Longevity Papers

Biomarkers of ageing serve as important outcome measures in longevity-promoting interventions. However, there is limited consensus on which specific biomarkers are most appropriate for human intervention studies. This work aimed to address this need by establishing an expert consensus on biomarkers of ageing for use in intervention studies via the Delphi method. A three-round Delphi study was conducted using an online platform. In Round 1, expert panel members provided suggestions for candidate biomarkers of ageing. In Rounds 2 and 3, they voted on 500 initial statements (yes/no) relating to 20 biomarkers of ageing. Panel members could abstain from voting on biomarkers outside their expertise. Consensus was reached when there was ≥70% agreement on a statement/biomarker. Of the 460 international panel members invited to participate, 116 completed Round 1, 87 completed Round 2, and 60 completed Round 3. Across the 3 rounds, 14 biomarkers met consensus that spanned physiological (e.g., insulin-like growth factor 1, growth-differentiating factor-15), inflammatory (e.g., high sensitivity c-reactive protein, interleukin-6), functional (e.g., muscle mass, muscle strength, hand grip strength, Timed-Up-and-Go, gait speed, standing balance test, frailty index, cognitive health, blood pressure), and epigenetic (e.g., DNA methylation/epigenetic clocks) domains. Expert consensus identified 14 potential biomarkers of ageing which may be used as outcome measures in intervention studies. Future ageing research should identify which combination of these biomarkers has the greatest utility.

Fatty acid oxidation is of uncertain importance in most stem cells. We show by

Aging and age-related cognitive impairment have emerged as a growing global public health concern and remain no effective preventive strategies. Excessive oxidative stress and neuroinflammation have been proven to contribute to cognitive decline. Vitamin D maintains the redox balance and exerts immunomodulatory effects, but the specific role of vitamin D in aging and age-related cognitive impairment remains elusive. This study explored the neuroprotective effects and the potential molecular mechanisms of 1α,25-Dihydroxyvitamin D3 in the aging model. An aging model was established by the treatment of D-galactose for 14 weeks in Male KM mice. 0.1, 0.5, or 1 μg/kg 1α,25-Dihydroxyvitamin D3 were used in the intervention group for 8 weeks. Cognitive performance was evaluated using the Morris water maze test, and the levels of oxidative stress and neuroinflammation in the hippocampus were further analyzed. D-galactose induced memory impairment, whereas 1α,25-Dihydroxyvitamin D3 intervention prevented cognitive decline, accompanied by a reduction in neuronal apoptosis, an enhancement of synaptic plasticity, and a decrease in Aβ deposition. Meanwhile, 1α,25-Dihydroxyvitamin D3 dramatically attenuated oxidative stress, mitigated microglial cell activation, and ameliorated neuroinflammation by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (AREs) axis and inhibiting the NF-κB signaling pathway. This study provides evidence that 1α,25-Dihydroxyvitamin D3 might be a promising nutritional strategy for preventing cognitive decline in aging, thereby facilitating the clinical application and expanding the insight of vitamin D.

The distribution of time across physical activity, sedentary behaviors, and sleep appears to be essential for the management of obesity. However, the impact of reallocating time among these behaviors, collectively known as 24-h movement behaviors, remains underexplored.

The alarmingly high prevalence of obesity in older adults coupled with the negative health effects of chronic inflammation in both obesity and aging highlight the importance of studies investigating the impacts of obesity on age-related inflammation. Since shifts in peripheral T-cell metabolism and function drive systemic inflammation in both obesity and aging, we hypothesize that obesity impacts the Th17-dominated inflammaging profile we identified in lean subjects and thus modifies the anti-inflammatory effects of geroprotective drugs like metformin. New cytokine profiling data showed that CD4

People living with HIV (PLHIV) demonstrate accelerated aging and immunosenescence in spite of immune-restoration following long-term antiretroviral treatment (ART). Low level inflammation leading to inflammaging plays an important role in mediating premature immunosenescence. Ongoing viral replication, antiretrovirals and subclinical infections with the common viruses like Cytomegalovirus (CMV) are known to induce inflammaging. However such data is scarce in India where persistent low level inflammation is common in general population due to various subclinical infections. Hence we conducted a study to determine the extent of immunosenescence in asymptomatic PLHIV on long term ART in comparison with their age-matched controls.

A globally aging population necessitates public health action that supports healthy aging. Although it is well established that participation in physical activity (PA), sport, and active recreation are important for healthy aging, PA levels remain generally lower among older adults. This study examines trends in physical activities that older adults engage in and identifies disparities in activities across subgroups as defined by age, gender, and socioeconomic status.

Nicotinamide adenine dinucleotide (NAD

Cellular senescence connects aging and cancer. Cellular senescence is a common program activated by cells in response to various types of stress. During this process, cells lose their proliferative capacity and undergo distinct morphological and metabolic changes. Senescence itself constitutes a tumor suppression mechanism and plays a significant role in organismal aging by promoting chronic inflammation. Additionally, age is one of the major risk factors for developing breast cancer. Therefore, while senescence can suppress tumor development early in life, it can also lead to an aging process that drives the development of age-related pathologies, suggesting an antagonistic pleiotropic effect. In this work, we identified Rian/MEG8 as a potential biomarker connecting aging and breast cancer for the first time. We found that Rian/MEG8 expression decreases with age; however, it is high in mice that age prematurely. We also observed decreased MEG8 expression in breast tumors compared to normal tissue. Furthermore, MEG8 overexpression reduced the proliferative and stemness properties of breast cancer cells both in vitro and in vivo by activating apoptosis. MEG8 could exemplify the antagonistic pleiotropic theory, where senescence is beneficial early in life as a tumor suppression mechanism due to increased MEG8, resulting in fewer breast tumors at an early age. Conversely, this effect could be detrimental later in life due to aging and cancer, when MEG8 is reduced and loses its tumor-suppressive role.

We study the changes in morphology of the photoplethysmography (PPG) signals-acquired from a select group of South Asian origin-through a low-cost PPG sensor, and correlate it with healthy aging which allows us to reliably estimate the vascular age and chronological age of a healthy person as well as the age group he/she belongs to.

Accumulation of critically short telomeres (CST) is implicated in decreased tissular regenerative capacity and increased susceptibility to degenerative diseases such as Alzheimer's disease (AD). Telomere shortening has also been associated with age-related brain changes. However, it remains unclear whether CST accumulation is directly associated with AD markers or instead amplifies age-related effects, potentially increasing susceptibility of developing AD in cognitively healthy older adults.

This special issue of the Journal of Experimental Gerontology explores the dynamic interplay between microbiomes and aging-related conditions. The four selected studies highlight the role of microbiota in Alzheimer's disease, cancer immunotherapy, myocardial infarction and tryptophan metabolism, providing insights into how microbiomes influence health and disease in aging. These studies underscore the potential for microbiome-targeted interventions to mitigate aging-related disorders and improve the quality of life for older adults.

Chronic atrophic gastritis (CAG) is a chronic disease of the gastric mucosa characterized by a reduction or an absolute disappearance of the original gastric glands, possibly replaced by pseudopyloric fibrosis, intestinal metaplasia, or fibrosis. CAG develops progressively into intestinal epithelial metaplasia, dysplasia, and ultimately, gastric cancer. Epidemiological statistics have revealed a positive correlation between the incidence of CAG and age. Mesenchymal stem cells (MSCs) are a type of adult stem cells derived from mesoderm, with strong tissue repair capabilities. Therefore, the restoration of the gastric mucosa may serve as an efficacious strategy to ameliorate CAG and avert gastric cancer. However, the mechanisms by which MSCs inhibit the relentless progression of aging atrophic gastritis remain to be elucidated. This study endeavored to assess a novel approach utilizing MSCs to treat CAG and forestall carcinogenics.

Disturbances in lipid metabolism are closely related to intervertebral disc degeneration (IDD). However, the lipid metabolism characteristics of nucleus pulposus (NP) cells during IDD are unclear. Exercise protects against IDD and acts as a potent mediator of organ metabolism, in which muscle-secreted myokines actively participate. However, whether exercise-induced myokines alleviate IDD by regulating lipid metabolism in NP cells remains unknown. The present study revealed that lipid accumulation is the metabolic reprogramming phenotype in NP cells during IDD, which was attributed to an imbalance between increased fatty acid/triglyceride synthesis and diminished utilization, and was further associated with extracellular matrix (ECM) degradation and cell senescence. To explore the interaction between exercise and IDD, Sprague-Dawley rats were subjected to five weeks of treadmill running exercise, and rats in the exercise group exhibited less severe IDD than did those in the sedentary group. The expression of meteorin-like protein (Metrnl), a newly-discovered myokine that participates in lipid metabolism regulation, was observed to increase in muscle, serum and NP tissue after exercise. Moreover, Metrnl ameliorated lipid accumulation in NP cells and further alleviated ECM degradation and cell senescence. Mechanistically, Metrnl activated the fatty acid β-oxidation rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A) via peroxisome proliferator-activated receptor α (PPARα) to increase lipid utilization in NP cells. This study provides insight into the lipid metabolic features of NP cells in IDD and reveals the intrinsic connections among exercise, metabolism and IDD, with the myokine Metrnl emerging as a pivotal mediator with therapeutic potential.

The senescence of smooth muscle is one of the independent risk factors in atherosclerosis progression in which the vascular inflammation plays an important role on vascular dysfunction. This study is designed to explore the novel vascular aging biomarkers and screen the potential molecular interventional targets through bioinformatic analysis.

Mitochondria transfer from human Wharton's Jelly-derived mesenchymal stem cells (hWJ-MSCs-mt) and human endometrium-derived mesenchymal stem cells (hE-MSCs-mt), along with curcumin, were explored as potential treatments for age-related macular degeneration (AMD) caused by mitochondrial inefficiency, using a retinal model to assess impacts of curcumin and hWJ-MSCs-mt or hE-MSCs-mt on AMD.

Telomeres are short repeating nucleotide sequences at the ends of chromosomes that shorten with every cellular replication. Despite the importance of keeping telomere length within a critical homeostatic range, adult telomere length can differ by two orders of magnitude across vertebrate species. Why telomere length varies so widely remains unknown, though popular hypotheses suggest that body size, lifespan, and endothermy are key variables that have coevolved with telomere length. To test the relationship among telomere length, telomerase activity (which extends telomeres), and these variables, we modeled the evolution of telomere length across 122 vertebrate species. We failed to find an influence of body mass, lifespan, or baseline metabolism on telomere length. However, we found a significant interactive effect between baseline metabolism and body mass. The presence of telomerase activity was positively correlated with telomere length across the 58 species where data for both existed. Taken together, our findings suggest that body mass may have differentially influenced the evolution of telomere length in endotherms and ectotherms and indicate that telomerase activity and telomere length may have coevolved.

Why people age at different rates is a fundamental, unsolved problem in biology. We created a model that predicts an individuals age from physiological traits that change with age in the large UK Biobank dataset, such as blood pressure, lung function, strength and stimulus- reaction time. The model best predicted a persons age when it heavily-weighted traits that together query multiple organ systems, arguing that most or all physiological systems (lung, heart, brain, etc.) contribute to the global phenotype of chronological age. Differences between calculated "biological" age and chronological age ({Delta}Age) appear to reflect an individuals relative youthfulness, as people predicted to be young for their age had a lower subsequent mortality rate and a higher parental age at death, even though no mortality data were used to calculate {Delta}Age. Remarkably, the effect of each year of physiological {Delta}Age on Gompertz mortality risk was equivalent to that of one chronological year. A Genome-Wide Association Study (GWAS) of {Delta}Age, and analysis of environmental factors associated with {Delta}Age identified known as well as new factors that may influence human aging, including genes involved in synapse biology and a tendency to play computer games. We identify a small number of readily measured physiological traits that together assess a persons biological age and may be used clinically to evaluate therapeutics designed to slow aging and extend healthy life.

