Longevity Papers

Amyloid beta (A{beta}) accumulation is associated with inflammation, neurodegeneration, and cognitive decline in the context of neurodegenerative diseases. However, the effect of A{beta} during normal - i.e., non-pathological - brain aging remains poorly understood. In this study, we investigated the natural impact of A{beta} precursor protein (app) on the aging brain using a short-lived vertebrate model, the turquoise killifish (Nothobranchius furzeri). We identified amyloid precursor protein derivatives in the killifish brain across different age groups and found that pyroglutamated amyloid beta --a neurotoxic A{beta} variant-- accumulates intra-neuronally in an age-dependent manner, co-localizing with the apoptosis marker TUNEL. The presence of intraneuronal pE11 was recapitulated in old (non-pathological) human brains, indicating that this phenotype is shared among vertebrates. To determine whether A{beta} contributes to spontaneous brain aging, we used CRISPR/Cas9 to generate an "amyloid precursor protein a" (appa) knock-out killifish strain. Notably, appa -/-mutants exhibited reduced cell death and inflammation, an overall younger proteome, as well as improved learning capacity in old age. Taken together, we found that A{beta} precursor protein broadly affects vertebrate brain aging, making it a promising target for anti-aging interventions.

Many neurodegenerative disorders share a common pathologic feature involving the deposition of abnormal tau protein in the brain (tauopathies). This suggests that there may be some shared pathophysiologic mechanism(s). The largest risk factor for the majority of these disorders is aging, suggesting involvement of the aging process in the shared pathophysiology. We test the hypothesis that an increase in bone morphogenetic protein (BMP) signaling that occurs during aging contributes to the onset and progression of tauopathies.

Distinguishing between normal and pathological cognitive aging is challenging because there is no typical older person. Some people in their eighties have cognitive abilities similar to many 30-year-olds, while others experience significant cognitive decline at a much younger age. The variation in age-related cognitive decline is not arbitrary. Several non-modifiable (e.g. genetic) and potentially modifiable (e.g. high blood pressure, smoking, and hearing loss) risk factors are associated with faster cognitive aging. Beyond these individual-level risk factors, a growing body of evidence has identified associations between cognitive impairment and social, economic, and environmental factors. These associations are even more pronounced in developing countries, notably because of greater disparities in education and socioeconomic status. However, people from these countries are rarely studied in scientific research: a citizen of a high-income country is 37 times more likely to appear in a study in top medical journals than a citizen of a low-income country. Here, we examine the association between sociodemographic factors and cognitive aging trajectories among 715,295 participants in 46 countries. Cognition is assessed using Sea Hero Quest, a spatial navigation video game that predicts spatial ability in the real world. We find that the social, economic, and environmental well-being of older adults, as measured by the Global AgeWatch Index (GAWI), is negatively associated with age-related decline in spatial ability. In particular, the GAWI Health and Environment subscores are strongly correlated with the effect of age on wayfinding performance. We also found that gender differences in spatial navigation skills increase with age, and even more so in countries with greater gender inequality, as estimated by the Gender Inequality Index. Our results show that cognitive aging must be understood as a dynamic, heterogeneous process that is strongly linked to potentially modifiable environmental and social factors.

Vascular aging refers to a series of processes where the elasticity of blood vessels diminishes, leading to stiffening, and deposition of fat components on the vessel walls, causing inflammation. Cardiovascular diseases, such as stroke and hypertension, play significant roles in morbidity and mortality rates among the elderly population. In this study, the Reactive Hyperemia Index (RHI) was measured to assess vascular endothelial function and aging-induced pathogenesis of vascular diseases in Korean subjects. We aimed to identify extracellular vesicle microRNAs (EV-miRNAs) with differential abundance between groups of individuals at the ends of a continuum in vascular aging acceleration, revealing miRNAs regulating genes in endocrine hormone regulation and tumor-related pathways. We also discovered that the principal component characterizing the global miRNA expression profile is significantly associated with clinical traits including cholesterol levels. Together, these data provide a foundation for understanding the role of miRNAs as modulators of longevity and for developing age-specific epigenetic biomarkers.

IntroductionSerum concentrations of androgens and oestrogens, the main male and female sex hormones, respectively, naturally fluctuate across the lifespan. Sex hormones are mainly produced in the gonads, but evidence suggests that they can also be locally synthesised in skeletal muscle. However, little is known about the purpose of intramuscular sex hormones biosynthesis and their role in skeletal muscle. This systematic review aimed to investigate 1) how intramuscular sex hormone levels vary across the lifespan, 2) whether intramuscular sex hormones are associated with skeletal muscle mass and function, and 3) whether exercise affects intramuscular sex hormone levels. MethodsFour databases were searched, and studies were included if they contained measurements of intramuscular sex hormones from healthy males and females free from any hormonal treatment, from rodents, or from cultured muscle cells. ResultsFifteen studies were included. Intramuscular testosterone was reduced in elderly males compared to their younger counterparts, but comparison of intramuscular sex hormone levels between pre- and postmenopausal females yielded inconclusive findings. Intramuscular androgens were positively associated with muscle mass and strength in males. In females, conflicting findings were reported for both oestradiol and androgens, and measures of muscle mass and function. Chronic exercise decreased androgens and oestradiol in females, but increased androgens in males. Acute exercise did not change intramuscular hormone levels in humans but increased them in rodents and cells. ConclusionCurrent evidence suggests that ageing and exercise differentially modulate intramuscular sex hormone levels, and their association with muscle mass and function, between males and females.

Temporal control of transgenes has advanced biomedical interventions, including in vivo reprogramming, often utilizing the doxycycline (Dox)-mediated Tet-ON system. Here, we developed the Dox-mediated Tet-ON or complementary Tet-OFF counterpart to thoroughly investigate spatial and temporal transgene regulation in adult tissues, revealing inherent limitations and unexpected capabilities of each system. In stark contrast with the Tet-ON system, which was effective only in particular tissues and cell types, primarily epithelial cells, the Tet-OFF system proved capable of gene induction across diverse cell types. Despite the drawback of the Tet-OFF system in inducibility and tunability identified in our study, we demonstrated that use of tetracycline (Tc) effectively addresses these issues, possibly through its pharmacologic properties. Our data suggest that the Tc-mediated Tet-OFF system not only enables more versatile control of transgene expression but also offers a more biocompatible alternative for in vivo applications such as tissue regeneration and organismal rejuvenation.

Neurodegenerative diseases typically emerge after an extended prodromal period, underscoring the critical importance of initiating interventions during the early stages of brain aging to enhance later resilience. Changes in presynaptic active zone proteins ("PreScale") are considered a dynamic, resilience-enhancing form of plasticity in the process of early, still reversible aging of the Drosophila brain. Aging, however, triggers significant changes not only of synapses but also mitochondria. While the two organelles are spaced in close proximity, likely reflecting a direct functional coupling in regard to ATP and Ca

The intestinal microbiome is increasingly regarded as a relevant modulator of the pathophysiology of several age-related conditions, including frailty, sarcopenia, and cognitive decline. Aging is in fact associated with alteration of the equilibrium between symbiotic bacteria and opportunistic pathogens, leading to dysbiosis. The microbiome is able to regulate intestinal permeability and systemic inflammation, has a central role in intestinal amino acid metabolism, and produces a large number of metabolites and byproducts, with either beneficial or detrimental consequences for the host physiology. Recent evidence, from both preclinical animal models and clinical studies, suggests that these microbiome-centered pathways could contribute to bone homeostasis, regulating the balance between osteoblast and osteoclast function. In this systematic review, we provide an overview of the mechanisms involved in the gut-bone axis, with a particular focus on microbiome function and microbiome-derived mediators including short-chain fatty acids. We also review the current evidence linking gut microbiota dysbiosis with osteopenia and osteoporosis, and the results of the intervention studies on pre-, pro-, or post-biotics targeting bone mineral density loss in both animal models and human beings, indicating knowledge gaps and highlighting possible avenues for future research.

