Longevity Papers

Aging in females predominantly impacts the ovaries before any other organ systems. This phenomenon is closely linked to a gradual depletion of the ovarian follicle reserve and a notable diminishment of oocyte quality. Studies have shown that cellular changes within ovaries can manifest even before the observable depletion of ovarian follicles. To understand the molecular mechanisms underlying these changes, we have conducted a comprehensive analysis of the changes in gene expression in aging mouse ovaries. Using efficient genomics software such as CLC Genomic Workbench, we could detect not only the differentially expressed genes but also delineate the various transcript variants present in the transcriptome of aging ovaries. We verified the results by comparing coding sequences of selected transcripts with the coding sequences of their canonical counterparts from young and aged mice. In general, the analysis methods yielded similar observations. Our findings revealed that traditional gene expression analyses often overlook the differential expression of numerous transcript variants. We identified significant alterations in the expression patterns of alternative transcripts in aging ovaries and found coding sequences that lead to profound functional outcomes. Notably, most of these differentially expressed transcript variants were affected upstream epigenetically and transcriptionally, then generated through alternative splicing events. This suggests that aging may lead to alterations in RNA-binding proteins and spliceosome components, which play a crucial role in mRNA processing within the mouse ovary. Our observations highlight the necessity of focusing on transcript variants and their functions in aging research, as they provide a more nuanced understanding of the biological processes at play.

Neurodegenerative diseases (NDDs) represent a rapidly escalating global health challenge, contributing significantly to the worldwide disease burden and posing substantial threats to public health systems across nations. Among the many risk factors for neurodegeneration, aging is the major risk factor. In the context of aging, multiple factors lead to the release of endogenous DNA (especially mitochondrial DNA, mtDNA), which is an important trigger for the activation of the cGAS-STING innate immune pathway. Recent studies have identified an increasing role for activation of the cGAS-STING signaling pathway as a driver of senescence-associated secretory phenotypes (SASPs) in aging and NDDs. The cGAS-STING pathway mediates the immune sensing of DNA and is a key driver of chronic inflammation and functional decline during the aging process. Blocking cGAS-STING signaling may reduce the inflammatory response by preventing mtDNA release and enhancing mitophagy. Targeted inhibition of the cGAS-STING pathway by biological macromolecules such as natural products shows promise in therapeutic strategies for age-related NDDs. This review aims to systematically and comprehensively introduces the role of the cGAS-STING pathway in age-related NDDs in the context of aging while revealing the molecular mechanisms of the cGAS-STING pathway and its downstream signaling pathways and to develop more targeted and effective therapeutic strategies for NDDs.

Osteoporosis (OP) represents a systemic disease causing reduced bone mass and fragility fractures. Qigu Capsule (QGC), a traditional Chinese medicine, shows potential in alleviating human OP, but its precise mechanisms remain unclear, limiting clinical application.

Study Objectives Animal research has demonstrated that sleep regulation heavily depends on a network of subcortical nuclei. In particular, whether the crosstalk between the Locus Coeruleus (LC) and hypothalamic nuclei influences sleep variability and age-related changes in humans remains unexplored. This study investigated whether the effective connectivity between the LC and subparts of the hypothalamus is associated with the electrophysiology of rapid eye movement sleep (REMS). Methods Thirty-three healthy younger (~22y, 27 women) and 18 older (~61y, 14 women) individuals underwent 7-Tesla functional magnetic resonance imaging during wakefulness to investigate the effective connectivity between LC and distinct hypothalamus subparts encompassing several nuclei. Additionally, we recorded their sleep electroencephalogram (EEG) to explore relationships between effective connectivity measures and REMS theta energy and sigma power prior to REMS episodes. Results The effective connectivity analysis revealed robust evidence of a mutual positive influence between the LC and the anterior-superior and posterior hypothalamus, supporting the idea that the connectivity patterns observed in animal models are also present in humans. Furthermore, our results suggest that in older adults, stronger effective connectivity from the anterior-superior hypothalamus, including the preoptic area, to the LC is associated with reduced REM theta energy. Specificity analysis showed that this association was not limited to REM theta energy but also extended to specific lower-frequency bands during REMS and NREMS. Conclusions These findings highlight the complex age-dependent modulation of the LC circuitry and its role in sleep regulation. Understanding these neural interactions offers valuable insight into the mechanisms driving age-related sleep changes.

Theobromine, a commonly consumed dietary alkaloid derived from cocoa, has been linked to extended lifespan in model organisms and to health benefits in humans. We examined associations between circulating theobromine intake, measured using serum metabolomics, and blood-based epigenetic markers of biological ageing in two European human population-based cohorts. Serum theobromine levels were significantly associated with reduced epigenetic age acceleration, as measured by GrimAge (p<2e-7) and DNAmTL (p<0.001) in over 500 individuals from the TwinsUK cohort, and both signals replicated in 1,160 individuals from the KORA cohort (p = 7.2e-08 and p = 0.007, respectively). Sensitivity analyses including covariates of other cocoa and coffee metabolites suggest that the effect is specific to theobromine. Our findings indicate that the reported beneficial links between theobromine intake on health and ageing extend to the molecular epigenetic level in humans.

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of vascular senescence and microvascular remodeling, processes that significantly contribute to the development of age-related diseases in organs such as the kidneys, heart, and lungs. Through mechanisms like chromatin remodeling, transcriptional regulation, and posttranscriptional modifications, lncRNAs modulate gene expression, thereby influencing cellular processes such as apoptosis, inflammation, fibrosis, and angiogenesis. In chronic kidney disease, cardiovascular disease, and pulmonary disorders, lncRNAs play a central role in promoting vascular dysfunction, endothelial cell aging, and fibrosis. This review focuses on how lncRNAs contribute to endothelial dysfunction, fibrosis, and vascular aging, emphasizing their roles in disease progression within the kidneys, heart, and lungs, where lncRNA-mediated vascular changes play a significant role in disease progression. Understanding the interactions between lncRNAs, vascular senescence, and microvascular remodeling offers promising avenues for developing targeted therapeutic strategies to mitigate the impact of aging on vascular health.

Age-related cognitive decline results from complex interactions between neuroendocrine and neurometabolic processes that undergo lifelong degradation, yet the mechanisms underlying these interactions remain poorly understood. This study examined the effects of diabetes and sex on functional brain networks across aging through analysis of two large cohorts (N=1,621 total) using both 3T and 7T functional MRI, complemented by spatial transcriptomic data from over 14,000 genes from six post-mortem brains. Four networks - cingulo-opercular, default mode, salience, and lateral somatomotor - exhibited significant functional decline in both individuals with diabetes and independently in males. Gene expression analysis of vulnerable networks revealed significant overexpression of insulin-dependent glucose transporters, dopaminergic and GABAergic synaptic genes, and VEGFA-VEGFR2 pathway components. These findings suggest functionally-specific circuit vulnerability to metabolic and hormonal dysregulation, potentially offering targets for early intervention before irreversible neurodegeneration occurs.

Growing evidence suggests that environmental factors play a significant role in the aging process. We established the Klemera and Doubal Method biological age acceleration (KDM-BAA) by using the KDM as a biological age predictor to assess the trace elements (ELEs) role. Generalized Linear Model (GLM) was used to assess the associations between single ELE (trace element) and KDM-BAA. Restricted cubic splines (RCS) were used to assess the nonlinear relationship between elemental levels and KDM-BAA. Quantile G-Computation (QGC) regression was employed to explore the direction and weight. Weighted Quantile Sum (WQS) Regression was used to study the weights of different groups of ELEs. Bayesian Kernel Machine Regression (BKMR) was utilized to analyze the overall effect of mixed elemental exposure. Mediation analysis was conducted to investigate the role of intermediate biomarkers and the moderating effects of physical activity (PA) was used on the pathway. The results showed serum Copper (Cu) levels positively correlated with KDM-BAA, while Zinc (Zn) and Iron (Fe) negatively correlated with it, respectively. The mixture of Zn, Cobalt (Co), Selenium (Se), and Fe exhibited a significant overall negative effect. Additionally, PA could ease the association between Cu and KDM-BAA through impacting the inflammation level. This study provides novel insights into how inflammation mediates the association between ELEs exposure and KDM-BAA, while PA acts as a potential protective factor.