Organ function declines with age, and large-scale transcriptomic analyses have highlighted differential aging trajectories across tissues. The mechanism underlying shared and organ-selective functional changes across the lifespan, however, still remains poorly understood. Given the central role of mitochondria in powering cellular processes needed to maintain tissue health, we therefore undertook a systematic assessment of respiratory activity across 33 different tissues in young (2.5 months) and old (20 months) mice of both sexes. Our high-resolution mitochondrial respiration atlas reveals: (1) within any group of mice, mitochondrial activity varies widely across tissues, with the highest values consistently seen in heart, brown fat, and kidney; (2) biological sex is a significant but minor contributor to mitochondrial respiration, and its contributions are tissue-specific, with major differences seen in the pancreas, stomach, and white adipose tissue; (3) age is a dominant factor affecting mitochondrial activity, especially across most brain regions, different fat depots, skeletal muscle groups, eyes, and different regions of the gastrointestinal tract; (4) age effects can be sex- and tissue-specific, with some of the largest effects seen in pancreas, heart, adipose tissue, and skeletal muscle; and (5) while aging alters the functional trajectories of mitochondria in a majority of tissues, some are remarkably resilient to age-induced changes. Altogether, our data provide the most comprehensive compendium of mitochondrial respiration and illuminate functional signatures of aging across diverse tissues and organ systems.

We present a novel method for routinely identifying disease resilience associations that offers powerful insights for the discovery of a new class of disease protective targets. We show how this can be used to identify mechanisms in the background of normal cellular biology that work to slow or stop progression of complex, chronic diseases. Actively protective combinatorial analysis identifies combinations of features that contribute to reducing risk of disease in individuals who remain healthy even though their genomic profile suggests that they have high risk of developing disease. These protective signatures can potentially be used to identify novel drug targets, pharmacogenomic and/or therapeutic mRNA opportunities and to better stratify patients by overall disease risk and mechanistic subtype. We describe the method and illustrate how it offers increased power for detecting disease-associated genetic variants relative to traditional methods. We exemplify this by identifying individuals who remain healthy despite possessing several disease signatures associated with increased risk of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or amyotrophic lateral sclerosis (ALS). We then identify combinations of SNP-genotypes significantly associated with reduced disease prevalence in these high-risk protected cohorts. We discuss how actively protective combinatorial analysis generates novel insights into the genetic drivers of established disease biology and detects gene-disease associations missed by standard statistical approaches such as meta-GWAS. The results support the mechanism of action hypotheses identified in our original causative disease analyses. They also illustrate the potential for development of precision medicine approaches that can increase healthspan by reducing the progression of disease.

The development of anti-aging drugs is challenged by both the apparent complexity of the physiological mechanisms involved in aging and the likelihood that many of these mechanisms remain unknown. As a consequence, the development of anti-aging compounds based on the rational targeting of specific pathways has fallen short of the goal. To date, the most impressive compound is rapamycin, a natural bacterial product initially identified as an antifungal, and only subsequently discovered to have anti-aging properties. In this review, we focus on two aminosterols from the dogfish shark, Squalus acanthias, that we discovered initially as broad-spectrum anti-microbial agents. This review is the first to gather together published studies conducted both in vitro and in numerous vertebrate species to demonstrate that these compounds target aging pathways at the cellular level and provide benefits in multiple aging-associated conditions in relevant animal models and in humans. The dogfish aminosterols should be recognized as potential anti-aging drugs.

Sarcopenia frequently occurs with aging and leads to major adverse impacts in elderly individuals. The protective effects of omega-3 polyunsaturated fatty acids against aging-related sarcopenia have been demonstrated; however, the effect and underlying mechanism of EPA or DHA alone remain inconclusive. Hence, the present study was aimed to clarify the differential effects and possible mechanisms of EPA and DHA on aging-related sarcopenia. In this study, two-month-old and eighteen-month-old male C57BL/6J mice were fed with an AIN-93M diet and an AIN-93M diet containing 1% EPA or 1% DHA for 24 weeks, respectively. The results revealed that EPA and DHA supplementation effectively alleviated the decline in grip strength, skeletal muscle mass, and myofiber cross-sectional areas in aged mice, with EPA exhibiting a better effect against aging-related sarcopenia than DHA. The ROS scavenging role of EPA in aged skeletal muscle was also superior to that of DHA. Additionally, EPA showed a stronger role in improving protein turnover and myogenesis in aged skeletal muscle, as evidenced by suppressing the activation of FoxO3a and NF-κB, blunting the expression levels of muscle atrophy markers MAFbx and MuRF1, activating the PI3K/Akt/mTOR signaling pathway, and elevating MyoD expression. Moreover, EPA also revealed a better effect on inhibiting mitochondria- and endoplasmic reticulum stress-mediated apoptosis in aged skeletal muscle. Furthermore, EPA manifested a more pronounced effect on improving mitochondrial damage of aged skeletal muscle than DHA, and the reason might be due to its superior capability of regulating mitochondrial quality control, as clearly shown by enhancing mitochondrial biogenesis through the AMPK/PGC-1α-dependent pathway, restraining the loss of mitochondrial fusion and fission proteins including Opa1, Mfn2, and Fis1, and promoting mitophagy

Work in many systems has shown large-scale changes in gene expression during aging. However, many studies employ just two, arbitrarily-chosen timepoints at which to measure expression, and can only observe an increase or a decrease in expression between young and old animals, failing to capture any dynamic, non-linear changes that occur throughout the aging process. We used RNA sequencing to measure expression in male head tissue at 15 timepoints through the lifespan of an inbred Drosophila melanogaster strain. We detected >6,000 significant, age-related genes, nearly all of which have been seen in previous fly aging expression studies, and which include several known to harbor lifespan-altering mutations. We grouped our gene set into 28 clusters via their temporal expression change, observing a diversity of trajectories; some clusters show a linear change over time, while others show more complex, non-linear patterns. Notably, re-analysis of our dataset comparing the earliest and latest timepoints mimicking a two-timepoint design revealed fewer differentially-expressed genes (around 4,500). Additionally, those genes exhibiting complex expression trajectories in our multi-timepoint analysis were most impacted in this re-analysis; Their identification, and the inferred change in gene expression with age, was often dependent on the timepoints chosen. Informed by our trajectory-based clusters, we executed a series of gene enrichment analyses, identifying enriched functions/pathways in all clusters, including the commonly seen increase in stress- and immune-related gene expression with age. Finally, we developed a pair of accessible shiny apps to enable exploration of our differential expression and gene enrichment results.

We fit ongoing 40+-year mark-recapture databases from the thriving southern right whale (SRW),

Accumulation of DNA damage can accelerate aging through cellular senescence. Previously, we established a Drosophila model to investigate the effects of radiation-induced DNA damage on the intestine. In this model, we examined irradiation-responsive senescence in the fly intestine. Through an unbiased genome-wide association study (GWAS) utilizing 156 strains from the Drosophila Genetic Reference Panel (DGRP), we identified meltrin {beta} (the drosophila orthologue of mammalian ADAM19) as a potential modulator of the senescence-associated secretory phenotype (SASP). Knockdown of meltrin {beta} resulted in reduced gut permeability, DNA damage, and expression of the senescence marker {beta}-galactosidase (SA-{beta}-gal) in the fly gut following irradiation. Additionally, inhibition of ADAM19 in mice using batimastat-94 reduced gut permeability and inflammation in the gut. Our findings extend to human primary fibroblasts, where ADAM19 knockdown or pharmacological inhibition decreased expression of specific SASP factors and SA-{beta}-gal. Furthermore, proteomics analysis of the secretory factor of senescent cells revealed a significant decrease in SASP factors associated with the ADAM19 cleavage site. These data suggest that ADAM19 inhibition could represent a novel senomorphic strategy.

Cellular senescence is a multifaceted process marked by irreversible cell cycle arrest in response to stressors such as DNA damage, oxidative stress, and telomere shortening, leading to significant cellular and mitochondrial alterations. These changes impact mesenchymal stem cell (MSC) function, affecting their differentiation, self-renewal, and regenerative abilities. Senescent MSCs adopt the senescence-associated secretory phenotype (SASP), characterized by the secretion of pro-inflammatory factors that propagate senescence to neighboring cells. Key features of senescent MSCs include altered morphology, reduced proliferative and differentiation capacity, and changes in their secretome. Mitochondrial dysfunction plays a central role in this process, impairing stemness, increasing oxidative stress, and contributing to cellular aging by generating reactive oxygen species (ROS). The chapter provides an overview of various methods to analyze senescent cells, including techniques to detect changes in cell proliferation, DNA damage, apoptosis, and mitochondrial function. It also highlights assays for mitochondrial alterations such as fluorescent staining, membrane potential analysis, and mitophagy evaluation. These tools are essential for understanding the complex mechanisms of cellular senescence and mitochondrial dysfunction, offering insights into aging and potential therapeutic strategies.

Dysregulated Wnt signaling causes age-related characteristics such as oxidative stress, stem cell senescence, and abnormal bone homeostasis. Here we explored whether supplemental n-acetyl-l-cysteine (NAC) recovers the age-associated complications relative to osteoblastic Wntless (Wls) ablation and examined the possible mechanisms therein. For this work, we administered Col2.3-Cre;Wls

An important hallmark of aging is the loss of proteostasis, which can lead to the formation of protein aggregates and mitochondrial dysfunction in neurons. Although it is well known that protein synthesis is finely regulated in the brain, especially at synapses, where mRNAs are locally translated in activity-dependent manner, little is known as to the changes in the synaptic proteome and transcriptome during aging. Therefore, this work aims to elucidate the relationship between transcriptome and proteome at soma and synaptic level during aging. Proteomic and transcriptomic data analysis reveal that, in young animals, proteins and transcripts are correlated and synaptic regulation is driven by changes in the soma. During aging, there is a decoupling between transcripts and proteins and between somatic and synaptic compartments. Furthermore, soma-synapse gradient of ribosomal genes changes upon aging, i.e. ribosomal transcripts are less abundant and ribosomal proteins are more abundant in synaptic compartment of old mice with respect to younglings. Additionally, transcriptomics data highlight a difference in the splicing of certain synaptic mRNA with aging. Taken together, our data provide a valuable resource for the study of the aging synapse.

Cellular senescence is a condition characterized by stable, irreversible cell cycle arrest linked to the aging process. The accumulation of senescent cells in the cardiac muscle can contribute to various cardiovascular diseases (CVD). Telomere shortening, epigenetic modifications, DNA damage, mitochondrial dysfunction, and oxidative stress are known contributors to the onset of cellular senescence in the heart. The link between mitochondrial processes and cellular senescence contributed to the age-related decline in cardiac function. These include changes in mitochondrial functions and behaviours that arise from various factors, including impaired dynamics, dysregulated biogenesis, mitophagy, mitochondrial DNA (mtDNA), reduced respiratory capacity, and mitochondrial structural changes. Thus, regulation of mitochondrial biology has a role in cellular senescence and cardiac function in aging hearts. Targeting senescent cells may provide a novel therapeutic approach for treating and preventing CVD associated with aging. CYP epoxygenases metabolize N-3 and N-6 polyunsaturated fatty acids (PUFA) into epoxylipids that are readily hydrolyzed to diol products by soluble epoxide hydrolase (sEH). Increasing epoxylipids levels or inhibition of sEH has demonstrated protective effects in the aging heart. Evidence suggests they may play a role in cellular senescence by regulating mitochondria, thus reducing adverse effects of aging in the heart. In this review, we discuss how mitochondria induce cellular senescence and how epoxylipids affect the senescence process in the aged heart.

Uncouplers of mitochondrial electron transport chain, such as 2,4-dinitrophehol (DNP), can mimic calorie restriction by decreasing efficiency of adenosine triphosphate (ATP) synthesis. However, DNP is also a toxic substance, whose overdosage can be lethal. In the fruit fly, Drosophila melanogaster model, we have found that DNP in concentrations of 0.05-0.2 g/L, led to a drastic decrease in fruit fly survival on a low caloric diet (1% sucrose and 1% yeast; 1S-1Y). On the 5S-5Y diet, DNP decreased lifespan of flies reared only in concentration 0.2 g/L, whilst on the diet 15S-15Y DNP either did not significantly shortened fruit fly lifespan or extended it. The lifespan extension on the high caloric 15S-15Y diet with DNP was accompanied by lower activity of lactate dehydrogenase and a decrease in activities of mitochondrial respiratory chain complexes I, II, and V, determined by blue native electrophoresis followed by in-gel activity assays. The exposure to DNP also did not affect key glycolytic enzymes, antioxidant and related enzymes, and markers of oxidative stress, such as aconitase activity and amount protein carbonyls. Consumption of DNP-supplemented diet did not affect flies' resistance to heat stress, though made male flies slightly more resistant to starvation compared with males reared on the control food. We also did not observe substantial changes in the contents of metabolic stores, triacylglycerols and glycogen, in the DNP-treated flies. All this suggest that a nutrient-rich diets provide effective protection against DNP, providing a mild uncoupling of the respiratory chain that allows lifespan extension without considerable changes in metabolism.