The T cell aging process can be modified by genotoxic factors, including ionizing radiation, and metabolic controls, such as caloric restriction; the former accelerates and the latter retards the process. However, the mechanisms by which these systemic factors interact to cause T cell aging remain unclear. This study investigated the naïve T-cell pool, thymic cellularity, and transcriptome in mice irradiated with 3.8 Gy at 5 weeks of age and treated 13 months later with 30 mM spermidine (SPD), a metabolism regulator. The number of conventional naïve CD4 and CD8 T cells in the peripheral blood decreased 14 months after irradiation whereas the number of virtual memory naïve T cells, which increased with age, further increased by irradiation. However, these radiation-related changes were not significant in similarly irradiated mice that were subsequently treated with SPD. The numbers of total, double-positive, and single-positive thymocytes were decreased by irradiation, whereas none were decreased in the irradiated mice treated with SPD. RNA sequencing of thymus cells revealed 803 upregulated genes in irradiated mice compared with those in non-irradiated control mice, with these genes enriched in leukocyte activation and inflammatory cytokine production. However, only 22 genes were upregulated in irradiated and SPD-treated mice, suggesting a reversal of many radiation-induced gene expression changes. These findings suggest that SPD may alleviate radiation-induced acceleration of T-cell aging, particularly by mitigating reduced thymopoiesis and inflammation. Further research is warranted to explore the rejuvenating potential of SPD and its mechanisms of action in accelerated T-cell aging.

The purpose of the present study was to prepare novel anti-senescent peptides from pearls, characterize their primary sequence and secondary structure, and investigate their protective effects and molecular mechanisms towards D-galactose (D-gal)-induced senescence on human dermal fibroblasts (HDFs). Novel pearl peptides with a purity of 96.58 % and maximum yield of 3.29 % were obtained using ultrasonic-assisted acetic acid extraction strategy under the optimal extraction conditions (ultrasonic power 200 W, ultrasonic time 70 min, and the ratio of pearl powder to acetic acid 1:20). It is sequenced mainly as five novel anti-senescent peptides with molecular weight < 2000 Da, and consisted of β-sheet (43.2 %), random coil (32.1 %), β-turn (21.2 %) and α-helix (3.5 %) analyzed by LC-MS/MS, FT-IR and CD spectroscopy. Further anti-senescent experiments showed that pearl peptides can increase cell viability, restore DNA damage, and suppress the accumulation of ROS as well as senescence-associated-β-galactosidase (SA-β-gal). The molecular mechanism may be that pearl peptides down-regulate the gene and protein expressions of senescence-associated proteins p53, p21, and p16. Therefore, novel pearl peptides could be developed as functional foods or nutritional supplements for the prevention of skin aging.

Chronological age has been the standard for quantifying the aging process. While it is simple to quantify it cannot fully discern the biological variability of aging between individuals. The growing body of interest in this variability of human aging has led to the introduction of new biomarkers to operationalize biological age. The inclusion of body composition may provide additional value to biological aging as a prediction and estimation factor of individual health outcomes. Diagnostic images based on radiomic techniques such as Computed Tomography contain an untapped wealth of patient-specific data that remain inaccessible to healthcare providers. These images are beneficial for collecting information from body composition that adds precision and granularity when compared to traditional measures. This information can subsequently be aggregated to construct models for changes in the human body associated with aging. In addition, aging leads to a natural decline in the best parameter of drug dosing in older adults, glomerular filtration rate. Since the conventional models of kidney function are correlated with age and body composition, the radiomic biomarkers representing age-related changes in body composition may also serve as potential new imaging biomarkers of kidney function for personalized dosing. Our review introduces potential radiomic biomarkers as measures of body composition change targeting the aging processes. As a functional example, we have hypothesized an age-related model of radiomics as a covariate of kidney function to improve personalized dosing. Future research focusing on evaluating this hypothesis in human subject studies is acknowledged.

The field of aging and longevity research is overwhelmed by vast amounts of data, calling for the use of Artificial Intelligence (AI), including Large Language Models (LLMs), for the evaluation of geroprotective interventions. Such evaluations should be correct, useful, comprehensive, explainable, and they should consider causality, interdisciplinarity, adherence to standards, longitudinal data and known aging biology. In particular, comprehensive analyses should go beyond comparing data based on canonical biomedical databases, suggesting the use of AI to interpret changes in biomarkers and outcomes. Our requirements motivate the use of LLMs with Knowledge Graphs and dedicated workflows employing, e.g., Retrieval-Augmented Generation. While naive trust in the responses of AI tools can cause harm, adding our requirements to LLM queries can improve response quality, calling for benchmarking efforts and justifying the informed use of LLMs for advice on longevity interventions.

Across all taxa of life, individuals within a species exhibit variable lifespans. Differences in genotype or environment are not sufficient to explain this variance, as even isogenic Caenorhabditis elegans nematodes reared under uniform conditions show significant variability in lifespan. To investigate this phenomenon, we used lifespan-predictive biomarkers to isolate, at mid-adulthood, prospectively long- and short-lived individuals from an otherwise identical population. We selected two biomarkers which correlated positively with lifespan, lin-4p::GFP and mir-243p::GFP, and two which correlated negatively, mir-240/786p::GFP and autofluorescence. The gene-expression signature of long versus short future lifespan was strikingly similar across all four biomarkers tested. Since these biomarkers are expressed in different tissues, these results suggest a shared connection to a global health state correlated with future lifespan. To further investigate this underlying state, we compared the transcriptional signature of long versus short future lifespan to that of chronologically young versus old individuals. By comparison to a high-resolution time series of the average aging transcriptome, we determined that subpopulations predicted to be long- or short-lived by biomarker expression had significantly different transcriptional ages despite their shared chronological age. We found that this difference in apparent transcriptional age accounted for the majority of differentially expressed genes associated with future lifespan. Interestingly, we also identified several genes whose expression consistently separated samples by biomarker expression independent of apparent transcriptional age. These results suggest that the commonalities in the long-lived versus short-lived state reported across different biomarkers of aging extends beyond simply transcriptionally young versus transcriptionally old.

Mechanical loading, essential for bone health, promotes bone formation and remodeling. However, the positive response diminishes in cases of disuse and aging, leading to bone loss and an increased fracture risk. This study demonstrates that activating hemichannels (HCs) using a connexin 43 (Cx43) antibody, Cx43(M2), in bone osteocytes revitalizes aging and disused bones. Using a hindlimb suspension (HLS) disuse model and a tibial mechanical loading model, we found that Cx43(M2) inhibited bone loss and osteocyte apoptosis induced by unloading in 16-week-old adult mice. Additionally, it enhanced bone mass in response to tibial loading in 22-month-old aged mice. The HC opening released bone anabolic factor prostaglandin E2 (PGE2) and suppressed catabolic factor sclerostin (SOST). This suppressed the increase of cortical bone formation and reduction of bone resorption during unloading and promoted trabecular and cortical bone formation during loading. Cx43(M2)-induced HC opening, coupled with PGE2 release, effectively rescued unloading-induced bone loss and restored the diminished anabolic response of aged bones to mechanical loading. Activating HCs with the Cx43 antibody holds promise as a de novo therapeutic approach, as it can overcome the limitations of existing treatment regimens for treating bone loss and osteoporosis associated with aging and disuse.

Increasingly, research suggests that aging is a coordinated multi-system decline in functioning that occurs at multiple biological levels. We developed and validated a transcriptomic (RNA-based) aging measure we call Transcriptomic Mortality-risk Age (TraMA) using RNA-seq data from the 2016 Health and Retirement Study using elastic net Cox regression analyses to predict 4-year mortality hazard. In a holdout test sample, TraMA was associated with earlier mortality, more chronic conditions, poorer cognitive functioning, and more limitations in activities of daily living. TraMA was also externally validated in the Long Life Family Study and several publicly available datasets. Results suggest that TraMA is a robust, portable RNAseq-based aging measure that is comparable, but independent from past biological aging measures (e.g., GrimAge). TraMA is likely to be of particular value to researchers interested in understanding the biological processes underlying health and aging, and for social, psychological, epidemiological, and demographic studies of health and aging.

While inflammation is a crucial response in injury repair and tissue regeneration, chronic inflammation is a prevalent feature in various chronic, non-communicable diseases such as obesity, diabetes, and cancer and in cardiovascular and neurodegenerative diseases. Long-term inflammation considerably affects disease prevalence, quality of life, and longevity. Our research indicates that the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is a pivotal regulator of inflammation in some tissues, including the hypothalamus, which is a key player in systemic metabolism regulation. Moreover, the GH/IGF-1 axis is strongly linked to longevity, as GH- or GH receptor-deficient mice live approximately twice as long as wild-type animals and exhibit protection against aging-induced inflammation. Conversely, GH excess leads to increased neuroinflammation and reduced longevity. Our review studies the associations between the GH/IGF-1 axis, inflammation, and aging, with a particular focus on evidence suggesting that GH receptor signaling directly induces hypothalamic inflammation. This finding underscores the significant impact of changes in the GH axis on metabolism and on the predisposition to chronic, non-communicable diseases.