Pericytes in the central nervous system are essential for maintaining blood-brain barrier function, regulating blood flow, modulating immune responses, and interacting closely with surrounding cells of the neurovascular unit to support brain homeostasis. Increasing evidence has highlighted their involvement in age-related neuroinflammation, where their dysfunction may contribute to sustained inflammatory states associated with neurodegenerative disorders. Here, we compared inflammatory responses to lipopolysaccharide (LPS) in primary cerebral pericytes from neonatal and adult mice and adult humans. Our findings indicate that neonatal mouse pericytes display heightened inflammatory activation, with elevated levels of ICAM-1 and several cytokines, compared to adult mouse pericytes reflecting a more reactive phenotype. In contrast, adult mouse pericytes exhibited a significantly reduced cytokine release profile, suggesting lower responsiveness. Notably, while cytokine secretion patterns in adult human pericytes, in part, mirrored those in neonatal mouse pericytes, nitric oxide production, which was observed in mouse pericytes, was absent in the human cells. These results underscore species- and age-dependent variations in cellular behavior, emphasizing the importance of utilizing human brain cell systems when conducting research on neuroinflammation. Understanding these distinctions is vital for designing accurate studies and developing targeted therapies for neuroinflammatory conditions.

Micronutrients are essential for maintaining physiological homeostasis and optimizing healthspan, defined as the years lived in good health without chronic diseases or disabilities. Despite increasing global life expectancy, improvements in healthspan have not kept pace, partly due to subclinical micronutrient deficiencies that often precede clinical symptoms. The triage theory highlights how micronutrient insufficiencies compromise long-term health by prioritizing critical metabolic functions. Micronutrients such as Vitamins B6, B9, B12, D, and K are particularly crucial to optimizing healthspan, by influencing energy metabolism, neurological health, immune regulation, and bone integrity. Traditional tools like Dietary Reference Intakes (DRIs) provide population-level guidelines but fail to account for individual factors such as genetics, lifestyle, and nutrient interactions. Quantitative assessment of micronutrient concentrations using biomarkers offers a more precise approach but faces challenges, including high costs and limited accessibility. National nutrition surveys demonstrate potential in addressing population-level deficiencies and form the basis for advancing precision supplementation strategies to improve health outcomes and extend healthspan by defining optimal micronutrient concentrations. Future efforts should aim to establish evidence-based thresholds for optimal micronutrient concentrations by integrating biomarker data with clinical outcomes, genetic profiles, and lifestyle factors, providing a framework to guide personalized and population-level supplementation strategies.

Efficient clearance of central nervous system (CNS) waste proteins and appropriate immune surveillance is essential for brain health. These processes are facilitated by lymphatic networks present in the meninges that drain cerebrospinal fluid (CSF). Age-related impairments to meningeal lymphatic drainage contribute to CNS waste accumulation and immune dysfunction, yet the underlying mechanisms remain poorly understood. Here, we identify extracellular matrix (ECM) remodeling in the aged dura as a key driver of CSF clearance deficits, demonstrating that peri-lymphatic collagen accumulation disrupts lymphatic function. Exploring immune-derived factors contributing to this ECM remodeling, we identify transforming growth factor beta 1 (TGFβ1) as a major regulator using primary human dural fibroblasts. Using a novel mouse model with constitutively active TGFβ receptor 1 (TGFβR1) signaling in dural fibroblasts, we show that excessive peri-lymphatic collagen deposition impairs meningeal lymphatic drainage and alters meningeal immunity. Mechanistically, we reveal that ECM-associated matrix stiffness disrupts lymphatic junction integrity and impairs lymphangiogenesis in human lymphatic endothelial cells. These findings establish dural immune cell and fibroblast-mediated ECM remodeling as a critical regulator of CSF clearance and highlight it as a potential therapeutic target for restoring brain waste clearance in aging.

Nicotinamide adenine dinucleotide (NAD) is a key coenzyme involved in cell metabolism associated with aging, cancer, neurodegenerative diseases and metabolic disorders. We recently showed that NAD

Aging is frequently associated with dysregulated lipid metabolism, while exercise may improve metabolic health, a process in which microRNAs (miRNAs) play a pivotal regulatory role. However, the specific modulation of miRNA expression profiles by different exercise modalities remains poorly characterized. This study aimed to investigate adipose tissue miRNA profiles in aged rats following high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). Eighteen-month-old female rats were divided into three groups (n = 12/group): sedentary (SED), MICT, and HIIT. After 8 weeks of exercise interventions, metabolic outcomes were assessed using Oil Red O staining to quantify intracellular lipid deposition, alongside Western blotting, immunofluorescence, and RT-qPCR to evaluate mRNA and protein expression of adipose tissue markers. Additionally, miRNA sequencing was performed on visceral adipose tissue to identify differentially expressed miRNAs (DEMs), followed by bioinformatic prediction of miRNA-mRNA interactions. Key findings revealed that the HIIT group exhibited more pronounced metabolic benefits compared to MICT, including reduced lipid accumulation (fewer Oil Red O-positive adipocytes) and upregulated expression of lipolytic and autophagy-related proteins (ATGL, HSL, PPAR-γ, ATG3, ATG5, ATG7, ATG12, and ATG16L). miRNA sequencing demonstrated greater divergence in expression profiles between HIIT and SED groups than between MICT and SED groups. KEGG pathway analysis highlighted significant enrichment in the MAPK, PI3K-Akt, and Rap1 signaling pathways. Furthermore, 11 DEMs (e.g., miR-34a, miR-146a) were identified as potential regulators of adipose aging, with hub genes including Shc1, Grb2, Itgb1, Ptpn11, Mapk14, Fyn, Plcg1, Sos1, and Actg1. In conclusion, HIIT significantly ameliorates age-related adipocyte inflammation and metabolic dysfunction. Exercise-induced miRNA reprogramming may alleviate the functional decline of aged adipose tissue, and HIIT-induced miRNA reprogramming is more abundant. The miRNA sequencing data pinpoint critical regulatory genes and pathways, providing novel insights into the molecular mechanisms by which exercise counteracts metabolic abnormalities in aged adipose tissue.

Cardiac aging represents a complex pathophysiological process characterized by progressive metabolic recombination and functional dedifferentiation of cardiac cellular components. Despite advancements in cardiovascular medicine, a critical research gap persists in understanding the precise epigenetic mechanisms that drive age-related cardiac dysfunction. This comprehensive review elucidates the pivotal role of histone modifications-including methylation, acetylation, and phosphorylation-in orchestrating the molecular landscape of cardiac aging. Significant gaps remain in our understanding of site-specific histone modification impacts on cardiac function, the intricate crosstalk between different histone marks, and their integration with metabolic alterations that characterize the aging myocardium. Current evidence reveals a dynamic epigenetic signature in aged cardiac tissue, typically featuring increased transcriptional activation markers alongside decreased repressive marks, though context-dependent variations exist. This review explores how histone modifications influence critical pathways governing mitochondrial dysfunction, DNA damage repair, inflammation, and fibrosis in aging hearts. Innovative therapeutic approaches targeting specific histone-modifying enzymes promise to mitigate age-related cardiac deterioration, potentially revolutionizing treatment paradigms for cardiovascular diseases in aging populations. Addressing these knowledge gaps requires multidimensional approaches that integrate epigenomics with functional assessment of cardiac performance.