Plant polysaccharides are effective components that widely present in traditional Chinese medicine(TCM), exhibiting rich biological activities. However, as most plant polysaccharides cannot be directly absorbed and utilized by the human digestive system, it is now believed that their mode of action mainly involves interaction with intestinal microbiota, leading to the production of functional small molecules. The efficacy of Astragalus polysaccharide(APS) is extensive, including weight loss, improvement of fatty liver, reduction of blood lipids, and enhancement of insulin sensitivity, which may also be related to the regulation of intestinal microbiota. Adipose tissue senescence is an important characteristic of the physiological aging process in the body, often occurring prior to the aging of other important organs. Its main features include the accumulation of senescent cells and exacerbation of inflammation within the tissue. Therefore, to explore the potential protective effects of APS on aging, the improvement of adipose tissue aging phenotype in naturally aging mice was observed using APS, and combined with metagenomic metabolomics, corresponding microbial metabolic functional molecules were identified. Furthermore, functional tests in cell aging models were conducted. The results showed that APS significantly improved the adipocyte aging characteristics of naturally aging mice: specifically reducing aging-induced adipocyte hypertrophy; decreasing the protein expression of aging markers cyclin-dependent kinase inhibitor p21(P21) and multiple tumor suppressor 1(P16); lowering the tissue inflammation reaction. Metagenomic metabolomic analysis of serum from mice in each group revealed that APS significantly increased the content of indole-3-lactic acid(ILA) in naturally aging mice. Further in vitro studies showed that ILA could improve the aging of 3T3-L1 mouse embryonic fibroblasts induced by bleomycin, reduce the protein expression of the aging marker P21, alleviate inflammation, and enhance the ability of preadipocytes to mature. Therefore, APS had the efficacy of protecting naturally aging mice, and its action may be related to the increase in the intestinal microbiota metabolite ILA. This study suggested that TCM may serve as an important entry point for explaining the mechanism of action of TCM by regulating intestinal microbiota and their functional metabolites.

Brain aging involves a complex interplay of cellular and molecular changes, including metabolic alterations and the accumulation of senescent cells. These changes frequently manifest as dysregulation in glucose metabolism and mitochondrial function, leading to reduced energy production, increased oxidative stress, and mitochondrial dysfunction-key contributors to age-related neurodegenerative diseases.

Background: Epigenetic age acceleration (EAA), defined as blood DNA methylation-derived biological age exceeding chronological age, has emerged as a potential biomarker of cardiovascular health and disease. EAA has been associated with symptomatic heart failure (HF); however, its connection to early-stage HF remains unclear. Moreover, the association of EAA with cardiovascular disease may differ by sex. Methods: We analyzed participants from the Project Baseline Health Study, a deeply-phenotyped longitudinal cohort. HF staging was performed using echocardiographic measures and clinical criteria, classifying participants into stage 0/B0 (no HF risk factors), stage A (HF risk factors only, without structural cardiac abnormalities), and stage B1 (structural changes without HF symptoms). EAA was calculated as the residual of Horvath methylation epigenetic age regressed on chronological age. We compared EAA across HF stages using ANOVA models adjusted for sex, and in secondary analyses, investigated associations between EAA and echocardiographic parameters as well as sex-specific differences. Results: Among 1,338 participants (mean age: 49.2 +/- 15.4 years; 53.5% female), 41.7% were stage 0/B0 (n=558), 39.4% were stage A (n=527), and 18.9% were stage B1 (n=253). EAA tended to differ across HF stages (p=0.07), with higher EAA in stage B1 participants compared to those in stage 0/B0 or A. Sex-stratified models suggested that this trend was more pronounced in males than females. Among individual echocardiographic parameters, greater left ventricular posterior wall thickness was associated with higher EAA (p=0.046). In analyses restricted to stage A and B1 participants, higher EAA in B1 approached significance only in males (p=0.051). Conclusions: These findings suggest that elevated EAA may occur even in the early, asymptomatic stages of HF, potentially reflecting underlying biological aging processes associated with early cardiac structural abnormalities. The effects may be sex-specific, with males showing a stronger relationship between EAA and stage B1 HF. Although validation through larger, longitudinal studies is necessary, our results support EAA as a potential biomarker for early cardiovascular risk assessment and underscore the need of considering sex differences in early HF pathophysiology.

Housing is an important social determinant of health. However, limited studies have focused on the relationship between housing quality and sarcopenia, especially in low- and middle-income countries. This study aims to examine the association between housing quality and sarcopenia in older adults in China and India.

To explore the effects of methionine (Met) supplementation on cognitive dysfunction and the associated mechanisms in aging mice. The mice were administrated 0.15 g/kg/day D-galactose subcutaneously and fed a normal (0.86% Met) or a Met-supplemented diet (1.72% Met) for 11 weeks. Behavioral experiments were conducted, and we measured the plasma metabolite levels, hippocampal and plasma redox and inflammatory states, and hippocampal transsulfuration pathway-related parameters. Met supplementation prevented aging-induced anxiety and cognitive deficiencies, and normalized the plasma levels of multiple systemic metabolites (e.g., betaine, taurine, and choline). Furthermore, dietary Met supplementation abolished oxidative stress and inflammation, selectively modulated the expression of multiple cognition-related genes and proteins, and increased flux via the transsulfuration pathway in the hippocampi of aging mice, with significant increase in H

Frailty, a reversible clinical geriatric syndrome, impairs the ability to maintain homeostasis, leading to severe consequences such as hospitalization and death. Cognitive frailty, characterized by the co-occurrence of physical frailty and cognitive impairment, has garnered increasing attention in recent years. Preclinical models, especially rodent studies, are essential for understanding frailty and developing interventions to mitigate associated conditions. Traditionally, animal studies have focused solely on physical frailty. We have pioneered the inclusion of cognitive parameters by developing a novel physical-cognitive frailty score (FS) in animal research, in order to assess the effectiveness of anti-aging interventions. Here, we provide a detailed example of the FS calculation at the group level, which can serve as a guide for other studies. This dual-focus approach also helps in understanding how physical frailty and cognitive impairment interact to exacerbate adverse health outcomes and provides an opportunity to evaluate potential interventions that target both physical and cognitive dimensions of frailty more reliably.

As individuals age, the risk of cardiovascular disease (CVD) increases, largely due to progressive stiffening of the arteries. This relationship underscores the critical need to monitor arterial stiffness as a predictor of CVD outcomes. While aerobic exercise has demonstrated benefits for vascular health, the influence of flexibility, particularly trunk flexibility, on arterial stiffness remains underexplored. Thus, this study aimed to analyse the overall relationship between trunk flexibility and arterial stiffness across different age groups (young, middle-aged, and older adults) and according to sex.

Schisandra chinensis (Turcz.) Baill, a traditional Chinese medicine with significant nourishing functions, has a regulatory effect on the cardiovascular system, digestive system, central nervous system, and endocrine and immune systems. It can protect the cardiovascular system, improve immunity, and has anti-oxidant and anti-aging properties. This study aimed to identify the S. chinensis components that increased NAD+ levels, by using spectrum-effect analysis and experimental validations. First, the quality of the S. chinensis extract was analyzed by HPLC-MS. The extract of S. chinensis increased the NAD+ levels of HUVECs during oxygen and glucose deprivation injury, and protected HUVEC s from injury from superoxide dismutase (SOD) and aging. The relationships of spectral effects were studied by partial least square regression. Coupled with target cell extraction, the material basis for increasing NAD+ levels in S. chinensis was obtained. The pharmacological activity of S. chinensis was verified at the cellular level. The related enzymes of the NAD+ synthesis and decomposition pathways were identified, showing that S. chinensis increased the level of NAD+ by increasing the activity of related enzymes in the synthesis pathways of NMNAT1, NMNAT2, NMNAT3, and NAMPT, but had no effect on the decomposition pathway. Finally, four constituents were confirmed, in vitro, to be the basis of S. chinensis-induced increases in the levels of NAD+. The EC

The analysis of lifespan and ageing involves a variety of calculations based on survival data. One of these is the comparison of survival curves. However, inspection of survival curves provides little information about the frequency of phenotypes within samples. Here we propose to divide the distribution into intervals to obtain information about the sample structure. Then, we apply the normality criterion to the distributions using the Kolmogorov-Smirnov and Shapiro-Wilk tests. Using this approach, we reveal the destabilising effect of mutations on ontogenesis and lifespan, and estimate the strength of the genetic background of the lines. The proposed methodology allows effective estimation of sample structure and adds a new layer of information to longevity studies.

Oleuropein (OLE) has the potential to reduce oxidative stress and inflammation. So, in the present investigation, we explored the protective effect of OLE on brain aging induced by d-galactose (D-Gal) in a rat model.

As the healthcare burden caused by an increasingly aging population rapidly rises, a pressing need exists for innovative geroscience research that can elucidate aging mechanisms and precipitate the development of therapeutic interventions to support healthy aging. The Fifth Annual Midwest Aging Consortium Aging Research symposium, held from April 28-30, 2024, was hosted by The Ohio State University in Columbus, Ohio and featured presentations from investigators across the Midwestern United States. This report summarizes the research presented at the symposium, whose topics included cellular senescence and the aging brain, metabolism and metabolic interventions, nutrition, redox mechanisms and biomarkers, and stress mechanisms. Abstract presentations and short talks highlighted early-stage and young investigators, while two keynote presentations anchored the symposium. Overall, this symposium showed the robustness of aging research in the Midwest and underscored the advantages of a collaborative approach to geroscience research.

Oxidative homeostasis plays important roles in physiology, for reactive oxygen species not only lead to damaging oxidative stress, but also regulate important physiological processes like immunity and longevity. ROS are therefore expected to be a key factor underlying many host-parasite interactions. We evaluated the role of the host oxidative status on the outcome of infection with the mosquito Anopheles gambiae infected by the microsporidian Vavraia culicis. To do so, we manipulated the oxidative status of the mosquitoes by feeding them early (the first four days after emergence) or late (from five days after emergence onwards) either a standard sugar source or one supplemented with a prooxidant (hydrogen peroxide) or antioxidant (vitamin C), and then measured the longevity and fecundity of uninfected and infected mosquitoes and (for infected mosquitoes) the parasite load at a given day (13 days after emergence) or when the mosquitoes died. The prooxidant generally increased longevity, but if consumed early after emergence its impact was lessened by the infection by Vavraia. In contrast the antioxidant increased fecundity, and the impact was not affected by the status of infection or by the timing of consumption. Finally, early consumption of both supplements increased Vavraia spore load at 13 days after emergence and at death. In contrast, late consumption enhanced the parasite growth late in the mosquito life. Thus, our experiment revealed complex effects of prooxidant and antioxidant consumption, emphasising the critical role of timing and context in shaping their influence on biological traits.

This study pursued to evaluate the tropisetron effects in attenuating D-galactose induced heart aging in mice. The study aimed to ascertain whether tropisetron affects apoptotic processes, mitochondrial oxidative stress, or inflammatory variables in cardiac tissue, presumably through the modulation of the SIRT1 signaling pathway or sirtuin 1. Aging was induced via administration of D-galactose (200 mg/kg, s.c.). Then, mice were treated with tropisetron (1, 3, and 5 mg/kg/day, i.p.). After 8 weeks, the key indicators of oxidative mitochondrial dysfunction, oxidative stress, pro-inflammatory cytokines, interleukin-6, tumor necrosis factor-α, and nitric oxide concentrations were evaluated. Additionally, the gene expressions of apoptotic regulators Bax and Bcl2, as well as SIRT1, were assessed using real-time PCR. Histological alterations and serum lactate dehydrogenase levels were also assessed. Tropisetron alleviated mitochondrial oxidative stress and inflammatory mediators while decreasing immune cell infiltration into cardiac tissue generated by D-galactose. The simultaneous injection of tropisetron effectively inhibited D-galactose-induced apoptosis by modulating the Bax/Bcl2 ratio and activating the SIRT1 pathway. The administration of tropisetron resulted in reduced serum lactate dehydrogenase levels compared to the group treated just with D-galactose. Moreover, tropisetron successfully reinstated mitochondrial activity and diminished D-galactose-induced aberrant nitric oxide generation. The research concludes that tropisetron may provide protection against cardiac aging by activating multiple mechanisms associated with the SIRT1 pathway.