Centenarians and their relatives possess a notable survival advantage, with higher longevity and reduced susceptibility to major age-related diseases. To date, characteristic omics profiles of centenarians have been described, demonstrating that these individuals with exceptional longevity regulate their metabolism to adapt and incorporate more resilient biomolecules into their cells. Among these adaptations, the lipidomic profile stands out. However, it has not yet been determined whether this lipidomic profile is specific to centenarians or is the consequence of extreme longevity genetics and is also present in centenarians' offspring. This distinction is crucial for defining potential therapeutic targets that could help delay the aging process and associated pathologies. We applied mass-spectrometry-based techniques to quantify 569 lipid species in plasma samples from 39 centenarians, 63 centenarians' offspring, and 69 noncentenarians' offspring without familial connections. Based on this profile, we calculated different indexes to characterize the functional and structural properties of plasma lipidome. Our findings demonstrate that extreme longevity genetics (centenarians and centenarians' offspring) determines a specific lipidomic signature characterized by (i) an enrichment of hexosylceramides, (ii) a decrease of specific species of ceramides and sulfatides, (iii) a global increase of ether-PC and ether-LPC, and (iv) changes in the fluidity and diversity of specific lipid classes. We point out the conversion of ceramides to hexosylceramides and the maintenance of the levels of the ether-linked PC as a phenotypic trait to guarantee extreme longevity. We propose that this molecular signature is the result of an intrinsic adaptive program that preserves protective mechanisms and cellular identity.

The endoplasmic reticulum (ER) is crucial in the development of numerous age-related bone disorders. Notably, ER stress can precipitate bone loss by orchestrating inflammatory responses, apoptosis, and autophagy through the activation of the p38 MAPK pathway. Age-related bone loss diseases pose a significant burden on society and healthcare as the global population ages. This review provides a comprehensive analysis of recent research advancements, delving into the critical role of ER stress-activated p38 MAPK in inflammation, apoptosis, and autophagy, as well as its impact on bone formation and bone resorption. This review elucidates the molecular mechanisms underlying the involvement of ER stress-activated p38 MAPK in osteoporosis, rheumatoid arthritis, periodontitis, and osteoarthritis and discusses the therapeutic potential of targeting p38 MAPK. Furthermore, this review provides a scientific foundation for new therapeutic strategies by highlighting prospective research directions.

During the last few decades, life expectancy has increased worldwide along with the prevalence of several age-related diseases. Among aging pathways, cellular senescence and chronic inflammation (or "inflammaging") appear to be connected to gut homeostasis and dysbiosis of the microbiome. Cellular senescence is a state of essentially irreversible cell cycle arrest that occurs in response to stress. Although senescent cells (SC) remain metabolically active, they do not proliferate and can secrete inflammatory and other factors comprising the senescence-associated secretory phenotype (SASP). Accumulation of SCs has been linked to onset of several age-related diseases, in the brain, bones, the gastrointestinal tract, and other organs and tissues. The gut microbiome undergoes substantial changes with aging and is tightly interconnected with either successful (healthy) aging or disease. Senotherapeutic drugs are compounds that can clear senescent cells or modulate the release of SASP factors and hence attenuate the impact of the senescence-associated pro-inflammatory state. Phytochemicals, phenolic compounds and terpenes, which have antioxidant and anti-inflammatory activities, could also be senotherapeutic given their ability to act upon senescence-linked cellular pathways. The aim of this review is to dissect links among the gut microbiome, cellular senescence, inflammaging, and disease, as well as to explore phytochemicals as potential senotherapeutics, focusing on their interactions with gut microbiota. Coordinated targeting of these inter-related processes might unveil new strategies for promoting healthy aging.

Neurofilament light chain (NfL) is a specific biomarker of neuroaxonal damage and related neurodegenerative diseases. Aging acceleration, which reflects the impact of modifiable factors on the aging process, is increasingly recognized for its relevance. While normal aging is known to contribute substantially to neuroaxonal damage and many neurodegenerative diseases, the effects of aging acceleration warrant further investigation. This study aimed to investigate the association and causality between aging acceleration and serum NfL levels.

In recent decades, the global population has aged rapidly while socioeconomic inequalities in health have widened, with older adults who are most disadvantaged experiencing the poorest health. Functional limitations are key predictors of disability and quality of life and are therefore considered an important measure of how well individuals and populations are aging. We determine if educational inequalities in functioning have widened over time and across countries.

The effects of aging on the satellite cell pool have primarily been studied in male mice, where the role of cell-intrinsic versus environmental changes on satellite cell function remains contentious. Estradiol is necessary for maintenance of satellite cell pool size in adult female mice-here we investigate the hypothesis that in females, estradiol is a major environmental driver of age-associated effects on satellite cells. In 24-26 month-old ovarian senescent mice, we find the satellite cell pool size is severely diminished in certain muscles (TA and EDL) but only marginally affected in others (soleus and gastrocnemius). Supplementation with 17-beta estradiol significantly increases satellite cell pool size in the TA and EDL. To assess cell-intrinsic versus environmental regulation, we perform two transplantation experiments, Adult or Aged satellite cells transplanted into Adult recipients, and Adult satellite cells transplanted into Adult or Aged mice. These results demonstrate that the aged environment dominates over cell-autonomous age in terms of the specification of satellite cell pool size. Transcriptional profiling on satellite cells from Adult, Aged and ovariectomized mice revealed commonalities across the two estradiol-deficient conditions, Aged and ovariectomized, in GO terms from differentially expressed genes. Our findings support the hypothesis that the lack of estradiol contributes to reductions in satellite cell number in Aged female muscle, yet cells that remain are functional in terms of proliferative potential and self-renewal capacity. These findings have implications for sex hormone treatment of menopausal women and highlight the vital role of estradiol in the maintenance of the satellite cell pool.

Carling et al. report that late-onset Alzheimer's disease (LOAD) risk alleles drive cellular senescence, a hallmark of aging, in a tau- and sex-dependent manner. Mechanistic insights into interactions among genetic risk, biological aging, and sex differences in LOAD are presented.

Individuals aged 70 and older frequently experience an increased risk of deficits in both physical and cognitive functions. However, the natural progression and interrelationship of these deficits, as well as their neurologic correlates, remain unclear. We aimed to classify the data-driven physical-cognitive phenotypes and then investigate their associations with neuroimaging markers.

The auditory system is constantly tasked with detecting acoustic cues in complex auditory environments. Difficulty hearing speech in noise, largely a result of energetic masking, is a major communication complaint of the elderly, which impacts a third of the global population over 65. The neural mechanisms responsible for processing sound in background noise and subsequently achieving release from energetic masking remain obscure. Furthermore, the senescence of signal-in-noise detection is poorly understood, a phenomenon which could have a myriad of clinical implications. We tested over 300 CBA/CaJ mice aged 1-27 months on tone-in-noise detection ability utilizing prepulse inhibition of the acoustic startle response with a machine learning startle classifier. We found that mice developed profound tone-in-noise detection deficits throughout their lifespan as evidenced by Rd', a detection metric derived from signal detection theory. The most severe decline in Rd' corresponded to a 2.54-fold decrease in tone-in-noise detection across the lifespan. Our findings suggest that CBA/CaJ mice are an appropriate model to study the role of age-related hearing loss in the context of signal-in-noise masking.

Musculoskeletal health among the elderly emerges as a pivotal public health concern against the backdrop of a globally aging population. Creatine, popular within fitness circles, has emerged as a subject of scientific inquiry for its potential benefits on elderly' musculoskeletal well-being. Despite extensive documentation of its effects on athletic performance, investigations into creatine's long-term contributions to the musculoskeletal health of the elderly are comparatively limited. Utilizing publicly accessible genetic datasets, this study aimed to explore the potential causal link between creatine levels and a variety of musculoskeletal health markers in the elderly population, such as osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis (OP), bone-specific alkaline phosphatase, bone mineral density(BMD), serum calcium levels, and reduced hand grip strength in individuals aged 60 and above.

Klotho, an anti-aging protein, is linked to energy metabolism. There is limited research on the association of serum klotho and triglyceride glucose (TyG) index-related indicators. Our research aims to investigate the relationship of serum klotho with TyG-BMI (body mass index), TyG-WC (waist circumference), and TyG-WHtR (waist-to-height ratio).