Traditional Chinese Medicine (TCM) represents a vast repository of therapeutic knowledge, but its integration with modern drug discovery remains challenging due to fundamental differences in theoretical frameworks. We developed an AI agent-driven framework combining Precious3GPT (P3GPT), a multi-omics transformer model, with the BATMAN-TCM2 database of TCM compound-target interactions to bridge this gap. As a proof-of-concept, we used P3GPT-generated cross-species and cross-tissue signatures to screen TCM compounds, herbs, and formulas to identify novel natural geroprotectors. The cross-species analysis identified 13 conserved aging-associated genes, leading to the identification of 34 TCM compounds with significant target overlap and enabling identification of HUA SHAN WU ZI DAN and other TCM formulations as a promising historical formula. Our work demonstrates the feasibility of using AI to systematically bridge TCM and modern pharmacology, enabling rational design of multi-component formulations targeting age-related processes across multiple tissues and species. This approach provides a framework for modernizing traditional medicine while maintaining its holistic therapeutic principles. To help other teams integrate AI experimentation in their research process, we publicly release all materials and codebase used in this work, including the multi-agent system, cross-species and cross-tissue signatures of aging, as well as TCM databases formatted for AI interactions.

p53 is with little doubt one of the most powerful genes in our genome, as it makes growth vs arrest, repair vs replacement, metabolism vs anabolism, life vs death decisions in the cell. An alteration or malfunction in p53 may lead to cancer or premature ageing. So, it is not surprising that p53 is also one of the most complex and tightly regulated genes. p53 alone encodes for at least 10 RNA variants and 12 widely accepted protein forms. Here we identify one new p53 protein isoform of around 18 kDa that we termed {Delta}246p53. {Delta}246p53 is translated from an alternative translation initiation site (TIS) in codon 246. TIS-246 is preceded by a strong Kozak sequence and appears conserved in vertebrates, from sea lamprey to humans. {Delta}246p53's origin and expression in cells were confirmed by frameshift and start codon mutations as well as siRNAs and an antisense oligo targeting TIS-246, which knocked-down {Delta}246p53 with little or no effect on full-length (FL) p53 protein levels. {Delta}246p53 was induced by DNA damage in several cancer and non-cancer cell lines and triggered senescence and impaired tumour formation/growth in colony formation assays. Lastly, we show that {Delta}246p53 inhibits Hdm2 expression and activates p21, a known senescence activator gene, through FLp53-dependent and -independent mechanisms, respectively. Our results add yet another regulated and naturally occurring factor to the list of p53 players, with specific roles in p53 activation and senescence. Further studies on {Delta}246p53's regulation and mode of action may help us better understand p53's still mystifying functions in senescence and ageing.

c-fos is an immediate early gene (IEG) that forms a heterodimeric activator protein-1 (AP-1) complex with c-Jun. Following stimulation by a variety of factors, it changes the expression of genes and participates in cellular growth, proliferation, differentiation, and apoptosis. Previous studies have reported that c-fos is linked to cellular senescence and is involved in aging-related signaling pathways or damage repair processes. However, there are limited studies related to this topic. This review summarizes the findings of the connection between c-fos and cellular senescence, including the regulatory role of c-fos in the senescence of stem cells and various kinds of somatic cells. In addition, we discussed the involvement of c-fos in the cellular senescence process and related signaling pathways, as well as the importance of regulating DNA damage repair. The current studies have demonstrated that c-fos has important roles in inhibiting stem cell senescence. They can pave the way for a more thorough examination of the aging process and the regeneration of stem cells and provide new therapeutic strategies for aging-related diseases.

T cell aging contributes to the lower vaccine efficacy in older adults, yet the molecular mechanism remains elusive. Here, we show the density of initially responding naïve CD4

Male fertility declines during aging. This process mainly affects spermatogonia and Sertoli cells, leading to impaired spermatogenesis and poor-quality sperm production. Circular RNAs (circRNAs) are covalently closed RNA molecules produced by backsplicing. In the field of male reproduction, circRNAs boast great potential in the regulation of spermatogenesis and sperm morpho-functional skills. However, their potential role in age-related male reproductive anomalies remains largely elusive. Here, we analyzed the reproductive phenotype of the aged male mouse experimental model, pointing our attention to a putative functional link between circRNAs and Sertoli cell survival. Our results confirm several testicular age-related defects including: (i) altered morphology of the seminiferous epithelium; (ii) affected spermatogenesis; and (iii) decreased sperm production. In particular, aged spermatozoa (SPZ) were decreased in number in association with low motility and abnormal morphology (sperm head anomalies and tail bents). The expression analysis of selective spermatic circRNAs demonstrated a de-regulated expression profile in Aged versus Young SPZ. Among them, we turned the lens on circAbcb9 as a spermatic circRNA potentially involved in the Sertoli cell senescence pathway via the circRNA/miRNA/mRNA network (ceRNET). Indeed, a significant shutdown of circAbcb9-dependent network associated with a prominent increase in Sertoli cell senescence occurred in Aged testis. Interestingly, circAbcb9 was also expressed in human SPZ at decreased levels in Aged men, suggesting a conserved role. Collectively, our study stimulates greater interest in circRNAs as involved in the molecular mechanisms behind the age-related effect on Sertoli cell survival, also providing new implications for fused protein in sarcoma (FUS) protein in sertolian circRNA biogenesis.

Healthy older adults typically show impaired episodic memory - memory for when and where an event occurred. This selective episodic memory deficit may arise from differential engagement in the retrieval state, a brain state in which attention is focused internally in an attempt to access prior knowledge, and the encoding state, a brain state which supports the formation of new memories and that trades off with the retrieval state. We hypothesize that older adults are biased toward a retrieval state. We recorded scalp electroencephalography while young, middle-aged and older adults performed a memory task in which they were explicitly directed to either encode or retrieve on a given trial. We used multivariate pattern analysis of spectral activity to decode retrieval vs. encoding state engagement. We find that whereas all age groups can follow task demands to selectively engage in encoding or retrieval, mnemonic brain state engagement is diminished for older adults relative to young and middle-aged adults. These findings suggest that differential mnemonic state engagement may underlie age-related memory changes.

Although the potential benefits of calorie restriction on human lifespan remain uncertain, it is currently one of the most extensively researched non-genetic approaches to extending both lifespan and healthspan in animals. Calorie restriction offers numerous health benefits, including a reduced incidence of age-related diseases. However, calorie restriction also produces a range of negative effects, which are not fully documented and require further investigation, particularly in humans. As the viability of calorie restriction in humans will depend on the balance of benefits and detrimental effects, it is crucial to understand the nature of these negative effects and what drives them. In this Review, we summarize the effects of calorie restriction on wound healing, hunger, cold sensitivity, bone health, brain size, cognition, reproductive performance and infection, primarily based on studies of rodents with some data from other species and from humans. Overall, the detrimental effects of calorie restriction seem to stem directly from prioritization of vital functions and downregulation or suppression of energy-demanding processes, which helps preserve survival but can also lead to impaired physiological performance and increased vulnerability to stressors. The exact mechanisms underlying these effects remain unclear. Whether it might be possible to engage in calorie restriction but avoid these negative effects remains uncertain.

Ergothioneine (ET) is an under recognised diet-derived compound which has the potential to be a "longevity vitamin". It was found to be beneficial for cognitive function and age-related neurodegenerative disorder (ARND). Thus, this study was conducted to synthesise the existing evidence of ET's effects on cognition and ARND, emphasizing its potential as a micronutrient for healthy aging. This study also highlights the future prospects of the research regarding ET's effects on cognition and ARND that are suggested in existing literature. Three databases (Pubmed, Scopus, and Web of Science) were used to search for the studies that meet the inclusion and exclusion criteria. A total of 19 studies were included after screening in this review. The risk of bias of each study was assessed using the Office of Health Assessment and Translation (OHAT) risk of bias rating tool. All studies' characteristics and main findings were tabulated according to their type of study. Mechanisms of ET in improving cognitive function and preventing ARND were found to be through its antioxidative, anti-inflammatory and antisenescence properties. Its role in neurotransmission and neuroprotection also contributed to improving cognition and preventing ARND. In conclusion, ET is a potential compound to be explored as its role in cognition and ARND have been discovered through several studies.

Hematopoietic aging is characterized by diminished stem cell regenerative capacity and an increased risk of hematologic dysfunction. We previously identified that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) regulates hematopoietic stem cell activity. Here, we expand on this work and demonstrate that in aged mice, (1) 15-PGDH expression and activity remain conserved in the bone marrow and spleen, suggesting it remains a viable therapeutic target in aging, (2) prolonged PGDH inhibition (PGDHi) significantly increases the frequency and number of phenotypic hematopoietic stem and progenitor cells across multiple compartments, with transcriptional changes indicative of enhanced function, (3) PGDHi-treated bone marrow enhances short-term hematopoietic recovery following transplantation, leading to improved peripheral blood output and accelerated multilineage reconstitution, and (4) PGDHi confers a competitive advantage in primary hematopoietic transplantation while mitigating age-associated myeloid bias in secondary transplants. Notably, these effects occur without perturbing steady-state blood production, suggesting that PGDHi enhances hematopoiesis under regenerative conditions while maintaining homeostasis. Our work identifies PGDHi as a translatable intervention to rejuvenate aged HSCs and mitigate hematopoietic decline.