The geroscience hypothesis proposes that underlying biological processes, such as the accumulation of senescent cells, have deleterious effects on multiple tissues and increase the risk of many chronic conditions with aging. Senescent cells produce heterogenous biomarkers, also called senescence-associated secretory phenotype (SASP). Circulating concentrations of senescence biomarkers may reflect an underlying burden of senescent cells in various tissues. Plasma levels of these proteins have been associated with increased mortality and poorer physical function. The associations of them with the incidence of major age-related conditions including heart failure, cardiovascular disease, stroke, and dementia, have not been studied. We measured 35 senescence biomarkers in baseline plasma samples from 1678 participants aged 70-79 years old in the longitudinal Health ABC cohort study. Clinical outcomes were ascertained and validated over an average 11.5 year follow-up. In models adjusted for age, sex, and race, higher levels of most of senescence biomarkers were associated with increased risk of all-cause mortality, mobility limitation, and heart failure. Several were also associated with an increased risk of coronary heart disease, stroke, and dementia. Very few were associated with the risk of cancer. Proteins that were selected by Lasso regression for each outcome that commonly included GDF15 and IL6, significantly improved the prediction of mortality, mobility limitation, and heart failure compared with age, sex, and race alone. These results indicate that levels of senescence biomarkers predict an increased risk of several age-related clinical outcomes and may identify individuals most likely to benefit from senotherapeutics.

Studies using mitophagy reporter mice have established steady-state landscapes of mitochondrial destruction in mammalian tissues, sparking intense interest in basal mitophagy. Yet how basal mitophagy is modified by healthy aging in diverse brain cell types has remained a mystery. We present a comprehensive spatiotemporal analysis of mitophagy and macroautophagy dynamics in the aging mammalian brain, reporting critical region- and cell-specific turnover trajectories in a longitudinal study. We demonstrate that the physiological regulation of mitophagy in the mammalian brain is cell-specific, dynamic and complex. Mitophagy increases significantly in the cerebellum and hippocampus during midlife, while remaining unchanged in the prefrontal cortex (PFC). Conversely, macroautophagy decreases in the hippocampus and PFC, but remains stable in the cerebellum. We also describe emergent lysosomal heterogeneity, with subsets of differential acidified lysosomes accumulating in the aging brain. We further establish midlife as a critical inflection point for autophagy regulation, which may be important for region-specific vulnerability and resilience to aging. By mapping

Autophagy is a vital cellular process responsible for the degradation of proteins, organelles, and other cellular components within lysosomes. In neurons, basal autophagy is indispensable for maintaining cellular homeostasis and protein quality control. Accordingly, lysosomal dysfunction has been proposed to be associated with neurodegeneration, and with Parkinson's disease (PD) in particular. Aging, dopamine metabolism, and PD-linked genetic mutations are thought to impair the autophagic-lysosomal pathway, disrupt cellular proteostasis, and contribute to PD pathogenesis. These alterations represent an opportunity to identify potential new therapeutic targets and disease biomarkers, thus laying the groundwork for the development of novel disease-modifying strategies for PD that are aimed at restoring cellular proteostasis and quality control systems.

Deciphering the complex interplay between neuronal activity and mitochondrial function is pivotal in understanding brain aging, a multifaceted process marked by declines in synaptic function and mitochondrial performance. Here, we identified an age-dependent coupling between neuronal and synaptic excitation and mitochondrial DNA transcription (E-TC

Climate change introduces greater thermal variability, profoundly affecting ectothermic species whose body temperatures rely heavily on the environment. Understanding the physiological and metabolic responses to such variability is crucial for predicting how these species will cope with changing climates. This study investigates how chronic thermal stress impacts mitochondrial metabolism and physiological parameters in Drosophila melanogaster, hypothesizing that a fluctuating thermal regime (FTR) activates protective mechanisms enhancing stress tolerance and longevity. To test this, Drosophila were exposed to constant 24°C or to an FTR of 24°C/15°C day/night cycle following an initial 5-day period at 24°C. The FTR group exhibited rapid transcript level changes after the first day of FTR, particularly those related to heat shock proteins, mitophagy and regulatory factors, which returned to initial levels after 5 days. Mitochondrial respiration rates initially decreased after 1 and 2 days of FTR, then recovered by Day 5, indicating rapid acclimation. Enhanced antioxidant enzyme activities were observed early in the FTR group, after 1 day for mtSOD and SODcyt+ext and 3 days for both SOD and catalase, followed by a decline by Day 5, suggesting efficient oxidative stress management. The FTR group showed lower CTmax on Day 3, reflecting possible physiological strain at that time point, and complete recovery by Day 5. Longevity increased under FTR, highlighting the activation of protective mechanisms with beneficial long-term effects. These suggest that FTR prompts a temporal succession of rapid physiological adjustments at different levels of organisation, enhancing long-term survival in D. melanogaster.

Mitochondria are versatile and complex organelles that can continuously communicate and interact with the cellular milieu. Deregulated communication between mitochondria and host cells/organelles has significant consequences and is an underlying factor of many pathophysiological conditions, including the process of aging. During aging, mitochondria lose function, and mitocellular communication pathways break down; mitochondrial dysfunction interacts with mitochondrial dyscommunication, forming a vicious circle. Therefore, strategies to protect mitochondrial function and promote effective communication of mitochondria can increase healthy lifespan and longevity, which might be a new treatment paradigm for age-related disorders. In this review, we comprehensively discuss the signal transduction mechanisms of inter- and intracellular mitochondrial communication, as well as the interactions between mitochondrial communication and the hallmarks of aging. This review emphasizes the indispensable position of inter- and intracellular mitochondrial communication in the aging process of organisms, which is crucial as the cellular signaling hubs. In addition, we also specifically focus on the status of mitochondria-targeted interventions to provide potential therapeutic targets for age-related diseases.

Ageing of the endometrium is a critical factor that affects reproductive health, yet its intricate mechanisms remain poorly explored. In this study, we performed transcriptome profiling and experimental verification of endometrium and endometrial organoids from young and advanced age females, to elucidate the underlying mechanisms and to explore novel treatment strategies for endometrial ageing. First, we found that age-associated decline in endometrial functions including fibrosis and diminished receptivity, already exists in reproductive age. Subsequently, based on RNA-seq analysis, we identified several changes in molecular processes affected by age, including fibrosis, imbalanced inflammatory status including Th1 bias in secretory phase, cellular senescence and abnormal signalling transduction in key pathways, with all processes been further validated by molecular experiments. Finally, we uncovered for the first time that PI3K-AKT-FOXO1 signalling pathway is overactivated in ageing endometrium and is closely correlated with fibrosis and impaired receptivity characteristics of ageing endometrium. Blocking or activation of PI3K by LY294002 or 740Y-P could attenuate the effect of ageing or accelerate dysfunction of endometrial organoids. This discovery is expected to bring new breakthroughs for understanding the pathophysiological processes associated with endometrial ageing, as well as treatment strategies to improve reproductive outcomes in women of advanced reproductive age.

Extracellular vesicles (EVs) play crucial roles in aging. In this National Institutes on Aging-funded study, we sought to identify circulating extracellular vesicle (EV) biomarkers indicative of longevity. The plasma EV proteome of 48 older adults (mean age 77.2 ± 1.7 years [range 72-80]; 50% female, 50% Black, 50% < 2-year survival, 50% ≥ 10-year survival) was analyzed by high-resolution mass spectrometry and flow cytometry. The ability of EV peptides to predict longevity was evaluated in discovery (n = 32) and validation (n = 16) datasets with areas under receiver operating characteristic curves (AUCs). Longevity-associated large EV (LEV) plasma subpopulations were mainly related to immune cells (HLA-ABC

Cellular senescence is a pivotal contributor to aging and age-related diseases. The targeted elimination of senescent cells, known as senolysis, has emerged as a promising therapeutic strategy for mitigating these conditions. Glutaminase 1 (GLS1), a key enzyme in the glutaminolysis pathway, has been implicated in various cellular senescence processes. However, its specific role in senescent renal tubular epithelial cells (TECs) remains unclear. This study investigates the role and underlying mechanisms of GLS1 in senescent TECs. Using D-galactose (D-gal)-induced senescence of HK-2 cells, we found that GLS1 inhibition eliminated senescent TECs by promoting excessive mitochondrial permeability transition pore (mPTP) opening. Mechanistically, the excessive mPTP opening is associated with upregulation of mitofusin 1 (MFN1). Inhibition of GLS1 in D-gal-treated HK-2 cells induced a shift in mitochondrial dynamics from fission to fusion, accompanied by a significant increase in MFN1 expression. Knocking down MFN1 reduced the mPTP opening and the expression of mPTP-related genes (PPIF, VDAC and BAX) in cells co-treated with D-gal and the GLS1 inhibitor BPTES. Moreover, treatment of aged mice with BPTES specifically eliminated senescent TECs and ameliorated age-associated kidney disease. These findings reveal that GLS1 inhibition eliminate senescent TECs by promoting excessive mPTP opening, suggesting that targeting GLS1 may be a novel senolytic strategy for alleviating aging-related kidney diseases.

Fish telomere lengths vary significantly across the numerous species, implicating diverse life strategies and environmental adaptations. Zebrafish have telomere dynamics that are comparable to humans and are emerging as a key model in which to unravel the systemic effects of telomere shortening on aging and interorgan communication. Here, we discuss zebrafish telomere biology, focusing on the organismal impact of telomere attrition beyond cellular senescence, with particular emphasis on how telomeric shortening in specific tissues can unleash widespread organ dysfunction and disease. This highlights a novel aspect of tissue communication, whereby telomere shortening in one organ can propagate through biological networks, influencing the aging process systemically. These discoveries position zebrafish as a valuable model for studying the complex interactions between telomeres, aging, and tissue cross talk, providing important insights with direct relevance to human health and longevity.

Aging is tightly associated with reduced immune protection but increased risk of autoimmunity and inflammatory conditions. Regulatory T cells are one of the key cells to maintaining immune homeostasis. The age-dependent changes in CD4

The vestibular processing regions of the cerebellum integrate vestibular information with other sensory modalities and motor signals to regulate balance, gaze stability, and spatial orientation. A class of excitatory glutamatergic interneurons known as unipolar brush cells (UBCs) are highly concentrated within the granule cell layer of these regions. UBCs receive vestibular signals directly from primary vestibular afferents and indirectly from mossy fibers. Each UBC excites numerous granule cells and could contribute to computations necessary for balance-related motor function. Prior research has implicated UBCs in motor function, but their influence on balance performance remains unclear, especially in aged mice that have age-related impairment. Here we tested whether UBCs contribute to motor coordination and balance by disrupting their activity with chemogenetics in aged and young mice. Age-related balance deficits were apparent in mice > 6 months old. Disrupting the activity of a subpopulation of UBCs caused aged mice to fall off a balance beam more frequently and altered swimming behaviors that are sensitive to vestibular dysfunction. These effects were not seen in young (7-week-old) mice. Thus, disrupting the activity of UBCs impairs mice with age-related balance issues and suggest that UBCs are essential for balance and vestibular function in aged mice.

Brown adipose tissue (BAT), a major subtypes of adipose tissues, is known for thermogenesis and promoting healthful longevity. Our hypothesis is that BAT protects against impaired healthful longevity, i.e., obesity, diabetes, cardiovascular disorders, cancer, Alzheimer's disease, and reduced exercise tolerance. While most prior studies have shown that exercise regulates BAT activation and improves BAT density, relatively few have shown that BAT increases exercise performance. In contrast, our recent studies with the regulator of G protein signaling 14 (RGS14) knockout (KO) model of extended longevity showed that it enhances exercise performance, mediated by its more potent BAT, compared with BAT from wild type mice. For example, when the BAT from RGS14 KO mice is transplanted to WT mice, their exercise capacity is enhanced at 3 days after BAT transplantation, whereas BAT transplantation from WT to WT mice increased exercise performance, but only at 8 weeks after transplantation. The goal of this research perspective is to review the role of BAT in mediating healthful longevity, specifically exercise capacity. In view of the ability of BAT to mediate healthful longevity and enhance exercise performance, it is likely that a pharmaceutical analog of BAT will become a novel therapeutic modality.