The question, "Can aging be modified, delayed, or reversed?" has profound social and economic implications for rapidly aging societies today. Interventions, ideally, would intercept functional decline and extend healthspan by delaying late-life morbidity (known as "squaring the curve"). These have proven elusive, but examples of differential aging in the animal world abound, suggesting aging itself is a malleable process. We present a novel multi-scale theoretical framework for entropic aging, and apply it to recently published DNA methylation data from 348 evolutionarily distant mammalian species. Our analysis identified modules or correlated DNA methylation changes associated with reversible pathway activation in key biological processes. We discovered a single species-dependent scaling factor controlling the magnitude of fluctuations across biological pathways. It acts as the organisms "effective temperature", quantifying intrinsic biological noise within networks and is unrelated to physical body temperature. Furthermore, we find a distinct stochastic damage signature and an associated extreme value (Gumbel) distribution of activation barriers controlling site-specific damage rates of individual CpG sites. This implies that aging is driven by rare, high-energy transitions on rugged energy landscape, most likely simultaneous and hence practically irreversible failures in highly redundant systems. While the overall rate of damage accumulation and hence the maximum lifespan does not depend on the effective temperature driving the noise in leading pathways, effective temperature does influence both initial mortality rate and the mortality rate doubling time - thereby shaping the survival curve. Lowering effective temperature must, therefore, be a promising Geroscience strategy, aimed directly at squaring the curve of aging. The example shows that targeting the thermodynamic forces driving mammalian aging may provide powerful strategies for the development of truly meaningful interventions to combat aging in humans.

Cell senescence is a natural response within our organisms. Initially, it was considered an effective anti-tumor mechanism. However, it is now believed that while cell senescence initially acts as a robust barrier against tumor initiation, the subsequent accumulation of senescent cells can paradoxically promote cancer recurrence and cause damage to neighboring tissues. This intricate balance between cell proliferation and senescence plays a pivotal role in maintaining tissue homeostasis. Moreover, senescence cells secrete many bioactive molecules collectively termed the senescence-associated secretory phenotype (SASP), which can induce chronic inflammation, alter tissue architecture, and promote tumorigenesis through paracrine signaling. Among the myriads of compounds, senotherapeutic drugs have emerged as exceptionally promising candidates in anticancer treatment. Their ability to selectively target senescent cells while sparing healthy tissues represents a paradigm shift in therapeutic intervention, offering new avenues for personalized oncology medicine. Senolytics have introduced new therapeutic possibilities by enabling the targeted removal of senescent cells. As standalone agents, they can clear tumor cells in a senescent state and, when combined with chemo- or radiotherapy, eliminate residual senescent cancer cells after treatment. This dual approach allows for the intentional use of lower-dose therapies or the removal of unintended senescent cells post-treatment. Additionally, by targeting non-cancerous senescent cells, senolytics may help reduce tumor formation risk, limit recurrence, and slow disease progression. This article examines the mechanisms of cellular senescence, its role in cancer treatment, and the importance of senotherapy, with particular attention to the therapeutic potential of senolytic drugs.

In a subset of participants from the CALERIE

Despite extensive research, the features associated with the aging phenotype are not all-inclusive and need to be updated on a regular basis to incorporate new findings. We propose to include the dysfunction of membrane-less organelle (MLO) as a new aging hallmark. Special scaffold proteins with a high degree of intrinsic disorder drive the formation of MLOs via the liquid-liquid phase separation (LLPS) process. Aberrant behavior of MLOs was shown to be associated with the pathogenesis of many neurodegenerative diseases. In this work, we challenge the aging through bidirectional bioinformatics analysis of human proteins found in Granulome consisting of 7264 protein and Ageome containing 1624 aging-related proteins. The analysis indicates the interconnectivity of MLOs and aging. Approximately 67 % of the Ageome are presented in Granulome thereby constituting the Intersectome that include 1084 proteins showing an enrichment significantly higher than for the random datasets of the same size. Furthermore, for proteins in 10 representative MLOs, we analyzed in detail molecular functions, association with the already known aging hallmarks, and the roles in MLO formation (scaffold, client, or regulator). Cumulatively, our results strengthen the hypothesis that the dysfunction of MLOs can serve as a potent new aging hallmark.

The accumulation of senescent cells, a hallmark of aging and age-related diseases, is also considered as a side effect of anticancer therapies, promoting drug resistance and leading to treatment failure. The use of senolytics, selective inducers of cell death in senescent cells, is a promising pharmacological antiaging and anticancer approach. However, more studies are needed to overcome the limitations of first-generation senolytics by the design of targeted senolytics and nanosenolytics and the validation of their usefulness in biological systems. In the present study, we have designed a nanoplatform composed of iron oxide nanoparticles functionalized with an antibody against a cell surface marker of senescent cells (CD26), and loaded with the senolytic drug HSP90 inhibitor 17-DMAG (MNP@CD26@17D). We have documented its action against oxidative stress-induced senescent human fibroblasts, WI-38 and BJ cells, and anticancer drug-induced senescent cutaneous squamous cell carcinoma A431 cells, demonstrating for the first time that CD26 is a valid marker of senescence in cancer cells. A dual response to MNP@CD26@17D stimulation in senescent cells was revealed, namely, apoptosis-based early response (2 h treatment) and ferroptosis-based late response (24 h treatment). MNP@CD26@17D-mediated ferroptosis might be executed by ferritinophagy as judged by elevated levels of the ferritinophagy marker NCOA4 and a decreased pool of ferritin. As 24 h treatment with MNP@CD26@17D did not induce hemolysis in human erythrocytes

The ovary is one of the first organs to exhibit signs of aging, characterized by reduced tissue function, chronic inflammation, and fibrosis. Multinucleated giant cells (MNGCs), formed by macrophage fusion, typically occur in chronic immune pathologies, including infectious and non-infectious granulomas and the foreign body response1, but are also observed in the aging ovary2-4. The function and consequence of ovarian MNGCs remain unknown as their biological activity is highly context-dependent, and their large size has limited their isolation and analysis through technologies such as single-cell RNA sequencing. In this study, we define ovarian MNGCs through a deep analysis of their presence across age and species using advanced imaging technologies as well as their unique transcriptome using laser capture microdissection. MNGCs form complex interconnected networks that increase with age in both mouse and nonhuman primate ovaries. MNGCs are characterized by high Gpnmb expression, a putative marker of ovarian and non-ovarian MNGCs5,6. Pathway analysis highlighted functions in apoptotic cell clearance, lipid metabolism, proteolysis, immune processes, and increased oxidative phosphorylation and antioxidant activity. Thus, MNGCs have signatures related to degradative processes, immune function, and high metabolic activity. These processes were enriched in MNGCs compared to primary ovarian macrophages, suggesting discrete functionality. MNGCs express CD4 and colocalize with T-cells, which were enriched in regions of MNGCs, indicative of a close interaction between these immune cell types. These findings implicate MNGCs in modulation of the ovarian immune landscape during aging given their high penetrance and unique molecular signature that supports degradative and immune functions.

Senescence is recognized as a principal risk factor for cardiovascular diseases, with a significant association between the senescence of cardiomyocytes and inferior cardiac function. Furthermore, type 2 diabetes exacerbates this aging process. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) has well-established cardiovascular benefits and, in recent years, has been posited to possess anti-aging properties. However, there are no reported data on their improvement of cardiomyocytes function through the alleviation of aging. Consequently, our study aims to investigate the mechanism by which SGLT2i exerts anti-aging and protective effects at the cardiac level through its action on the FOXO1-ANGPTL4 pathway.

TP53-induced glycolysis and apoptosis regulator (TIGAR) regulates redox homeostasis and provides the intermediates necessary for cell growth by reducing the glycolytic rate. During cellular senescence, cells undergo metabolic rewiring towards the glycolytic pathway, along with the development of the senescence-associated secretory phenotype (SASP), also known as the secretome. We observed that TIGAR expression increased during replicative senescence following the in vitro expansion of human mesenchymal stromal cells (MSCs) and that TIGAR knockout (KO) decreased SASP factors and triggered premature senescence with decelerated progression. Additionally, TIGAR KO impaired flexible lysosomal movement to the perinuclear region and decreased the autophagic flux of MSCs. Research on the mechanism of lysosomal movement revealed that, while native senescent MSCs presented low levels of Ac-α-tubulin (lysine 40) and increased sirtuin 2 (SIRT2) activity compared with those in growing cells, TIGAR KO-MSCs maintained Ac-α-tubulin levels and exhibited decreased SIRT2 activity despite being in a senescent state. The overexpression of SIRT2 reduced Ac-α-tubulin as a protein target of SIRT2 and induced the positioning of lysosomes at the perinuclear region, restoring the cytokine secretion of TIGAR KO-MSCs. Furthermore, TIGAR expression was positively correlated with SIRT2 activity, indicating that TIGAR affects SIRT2 activity partly by modulating the NAD

Growing evidence suggests that somatic mutations may be a major cause of the aging process. However, it remains to be tested whether the predictions of the theory also apply to species with longer life spans than humans.