Replicative senescence presents a significant challenge in mesenchymal stem cell (MSC) expansion due to high reactive oxygen species (ROS) levels generated during culture. Elevated ROS levels lead to oxidative stress, cellular damage, and senescence, limiting the biomedical applications of MSCs. In this study, a supramolecular thermo-reversible hydrogel composed of the natural polyphenolic compound gallic acid (GA) and polyvinyl alcohol (PVA) was designed to scavenge ROS and mitigate MSC senescence. The PVA-GA hydrogel, stabilized by strong hydrogen bonding forces, exhibited an elastic modulus comparable to that of human soft tissue and facilitated the sustained release of GA over 14 days. It enhanced MSC survival, protected against oxidative stress, reduced intracellular ROS levels, diminished mitochondrial damage, and decreased cellular senescence. The hydrogel maintained the multilineage differentiation potential and typical phenotype of MSCs. Additionally, it preserved vascular endothelial growth factor (VEGF) secretion from MSCs under oxidative stress and enhanced their pro-angiogenic effect. The conditioned medium derived from MSCs in the hydrogel group promoted migration and tube formation of human umbilical vein endothelial cells (HUVECs). These findings suggest that the PVA-GA hydrogel holds significant promise for the biomedical applications of MSCs, potentially addressing the challenges posed by oxidative stress and cellular senescence.

Pulmonary fibrosis (PF) is an insidious, progressive, and fatal age-associated disease that occurs primarily in older adults and has a poor prognosis. Alveolar epithelial cell (AEC) senescence is the critical pathological mechanism of PF. The accumulation of oxygen radicals, commonly referred to as reactive oxygen species (ROS), strongly contributes to cellular senescence. The triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor. Triggering via TREM-1 results in ROS, leading to the amplification of inflammation. However, whether TREM-1 is involved in PF by inducing oxidative stress to exacerbate AEC senescence remains unclear. We first observed that blockade of TREM-1 during the fibrotic phase attenuated bleomycin (BLM)-induced PF in mice, with decreased expression of senescence-related proteins, including p16, p21, p53, and γ-H2AX, in the lung tissue. Moreover, TREM-1 blockade during the fibrosis stage restored antioxidant levels by increasing the percentage of Nrf2- and HO-1-positive cells in mice with PF. Notably, TREM-1 was highly expressed in surfactant-associated protein (SPC)-positive AECs in mice with PF. In vitro, blocking TREM-1 activated Nrf2 antioxidant signaling, thereby decreasing intracellular ROS levels and diminishing BLM-induced senescence in AECs. Furthermore, inhibition of Nrf2/HO-1 partially counteracted the anti-senescence effect of blocking TREM-1 in BLM-treated AECs. In this study, we reported that TREM-1 stimulated the senescence of AECs, induced ROS and exacerbated PF. We also provide compelling evidence suggesting that the Nrf2/HO-1 signaling pathway underpins TREM-1-triggered senescence. Therefore, our findings provide new insights into the molecular mechanisms associated with TREM-1 and AEC senescence in the pathogenesis of PF.

Moment-to-moment neural variability has been shown to scale positively with the complexity of stimulus input. However, the mechanisms underlying the ability to align variability to input complexity are unknown. Using a combination of behavioral methods, computational modeling, fMRI, MR spectroscopy, and pharmacological intervention, we investigated the role of aging and GABA in neural variability during visual processing. We replicated previous findings that participants expressed higher variability when viewing more complex visual stimuli. Additionally, we found that such variability modulation was associated with higher baseline visual GABA levels and was reduced in older adults. When pharmacologically increasing GABA activity, we found that participants with lower baseline GABA levels showed a drug-related increase in variability modulation while participants with higher baseline GABA showed no change or even a reduction, consistent with an inverted-U account. Finally, higher baseline GABA and variability modulation were jointly associated with better visual-discrimination performance. These results suggest that GABA plays an important role in how humans utilize neural variability to adapt to the complexity of the visual world.

Peripheral arterial disease is a common vascular disease in the elderly. Therapeutic revascularization, including angiogenic and arteriogenic therapy, is a promising treatment approach for peripheral arterial disease. However, the progress of clinical trials is not ideal, possibly due to insufficiency of preclinical models, such as not taking into account the effect of aging on vascular regeneration. Macrophages are crucial in angiogenesis and arteriogenesis. The aging microenvironment typically makes recruited monocytes and macrophages more susceptible to senescence. However, the feature of macrophages in ischemic hindlimb muscle of old individuals and their underlying role remains unclear. In this study, we reveal that macrophages of ischemic skeletal muscle in old mice are more senescent and proinflammatory. By transplanting macrophages into mice following hindlimb ischemia, we find senescent macrophages inhibit revascularization. Mechanistically, these senescent macrophages induce endothelial dysfunction via increasing vascular endothelial growth factor A-165B (VEGF-A165B) expression and secretion, and eventually impair revascularization. Notably, plasma VEGF-A165B levels are elevated in old patients with PAD and positively associated with a lower ankle brachial index (ABI). Our study suggests that targeting the senescent macrophages presents an avenue to improve age-related revascularization damage.

Machine learning has emerged as a valuable tool in precision medicine and aging research. Here, we introduce the autonomic age gap, a novel metric quantifying the individual deviation between machine-learning-estimated biological age and chronological age, based on autonomic nervous system function. We collected high-resolution electrocardiograms and continuous blood pressure recordings at rest from 1,012 healthy individuals. From these signals, 29 autonomic indices were extracted, encompassing time-, frequency-, and symbol-domain heart rate variability, cardiovascular coupling, pulse wave dynamics, and QT interval features. Based on those parameters, a Gaussian process regression model was trained on 879 participants to estimate chronological age referred to as autonomic age. The model was used to estimate the deviation from expected healthy aging, the autonomic age gap, in an independent validation set and two test sets stratified by cardiovascular risk (CVR) using the Framingham. The was evaluated via the autonomic age gap. High CVR individuals had a significantly increased autonomic age gap of 9.7 years compared to the low CVR group and the validation set. In contrast, the low CVR group had a negative age gap of -2.2 years on average. Predictions in the validation sample closely matched calendar age with a deviation below 0.5 years. Additionally, in the high-risk group, the slope of predicted versus actual age suggested accelerated physiological aging. These findings highlight the autonomic age gap as a sensitive and interpretable marker of cardiovascular risk and aging, offering potential clinical utility for early risk detection and longitudinal health monitoring.

Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare genetic disease caused by progerin, a broadly expressed mutant variant of lamin A protein that accelerates aging and leads to premature death typically in adolescence. Progerin affects many organs and reproduces many characteristics of physiological aging, with the main cause of death in HGPS being atherosclerotic cardiovascular disease (CVD). Due to the rarity of HGPS, advances in understanding the disease and progress toward new therapeutic approaches are crucially dependent on preclinical models. We discuss recent research developments from a variety of HGPS experimental systems, with a special focus on in vivo studies of the role of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) that are key players in atherosclerosis.

Physical activity (PA) engagement declines with age in late adulthood. Therefore, understanding factors underlying PA engagement is needed for PA promotion in older adults. Executive function is a potential key neurocognitive resource that supports PA engagement. The current study aims to provide neurobiological evidence for this hypothesis by examining the role of the executive function networks in PA engagement.

Health span, that period between birth and onset of major disease(s), when adequate physical and cognitive function permit those daily living activities essential to life quality, is lower in the United States than other developed countries. Physical inactivity and excessive calorie intake occupy dominant roles both in the problem, and by redressing them, in the solution. Consequently, this review focuses on evidence that appropriate exercise engagement and calorie restriction can improve physical and mental health with a view to extending the health span. Humanity, writ large, has grasped these underlying concepts for Millennia but has been largely intransigent to them. Thus, the final section proposes a novel Monty Python-esque approach that encompasses humanity's inimical sense of humor to increase physical fitness and mental health, restore energy balance, sustain better cognitive function and extend the health span.