With the accumulation of knowledge on aging, people have gradually realized that among the many factors that cause individual aging, the accumulation of aging cells is an essential cause of organ degeneration and, ultimately, age-related diseases. Most cells present in the bone microenvironment gradually age over time, leading to an imbalance of osteogenesis, osteoclastogenesis, adipogenesis, and chondrogenesis. This imbalance contributes to age-related bone loss and the development of age-related bone diseases, such as osteoporosis. Bone aging can prolong the lifespan and delay the development of age-related diseases. Nanoparticles have controllable and stable physical and chemical properties and can precisely target different tissues and organs. By preparing multiple easily modified and biocompatible nanoparticles as different drug delivery carriers, specifically targeting various diseased tissues for controlled-release and sustained-release administration, the delivery efficiency of drugs can be significantly improved, and the toxicity and side effects of drugs can be substantially reduced, thereby improving the therapeutic effect of age-related bone diseases. In addition, other novel anti-aging strategies (such as stem cell exosomes) also have significant scientific and practical significance in anti-aging research on age-related bone diseases. This article reviews the research progress of various nano-drug-loaded particles and emerging anti-aging methods for treating age-related bone diseases, offering new insights and directions for precise targeted clinical therapies.

This study evaluated the impact of masticatory difficulty on the development and progression of malnutrition, frailty, sarcopenia, and disability in community-dwelling adults, using data from the Korean Frailty and Aging Cohort Study.

Lithocholic acid (LCA) is accumulated in mammals during calorie restriction and it can activate AMP-activated protein kinase (AMPK) to slow down ageing

The objective of this investigation was to examine the frequency and determinants related to body composition of sarcopenia among aging individuals residing in the Beijing community through implementation of the diagnostic criteria for sarcopenia outlined by the 2019 Asian Working Group for Sarcopenia (AWGS).

Sleep quality and quantity decrease with age, and sleep disturbance increases the risk of many age-associated diseases. There is a significant relationship between nutritional status and sleep outcomes, with malnutrition inducing poor sleep quality in older adults. However, it remains elusive whether, and if so how, nutritional supplementation prevents age-associated sleep problems. Here, we utilized Drosophila to investigate the effects of a malnutrition diet with restricted yeast, a primary protein source, and supplementation of ten essential amino acids (EAAs) on sleep profiles during aging. Compared with the standard diet containing 2.7% yeast, the malnutrition diet containing 0.27% yeast significantly decreased target of rapamycin (TOR) signaling and shortened the lifespan of male Canton-S flies. By contrast, age-associated sleep loss, sleep fragmentation, and loss of rhythm strength were similarly observed under both diets. Supplementation of the malnutrition diet with EAAs in restricted yeast significantly ameliorated age-associated sleep loss and sleep fragmentation without altering loss of rhythm strength. It also rescued decreased TOR signaling activity but not the shortened lifespan, suggesting that the effects of EAAs on sleep integrity are independent of TOR activity and lifespan regulation. These results may help to develop dietary interventions that improve age-related sleep problems in humans.

Population aging is a major global trend with significant social, economic, and health implications. In China, the increasing aging population presents challenges, including increased chronic diseases and disabilities. Social capital has emerged as vital in determining health outcomes for middle-aged and older adults. This study seeks to examine the impact of social capital and educational attainment on physical functioning in middle-aged and older adults, with particular emphasis on the moderating effect of education within this relationship.

Worldwide population is ageing rapidly. Lifestyle factors are essential targets for leading to behaviour change interventions that promote healthy aging.

Extensive accumulation of senescent cells contributes to organismal aging, and slowing down the process of cellular senescence may ameliorate age-related pathologies. Targeted inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) is found to suppress the conversion of cells to senescence. The regulatory-associated protein of mTOR (Raptor), a key component of mTORC1, has been implicated as important in the aging process, and its druggability deserves to be investigated. Due to high efficiency and high convenience in drug construction, siRNA shows great potential in silencing Raptor expression via RNA interfering therapy. Here, we developed a functionalized anti-aging nanoplatform based on tetrahedral DNA nanostructures (TDNs) encapsulating siRNA targeting Raptor for synergistic anti-aging therapy, named siR-TDN

Drugs that eliminate senescent cells, senolytics, can be powerful when combined with prosenescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a pyroptosis-apoptosis-necroptosis (PAN)optosis-like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis. Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death receptor 5 via Jun N-terminal protein kinase (JNK) pathway activation. We show that a combination of a death receptor 5 (DR5) agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent natural killer (NK) and CD8+ T cell-mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine interleukin 18 (IL18).

Unfit cells with defective signalling or gene expression are eliminated through competition with neighbouring cells. However, physiological roles and mechanisms of cell competition in vertebrates remain unclear. In addition, universal mechanisms regulating diverse cell competition are unknown. Using zebrafish imaging, we reveal that cell competition ensures robust patterning of the spinal cord and muscle through elimination of cells with unfit sonic hedgehog activity, driven by cadherin-mediated communication between unfit and neighbouring fit cells and subsequent activation of the Smad-Foxo3-reactive oxygen species axis. We identify Foxo3 as a common marker of loser cells in various types of cell competition in zebrafish and mice. Foxo3-mediated physiological cell competition is required for eliminating various naturally generated unfit cells and for the consequent precise patterning during zebrafish embryogenesis and organogenesis. Given the implication of Foxo3 downregulation in age-related diseases, cell competition may be a defence system to prevent abnormalities throughout development and adult homeostasis.

Cellular senescence (CS) is a hallmark of Alzheimer's disease (AD). However, the mechanisms through which CS contributes to AD pathogenesis remain poorly understood. We found that CS level in AD was higher compared with the healthy control group. Transcriptome-based differential expression analysis identified 113 CS-related genes in blood and 410 in brain tissue as potential candidate genes involved in AD. To further explore the causal role of these genes, an integrative mendelian randomization analysis was conducted, combining AD genome-wide association study summary statistics with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) data from blood samples, which identified five putative AD-causal genes (CENPW, EXOSC9, HSPB11, SLC44A2, and SLFN12) and 18 corresponding DNA methylation probes. Additionally, integrative analysis between eQTLs and mQTLs from blood uncovered two genes and 12 corresponding regulatory elements involved in AD. Furthermore, two genes (CDKN2B and ITGAV) were prioritized as putative causal genes in brain tissue and were validated through in vitro experiments. The multi-omics integration study revealed the potential role and underlying biological mechanisms of CS driven by genetic predisposition in AD. This study contributed to fundamental understanding of CS in AD pathogenesis and facilitated the identification of potential therapeutic targets for AD prevention and treatment.

Calorie restriction (CR) and physical exercise (EX) are well-established interventions known to extend health span and lifespan in animal models. However, their impact on human biological aging remains unclear. With recent advances in omics technologies and biological age (BioAge) metrics, it is now possible to assess the impact of these lifestyle interventions without the need for long-term follow-up. This study compared BioAge biomarkers in 41 middle-aged and older adult long-term CR practitioners, 41 age- and sex-matched endurance athletes (EX), and 35 sedentary controls consuming Western diets (WD), through PhenoAge: a composite score derived from nine blood-biomarkers. Additionally, a subset of participants (12 CR, 11 EX, and 12 WD) underwent multi-omic profiling, including DNA methylation and RNAseq of colon mucosa, blood metabolomics, and stool metagenomics. A group of six young WD subjects (yWD) served as a reference for BioAge calculation using Mahalanobis distance across six omic layers. The results demonstrated consistently lower BioAge biomarkers in both CR and EX groups compared to WD controls across all layers. CR participants exhibited lower BioAge in gut microbiome and blood-derived omics, while EX participants had lower BioAge in colon mucosa-derived epigenetic and transcriptomic markers, suggesting potential tissue-specific effects. Multi-omic pathway enrichment analyses suggested both shared and intervention-specific mechanisms, including oxidative stress and basal transcription as common pathways, with ether lipid metabolism uniquely enriched in CR. Despite limitations due to sample size, these findings contribute to the broader understanding of the potential anti-aging effects of CR and EX, offering promising directions for further research.

Healthy aging is associated with deficits in cognitive performance and brain changes, including in the cerebellum. Cerebellar communication with the cortex via closed-loop circuits through the thalamus have been established and these circuits are closely related to the functional topography of the cerebellum. In this study, we sought to elucidate relationships between cerebellar structure and function with cognition in healthy aging. We explored this relationship in 138 healthy adults (aged 35-86, 53% female) using resting-state functional connectivity MRI (fcMRI), cerebellar volume, and cognitive and motor assessments. Behavioral tasks assessed attention, processing speed, working memory, episodic memory, and motor abilities. We expected to find negative relationships between lobular volume with age, and positive relationships between specific lobular volumes with motor and cognitive behavior, respectively. We predicted lower cerebello-cortical fcMRI with increased age. Behaviorally, we expected higher cerebello-frontal and cerebello-association area fcMRI cerebellar connectivity to correlate with better behavioral performance. Correlations were conducted between cerebellar lobules I-IV, V, Crus I, Crus II, vermis VI and behavioral measures. We found lower volumes with increased age as well as both higher and lower cerebellar connectivity relationships with increased age, consistent with literature on functional connectivity and network segregation in aging. Further, we revealed unique associations between cerebellar structure and connectivity with comprehensive behavioral measures in a healthy aging population. Our findings further highlight the role of the cerebellum in aging.

The population of older adults is exponentially expanding. Alongside aging comes the onset of chronic disease, decline of functional capacity, and reduced quality of life. Thus, this population increase will stress the capacity and financial viability of health and long-term care systems. Developing pre-clinical models for age-related functional decline is imperative to advancing therapies that extend healthspan and prolong independence. Previously in a cross-sectional study, we established a powerful composite scoring system we termed CFAB (comprehensive functional assessment battery). CFAB measures physical function and exercise capacity using well-validated determinants to measure overall motor function, fore-limb strength, four-limb strength/endurance, aerobic capacity, and volitional exercise/activity rate. In the current work, we used CFAB to track cohorts of male and female C57BL/6 mice over the lifespan (measuring CFAB at 6, 12, 18, 24, and 28 months of age). Overall, we found statistically significantly declining function as the mice aged, with some differences between males and females in trajectory and slope. We also determined that body mass changes presented differently between sexes, and tracked body composition (fat percentage, using magnetic resonance imagery) in females. In a subset of mice, we tracked in vivo contractile physiology noting declines in plantar flexor maximum isometric torque. In summary, our data suggest that males and females declined at different rates. We confirmed the efficacy of CFAB to track longitudinal changes in exercise capacity and physical fitness in both males and females, further validating the system to track age-related functional decline.

Diet is a key modifiable risk factor in many chronic diseases, including age-related diseases. The Mediterranean diet (MedDiet) is an extensively studied dietary pattern which has been proposed as a lifestyle intervention to promote healthy aging in the general population, due to its numerous health benefits. Randomized controlled trials (RCTs) have attempted to explore the mechanism(s) by which the MedDiet exerts its beneficial effects on aging. One proposed mechanism is that the MedDiet helps to slow down a process called 'inflamm-aging', a type of chronic, low-grade inflammation which contributes to aging. To explore the evidence supporting this hypothesized mechanism, we conducted a scoping review of existing RCTs which used a MedDiet intervention and assessed at least one molecular outcome of potential relevance to inflamm-aging. We identified 14 papers representing 12 unique RCTs. Based on our findings, we present 10 recommendations for the next clinical trial of the MedDiet in inflamm-aging.

In this paper, we advance the network theory of aging and mortality by developing a causal mathematical model for the mortality rate. First, we show that in large networks, where health deficits accumulate at nodes representing health indicators, the modeling of network evolution with Poisson processes is universal and can be derived from fundamental principles. Second, with the help of two simplifying approximations, which we refer to as mean-field assumption and homogeneity assumption, we provide an analytical derivation of Gompertz law under generic and biologically relevant conditions. We identify the parameters in Gompertz law as a function of the parameters driving the evolution of the network, and illustrate our computations with simulations and analytic approximations.