Oral health is recognized as integral to general health and impaired dentition status may affect physical performance among older adults. This study evaluated the longitudinal association between clinical and self-reported oral health measures and physical performance (outcome) in Brazilian older adults.

Cancer and its treatments may accelerate the aging process. However, accelerated aging among cancer survivors is not well understood. This study examines accelerated aging among adults with and without a cancer history in a nationally representative sample and identifies health-related social needs and behavioral factors associated with accelerated aging.

3-Hydroxybutyrate (3HB), predominantly found in the liver, muscles, and brain, is the most important endogenous ketone body in humans. During prolonged fasting and starvation, 3HB can partially replace glucose to meet some of the body's energy needs. In recent years, the resurgence of the ketogenic diet (KD) and systematic exploration of the favorable biocompatibility of polyhydroxyalkanoates (PHAs), the precursor polymer to 3HB, have led to numerous reports indicating that the benefits of exogenous 3HB supplementation outweigh the drawbacks, particularly for middle-aged and elderly individuals. In this review, the physicochemical properties, physiological functions, and biosafety of 3HB in the elderly population are introduced. The effects of exogenous 3HB supplements, including KD, ketone esters, 1,3-butanediol, and ketone salts, on the elderly are compared. It is proposed that exogenous 3HB derived from PHAs is optimal for this population. Exogenous 3HB supplementation for elderly health maintenance and disease treatment is summarized, with an outline of four challenges related to the mechanistic and clinical research of exogenous 3HB supplementation for elderly health. This aims to explore its novel therapeutic potential as a small molecule in the context of aging.

Male infertility has been a primary cause of global infertility, affecting 8-12% of couples worldwide. Previous studies have shown that semen quality decreases with advanced aging with an increased presence of inflammatory cells. In this study, we examined changes in the epigenome across a diverse cohort that includes both fertile and infertile men. We also compare the age-associated changes in semen to those observed in buccal swabs in order to characterize differences in epigenetic aging across diverse tissues. We found that variations in the semen methylome associated with aging are linked to inflammatory genes. Many age-associated sites are demethylated with advanced aging and are associated with the activation of inflammatory pathways. By contrast, we do not observe age-associated changes in inflammatory genes in buccal swab methylomes, which instead are characterized by changes to bivalent promoters. Our findings highlight the potential of epigenetic markers as indicators of male reproductive health.

Aging is a complex process marked by a gradual decline in physiological function and increased susceptibility to diseases. Telomere length is frequently regarded as one of the primary biomarkers of aging. Metabolic profiles are key features in longevity and have been associated with both age and age-related diseases. We previously reported an increase in the telomere length in healthy female subjects when Ramadan fasting was combined with physical training. This study aims to characterize the metabolic signature differentiating the combined effects of exercise and fasting from exercise alone and explore the correlations with the previously reported telomere length changes.

A growing number of aging adults are living with multiple chronic conditions (MCC). Older adults living with MCC are predisposed to developing frailty, a state of decreased physiologic reserve that increases risk for geriatric syndromes and associated morbidity and mortality. The electronic frailty index (eFI) is computed passively using structured EHR data and can aid in prospective screening. Unfortunately, certain diagnoses, such as functional status assessments in unstructured documentation, are less likely captured by eFI, potentially underestimating the degree of frailty. Here, we discuss current gaps for using eFI to identify frail older adults living with MCC, and artificial intelligence (AI) approaches to enhance eFI accuracy. Accurate and routine frailty assessment can aid the generalist providing care to older adults living with MCC across multiple care settings to optimize physiologic reserve for these vulnerable patients.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by features of accelerated aging, and individuals with HGPS seldom live beyond their mid-teens. The syndrome is commonly caused by a point mutation in the LMNA gene which codes for lamin A and its splice variant lamin C, components of the nuclear lamina. The mutation causing HGPS leads to production of a truncated, farnesylated form of lamin A referred to as "progerin." Progerin is also expressed at low levels in healthy individuals and appears to play a role in normal aging. HGPS is associated with an accumulation of genomic DNA double-strand breaks (DSBs) and alterations in the nature of DSB repair. The source of DSBs in HGPS is often attributed to stalling and subsequent collapse of replication forks in conjunction with faulty recruitment of repair factors to damage sites. In this work, we used a model system involving immortalized human cell lines to investigate progerin-induced genomic damage. Using an immunofluorescence approach to visualize phosphorylated histone H2AX foci which mark sites of genomic damage, we report that cells engineered to express progerin displayed a significant elevation of endogenous damage in the absence of any change in the cell cycle profile or doubling time of cells. Genomic damage was enhanced and persistent in progerin-expressing cells treated with hydroxyurea. Overexpression of wild-type lamin A did not elicit the outcomes associated with progerin expression. Our results show that DNA damage caused by progerin can occur independently from global changes in replication or cell proliferation.

The DrugAge database serves as a comprehensive resource for the study of compounds that increase lifespan in model organisms. In the latest version of DrugAge, we have implemented multiple updates, predominantly focusing on mouse (Mus musculus) studies to enhance data accuracy and consistency. Key improvements include the re-recording of mouse data from original sources, standardization of drug dosages to parts per million (ppm), and detailed recording of administration routes, treatment initiation ages, and durations. The user interface has also been upgraded. Additionally, weight change data were included to address the potential impact of caloric restriction induced by drug administration on lifespan. Our analysis revealed significant correlations between weight loss and lifespan extension in male mice, particularly in studies conducted by the Interventions Testing Program (ITP), highlighting the importance of considering weight change in lifespan studies. We also observed notable sex-related differences in lifespan and weight change responses, underscoring the need for gender-specific analyses in aging research.

The population is aging rapidly worldwide, impacting public health, with countries in the Global South, such as Brazil, aging faster than developed nations. The 24-hour movement behavior is crucial for healthy aging, but its relationship with the neighborhood built environment is underresearched, especially for older adults. The EpiMove Study uses accelerometers and GPS to investigate the relationships between 24-hour movement behavior, community mobility and the neighborhood built environment for healthy aging in older Brazilian adults.

Aging involves metabolic changes that lead to reduced cellular fitness, yet the role of many metabolites in aging is unclear. Understanding the mechanisms of known geroprotective molecules reveals insights into metabolic networks regulating aging and aids in identifying additional geroprotectors. Here we present AgeXtend, an artificial intelligence (AI)-based multimodal geroprotector prediction platform that leverages bioactivity data of known geroprotectors. AgeXtend encompasses modules that predict geroprotective potential, assess toxicity and identify target proteins and potential mechanisms. We found that AgeXtend accurately identified the pro-longevity effects of known geroprotectors excluded from training data, such as metformin and taurine. Using AgeXtend, we screened ~1.1 billion compounds and identified numerous potential geroprotectors, which we validated using yeast and Caenorhabditis elegans lifespan assays, as well as exploring microbiome-derived metabolites. Finally, we evaluated endogenous metabolites predicted as senomodulators using senescence assays in human fibroblasts, highlighting AgeXtend's potential to reveal unidentified geroprotectors and provide insights into aging mechanisms.

Aging is marked by a decline in tissue regeneration, posing significant challenges to an increasingly older population. Here, we investigate age-related impairments in calvarial bone healing and introduce a novel two-part rejuvenation strategy to restore youthful repair. We demonstrate that aging negatively impacts the calvarial bone structure and its osteogenic tissues, diminishing osteoprogenitor number and function and severely impairing bone formation. Notably, increasing osteogenic cell numbers locally fails to rescue repair in aged mice, identifying the presence of intrinsic cellular deficits. Our strategy combines Wnt-mediated osteoprogenitor expansion with intermittent fasting, which leads to a striking restoration of youthful levels of bone healing. We find that intermittent fasting improves osteoprogenitor function, benefits that can be recapitulated by modulating NAD+ dependent pathways or the gut microbiota, underscoring the multifaceted nature of this intervention. Mechanistically, we identify mitochondrial dysfunction as a key component in age-related decline in osteoprogenitor function and show that both cyclical nutrient deprivation and Nicotinamide mononucleotide rejuvenate mitochondrial health, enhancing osteogenesis. These findings offer a promising therapeutic avenue for restoring youthful bone repair in aged individuals, with potential implications for rejuvenating other tissues.

