming fermented dairy products for the health of older adults, highlighting how the bioactive peptides present in these foods may aid control health conditions associated with aging. By exploring the processes of fermentation and digestion, and the mechanisms involved in the release of these peptides, the review provides a detailed overview of the potential benefits of consuming fermented dairy products in promoting health and preventing diseases in older adults.

The universality of the trade-off between fecundity and longevity in life-history theory is sometimes contested. Social insects present the arguably strongest challenge, as (i) queens not only monopolize reproduction, but also live much longer than workers, and (ii) within a caste, those individuals that lay more eggs are also observed to live longer. Positive fecundity-longevity relationships can appear in observational data even though an underlying trade-off exists, as individual variation in resource acquisition (e.g., variation in habitat quality) can mask the trade-off. Here, we demonstrate theoretically that the fecundity-longevity trade-off in social insects can be easily masked even without differences in individual quality. Demographic stochasticity, caused by variable worker lifespans, leads to self-reinforcing dynamics (equivalent to the well-known Matthew effect), where "lucky" colonies exhibit healthy growth and long-lived, productive queens, while "unlucky" colonies show the opposite combination of traits. Allocation variation between individual queens, if present, can unmask the trade-off in principle, but the trade-off remains commonly concealed not only when measuring fecundity as a cumulative total (a strongly confounded measure as longer-lived queens have more time to produce eggs), but also when measuring fecundity as a rate. Our results help align superorganismal fitness components with general life-history principles, and highlight the necessity of experimental manipulations when making statements regarding trade-offs or the lack thereof.

Aging increases the risk of health deterioration, which is a complex process driven by many interconnected mechanisms through multiple signaling pathways, including oxidative stress, inflammation, mitochondrial dysfunction, and intestinal environmental disorders. Plant polyphenols are secondary metabolites found in various plants, including phenolic acids, flavonoids, lignans, stilbenes and other phenolic compounds. These compounds exhibit a range of physiological functions, such as metabolic regulation, cardiovascular protection. Recently, plant polyphenols have gained considerable interest due to their potential to delay aging by suppressing oxidative stress, inhibiting inflammation, and improving mitochondrial function and intestinal environment. However, age-related changes in digestion, absorption, and gut microbiota composition can adversely affect the bioavailability of plant polyphenols, thereby diminishing their therapeutic efficacy. This article reviews the significant role of plant polyphenols in delaying the aging process and explores the underlying mechanisms involved. It also presents the current research status on the bioavailability of plant polyphenols and emphasizes that age-related gastrointestinal changes, such as decreased enzyme activity, altered gastrointestinal motility and imbalances in the gut microbiota, are key factors influencing polyphenol bioavailability in the elderly, encouraging to carry out research on the bioavailability of plant polyphenols in the elderly in the hope of developing novel anti-aging strategies.

Transglutaminase-2 (TG2) plays a key role in age-related vascular stiffness. This study aims to evaluate the effects of calorie restriction (CR) on TG2 mRNA and protein levels and identify differentially expressed microRNAs (miRNA) predicted to target TG2.

Cardiorespiratory fitness (CRF) is a strong predictor of mortality and non-communicable disease risk, but its underlying molecular mechanisms are poorly understood. In this study, we identified CRF associated metabolomics (n=30,010) and proteomics (n=4,235) signatures in UK Biobank participants. These signatures were validated in an independent sample of UK participants with data on metabolomics (n=198,871) and proteomics (n=29,961) to investigate prospective associations with all-cause mortality and non-communicable diseases. Our findings reveal that higher CRF is characterized by downregulation of pathways related to inflammation, triglyceride metabolism, glycolysis, and vascular dysfunction, and upregulation of pathways related to cholesterol transport, apolipoprotein particle size, and cytoskeletal remodeling. Leveraging these insights, we developed two novel metabolic CRF signatures, one metabolomic and one proteomic, that robustly reflect CRF levels (R2: 0.49-0.60). Over an average of 9 years of follow-up, we observed 27,659 cases of all-cause mortality. Across the discovery and validation cohorts, we found that the metabolomic CRF signature was strongly associated with a 34-39% lower risk of all-cause mortality and markedly reduced risk of type 2 diabetes (89-91%), cardiovascular disease (35-39%), and colorectal cancer (32-54%). Additionally, the proteomic CRF signature was associated with a 17% lower risk of all-cause mortality, and with a 22-39% lower risk of type 2 diabetes and cardiovascular disease. Together, these findings suggest that circulating metabolites and proteins can capture the physiological imprint of CRF and may serve as indirect biomarkers for predicting mortality and non-communicable disease risk.

Using 100 technical replicate samples from two adult buccal cohorts, we compared technical methylation variability and signal strength between the Infinium MethylationEPIC v2.0 array and the Twist Human Methylome Panel across 753,648 shared CpGs. Twist methylation sequencing showed skewed methylation distributions and fewer highly correlated CpGs than MethylationEPIC arrays. Variance analysis revealed a skew toward higher signal strength in MethylationEPIC datasets, with a subset of CpGs showing high signal strength in both methylation sequencing and array datasets. Despite these biases, four principal component (PC) trained epigenetic clocks (pcHorvath1, pcHorvath2, pcHannum, and pcDNAm PhenoAge) were robust across both technologies, even with missing data. While pcHannum and pcDNAm PhenoAge were similarly reproducible with mean absolute replicate difference (MRD) values ranging from 1.014 years to 1.194 years, pcHorvath1 was more reproducible in arrays (MRD = 0.459 years) than methylation sequencing (MRD = 2.320 years) and pcHorvath2 was more reproducible in methylation sequencing (MRD = 0.760 years) than arrays (MRD = 1.011 years). Furthermore, original non-PC versions of these clocks were less reproducible in Twist datasets and, as an example of this, MRD for uncorrected clocks went as high as 15.498 years in arrays and as high as 20.180 years in methylation sequencing. Obvious differences in age prediction were also observed in original clocks compared to their PC-trained versions across both technologies (with a mean absolute difference ranging from 4.492 years to 46.724 years). This underscores the need for careful selection of epigenetic clocks and technology-specific adjustments when optimizing for accuracy and reproducibility.