Evidence that life-extending interventions are not uniformly effective across the lifespan calls for an analytic tool that can estimate age-specific treatment effects on mortality hazards. Here we report such a tool, applying it to mouse data from 42 compounds tested in the NIA Interventions Testing Program. This tool identified agents that either reduced (22) or increased (15) mortality hazards or did both (2) in at least one sex, most with marked variation in the duration of efficacy and magnitude of effect size. Only 8 reduced mortality hazards after 90% mortality, when the burden of senescence is the greatest. Sex differences were common. This new analytic tool complements the commonly used log-rank test. It detects more potential life-extending candidates (22 versus 10) and indicates when during the life course they are effective. It also uncovers adverse effects.

Biological age (BA) is a marker to accurately assess aging, facilitating the prediction of age-related diseases and promoting healthy aging. In recent years, first- and second-generation organ-system-specific BA has been developed using chronological age (CA) or aging-related outcomes (mortality) as training phenotypes and data from questionnaires, physical examinations, clinical biochemistry, imaging, and multi-omics to investigate the specificity of organ systems aging. Here, we review the methodologies for constructing BA, current efforts to assess organ system-specific BA, and related genome-wide association studies (GWAS). Previous studies predominantly used the first-generation BA method, using CA as training phenotypes. Organ-system-specific BA can accurately predict the disease risk of corresponding organ systems. We propose the development of organ system-specific BA through second-generation BA models and conducting GWAS and Mendelian randomization studies to explore organ system-specific aging processes, which will provide a theoretical foundation for the clinical application of organ system-specific BA.

Epigenetic clocks have been developed to track both chronological age and biological age, which is defined by physiological biomarkers and the risk of adverse health outcomes. Epigenetic age acceleration (EAA) has been found to predict various diseases, aging-related factors, and mortality. However, epigenetic clocks have predominantly been developed with individuals of European or Hispanic ancestry, and their association with health outcomes and environmental factors has not been sufficiently assessed in East Asian populations. Here, we investigated nine epigenetic clocks: five trained on chronological age (first-generation) and four on biological age (second-generation), using DNA methylation data from blood samples of South Koreans. EAAs of second-generation epigenetic clocks reflected the risk of chronic diseases (type 2 diabetes and hypertension), levels of health-related blood markers (alanine aminotransferase, aspartate aminotransferase, high density lipoprotein, triglyceride, and high sensitivity C-reactive protein), and lung functions (percentage of predicted FEV1 and percentage of predicted FVC), while EAAs of first generation clocks did not. Using follow-up data, we also found that EAAs of second-generation clocks were associated with the time to onset risks of chronic diseases. Health behavior factors (drinking, smoking, exercise, body mass index, and waist-hip ratio), socioeconomic status (income level and educational attainment), and psychosocial status were associated with EAAs of second-generation clocks, while only smoking status was associated with EAAs of first-generation clocks. We conducted validation analyses in an independent South Korean cohort and replicated the association of EAAs with health outcomes and environmental factors. Age acceleration of epigenetic clocks is influenced by various environmental factors and can serve as an effective predictor of health in South Korea.

BackgroundCompared to chronological age, biological age (BA), a concept introduced in recent years, more accurately reflects the true aging status of the body. While biological aging has been found to be associated with various cardiovascular diseases, its relationship with abdominal aortic aneurysm (AAA) remains unclear. MethodsThis study utilized data extracted from UK Biobank for analysis. Telomere length (TL), and BA acceleration calculated using the Klemera-Doubal (KDM) and PhenoAge methods, were employed as surrogate measures to assess biological aging. Cox regression was primarily performed to explore the association between biological aging and AAA risk. Genetic susceptibility was assessed by constructing a polygenic risk score (PRS). ResultsThis study included 311,646 participants, predominantly women and White, with a median age of 58 years. During a median follow-up of 12.54 years, 1,339 new cases of AAA (4.3{per thousand}) were reported. Each standard deviation (SD) decrease in TL was associated with a 20% increased risk of AAA (HR=1.20, 95% CI=1.14-1.27); each SD increase in KDM-BA acceleration was associated with a 21% increased risk (HR=1.21, 95% CI=1.12-1.29); and each SD increase in PhenoAge acceleration was associated with a 40% increased risk (HR=1.40, 95% CI=1.32-1.48). These associations were independent of genetic risk, as assessed by the PRS, and demonstrated a joint effect with genetic predisposition on the long-term risk of AAA. ConclusionAccelerated biological aging was longitudinally associated with an increased risk of AAA, suggesting it may be a significant factor and potential biomarker for the occurrence of the condition.

Hesperetin (Hst) is a common citrus fruit flavonoid with antioxidant, anti-inflammatory, and anti-neurodegenerative effects. To explore the antioxidant and anti-aging effects and mechanisms of Hst, we induced chronic oxidative stress in

Mesenchymal stem/stromal cells (MSCs) are becoming increasingly important for biomedical applications, such as cell therapy, disease modeling, and drug screening. At the same time, long-term cultivation, which is necessary to prepare a sufficient amount of cellular material for therapeutic and research purposes, is accompanied by the development of replicative senescence. Partial reprogramming emerged as a novel method that shows promising results in the rejuvenation of cells in vitro and in vivo; however, it has not yet been applied for human MSCs that have undergone replicative senescence in culture. In the present study, we subjected senescent human endometrial MSCs to partial reprogramming using Sendai virus vectors containing genes encoding Yamanaka transcription factors Oct4, Sox2, Klf4, and c-Myc. Characterization of the MSCs 5 days after transduction showed the loss of key markers of senescence: the youthful morphology was restored, the expression of senescent-associated β-galactosidase and the number of double-strand DNA breaks decreased, proliferation was activated, and the DNA damage response was enhanced. Further, using an in vitro wound-healing assay, we demonstrated that conditioned medium from partially reprogrammed MSCs showed higher therapeutic activity than that from senescent cells. However, a biosafety test revealed the presence of viral components in conditioned medium, which caused the agglutination of erythrocytes. Collectively, our data suggest that partial reprogramming is a potentially effective strategy for the rejuvenation of cultured MSCs in late passages but requires the use of virus-free protocols, such as chemical reprogramming.

Estimators of biological age hold promise for use in preventive medicine, for early detection of chronic conditions, and for monitoring the effectiveness of interventions aimed at improving population health. Among the promising biomarkers in this field are DNA methylation-based biomarkers, commonly referred to as epigenetic clocks. This review provides a survey of these clocks, with an emphasis on second-generation clocks that predict human morbidity and mortality. It explores the validity of epigenetic clocks when considering factors such as race, sex differences, lifestyle, and environmental influences. Furthermore, the review addresses the current challenges and limitations in this research area.

Telomeres are DNA-protein structures that primarily protect chromosomes and serve multiple functions of gene regulation. When cells divide, telomeres shorten and their main repair system in ectotherms - telomerase - replaces lost nucleotide complexes ((T2AG3)n in vertebrates). It remains a challenge to experimentally investigate resource requirements for telomere maintenance and its effects on lifespan-reproductive tradeoffs in the wild. In sand lizards (Lacerta agilis), we show that higher female investments into reproduction results in corresponding shortening of telomeres and that males have less frequent and less profound telomere shortening than females; a contributing factor to this may be males' higher telomerase levels. To manipulate resource access for telomere maintenance, we exploit a pseudo-experimental opportunity to analyze 'onboard' resources long-term using lizards that drop their tails with fat and nutrient deposits when attacked by predators. Females with less resources due to regrown tails less often and less profoundly elongate telomeres. Adult lizards with the most TL elongation live the longest, females with the highest lifetime reproductive success shorten telomeres the most, whereas males with the most telomere elongation have the highest lifetime reproductive success. This suggests ongoing evolution of resource-constrained telomere maintenance.

Forecasts about the aging trend of the world population agree on identifying increased life expectancy as a serious risk factor for the financial sustainability of social healthcare systems if not properly supported by innovative care management policies. Such policies should include the integration within traditional healthcare services of assistive technologies as tools for prolonging healthy and independent living at home, but also for introducing innovations in clinical practice such as long-term and remote health monitoring. For their part, solutions for active and assisted living have now reached a high degree of technological maturity, thanks to the considerable amount of research work carried out in recent years to develop highly reliable and energy-efficient wearable sensors capable of enabling the development of systems to monitor activity and physiological parameters over time, and in a minimally invasive manner. This work reviews the role of wearable sensors in the design and development of assisted living solutions, focusing on human activity recognition by joint use of onboard electromyography sensors and inertial measurement units and on the acquisition of parameters related to overall physical and psychological conditions, such as heart activity and skin conductance.

Serotonin (5-HT) is an important neurotransmitter for cognition and neurogenesis in the dentate gyrus (DG), which occurs via movement stimulation such as physical activity. Brain 5-HT function changes secondary to aging require further investigation. We evaluated whether aged animals would present changes in the number of 5-HT neurons in regions such as the dorsal (DRN) and median (MRN) raphe nuclei and possible changes in the rate of cellular activation in the DG in response to acute running, as a reduction in 5-HT neurons could contribute to a decline in neuronal activation in the DG in response to physical activity in aged mice. This study was conducted on adult (3 months old) and aged (19 months old) male and female mice. Immunohistochemistry, microscopic analysis, and treadmill-running tests were also performed. The data revealed that in aged mice, a reduction in the number of 5-HT neurons in the DRN and MRN of male and female mice was observed. The reduction in the DRN was greater in females. Furthermore, aged animals demonstrate a lower rate of c-Fos labeling in the DG when stimulated by physical exercise. These data indicate that aging may be associated with a reduction in the number of 5-HT neurons in the DRN and MRN, which may lead to a decline in 5-HT availability in the target regions, including the DG. The reduced c-Fos expression in the DG after running in aged mice indicates a decreased response to physical activity, which is potentially linked to serotonergic deficits.

Frailty, particularly cognitive frailty, is an escalating public health issue. Cognitive frailty is defined by the simultaneous presence of physical frailty and cognitive impairment, without a confirmed diagnosis of dementia, and has become a significant geriatric syndrome. This study aimed to explore the association between chronic pain and the risk of cognitive frailty.

In the context of population aging, activities of daily living (ADL) disability has brought great challenges to the health of the elderly. The relationship between plant-based dietary patterns and the health of the elderly has been widely discussed. However, few studies have explored the correlation between plant-based dietary patterns and ADL disability in older adults.

The Mediterranean diet (MD) plays an important role in delaying vascular aging. The main objective of this study was to analyze the association between adherence to the MD and vascular aging estimated with brachial-ankle pulse wave velocity (ba-PWV) in a Spanish population sample and the differences by sex.

Naked mole-rats (NMRs, Heterocephalus glaber) are highly unusual rodents exhibiting remarkable adaptations to their subterranean habitat and resistance to developing various age-related diseases such as those related to abnormal cell proliferation or cancer, neurodegeneration and inflammation. In other rodents, as well as humans, a ubiquitous Ca2+ influx pathway, namely the store-operated Ca2+ entry (SOCE), has been implicated in all these diseases. SOCE is triggered by intracellular Ca2+ store depletion resulting in interaction of Stim proteins with Orai proteins, the putative homologs of which appear be present in the NMR genome, but no characterisation of SOCE in NMRs has yet been conducted. In this study, we provide the first functional and pharmacological characterization of SOCE in NMR cells using both excitable and non-excitable cells.

Frailty is a complex aging-related syndrome characterized by a cumulative loss of physiological reserve and increased vulnerability to adverse clinical outcomes, including falls, disability, incapacity and death. While an increasing number of studies suggest that the gut microbiota may play a key role in the pathophysiology of frailty, direct evaluation of the association between gut microbiome alterations and frailty in older adults remains limited.

Increasing evidence on the adverse health impacts of microplastics (MPs) is available, but their associated risks to the well-being of humans and long-term impacts are poorly understood. An indicator of the remote effects of MPs may be their influence on the rate of aging. To assess the effects of MPs on the aging process, we used accelerated senescence OXYS rats that develop a complex of geriatric diseases. We prepared the polyethylene terephthalate MPs (2-6 microns in size) and in OXYS and Wistar (maternal strain) rats assessed the influence of chronic administration of MPs (10 or 100 mg/kg per day from age 1.5 to 3.5 months,) on the hematological and biochemical blood parameters, spatial learning, and memory. In addition, the effects of MPs on the development of cataracts and retinopathy, similar to age-related macular degeneration (AMD), in OXYS rats were assessed. We found that in the absence of significant changes in standard clinical blood parameters, chronic MP administration negatively affected the cognitive functions of both Wistar rats and OXYS rats. Additionally, a dose of 100 mg/kg MPs contributed to cataract and AMD progression in OXYS rats. Our results suggest that MPs may increase the rate of aging and, in the long term, lifespan.