Speech intelligibility declines with age and sensorineural hearing damage (SNHL). However, it remains unclear whether cochlear synaptopathy (CS), a recently discovered form of SNHL, significantly contributes to this issue. CS refers to damaged auditory-nerve synapses that innervate the inner hair cells and there is currently no go-to diagnostic test available. Furthermore, age-related hearing damage can comprise various aspects (e.g., hair cell damage, CS) that each can play a role in impaired sound perception. To explore the link between cochlear damage and speech intelligibility deficits, this study examines the role of CS for word recognition among older listeners. We first validated an envelope-following response (EFR) marker for CS using a Budgerigar model. We then applied this marker in human experiments, while restricting the speech materials frequency content to ensure that both the EFR and the behavioral tasks engaged similar cochlear frequency regions. Following this approach, we identified the relative contribution of hearing sensitivity and CS to speech intelligibility in two age-matched (65-year-old) groups with clinically normal (n=15, 8 females) or impaired audio-grams (n=13, 8 females). Compared to a young normal-hearing control group (n = 13, 7 females), the older groups demonstrated lower EFR responses and impaired speech reception thresholds. We conclude that age-related CS reduces supra-threshold temporal envelope coding with subsequent speech coding deficits in noise that cannot be explained based on hearing sensitivity alone. Significance StatementTemporal bone histology reveals that cochlear synaptopathy (CS), characterized by damage to inner hair cell auditory nerve fiber synapses, precedes sensory cell damage and hearing sensitivity decline. Despite this, clinical practice primarily evaluates hearing status based on audiometric thresholds, potentially overlooking a prevalent aspect of sensorineural hearing damage due to aging, noise exposure, or ototoxic drugs--all of which can lead to CS. To address this gap, we employ a novel and sensitive EEG-based marker of CS to investigate its relationship with speech intelligibility. This study addresses a crucial unresolved issue in hearing science: whether CS significantly contributes to degraded speech intelligibility as individuals age. Our study-outcomes are pivotal for identifying the appropriate target for treatments aimed at improving impaired speech perception.

PurposeThe aim of this study was to test whether oral administration of nicotinamide riboside (NR), the nicotinamide adenine dinucleotide (NAD+) precursors, protect retina ganglion cells (RGCs) from neurodegeneration in DBA/2J (D2) mice, which is a widely used mouse model of age-related inherited glaucoma. MethodOral NR or NAM administration (NR low dose: 1150mg/kg; NR high dose: 4200mg/kg; NAM low dose group: 500mg/kg; NAM high dose: 2000mg/kg of body weight per day) essentially started when D2 mice were 4 or 9 months old and continued up to 12 months old. Control cohort identically received food/water without NAM or NR. Intraocular pressure (IOP) was measured every month until experiment completion. Pattern electroretinography (PERG) was recorded. Retinas were harvested for whole mount immunofluorescence staining with RGCs marker Brn3a and imaged by fluorescent confocal microscopy. Optic nerves were harvested for axon staining and quantification. Retinal NAD+ levels were enzymatically assayed. ResultsNR oral supplementary treatment started at 4 months old robustly increased retinal NAD+ levels in D2 mice (NRHigh vs. vehicle: 273.7{+/-}23.59% vs. 108.70{+/-}12.10%, p<0.001). In aged vehicle group (12 months old), there was significantly diminution of the P1 and N2 components of PERG response compare with naive group (naive vs. vehicle: P1: 7.82{+/-} 0.70uV vs 1.63{+/-} 0.17uV, p<0.0001; N2: -13.29{+/-} 0.83uV vs. -3.22{+/-} 0.27uV, p<0.0001; Kruskal-Wallis test with Dunn s multiple comparison test). NR treatment preserved aged D2 visual function when mice were 9 and 12 months old. In addition, long-term NR high dose treatment significantly protected against total RGCs loss and optic nerve atrophy (RGC: NRHigh vs. vehicle: 1412{+/-}62.00vs 475.2{+/-}94.68 cells/field, p<0.00001; axon numbers: NRHigh vs. vehicle: 23990{+/-}1159 vs 8573{+/-}1160, n=41-53, p<0.0001). Furthermore, long-term NR supplementation prevent iris depigmentation and delayed IOP elevation. ConclusionNR oral supplementary treatment significantly preserved RGC and axon numbers, potentially preserves retinal function via elevated retinal NAD+ level in aged D2 mice. Interestingly, NR treatment also prevented iris atrophy, delayed IOP elevation associated with this glaucoma model. NR oral supplementation thus treated several aspects of murine pigment dispersion glaucoma. Given parallels between this model and glaucoma in human, out data indicate that NR is worth exploring as a therapeutic candidate in treatment of glaucoma.

Aging is associated with a progressive decline in cellular function. To reset the aged cellular phenotype, various reprogramming approaches, including mechanical routes, have been explored. However, the epigenetic mechanisms underlying cellular rejuvenation are poorly understood. Here, we studied the cytoskeletal, genome-wide chromatin and transcriptional changes in young, aged, and mechanically rejuvenated fibroblasts using immunofluorescence, RNA sequencing, and Hi-C experiments. The mechanically rejuvenated aged fibroblasts, that had partially reset their transcription to a younger cell state, showed a local reorganization of the interchromosomal contacts and lamina-associated domains. Interestingly, the observed chromatin reorganization correlated with the transcriptional changes. Immunofluorescence experiments in the rejuvenated state confirmed increased actomyosin contractility like younger fibroblasts. In addition, the rejuvenated contractile properties were maintained over multiple cell passages. Overall, our results give an overview of how changes in the cytoskeleton, chromatin, and gene activity are connected to aging and rejuvenation.

The Tabula Sapiens is a reference human cell atlas containing single cell transcriptomic data from more than two dozen organs and tissues. Here we report Tabula Sapiens 2.0 which includes data from nine new donors, doubles the number of cells in Tabula Sapiens, and adds four new tissues. This new data includes four donors with multiple organs contributed, thus providing a unique data set in which genetic background, age, and epigenetic effects are controlled for. We analyzed the combined Tabula Sapiens data for expression of transcription factors, thereby providing putative cell type specificity for nearly every human transcription factor and as well as new insights into their regulatory roles. We analyzed the molecular phenotypes of senescent cells across the entire data set, providing new insight into both the universal attributes of senescence as well as those aspects of human senescence that are specific to particular organs and cell-types. Similarly, we analyzed sex-specific gene expression across all of the identified cell types and discovered which cell types and genes have the most distinct sex based gene expression profiles. Finally, to enable accessible analysis of the voluminous medical records of Tabula Sapiens donors, we created a web application powered by a large language model that allows users to ask general questions about the health history of the donors.

Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). We identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility. βHB primarily provides ATP substrate during periods of reduced glucose availability, and regulates other cellular processes through protein interactions. We demonstrate βHB-induced protein insolubility is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a ketone ester. This mechanism is selective for pathological proteins such as amyloid-β, and exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity. We generate libraries of the βHB-induced protein insolublome using mass spectrometry proteomics, and identify common protein domains and upstream regulators. We show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain. These data indicate a metabolically regulated mechanism of proteostasis relevant to aging and AD.