Falls are the leading cause of accidental injury among older adults. Current fall prevention programs are useful but do not target the key variable for injury (i.e., impact force). An approach, which has shown promise in robust older adults, is to teach safe-falling strategies to reduce impact forces. In this single-blinded, pilot randomized controlled trial, we explored the feasibility and preliminary efficacy of a safe-falling program.

Most living organisms experience time-dependent functional deterioration as they age. To combat aging, aspirin was proposed as an already well-studied drug. However, its antiaging effect is neither well studied nor understood. So, this study intended to assess the proposed antiaging effect of aspirin. Three groups of seven adult male albino rats were established. The control group received saline, the aging model group got a daily single D-galactose subcutaneous injection (300 mg/kg), and the aspirin group consisted of D-galactose-induced aged rats that received a daily aspirin oral dose (60 mg/kg). Drugs were given for 8 weeks. Then, malondialdehyde (MDA) blood level was evaluated, and rats were euthanized. Buccal mucosa samples were obtained for inducible nitric oxide synthase (iNOS) gene expression, histopathological, ultrastructural, and comet analyses. MDA blood level, iNOS gene expression and DNA damage examined by comet assay displayed a significant reduction in the aspirin group when compared to the aging model group. Histopathological and ultrastructural results showed that aspirin ameliorated most of the degenerative signs caused by D-galactose. Thus, it was deduced that aspirin had promising results as an antiaging pharmaceutical agent. However, more studies are needed regarding its translation to human trials.

Aging results from the gradual accumulation of molecular damage as a result of cellular processes and is characterized by impaired functions, most notably an age-related decline in ATP production. However, the causal relationship between cellular ATP homeostasis and aging has not been established. In this study, we employed a nucleotide transporter from a eukaryotic intracellular parasite to directly alter ATP levels in budding yeast cells and exchange it with the extracellular milieu. We found that ATP depletion significantly shortens lifespan, whereas supplementation of the medium with ATP fully restores it. Analysis of gene expression showed inhibition of catabolic processes suggesting that increased ATP suppresses glucose metabolism. Our results also showed that ATP supplementation leads to lifespan extension. Overall, our study revealed the direct impact of cellular ATP homeostasis on the regulation of lifespan. This work offers new insights into the bioenergetic control of aging and positions energy metabolism as a promising target for longevity interventions.

Per- and polyfluoroalkyl substances (PFASs) can impact various systems in the human body. However, their influence on biological aging remains unclear. This study aims to investigate the association between PFASs exposure and biological aging based on data from 9756 participants in the China National Human Biomonitoring Program and assesses the potential moderating effect of Dietary Diversity Score (DDS). Biological age indexes were calculated using the Klemera-Doubal method (KDM) and Mahalanobis distance (MD). The DDS was calculated based on the consumption frequency of 13 food groups over the past 12 months. Most PFASs showed positive associations with KDM-age acceleration (KDM-AA), while no statistically significant associations were observed with MD. The dose-response relationships of PFASs with KDM-AA and MD were steeper at low concentrations of PFASs, and then the slope appeared flat at higher concentrations. The weighted quantile sum revealed positive mixture effects of PFASs on biological aging. PFHpS and PFNA were both major contributors to KDM-AA and MD. DDS appeared to potentially modify the association between PFASs and biological aging. Our findings demonstrate that PFASs were significantly associated with accelerated biological aging, whereas higher DDS mitigates these adverse effects, highlighting the importance of this preventive measure.

Environmental enrichment (EE) represents a robust experimental framework exploring the intricate interplay between genes and the environment in shaping brain development and function. EE is recognized as a non-invasive intervention, easily translatable to elderly human cohorts, and extrapolated from research on animal aging models. Age is the most important risk factor for ischemic stroke. Research indicates that EE, characterized by increased sensory, cognitive, and social stimulation, leads to structural changes in the brain, such as enhanced dendritic complexity and synaptic density, particularly in the hippocampus and cortex. Tailored EE interventions for elderly stroke survivors include cognitively stimulating activities and participation in social groups. These interventions enhance cognitive function and support recovery by promoting neural repair. Additionally, EE helps to mitigate sensory deficits commonly observed in older adults, ultimately improving mental performance and quality of life. EE has shown promise in preventing relapse, enhancing attention, reducing anxiety, forestalling age-related DNA methylation alterations, and amplifying neurogenesis through heightened neural progenitor cell (NPC) populations. Aligning preclinical studies with clinical trials can enhance neurorehabilitation conditions for stroke patients, thereby optimizing the environments in which they recover. This can be achieved through the concerted efforts of multidisciplinary teams working collaboratively. This review explores how EE specifically impacts the aging brain and ischemic stroke, a major age-related neurological disorder with global health implications. The potential of enviro-mimetics and relevant clinical studies on EE's effects on ischemic stroke survivors are discussed. This review enhances our understanding of the effects of EE on aging and ischemic stroke, motivating further research aimed at refining strategies for stroke management and recovery.

The relationship between physical activity (PA), telomere length, and phenotypic age (PhenoAge) represents a pivotal area of investigation in aging research.

Skeletal muscle health and function deteriorate with age, ultimately leading to impaired mobility and disability. Exercise is among the most effective interventions to mitigate muscle dysfunction in aging and reverse deficits. However, low attrition and an impaired capacity to exercise may limit its utility in improving muscle function in aged persons. Therefore, it is crucial to advance our mechanistic understanding of the molecular transducers of exercise to identify new and innovative drug targets to improve muscle health. Transcriptomic profiling of the human response to exercise has revealed that the nuclear receptor NR4A3 (NOR-1) is among the most responsive genes to acute exercise. Previously, we observed that in vitro knockdown of NOR-1 alters metabolic signaling in C2C12 myotubes. Specifically, we found that expression of PERM1, CKMT2, myoglobin, and mTORC1 signaling were perturbed during the knockdown of NOR-1. Herein, we extend these findings and observe that a NOR-1-PERM1-myoglobin axis regulates myoglobin expression in vitro. Furthermore, we found that aging is associated with reduced skeletal muscle NOR-1 expression. Although it is well known that exercise improves aged muscle function, whether overexpression of the exercise-responsive gene NOR-1 can confer benefits and improve muscle function in an aged context has not been evaluated. We found that the overexpression of NOR-1 in aged muscle results in enhanced muscle endurance, mitochondrial respiration, and elevated expression of NOR-1 responsive genes that we previously identified in loss of function studies. However, we also observed that overexpression of NOR-1 did not improve maximal muscle torque production and resulted in a small but significant loss of muscle wet weight that was concomitant with elevated autophagy signaling. Our data suggest that NOR-1 expression may reduce muscle fatigability and that NOR-1 drives myoglobin expression in a PERM1-dependent manner.

Mitochondria are central hubs of cellular metabolism and their dysfunction has been implicated in a variety of human pathologies and the onset of aging. To ensure proper mitochondrial function under misfolding stress, a retrograde mitochondrial signaling pathway known as UPR

Aging contributes to various pathologies, including kidney injury, but the therapeutic potential of natural drugs in these contexts remains inadequately assessed. The roots of Panax ginseng C.A. Meyer, a widely used traditional Chinese medicine, are reputed for their anti-aging properties and life-prolonging effects, yet their specific medicinal components and mechanisms of action require further exploration.

Alcohol use is associated with cognitive impairment and dysregulated inflammation. Oral nitrate may benefit cognitive impairment in aging through altering the oral microbiota. Similarly, the beneficial effects of nitrate on alcohol-induced cognitive decline and the roles of the oral microbiota merit investigation. Here we found that nitrate supplementation effectively mitigated cognitive impairment induced by chronic alcohol exposure in mice, reducing both systemic and neuroinflammation. Furthermore, nitrate restored the dysbiosis of the oral microbiota caused by alcohol consumption. Notably, removing the oral microbiota led to a subsequent loss of the beneficial effects of nitrate. Oral microbiota from donor alcohol use disordered humans who had been taking the nitrate intervention were transplanted into germ-free mice which then showed increased cognitive function and reduced neuroinflammation. Finally, we examined 63 alcohol drinkers with varying levels of cognitive impairment and found that lower concentrations of nitrate metabolism-related bacteria were associated with higher cognitive impairment and lower nitrate levels in plasma. These findings highlight the protective role of nitrate against alcohol-induced cognition impairment and neuroinflammation and suggest that the oral microbiota associated with nitrate metabolism and brain function may form part of a "microbiota-mouth-brain axis".