Cartilage degeneration is a key feature of aging and osteoarthritis, characterized by the progressive deterioration of joint function, pain, and limited mobility. Current treatments focus on symptom relief, not cartilage regeneration. Mesenchymal stromal cells (MSCs) offer a promising therapeutic option due to their capability to differentiate into chondrocytes, modulate inflammation, and promote tissue regeneration. This review explores the potential of MSCs for cartilage regeneration, examining their biological properties, action mechanisms, and applications in preclinical and clinical settings. MSCs derived from bone marrow, adipose tissue, and other sources can self-renew and differentiate into multiple cell types. In aging cartilage, they aid in tissue regeneration by secreting growth factors and cytokines that enhance repair and modulate immune responses. Recent preclinical studies show that MSCs can restore cartilage integrity, reduce inflammation, and improve joint function, although clinical translation remains challenging due to limitations such as cell viability, scalability, and regulatory concerns. Advancements in MSC delivery, including scaffold-based approaches and engineered exosomes, may improve therapeutic effectiveness. Potential risks, such as tumorigenicity and immune rejection, are also discussed, emphasizing the need for optimized treatment protocols and large-scale clinical trials to develop effective, minimally invasive therapies for cartilage regeneration.

The efficacy of assisted reproductive technologies (ARTs) in older women remains constrained, largely due to an incomplete understanding of the underlying pathophysiology. This review aims to consolidate the current knowledge on age-associated mitochondrial alterations and their implications for ovarian aging, with an emphasis on the causes of mitochondrial DNA (mtDNA) mutations, their repair mechanisms, and future therapeutic directions. Relevant articles published up to 30 September 2024 were identified through a systematic search of electronic databases. The free radical theory proposes that reactive oxygen species (ROS) inflict damage on mtDNA and impair mitochondrial function essential for ATP generation in oocytes. Oocytes face prolonged pressure to repair mtDNA mutations, persisting for up to five decades. MtDNA exhibits limited capacity for double-strand break repair, heavily depending on poly ADP-ribose polymerase 1 (PARP1)-mediated repair of single-strand breaks. This process depletes nicotinamide adenine dinucleotide (NAD⁺) and ATP, creating a detrimental cycle where continued mtDNA repair further compromises oocyte functionality. Interventions that interrupt this destructive cycle may offer preventive benefits. In conclusion, the cumulative burden of mtDNA mutations and repair demands can lead to ATP depletion and elevate the risk of aneuploidy, ultimately contributing to ART failure in older women.

Emanating from several decades of study into the effects of the aging process after spinal cord injury (SCI), "accelerated aging" has become a common expression as the SCI accelerates the onset of age-related pathologies. However, the aging process follows a distinct trajectory, characterized by unique patterns of decline that differ from those observed in the general population without SCI. Aging brings significant changes to muscles, bones, and hormones, impacting overall physical function. Muscle mass and strength begin to decrease with a reduction in muscle fibers and impaired repair mechanisms. Bones become susceptible to fractures as bone density decreases. Hormonal changes combined with decreased physical activity accelerate the reduction of muscle mass and increase in body fat. Muscle atrophy and skeletal muscle fiber type transformation occur rapidly and in a unique pattern after SCI. Bone loss develops more rapidly and results in an increased risk of fractures in body regions unique to individuals with SCI. Other factors, such as excessive adiposity, decreased testosterone and human growth hormone, and increased systemic inflammation, contribute to a higher risk of neuropathically driven obesity, dyslipidemia, glucose intolerance, insulin resistance, and increasing cardiovascular disease risk. Cardiorespiratory changes after SCI result in lower exercise heart rates, decreased oxygenation, and mitochondrial dysfunction. While it is important to acknowledge the accelerated aging processes after SCI, it is essential to recognize the distinct differences in the aging process between individuals without physical disabilities and those with SCI. These differences, influenced by neuropathology, indicate that it may be more accurate to describe the aging process in individuals with chronic SCI as neurogenic accelerated aging (NAA). Research should continue to address conditions associated with NAA and how to ameliorate the accelerated rate of premature age-related conditions. This review focuses on the NAA processes and the differences between them and the aging process in those without SCI. Recommendations are provided to help slow the development of premature aging conditions.

Amyloid beta (Aβ) is a neuronal metabolic product that plays an important role in maintaining brain homeostasis. Normally, intensive brain Aβ formation is accompanied by its effective lymphatic removal. However, the excessive accumulation of brain Aβ is observed with age and during the development of Alzheimer's disease (AD) leading to cognitive impairment and memory deficits. There is emerging evidence that plasmalogens (Pls), as one of the key brain lipids, may be beneficial for AD and cognitive aging. Here, we studied the effects of Pls on cognitive functions and the lymphatic clearance of Aβ from the brain of AD mice and mice of different ages. The results showed that Pls effectively reduce brain Aβ levels and facilitate learning in aged but not old mice. In AD mice, Pls improve the lymphatic clearance of Aβ that is accompanied by an increase in general motor activity and an improvement of the emotional status and learning ability. Thus, these findings suggest that Pls could be a promising candidate for the alternative or concomitant therapy of AD and age-related brain diseases to enhance the lymphatic clearance of Aβ from the brain and cognitive functions.

Genetic manipulations, dietary composition and supplementations with varied drugs and natural compounds were shown to extend both the life- and health-span in different model organisms. An understanding of the mechanisms behind the beneficial properties of intervention includes the evaluation of physiological and molecular traits at certain time points that reflect the values at distinguished chronological age. Thus, if one cohort has a long-lived phenotype than measurements at certain time points represent the difference between organisms of different biological ages. We have compared reproduction and consumption of specific macronutrients for flies of the same cohort but related to different quartiles of chronological and biological age. We found that the decline in carbohydrate or protein consumption was stronger in the case of chronological rather than biological age. However, flies of biological or chronological quartile 4 consumed virtually the same amounts of macronutrients. The decline in reproduction was significantly reduced in relation to biological age. Thus, the decline was about 38-68% when within chronological quartiles 2 and 1 but only 4-31% for biological ones. The reproductive capacity was reduced by 86-93% in flies of chronological Q4 as compared to a 60-77% decrease for those of biological. Starting from quartile 2 biologically aged flies laid significantly higher number of eggs than flies of the same chronological quartile. Our results point out the significant difference in flies of the same biological and chronological quartile and raise the question about the suitability of comparison traits of organisms with different lifespans same chronological age.

The dietary index for gut microbiota (DI-GM) is a newly proposed metric for assessing diet quality, and its relationship with biological age is unclear. We hypothesize that consuming foods conducive to a healthy gut microbiota environment may decelerate aging.

The average life expectancy is increasing worldwide, but the same cannot be said for a healthy life expectancy (defined as the period during which a person can live a healthy and independent life). Therefore, a major challenge is how to extend healthy life expectancy. One option is to reduce age-related muscle atrophy (sarcopenia) and cognitive decline. Since there is no specific cure for frailty, the prevention of frailty based on nutrition and exercise is a new approach to achieve healthy longevity. Studies have shown that interventions combining nutritional supplements and exercise are effective in improving muscle strength, muscle mass, and walking speed. Thus, the search for drugs and functional foods to combat frailty has attracted researchers' attention. Whale meat extract (WME) contains many imidazole dipeptides, especially the unique component balenine, which has various functional anti-fatigue and antioxidant properties, and hypermobility effects. Here, we investigated the effects of WME on the aging and health of

Mosaic loss of Y chromosome (mLOY) is an acquired condition wherein a sizeable proportion of an organ's cells have lost their Y. Large-scale cohort studies have shown that mLOY is age-dependent and a strong risk factor for all-cause mortality and adverse outcomes of age-related diseases. Emerging multi-omics approaches that combine gene expression, epigenetic and mutational profiling of human LOY cell populations at single-cell levels, and contemporary work in in vitro cell and preclinical mouse models have provided important clues into how mLOY mechanistically contributes to disease onset and progression. Despite these advances, what has been missing is a system-level insight into mLOY. By integrating the most recent advances in wide-ranging aspects of mLOY research, we summarize a unified model to understanding the cause and consequence of mLOY at the molecular, cellular, and organismal levels. This model, referred to as the "Unstable Y Cascade model," states that (i) the rise and expansion of LOY result from interaction by the inherently unstable Y, germline genetic and epigenetic variants, and numerous cell-intrinsic and external factors; (ii) LOY initiates genomic, epigenomic, and transcriptomic alterations in X and autosomes, thereafter induces a cascade of tissue-specific cellular alterations that contribute locally to the onset and progression of diseases; and (iii) LOY cells exert paracrine effects to non-LOY cells, thereby amplifying LOY-associated pathological signaling cascades to remote non-LOY cells. This new model has implications in the development of therapeutic interventions that could prevent or delay age-related diseases via mitigating mLOY burden.

The critical role of some RAB family members in oocyte meiosis has been extensively studied, but their role in oocyte aging remains poorly understood. Here, we report that the vesicle trafficking regulator, RAB9 GTPase, is essential for oocyte meiosis and aging in humans and mice. RAB9 was mainly located at the meiotic spindle periphery and cortex during oocyte meiosis. In humans and mice, we found that the RAB9 protein level were significantly increased in old oocytes. Age-related accumulation of RAB9 inhibits first polar body extrusion and reduces the developmental potential of oocytes. Further studies showed that increased Rab9 disrupts spindle formation and chromosome alignment. In addition, Rab9 overexpression disrupts the actin cap formation and reduces the cortical actin levels. Mechanically, Rab9-OE increases ROS levels, decreases mitochondrial membrane potential, ATP content and the mtDNA/nDNA ratio. Further studies showed that Rab9-OE activates the PINK1-PARKIN mitophagy pathway. Importantly, we found that reducing RAB9 protein expression in old oocytes could partially improve the rate of old oocyte maturation, ameliorate the accumulation of age-related ROS levels and spindle abnormalities, and partially rescue ATP levels, mtDNA/nDNA ratio, and PINK1 and PARKIN expression. In conclusion, our results suggest that RAB9 is required to maintain the balance between mitochondrial function and meiosis, and that reducing RAB9 expression is a potential strategy to ameliorate age-related deterioration of oocyte quality.

Chondrocyte senescence is a key driver of osteoarthritis (OA). Mitochondrial dysfunction and oxidative stress can induce chondrocyte senescence. However, the specific mechanisms by which senescence contributes to OA progression are not fully understood. Here, it is attested that Dipeptidyl peptidase 4 (DPP4) is significantly upregulated in osteoarthritic chondrocytes in both humans and mice. DPP4 promotes oxidative stress and cellular senescence in chondrocytes through excessive mitochondrial fission in an enzyme-independent manner. Intra-articular injection of adeno-associated virus 2 to upregulate DPP4 in chondrocytes promotes post-traumatic and aging-induced OA in mice in an enzyme-independent manner. Mechanistically, DPP4 competitively binds to Myosin heavy chain 9 (MYH9), interfering with its E3 ubiquitin ligase Carboxyl terminus of Hsc70-interacting protein (CHIP), and thereby upregulates MYH9 expression. Finally, a small molecule, 4,5-Dicaffeoylquinic acid is identified, which disrupts the interaction between DPP4 and MYH9, thereby ameliorating post-traumatic and aging-induced OA in mice caused by DPP4 upregulation. The study indicates that the non-enzymatic activity of DPP4 is a promising target for OA treatment.