The pupil is modulated by luminance, arousal, bottom-up sensory, and top-down cognitive signals, and has increasingly been used to assess these aspects of brain functioning in health and disease. However, changes in pupil dynamics across the lifespan have not been extensively examined, hindering our ability to fully utilize the pupil in probing these underlying neural processes in development and aging in healthy and clinical cohorts. Here, we examined pupil responses during the interleaved pro-/anti-saccade task (IPAST) in healthy participants across the lifespan (

Ultraviolet radiations (UVR) produce harmful entities and reactive oxygen species (ROS) in skin cells, leading to skin photoaging. Caviar extract (CE) showed outstanding effects in delaying skin aging, but the underlying mechanism remains largely unknown. In this study, we prepared CE with acid protease and examined the anti-skin photoaging effects. The results showed that CE performed no cytotoxicity to HaCaT cells. For antioxidant properties, the EC50 values of DPPH and ABTS radical scavenging activity for CE were 1.27 and 5.20 mg/mL, respectively. It significantly reduced NF-κB, MMP-3 and MMP-9 protein expression levels, and increased IκB and TIMP-1 expression level in UVA-irradiated HaCaT cells. In the skin aging mice model, CE reduced the degree of UV-induced skin photoaging. Histological study confirmed that CE can ameliorate the adverse effects of UV exposure on the skin. Moreover, we found that CE could enhance the activities of Superoxide dismutase (SOD), and increased the contents of hydroxyproline (HYP) in photoaged mice skin. And CE elevated the protein expression level of COL17A1, KRT10, and KRT14 in mice skin. Taken together, our results bright systemic and new insights of CE into preventing UV-induced skin photoaging.

Fasting regimens have shown profound impact on pro-longevity and tissue regeneration in diverse species. Physiological events can induce a regenerative response in adult stem cells. However, little is known about signaling and activation of adult stem cells which are modulated by fasting. This study analyzed the presence of hematopoietic stem/progenitor cells (HSPCs) and their circulation in the peripheral blood (PB) of healthy male adults practicing Ramadan fasting. Ten healthy male volunteers were enrolled in this prospective observational study. PB samples were collected twice daily on days 0, 10, 20, and 30 of Ramadan fasting (RF). Populations of stem cells and serum soluble factors were analyzed by flow cytometry. As a response to RF, we report an increase in the average absolute count of circulating of HSPCs, defined as LIN

Endothelial dysfunction is a pivotal early event in the development of major cardiovascular diseases including hypertension, atherosclerosis, diabetes, and aging. The alteration of the endothelial function is often triggered by an imbalance between the endothelial formation of vasoprotective factors, including nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH), and vasocontracting factors, such as arachidonic acid-derived mediators generated by cyclooxygenases, and an increased level of oxidative stress. Recently, endothelial senescence was reported to be an early trigger of endothelial dysfunction. Preclinical studies indicate that polyphenol-rich food, including anthocyanin-rich products, can activate pathways promoting an increased formation of vasoprotective factors and can prevent the induction of endothelial dysfunction in endothelial cells and isolated blood vessels. Similarly, intake of anthocyanin-rich products has been associated with the prevention and/or the improvement of an endothelial dysfunction in several experimental models of cardiovascular diseases, including physiological aging. Moreover, clinical data indicate that polyphenol-rich and anthocyanin-rich products can improve endothelial function and vascular health in humans with cardiovascular diseases. The present review will discuss both experimental and clinical evidence indicating that several polyphenol-rich foods and natural products, and especially anthocyanin-rich products, can promote endothelial and vascular health, as well as the underlying mechanisms.

A common impairment in aging is age-related hearing loss (presbycusis), which manifests as impaired spectrotemporal processing. Presbycusis can be caused by a dysfunction of the peripheral and central auditory system and these dysfunctions might differ between the sexes. To date, the circuit mechanisms in the central nervous system responsible for age-related auditory dysfunction remain mostly unknown. In the auditory cortex (ACtx), aging is accompanied by alteration in normal inhibitory (GABA) neurotransmission and changes in excitatory (NMDA and AMPA) synapses, but which circuits are affected has been unclear. Here we investigated how auditory cortical microcircuits change with age and if sex-dependent differences existed. We performed laser-scanning photostimulation (LSPS) combined with whole-cell patch clamp recordings from Layer (L) 2/3 cells in primary auditory cortex (A1) in young adult (2-3 months) and aged (older than 18 months) male and female CBA/CaJ mice which have normal peripheral hearing. We found that L2/3 cells in aged male animals display functional hypoconnectivity of inhibitory circuits originating from L2/3 and L4. Compared to cells from young adult mice, cells from aged male mice have weaker excitatory connections from L2/3. We also observed an increased diversity of excitatory and inhibitory inputs. These results suggest a sex-specific reduction and diversification in excitatory and inhibitory intralaminar cortical circuits in aged mice compared with young adult animals. We speculate that these unbalanced changes in cortical circuits contribute to the functional manifestations of age-related hearing loss in both males and females.

Age-related alterations in immune function are believed to increase risk for a host of age-related diseases leading to premature death and disability. Programming of the immune system by diet, lifestyle, and environmental factors occurs across the lifespan and influences both makeup and function of the immune system, including immunometabolism. This programming is believed to act in large part through epigenetic modification. Among dietary components that affect this process, polyphenols may play an outsized role. Polyphenols are a widely distributed group of plant nutrients consumed by humans. Certain foods possess distinctive and relatively higher levels of these compounds. One such food is Tartary buckwheat (

The accumulation of senescent cells can lead to tissue degeneration, chronic inflammatory disease and age-related tumorigenesis. Interventions such as senolytics are currently limited by off-target toxicity, which could be circumvented by instead enhancing immune-mediated senescent cell clearance; however, immune surveillance of senescent cells is often impeded by immunosuppressive factors in the inflammatory microenvironment. Here, we employ a chimeric peptide as a 'matchmaker' to bind to the urokinase-type plasminogen activator receptor, a cell surface marker of senescent cells. This peptide modifies the cell surface with polyglutamic acid, promoting immune cell-mediated responses through glutamate recognition. By enhancing the recruitment of immune cells and directly coupling senescent cells and immune cells, we show that this chimeric peptide induces immune clearance of senescent cells and restores tissue homeostasis in conditions such as liver fibrosis, lung injury, cancer and natural aging in mice. This chimeric peptide introduces an immunological conversion strategy that rebalances the senescent immune microenvironment, offering a promising direction for aging immunotherapy.

Artificial intelligence (AI) algorithms in 12-lead electrocardiogram (ECG) provides promising age prediction methods. This study investigated whether the discrepancy between ECG-derived AI-predicted age (AI-ECG age) and chronological age, termed electrocardiographic aging (ECG aging), is associated with atrial fibrillation (AF) risk.

Characterized by UCP1 expression and abundant mitochondria, brown adipose tissue (BAT) plays a crucial role in energy balance by converting chemical energy into heat through the cost of ATP production. In this study, it was demonstrated that Trib3 is a critical determinant of BAT-mediated energy expenditure and whole-body energy homeostasis. Under 60% high-fat diet conditions, Trib3 expression in BAT was elevated. Mice deficient in Trib3 are resistant to diet-induced obesity and exhibit improved glucose homeostasis due to enhanced BAT activity. Furthermore, brown adipocyte progenitor cells (APCs) lacking Trib3 exhibited increased proliferation and promoted brown adipocyte differentiation and mitochondrial biogenesis, contributing to the increase in the maximal thermogenic capacity of BAT in Trib3-deficient mice. Mechanistically, it was discovered that Trib3 expression is upregulated by free fatty acids at the transcriptional level and synergistically upregulated by DAG-PKC at the posttranslational level. This occurs through the modulation of COP1-mediated Trib3 protein turnover. Interestingly, the level of Trib3 expression in BAT increased with age. Trib3 knockout mice were protected from aging-related weight gain and impaired glucose homeostasis. These results suggest that Trib3 acts as an obesity- and aging-associated factor that negatively regulates BAT activity and that the loss of Trib3 may provide a beneficial approach to prevent obesity and aging-associated metabolic syndrome by increasing the thermogenic capacity of BAT.

Hematopoietic stem cells (HSCs) are critical for maintaining lifelong blood production and immune function, especially in the context of bone marrow transplantation, where their ability to reconstruct multiple blood lineages is essential. However, recent studies have revealed that certain HSCs exhibit a bias toward platelet differentiation, termed platelet-biased HSCs (P-HSCs). This lineage bias, particularly pronounced with aging, can lead to imbalances in post-transplant blood recovery, negatively affecting patient outcomes. Research by Claus Nerlov's team has provided key insights into the heterogeneity of HSCs, focusing on the age-related expansion of P-HSCs. Using advanced techniques such as single-cell RNA sequencing and molecular barcoding, their work highlights the evolutionary conservation of platelet bias in HSCs across species. This work delves into these findings, discussing their clinical implications for bone marrow transplantation, aging-related blood disorders, and potential therapeutic strategies. Moreover, we address limitations in current methodologies and propose future directions for research to optimize HSC-based therapies and improve clinical outcomes in hematological diseases.