Navigational skills are essential for interacting with our environment, supported by multiple types of spatial representations. We investigated age-related differences in spatial memory using a virtual reality task that manipulated viewpoints between the encoding and retrieval of one or four-object locations. The task investigates compensatory mechanisms in aging, specifically how spatial updating via self-motion affects spatial memory. We tested 21 young adults (ages 19-36) and 23 older adults (ages 63-80). The task involved three movement conditions: same-viewpoint condition, where participants walked away and returned to the same viewpoint; shifted-viewpoint (walking) condition where participants walked to a different viewpoint, enabling continuous updates of their egocentric representations through self-motion; and shifted-viewpoint (teleport) condition where participants teleported to the other viewpoint, involving both a virtual translation and rotation of the participant's view. Retrieval was tested by asking participants to place each object at its previously seen location. Average displacement error was affected by age group, object configuration, and movement condition, with an interaction between age and movement condition. Differences in movement conditions were primarily driven by older participants, who were most accurate from the same viewpoint. In shifted-viewpoint conditions, teleportation-where self-motion cues were absent-led to significantly greater errors than walking in the older group. Our results highlight the role of spatial updating in supporting spatial memory and suggest that age-related decline in allocentric representations can be mitigated by continuous updating of egocentric representations by self-motion. We speculate that the use of spatial updating might be impaired early in the progression to Alzheimer's dementia due to entorhinal cortical pathology. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

While it is well-documented that plasma oxytocin (OXT) levels decline with age, the underlying mechanisms remain elusive. This study aimed to elucidate the physiological mechanisms contributing to this age-related decrease in plasma OXT and the possible use of OXT supplementation on improving age-related decline of neural function. Comparing young (9 weeks) and aged (> 45 weeks) mice, aged mice showed reduced plasma OXT levels, an increase in the inflammation marker hs-CRP, and decreased OXT-positive neurons in the hypothalamus. Aged mice showed signs of epigenetic changes in the hypothalamus as indicated by decreased ten-eleven translocation (TET) family mRNA expression, decreased 5-hydroxymethylcytosine (5hmC) positive neurons, and downregulated mitochondrial respiratory complex IV (COX IV) expression. Nasal application of OXT (10 μg/day) for 10 days to aged mice resulted in normalized plasma OXT and inflammation levels and a recovery of OXT-positive neurons, TET2 mRNA levels, 5hmC positive neurons, and COX IV expression. Directly confirming a role for OXTR signaling, TET2, COX IV, and 5hmC in the hypothalamus and hippocampus were also found to be decreased in oxytocin receptor (OXTR) null mice, compared with age-matched WT mice. Furthermore, we show that methylation as a result of aging decreases OXT production in hypothalamic neurons, thereby reducing circulating plasma OXT levels, which can be reversed by nasal OXT treatment. The data presented here suggest that aging, DNA methylation, mitochondrial dysfunction, inflammation, and senescence are interconnected in a vicious cycle, which can be successfully interrupted by OXT treatment.

Antioxidant decline is crucial to driving age-related macular degeneration (AMD). Ferroptosis, a regulated cell death mediated by iron-dependent hydroxyl radical-catalyzed phospholipid peroxidation through the Fenton reaction, is implicated in various chronic degenerative diseases. Here, we show that superoxide activates ferroptosis in retinal pigment epithelium (RPE) cells via the Haber-Weiss reaction, thereby contributing to dry AMD. We silenced manganese superoxide dismutase (MnSOD/SOD2) in RPE cells and exposed the cells to blue light to induce ferroptosis by increasing superoxide anions. Additionally, MnSOD deficiency triggered the Hsp70-linked ubiquitin-dependent degradation of GPX4, further aggravating ferroptosis. We validated blue light-induced ferroptosis in the RPE layer as a driver of the dry AMD phenotype in Sod2

Physical activity and exercise confer health benefits through actions on several physiological systems; however, the mechanisms by which they impact renal health remain poorly understood. Studies show exercise slows age-related decline in kidney function and protects against AKI. We hypothesize that exercise triggers adaptative responses, which preserve hemodynamic balance in the kidneys under stress. We evaluated running-induced adaptations in 10-14-wk-old C57BL/6J male and female mice subjected to voluntary running or in male mice subjected to forced treadmill running. We evaluated renal perfusion with contrast-enhanced ultrasound and assessed kidney function by measuring the ability to clear a volume load. Additionally, we performed flow cytometry, cytokine array, histopathology, and bulk mRNA sequencing. We found exercise significantly increased cortical microvascular blood volume (p=0.0085), as indicated by increased plateau contrast signal intensity. Additionally, exercised male, but not female, mice excreted significantly more urine in the first hour after a saline bolus (p=0.0055). At the cellular level, we observed a significant increase in kidney resident macrophages (KRMs; CD45

Erxian decoction (EXD) is widely used in the treatment of various gynecological conditions, including menopausal syndrome, ovarian insufficiency, and premature ovarian failure (POF). As society ages, the prevalence of postmenopausal osteoporosis (PMOP) rises annually, accompanied by a progressive increase in the incidence of sarcopenia, a skeletal muscle disorder associated with osteoporosis. Recent studies have revealed that the diverse pharmacological agents and active compounds in EXD have been utilized in clinical and experimental contexts for sarcopenia; nevertheless, the mechanism by which EXD addresses postmenopausal sarcopenia remains unclear.