Aflatoxin B1 (AFB1), a known human carcinogen, represents the most toxic aflatoxin metabolite. Exposure to AFB1 causes increased oxidative stress and immunotoxicity, which are important factors contributing to aging. However, the role of AFB1-induced toxicity in altered innate immunity and aging remains largely unclear. The nematode Caenorhabditis elegans is a suitable model organism for studying aging and toxicology due to its well-studied molecular mechanisms and short life cycle. Effects of AFB1 at 1, 2.5, and 5 μM (312, 781, and 1561 μg/L) on growth, reproduction, and lifespan were examined. The Pseudomonas aeruginosa PA14 slow-killing assay was performed to investigate innate immunity, followed by studying the possible mechanisms using transgenic strains and qPCR analysis. The results showed that early life long-term AFB1 exposure (2.5 and 5 μM) delayed development, reduced reproduction, and shortened lifespan in C. elegans. Furthermore, in aged worms, AFB1 exposure caused a dose-dependent decrease in survival of C. elegans against P. aeruginosa PA14 infection. At adulthood day 4 in the presence of live Escherichia coli OP50, AFB1 (2.5 μM) significantly increased lipofuscin levels (a hallmark of aging) compared to adult day 0, whereas no increase in lipofuscin was observed in nematodes (adulthood day 4) fed with dead E. coli OP50. Additionally, the increased lipofuscin was abolished in the skn-1 mutant with either live or dead E. coli OP50. Furthermore, AFB1 suppressed intestinal SKN-1::GFP translocation. Two-way ANOVA analysis revealed that the activity of E. coli OP50 and AFB1 interactively affected the expression of genes: skn-1, gst-4, hsp-16.1, hsp-16.49, and hsp-70. Our findings highlight the role of AFB1-induced toxicity in altered innate immunity and aging through the involvement of the transcription factor SKN-1/Nrf2.

The rise in global life expectancy has led to an increase in the older population, presenting significant challenges in managing infectious diseases. Aging affects the innate and adaptive immune systems, resulting in chronic low-grade inflammation (inflammaging) and immune function decline (immunosenescence). These changes would impair defense mechanisms, increase susceptibility to infections and reduce vaccine efficacy in older adults. Cellular senescence exacerbates these issues by releasing pro-inflammatory factors, further perpetuating chronic inflammation. Moreover, comorbidities, such as cardiovascular disease and diabetes, which are common in older adults, amplify immune dysfunction, while immunosuppressive medications further complicate responses to infections. This review explores the molecular and cellular mechanisms driving inflammaging and immunosenescence, focusing on genomic instability, telomere attrition, and mitochondrial dysfunction. Additionally, we discussed how aging-associated immune alterations influence responses to bacterial, viral, and parasitic infections and evaluated emerging antiaging strategies, aimed at mitigating these effects to improve health outcomes in the aging population.

In this study we tested the hypothesis that the immunosenescence profile could account for the disproportional susceptibility of the elderly to severe forms of COVID-19. The immunological profiles of volunteers residing in endemic and non-endemic areas for chronic infectious diseases were analyzed at early stage of SARS-CoV-2 infection. A unique signature of inflammatory plasma mediators was identified in COVID-19 volunteers when compared to individuals with other flu-like syndromes. COVID-19 severity correlated with high levels of inflammatory mediators; among them, CXCL9, a serum marker of aging. Patients who progressed to hospitalization displayed high frequencies of CD8+ and CD4+ T cells expressing exhaustion and senescence markers and showed reduced and more mature B cell repertoires, which are typical of senescence. They also had an acceleration of epigenetic age measured by DNA methylation. Therefore, severe COVID-19 correlated with phenotypic, functional, and epigenetic features of accelerated immunosenescence at onset of infection.

Cellular senescence, an irreversible state of cell cycle arrest characterized by phenotypic changes and a specific secretory profile, plays a dual role in liver health and disease. Under physiological conditions, senescence aids organ repair and regeneration, but its accumulation due to aging or pathological stress significantly contributes to chronic liver diseases, including alcoholic liver disease, metabolic dysfunction-associated steatohepatitis, liver fibrosis, and hepatocellular carcinoma. Senescence is identified by a range of cellular and molecular changes, such as morphological alterations, expression of cell cycle inhibitors, senescence-associated β-galactosidase activity, and nuclear membrane changes. The onset of senescence in organ cells can affect the entire organism, primarily through the senescence-associated secretory phenotype, which has autocrine, paracrine, and endocrine effects on tissue microenvironments. The objective of this review is to offer a contemporary overview of the pathophysiological events involving hepatic senescent cells and to elucidate their role in the onset and progression of liver diseases, particularly through mechanisms like telomere shortening, genomic and mitochondrial DNA damage, and inflammation. Additionally, this review discusses the emerging senolytic therapies aimed at targeting senescent cells to delay or mitigate liver disease progression. The therapeutic potential of these interventions, alongside their safety and effectiveness, highlights the need for further research to refine these approaches and address unresolved problems in the field of hepatic cellular senescence.

In aging and metabolic disease, sarcopenic obesity (SO) correlates with intramuscular adipose tissue (IMAT). Using bioinformatics analysis, we found a potential target protein Extended Synaptotagmin 1 (E-syt1) in SO. To investigate the regulatory role of E-syt1 in muscle metabolism, we performed in vivo and in vitro experiments through E-syt1 loss- and gain-of-function on muscle physiology. When E-syt1 is overexpressed in vitro, myoblast proliferation, differentiation, mitochondrial respiration, biogenesis, and mitochondrial dynamics are impaired, which were alleviated by the silence of E-syt1. Furthermore, overexpression of E-syt1 inhibited mitophagic flux. Mechanistically, E-syt1 overexpression leads to mitochondrial calcium overload and mitochondrial ROS burst, inhibits the fusion of mitophagosomes with lysosomes, and impedes the acidification of lysosomes. Animal experiments demonstrated the inhibition of E-syt1 increased the capacity of endurance exercise, muscle mass, mitochondrial function, and oxidative capacity of the muscle fibers in OVX mice. These findings establish E-syt1 as a novel contributor to the pathogenesis of skeletal muscle metabolic disorders in SO. Consequently, targeting E-syt1-induced dysfunction may serve as a viable strategy for attenuating SO.

Increasing evidence suggests the involvement of metabolic alterations in neurological disorders, including Alzheimers disease (AD), and highlights the significance of the peripheral metabolome, influenced by genetic factors and modifiable environmental exposures, for brain health. In this study, we examined 1,387 metabolites in plasma samples from 1,082 dementia-free middle-aged participants of the population-based Rotterdam Study. We assessed the relation of metabolites with general cognition (G-factor) and magnetic resonance imaging (MRI) markers using linear regression and estimated the variance of these metabolites explained by genes, gut microbiome, lifestyle factors, common clinical comorbidities, and medication using gradient boosting decision tree analysis. Twenty-one metabolites and one metabolite were significantly associated with total brain volume and total white matter lesions, respectively. Fourteen metabolites showed significant associations with G-factor, with ergothioneine exhibiting the largest effect (adjusted mean difference = 0.122, P = 4.65x10-7). Associations for nine of the 14 metabolites were replicated in an independent, older cohort. The metabolite signature of incident AD in the replication cohort resembled that of cognition in the discovery cohort, emphasizing the potential relevance of the identified metabolites to disease pathogenesis. Lifestyle, clinical variables, and medication were most important in determining these metabolites blood levels, with lifestyle, explaining up to 28.6% of the variance. Smoking was associated with ten metabolites linked to G-factor, while diabetes and antidiabetic medication were associated with 13 metabolites linked to MRI markers, including N-lactoyltyrosine. Antacid medication strongly affected ergothioneine levels. Mediation analysis revealed that lower ergothioneine levels may partially mediate negative effects of antacids on cognition (31.5%). Gut microbial factors were more important for the blood levels of metabolites that were more strongly associated with cognition and incident AD in the older replication cohort (beta-cryptoxanthin, imidazole propionate), suggesting they may be involved later in the disease process. The detailed results on how multiple modifiable factors affect blood levels of cognition- and brain imaging-related metabolites in dementia-free participants may help identify new AD prevention strategies.

Aging negatively affects the capacity of muscle stem cells (MuSCs) to regenerate muscle. In this issue of the JCI, Ancel, Michaud, and colleagues used a high-content imaging screen to identify nicotinamide and pyridoxine as promoters of MuSC function. The combination of the two compounds promoted MuSC function in vivo in aged mice and in primary cells isolated from older individuals. Furthermore, the two compounds were lower in the circulation of older men, paralleling decreases in lean mass and gait speed. These results advance the translational perspective of rejuvenating MuSC function through nutraceuticals.

Close social ties are important for health but these can decline as people age. Moreover, losses of close social ties may be worse for women, older age and low socioeconomic groups. We characterized alterations in both marital status or living arrangement over 6 years by gender, and assessed patterns by age, country of origin, geographic location, education, wealth, and household income. We used three waves of Canadian Longitudinal Study on Aging data on 25,327 adults (45-85 years at baseline) to construct transition variables and multinomial logistic regressions with post-estimated predicted probabilities. Close social ties were stable over time, with most Canadians remaining partnered (77 % of men and 62 % of women) or co-living (82 % of men and 72 % of women). Adverse close social ties over time were gendered and socially patterned, with women 75+ years and of low socioeconomic status (SES) having the greatest risks. Becoming widowed or remaining non-partnered was relatively more likely for women with oldest age (RRR range: 6.08-15.64) or with low SES (RRRs: 2.29-47.06), and for men with oldest age (RRRs: 1.07-8.77) or low SES (RRRs: 2.03-31.72). Becoming or remaining lone-living was relatively more likely for women of oldest age (RRRs: 5.57-8.72) or low SES (RRRs: 2.16-65.78) and also for men of oldest aged (RRRs: 2.33-2.57) or low SES (RRRs: 2.08-49.62). Tailored healthy aging strategies to foster close social connections of women or men in older and low SES groups seems warranted.

Adipocyte senescence is one of the major common features correlated with aging, which can also lead to obesity, and aggravated oxidative stress contributes to cell senescence. Sesamol, a lignan from plants found in sesame, has been proven to alleviate obesity. However, the effects and mechanisms of sesamol on adipose tissue senescence remain unclear. In the current research, we used an aged model of obesity by feeding old mice high-fat diet (HFD), and a senescent cell model by treating 3T3-L1 mature adipocytes with repeated exposure to hydrogen peroxide (H

Nicotinamide mononucleotide (NMN) presents significant therapeutic potential against aging-related conditions, such as Alzheimer's disease, due to its consistent and strong pharmacological effects. Aside from its anti-aging effect, NMN is also an emerging noncanonical cofactor for orthogonal metabolic pathways in the field of biomanufacturing. This has significant advantages in the field of metabolic engineering, allowing cells to produce unnatural chemicals without disrupting the natural cellular processes. NMN is produced through both the chemical and biological methods, with the latter being more environmentally sustainable. The primary biological production pathway centers on the enzyme nicotinamide phosphoribosyltransferase, which transforms nicotinamide and phosphoribosyl pyrophosphate to NMN. Efforts to increase NMN production have been explored in microorganisms, such as:

Age-related macular degeneration (AMD) is a major cause of irreversible visual impairment, with dry AMD being the most prevalent form. Programmed cell death of retinal pigment epithelium (RPE) cells is a central mechanism in the pathogenesis of dry AMD. Ferroptosis, a recently identified form of programmed cell death, is characterized by iron accumulation-induced lipid peroxidation. This study aimed to investigate the involvement of ferroptosis in the progression of AMD.

Tai Chi, an Asian martial art, is renowned for its health benefits, particularly in promoting healthy aging among older adults, improving balance, and reducing fall risk. However, methodological challenges hinder the objective measurement of adherence to and proficiency in performing a training protocol, critical for health outcomes. This study introduces a framework using wearable sensors and machine learning to monitor Tai Chi training adherence and proficiency. Data were collected from 32 participants with inertial measurement units (IMUs) while performing six Tai Chi movements evaluated and scored for adherence and proficiency by experts. Our framework comprises a model for identifying the specific Tai Chi movement being performed and a model to assess performance proficiency, both employing Random Forest algorithms and features from IMU signals. The movement identification model achieved a micro F1 score of 90.05%. The proficiency assessment models achieved a mean micro F1 score of 78.64%. This study shows the feasibility of using IMUs and machine learning for detailed Tai Chi movement analysis, offering a scalable method for monitoring practice. This approach has the potential to objectively enhance the evaluation of Tai Chi training protocol adherence, learnability, progression in proficiency, and safety in Tai Chi programs, and thus inform training program parameters that are key to achieving optimal clinical outcomes.