All-trans retinoic acid (ATRA), the active form of retinoids, is a potent anti-aging and anti-inflammatory agent with pleiotropic effects on various skin conditions. In the interfollicular epider-mis, tissue turnover is maintained by heterogeneous epidermal stem cell populations located at the basal layer. Mouse tail skin contains slow- and fast-cycling epidermal stem cell populations. The reduction of fast-cycling epidermal regions after ATRA application was first documented in 1987; however, stem cell-level changes remained largely unexplored. This study demonstrates that ATRA treatment leads to reversible changes which decrease the fast-cycling epidermal compartment while expanding the slow-cycling one. ATRA biases both slow- and fast-cycling epidermal stem cell populations toward differentiation, with the remaining Slc1a3-CreER+ fast-cycling clones in the basal layers biasing to the slow-cycling lineage. Similar changes in slow- and fast-cycling epider-mal stem cell populations are also evident in human primary cultures in vitro. These findings shed light on the role of retinoic acid signaling in regulating the balance of epidermal stem cell heteroge-neity and lineages.

The first generation who engaged with digital technologies has reached the age where risks of dementia emerge. Has technological exposure helped or harmed cognition in digital pioneers? The digital dementia hypothesis predicts that a lifetime of technology exposure worsens cognitive abilities. An alternative hypothesis is that such exposures lead to technological reserve, wherein digital technologies promote behaviours that preserve cognition. We tested these hypotheses in a meta-analysis and systematic review of studies published in Medline, PsycInfo, CINAHL, Science Direct, Scopus, Cochrane Library, ProQuest and Web of Science. Studies were included if they were observational or cohort studies focused on general digital technology use in older adults (over age 50) and included either a cognitive or dementia diagnosis outcome. We identified 136 papers that met inclusion criteria, of which 57 were compatible with odds ratio or hazard ratio meta-analysis. These studies included 411,430 adults (baseline age M = 68.7 years; 53.5% female) from cross-sectional and longitudinal observational studies (range: 1-18 years, M = 6.2 years). Use of digital technologies was associated with reduced risk of cognitive impairment (OR = 0.42, 95% CI 0.35-0.52) and reduced time-dependent rates of cognitive decline (HR = 0.74, 95% CI 0.66-0.84). Effects remained significant when accounting for demographic, socioeconomic, health and cognitive reserve proxies. All studies were evaluated for quality on the basis of a standardized checklist; the primary outcomes replicated when limiting analyses to the highest-quality studies. Additional work is needed to test bidirectional causal interpretations, understand mechanisms that underpin technological reserve, and identify how types and timings of technology exposures influence cognitive health.

In this study, we investigated the contribution of rare coding variants to human longevity by analyzing whole exome sequencing data from 1245 German long-lived individuals (LLI) and 4105 geographically matched younger controls. We identified novel exome-wide significant associations at both the single-variant and gene level, with a significant over-representation of genes involved in mechanistic target of rapamycin (mTOR) signaling. As such, three rare single variants in the mTOR-pathway genes RPS6, FLCN, and SIK3 were enriched in LLI. Additionally, RWDD1 emerged as a strong candidate gene for longevity, with LLI exhibiting a statistically significant burden of rare missense variants in this gene. Other associations involved PRAC2, SLC16 A6, FOCAD, IHH, MESD, HOXA4, and DNAJB13. Furthermore, we observed an enrichment of protein-truncating variants in the genes ASXL1 and TET2 amongst LLI, likely as a result of clonal haematopoiesis. The study emphasizes the role of rare variants in human longevity, particularly through mTOR signaling.

Cellular senescence is known to drive age-related pathology through the senescence-associated secretory phenotype (SASP). However, it also plays important physiological roles such as cancer suppression, embryogenesis and wound healing. Wound healing is a tightly regulated process which when disrupted results in conditions such as fibrosis and chronic wounds. Senescent cells appear during the proliferation phase of the healing process where the SASP is involved in maintaining tissue homeostasis after damage. Interestingly, SASP composition and functionality was recently found to be temporally regulated, with distinct SASP profiles involved: a fibrogenic, followed by a fibrolytic SASP, which could have important implications for the role of senescent cells in wound healing. Given the number of factors at play a full understanding requires addressing the multiple levels of complexity, pertaining to the various cell behaviours, individually followed by investigating the interactions and influence each of these elements have on each other and the system as a whole. Here, a systems biology approach was adopted whereby a multi-scale model of wound healing that includes the dynamics of senescent cell behaviour and corresponding SASP composition within the wound microenvironment was developed. The model was built using the software CompuCell3D, which is based on a Cellular Potts modelling framework. We used an existing body of data on healthy wound healing to calibrate the model and validation was done on known disease conditions. The model clearly shows how differences in the spatiotemporal dynamics of different senescent cell phenotypes lead to several distinct repair outcomes. These differences in senescent cell dynamics can be attributed to variable SASP composition, duration of senescence and temporal induction of senescence relative to the healing stage. The range of outcomes demonstrated strongly highlight the dynamic and heterogenous role of senescent cells in wound healing, fibrosis and chronic wounds, and their fine-tuned control. Further specific data to increase model confidence could be used to explore senolytic treatments in wound disorders.

This study employs a data-driven, voxelwise analysis of high-resolution ex vivo quantitative MRI (qMRI) to examine age-related differences in brain morphometry and microstructure in female bonnet macaques. A binary classifier differentiated mid- and late-age groups, achieving the highest accuracy when integrating all MRI metrics rather than using diffusion or relaxometry alone. Diffusion-only and relaxometry-only classifiers revealed distinct, minimally overlapping spatial patterns, while the multi-metric approach captured a broader range of age-related differences. Tensor-based morphometry (TBM) differences were most pronounced in the neocortex, whereas the thalamus showed the highest classification accuracy despite minimal morphometric differences, suggesting unique tissue composition alterations. These findings highlight the complementary nature of diffusion, relaxometry, and morphometry qMRI metrics in aging research. Our results support the use of multi-parametric qMRI to identify age-vulnerable brain regions and highlight its potential for improving qMRI biomarkers in larger, longitudinal aging studies.

Animals select food based on hungers that reflect dynamic macronutrient needs, but the hormonal mechanisms underlying nutrient-specific appetite regulation remain poorly defined. Here, we identify tachykinin (Tk) as a protein-responsive gut hormone in Drosophila and female mice, regulated by conserved environmental and nutrient-sensing mechanisms. Protein intake activates Tk-expressing enteroendocrine cells (EECs), driving the release of gut Tk through mechanisms involving target of rapamycin (TOR) and transient receptor potential A1 (TrpA1). In flies, we delineate a pathway by which gut Tk controls selective appetite and sleep after protein ingestion, mediated by glucagon-like adipokinetic hormone (AKH) signalling to neurons and adipose tissue. This mechanism suppresses protein appetite, promotes sugar hunger and modulates wakefulness to align behaviour with nutritional needs. Inhibiting protein-responsive gut Tk prolongs lifespan through AKH, revealing a role for nutrient-dependent gut hormone signalling in longevity. Our results provide a framework for understanding EEC-derived nutrient-specific satiety signals and the role of gut hormones in regulating food choice, sleep and lifespan.

Aging clocks are an essential tool for biogerontological research that enables a quick assessment of one's pace of aging. In research settings, clocks trained on -omics data types are the most popular since they allow for an inspection of the most basic cellular processes of aging. In clinical settings, however, omics biomarkers of aging are impractical since they are linked to extra logistical load and costs, and they require personnel training. In this article, we present a cost-efficient aging clock that can be implemented easily in most clinics and hospitals to measure patients' aging rates. The clock requires only 22 biomarkers, including 17 blood test parameters, and four biometric measures (blood pressure, body mass index, and waist circumference). The clock predicts one's chronological age with a mean average error of 7.35 years, and it reveals associations with hypertension, cancer, and obesity.

Mitochondrial dysfunction is a critical contributor to age-related functional declines in skeletal muscle and brain. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is essential for mitochondrial biogenesis and function during aging. While skeletal muscle-specific overexpression of PGC-1α is known to mimic exercise-induced benefits in young animals, its chronic systemic effects on aging tissues remain unclear. This study aimed to determine the lifelong impact of skeletal muscle-specific PGC-1α overexpression on mitochondrial health, oxidative stress, inflammation, and cognitive function in aged mice. We established three experimental groups: young wild-type mice (3-4 months old), aged wild-type mice (25-27 months old), and aged mice with skeletal muscle-specific PGC-1α overexpression (24-27 months old). In skeletal muscle, aging led to significant reductions in mitochondrial biogenesis markers, including PGC-1α, FNDC5, and mtDNA content. PGC-1α overexpression reversed this decline, elevating the expression of PGC-1α, SIRT1, LONP1, SDHA, CS, TFAM, eNOS, and mtDNA levels, suggesting preserved mitochondrial biogenesis. However, FNDC5 and SIRT3 were paradoxically suppressed, indicating potential compensatory feedback mechanisms. PGC-1α overexpression also enhanced anabolic signaling, as evidenced by increased phosphorylation of mTOR and S6, and reduced FOXO1 expression, favoring a muscle growth-promoting environment. Moreover, aging impaired mitochondrial dynamics by downregulating MFN1, MFN2, OPA1, FIS1, and PINK1. While PGC-1α overexpression did not restore fusion-related proteins, it further reduced fission-related protein and enhanced mitophagy proteins, as evidenced by increased PINK1 phosphorylation. In contrast, in the hippocampus, muscle-specific PGC-1α overexpression exacerbated age-associated mitochondrial biogenesis decline. Expression levels of key mitochondrial markers, including PGC-1α, SIRT1, CS, FNDC5, Cytochrome C, and TFAM, were further reduced compared to aged wild-type controls. mTOR phosphorylation was also significantly suppressed, whereas cognition-related proteins (BDNF, VEGF, eNOS) and performance in behavioral tests remained unchanged. Importantly, skeletal muscle-specific PGC-1α overexpression triggered pronounced oxidative stress and inflammatory responses in both skeletal muscle and the hippocampus. In skeletal muscle, elevated levels of protein carbonyls, IκB-α, NF-κB, TNF-α, SOD2, and NRF2 were observed, accompanied by a reduction in the DNA repair enzyme OGG1. Notably, similar patterns were detected in the hippocampus, including increased expression of protein carbonyls, iNOS, NF-κB, TNF-α, SOD2, GPX1, and NRF2, alongside decreased OGG1 levels. These findings suggest that the overexpression of PGC-1α in skeletal muscle may have contributed to systemic oxidative stress and inflammation. In conclusion, skeletal muscle-specific PGC-1α overexpression preserves mitochondrial biogenesis and enhances anabolic signaling in aging muscle but concurrently induces oxidative stress and inflammatory responses, which may adversely affect mitochondrial health in the brain. These results emphasize the complex role of the skeletal muscle PGC-1α during aging.

Wounds in the elderly are frequently recalcitrant and chronic as a result of the effects of skin aging and associated complications. The objective of this study is to utilize an α-Klotho knockout (KO) mice wound model to assess the capacity of amnion-derived mesenchymal stem cells (AMSCs) to facilitate wound healing in aging skin.

The role of frailty in all-cause, cardiovascular, and cancer mortality is debatable, and the modification effect of biological aging remains unclear. Therefore, we aimed to evaluate the joint association of frailty index and biological aging with all-cause and cause-specific mortality.

Although early adversity is strongly related to lifelong health disparities, it is unclear how adversity might confer risk across generations. To investigate, we tested the hypothesis that mothers' childhood adversity was associated with their epigenetic aging and that of their children and examined whether associations differed for Black and White mothers.

At the neuromuscular junction (NMJ), which coordinates movement, postsynaptic-derived neurotrophic factors have neuroprotective functions and retrogradely regulate the exocytotic machinery involved in neurotransmitter release. In parallel, presynaptic autocrine muscarinic signaling plays a fundamental modulatory role in this synapse. We previously found that these signaling pathways are impaired in the aged neuromuscular system. In this follow-up study, we investigated an anti-aging strategy using grape seed procyanidin extract (GSPE), a common dietary antioxidant known for its neuroprotective properties in various pathologies, but its effects on the aged neuromuscular system remain unexplored. This study analyses whether GSPE can mitigate age-associated impairments in neurotrophic and muscarinic signaling within the neuromuscular system. We assessed the expression (protein levels) and activation (phosphorylation) of the key proteins in the brain-derived-neurotrophic-factor (BDNF)/neurotrophin 4 (NT-4) and muscarinic pathways in the

The use of antibodies to neutralize cytotoxic soluble amyloid-β aggregates rather than remove plaque has raised cautious hope since the monoclonal antibody BAN2401 seems to halt the course of prodromal Alzheimer's Disease (AD). By immobilizing cytotoxic amyloid-β, rather than the causative factor, plaques can help prevent Alzheimer's disease. A preventive immunity against Alzheimer's disease is shown by natural antibodies against cytotoxic amyloid-β. Vaccines should include adjuvants that promote anti-inflammatory Th2 immunity and immunogens that guard against different cytotoxic amyloid-β conformers to prevent or delay the onsetof Alzheimer's disease. The lack of long-term protection with monoclonal antibodies that neutralize single conformers, such as aducanumab, may be due to amyloid-β pleomorphism. In this scenario, novel cytotoxic conformers might evade neutralization by monoclonal antibodies that were previously successful. A vaccine's ability to elicit a polarized Th2 immunity would depend on both priming and the simultaneous delivery of immunogen to dendritic cells. In addition to neutralizing antibodies against neurotoxic amyloid-β oligomers, an immune response may also release anti-inflammatory cytokines, which can help prevent inflammation that exacerbates Alzheimer's disease. Vaccines would be significantly more successful in preventing Alzheimer's disease than treating it because of age-related immunological decrease. Since both amyloid-β and tau contribute to pathological hyperphosphorylation and work in tandem to cause Alzheimer's disease, preventive vaccinations against both should be taken into consideration. Given their affordability and simplicity, vaccines may be the only way to stop the looming Alzheimer's pandemic in many nations.

Physical activity (PA) is one of the most fundamental of all traits in the animal kingdom, has pervasive health benefits, and is genetically influenced. Using data from the Million Veteran Program (MVP), we conducted genetic analyses of leisure, work, and home-time PA. For leisure, for individuals of European (EUR) ancestry, n=189,812 and SNP-based heritability (h2)=0.083+/-0.005; for African ancestry, n=27,044; h2= 0.034+/-0.017; and for Latin-American ancestry, n=10,263; h2= 0.083+/-0.036. EUR and cross-ancestry meta-analyses with UK Biobank identified 67 and 70 lead variants. Leisure-time PA was genetically distinct from PA at home or work, with the latter two showing less health benefit on pathologies and lifespan. Mendelian randomization analyses showed protective effects of leisure-time PA on cardiovascular and respiratory system diseases, metabolic traits, aging, and other traits, and there was protective role of leisure-time PA against COVID-19 hospitalization ({beta}=-0.067+/-0.016; p-value=2.8x10-5). These findings provide new insights into the biology of PA, showing the causal health benefits of leisure-time PA.

Autophagy, a dynamic intracellular degradation system, is critical for cellular renovation and maintaining equilibrium. By eliminating damaged components and recycling essential molecules, autophagy safeguards cellular integrity and function. The versatility of the autophagy process across various biological functions enable cells to adapt and maintain homeostasis under unfavourable conditions. Disruptions in autophagy can shift a cell from a healthy state to a disease state or, conversely, support a return to health. This review delves into the multifaceted role of autophagy during aging and age-related diseases such as cancer, highlighting its significance as a unifying target with promising therapeutic implications. Cancer development is a dynamic process characterized by the acquisition of diverse survival capabilities for proliferating at different stages. This progression unfolds over time, with cancer cells exploiting autophagy to overcome encountered stress conditions during tumor development. Notably, there are several common pathways that utilize the autophagy process during aging and cancer development. This highlights the importance of autophagy as a crucial therapeutic target, holding the potential to not only impede the growth of tumor but also enhance the patient's longevity. This review aims to simplify the intricate relationship between cancer and aging, with a particular focus on the role of autophagy.

Vascular aging is a key driver of age-related cardiovascular and metabolic diseases, with endothelial dysfunction and senescence as a central mechanism. In our recent study, we observed elevated ADAM10 protein levels in senescent endothelial cells, which worsened endothelial dysfunction and senescence. However, the regulatory mechanisms controlling ADAM10 expression are poorly understood. In this study, we show that ADAM10 undergoes post-transcriptional modification in senescent human umbilical vein endothelial cells (HUVECs), with the E3 ubiquitin ligase MARCHF8 predicted to facilitate its ubiquitination-dependent degradation. We also found that MARCHF8 expression was significantly reduced in senescent HUVECs. Knockdown of MARCHF8 in young HUVECs induced endothelial senescence and impaired key endothelial functions, including migration, proliferation, angiogenesis, and nitric oxide production. Conversely, overexpression of MARCHF8 in senescent HUVECs ameliorated senescence-associated dysfunctions. RNA sequencing analysis revealed that MARCHF8 knockdown disrupted pathways linked to cell senescence and atherosclerosis. In vivo, MARCHF8 overexpression in high-fat diet-fed apoE

Identifying deficiencies in physical function in older adults is critical to evaluate important health outcomes like sarcopenia, but current protocols are expensive and require complex equipment. This study evaluates the reliability and validity of an inexpensive, simple new Get-Up test in older adults. It involves participants moving quickly from standing upright, to lying flat, then rising to a standing position unassisted. A total of 293 relatively healthy older adults without severe health conditions (e.g., cardiovascular, psychological, degenerative, or physical impairments) completed the Get-Up test twice for familiarization and twice for timed trials on two separate days alongside numerous validated clinical tests commonly used to assess strength, function, and fitness in older adults. ANOVA with post-hoc analysis and intraclass correlation (0.928 (95% CI [0.914, 0.940])) indicated strong reliability, with the second timed trial comparable to trials on a separate day. The Get-Up test was significantly (p <.0001) negatively correlated with all referenced measures of strength (Biodex peak torque, r = -.41, 1-repetition maximum, r = -.26, handgrip, r = -.38) and function (Short Physical Performance Battery, r = -.49, gait speed, r = -.39) and significantly (p <.0001) positively correlated with fitness (400-m walk, r =.70), which strongly predicted Get-Up test performance, suggesting good validity. Poor performance was associated with baseline sarcopenia prevalence (bottom tertile vs. top tertile: odds ratio 3.99 (95% CI 1.64-9.67)) and sarcopenia incidence after 1-year follow-up (hazard ratio 3.47 (1.10, 10.98)), suggesting potential to evaluate sarcopenia. This simple and safe Get-Up test requires minimal equipment, personnel, and expertise, yet it has good reliability and validity as a potential novel tool for full-body physical function in older adults that is associated with sarcopenia prevalence and incidence.

Research on brain aging is crucial for understanding age-related neurodegenerative disorders and developing several therapeutic interventions. Numerous models ranging from two-dimensional (2D) cell-based, invertebrate, vertebrate, and sophisticated three-dimensional (3D) models have been used to understand the process of brain aging. Invertebrate models are ideal for researching conserved aging processes because of their simplicity, short lifespans, and genetic tractability. Moreover, vertebrate models, including zebrafish and rodents, exhibit more complex nervous systems and behaviors, enabling the exploration of age-related neurodegeneration and cognitive decline. 2D cell culture models derived from primary cells or immortalized cell lines are widely used for mechanistic studies at the cellular level but lack the physiological complexity of brain tissue. Recent advancements have shifted focus to 3D models, which better recapitulate the brain's microenvironment. Organoids derived from induced pluripotent stem cells mimic human brain architecture and enable the study of cell-cell interactions and aging in a human-specific context. Brain-on-a-chip systems integrate microfluidics and 3D cultures to model blood-brain barrier dynamics and neuronal networks. Additionally, scaffold-based 3D cultures and spheroids provide intermediate complexity, allowing researchers to study extracellular matrix interactions and age-related changes in neuronal function. These 3D models bridge the gap between traditional 2D cultures and animal-based in vivo studies, offering unprecedented insights into brain aging mechanisms. By combining these diverse models, researchers can unravel the multifaceted processes of brain aging and accelerate the development of targeted therapies for age-related neurodegenerative disorders.

Mitochondrial dysfunction has been implicated in a broad range of age-related pathologies and has been proposed as a causative factor in Alzheimer's disease (AD). Analysis of post-mortem brains from AD patients showed increased levels of Voltage-dependent anion-selective channel 1 (VDAC1) in the dystrophic neurites surrounding amyloid-β (Aβ) deposits, suggesting a direct association between VDAC1 and mitochondrial toxicity. VDAC1 is the most abundant pore-forming protein of the outer mitochondrial membrane and, as a channel, it plays a pivotal role in regulating cellular bioenergetics, allowing the continuous exchange of ions and metabolites (ATP/ADP, Krebs cycle intermediates) between cytosol and mitochondria. In light of this evidence, we looked into the effects of Aβ oligomers on VDAC1 functions through electrophysiological and respirometric techniques. Our findings indicate that Aβ oligomers significantly modify the conductance, voltage dependency, and kinetic features of VDAC1, as well as its slight selectivity for anions, leading to a marked preference for cations. Given that VDAC1 is mainly involved in the trafficking of charged molecules in and out of mitochondria, a general reduction of cell viability and mitochondrial respiration was detected in neuroblastoma cells and primary cortical neurons exposed to Aβ oligomers. Interestingly, the toxic effect mediated by Aβ oligomers was counteracted by the use of NHK1, a small synthetic, cell-penetrating peptide that binds and modulates VDAC1. On these results, VDAC1 emerges as a crucial molecule in mitochondrial dysfunction in AD and as a promising pharmacological target for the development of new therapeutic avenues for this devastating neurodegenerative disease still without a cure.

Sex chromosomes impact chromatin organization and histone modification dynamics differently between males and females, particularly those involved in dosage compensation (DC). The stability of DC mechanisms may shape sex-specific phenotypes and traits such as lifespan. However, the tissue- and age-dependent variations as well as the evolutionary diversity of DC mechanisms are incompletely understood. Here, we investigate the occurrence of histone H4 lysine 16 acetylation (H4K16ac), previously known for its role in sex chromosome DC in the male-heterogametic fruit fly Drosophila melanogaster and the green anole lizard Anolis carolinensis. By sampling multiple arthropods, we find the convergent evolution of H4K16ac for DC in a female-heterogametic (ZW) species, the crustacean Artemia franciscana. CUT&Tag analysis demonstrates that H4K16ac is confined to the non-recombining stratum of the Z chromosome in females. H4K16ac-mediated DC is established during embryogenesis, sustained until adulthood, but then becomes reconfigured and variable in aged females. Interfering with acetylation alleviates male-female differences in lifespan. Our findings shed light on the evolutionary diversity of DC across species. They highlight histone acetylation as a sex-specific vulnerability linked to the chromatin landscape of sex chromosomes and its potential role in driving male-female differences.

For the high-value utilization of sake lees (SL), it is essential to explore its potential as a resource for anti-aging bioactives. However, the efficient extraction of SL, the compositional benefits provided, and the resulting anti-aging efficacy

Aging serves as a pivotal factor in the etiology of numerous diseases, such as Alzheimer's disease (AD), Parkinson's disease, diabetes, osteoarthritis, atherosclerosis and aging-related macular degeneration. Notably, these diseases often interact with AD through various pathways, facilitating the onset or progression of one another. Semaphorin 3 A (Sema3A), a protein that is essential for axonal guidance during neural development, has recently been identified as a novel regulator in the pathogenesis and progression of multiple aging-related diseases. This article provides a comprehensive review of the expression patterns and mechanisms of action of Sema3A in these diseases. Specifically, Sema3A influences the occurrence and development of aging-related diseases by participating in oxidative stress, inflammatory responses, apoptosis, and synaptic plasticity. Therefore, therapeutic strategies targeting Sema3A present promising avenues for delaying the progression of aging-related diseases and offer novel insights and strategies for their treatment.