Beneficial remodeling of the immune system in successful ageing individuals (centenarians and supercentenarians) is critical for healthy ageing. However, mechanisms for dynamic regulation of immunity during ageing remain unclear. We use single-cell RNA sequencing (scRNA-seq) as an analytical strategy to study the dynamic regulation of immunity during aging and its molecular mechanisms at the single-cell level. We performed an integrative analysis of 87,215 peripheral blood mononuclear cells, from seven supercentenarians, three centenarians, and four elderly controls, generated by single-cell transcriptomics complemented with fluorescence-activated cell sorting. Animals experiments were also conducted to validate the makers of healthy aging found by our bioinformatic analysis and further explore the dynamic of immune changes during aging process. We found that CD8

During oncogene-induced senescence there are striking changes in the organisation of heterochromatin in the nucleus. This is accompanied by activation of a pro-inflammatory gene expression programme - the senescence-associated secretory phenotype (SASP) - driven by transcription factors such as NF-κB. The relationship between heterochromatin re-organisation and the SASP has been unclear. Here, we show that TPR, a protein of the nuclear pore complex basket required for heterochromatin re-organisation during senescence, is also required for the very early activation of NF-κB signalling during the stress-response phase of oncogene-induced senescence. This is prior to activation of the SASP and occurs without affecting NF-κB nuclear import. We show that TPR is required for the activation of innate immune signalling at these early stages of senescence and we link this to the formation of heterochromatin-enriched cytoplasmic chromatin fragments thought to bleb off from the nuclear periphery. We show that HMGA1 is also required for cytoplasmic chromatin fragment formation. Together these data suggest that re-organisation of heterochromatin is involved in altered structural integrity of the nuclear periphery during senescence, and that this can lead to activation of cytoplasmic nucleic acid sensing, NF-κB signalling, and activation of the SASP.

Excessive exposure to ultraviolet radiation B (UVB) has been shown to contribute to the aging of human skin cells. Previous research has demonstrated that atorvastatin calcium (Ato) can mitigate the aging effects caused by chemotherapy drugs. However, it remains unclear whether Ato can alleviate skin aging induced by ultraviolet radiation. In this study, through in vitro experiments with Hacat cells, we found that Ato can significantly reduce the UVB-induced increased expression of age-related protein p16 and age-related gene p21, and also reduce the up-regulation of inflammatory factors such as IL-1 and IL-6. Besides, it can reduce the expression of metallomatrix protein (MMP1 and MMP9), and inhibit cell senescence and inflammatory damage. Similarly, we found that Ato can enhance skin collagen fiber reduction and collagen volume decrease, repair skin photoaging and damage induced by UVB rays, and speed up the rate at which the wounded location heals in vivo using Balb/c mice. In the mechanism, Ato markedly decreased the expression of p-p38, p-p65, p-mTOR in vivo and in vitro, suggesting that it may act on Mitogen-activated protein kinase (MAPK), Nuclear factor κB (NF- κB) and Mammalian target of rapamycin (mTOR) signaling pathways to produce above marked effects. In conclusion, Ato obviously relieved UVB-induced photoaging and damage, thus providing evidence for its potential in mitigating skin aging caused by ultraviolet radiation.

Aging is associated with increased pathology in musculoskeletal tissues. Aging results in the accumulation of senescent cells, stem cell exhaustion, sterile inflammation, and immune cell dysfunction systemically and locally. Improving healing and regeneration during musculoskeletal aging is a significant area of clinical need. Recently, the targeting of senescent cells has become an exciting area of research. Pathological accumulation of senescent cells in tissues is associated with tissue dysfunction. Immune system dysfunction has also been a proposed mechanism for the accumulation of senescent cells, where the immune system fails to clear senescent cells from tissues. Therapeutics that target senescent cells are an active area of research. Additionally, stem cell exhaustion is one proposed mechanism for the decline in regeneration and healing that is found with aging. Declines in stem cells have been noted in patients with musculoskeletal injuries, including rotator cuff tears. The systemic increase in sterile inflammation is also associated with this shift in immune cell function. Polarized regenerative macrophages have been suggested to attenuate inflammation and promote healing. Exosomes from mesenchymal stem cells and immune cells, such as macrophages, are actively being pursued as important biologic therapies to improve regeneration and healing. Exosomes are small extracellular vesicles that are released from cells and carry DNA, RNA, lipids, and metabolites. It is essential in this work to thoroughly define the cell sources of exosomes and determine their mechanistic responses in tissues. Rigorous evidence-based research is needed to determine the potential efficacy of exosomes to improve tissue healing for patients.

Stiffening of the vascular network is associated with the early stages of vascular aging, leading to cardiovascular disorders (hypertension), renal failures, or neurodegenerative diseases (Alzheimer's). Unfortunately, many people remain undiagnosed because diagnostic methods are either unsuitable for a large population or unfamiliar to clinicians which favor the hypertension evaluation. In preclinical research, stiffness studies are often partially conducted. We think that the evaluation of aortic stiffness is essential as it would improve our understanding of aging diseases progression. We propose here a systematic method using decision trees in a multi-scale and multimodal approaches. Our method was evaluated by analyzing the aortic situation in old and young mice. We demonstrate that both the endothelial and smooth muscle cells exhibit pronounced functional alterations in favor of constriction. Additionally, there is significant remodeling of the extracellular matrix, leading to a drastic degradation of elastic fibers and the accumulation of collagen in the aortic wall. This series of changes contributes to the development of vascular rigidity, a preliminary stage of arterial hypertension. Our results suggest that our method should improve preclinical understanding and encourage clinicians to equip themselves with tools for assessing vascular function, as it is an essential issue for preventing numerous pathologies.

Osteosarcopenia, characterized by the simultaneous loss of bone and muscle mass, is a serious health problem in the aging population. This study investigated the interplay between host genetics, gut microbiota, and musculoskeletal health in a mouse model of osteosarcopenia, exploring the therapeutic potential of gut microbiota modulation.

The phenomenon of brain-bone crosstalk pertains to the intricate interaction and communication pathways between the central nervous system and the skeletal system. Disruption in brain-bone crosstalk, particularly in disorders such as osteoporosis, can result in skeletal irregularities. Consequently, investigating and comprehending this communication network holds paramount importance in the realm of bone disease prevention and management. In this study, we found that Staphylococcus aureus lipoteichoic acid promoted the conversion of arachidonic acid to PGE2 by interacting with TLR2 receptors acting on the surface of microglial cells in the pituitary gland, leading to the upregulation of COX-2 expression. Subsequently, PGE2 bound to the EP4 receptor of growth hormone-secreting cells and activated the intracellular CREB signalling pathway, promoting GH secretion and ameliorating age-related bone loss.

Health behaviors of older people are influenced by many factors, and physical activity are important lifestyle behaviors that promote healthy aging.

Owning a home has long been touted as a key component of the idealized "American Dream." Homeownership is associated with greater wealth and better health, but the causal impact of homeownership on health remains unclear. Using linked complete-count census and Social Security mortality records, I document Black-White disparities in homeownership rates and produce the first U.S.-based estimates of the association between homeownership in early adulthood and longevity. I then use a sibling-based identification strategy to estimate the causal effect of homeownership on longevity for cohorts born in the first two decades of the twentieth century. The results indicate that homeownership has a significant positive impact on longevity, which I estimate at approximately 4 months.

Ageing is one of the most important risk factors for chronic health conditions, including neurodegenerative diseases. Inflammation is a feature of ageing, as well as a key pathophysiological mechanism for degenerative diseases. Microglia play multiple roles in the central nervous system; their states entail a complex assemblage of responses reflecting the multiplicity of functions they fulfil both under homeostatic basal conditions and in response to stimuli. Whereas glial cells can promote neuronal homeostasis and limit neurodegeneration, age-related inflammation (i.e. inflammaging) leads to the functional impairment of microglia and astrocytes, exacerbating their response to stimuli. Thus, microglia are key mediators for age-dependent changes of the nervous system, participating in the generation of a less supportive or even hostile environment for neurons. Whereas multiple changes of ageing microglia have been described, here we will focus on the neuron-microglia regulatory crosstalk through fractalkine (CX3CL1) and CD200, and the regulatory cytokine Transforming Growth Factor β1 (TGFβ1), which is involved in immunomodulation and neuroprotection. Ageing results in a dysregulated activation of microglia, affecting neuronal survival, and function. The apparent unresponsiveness of aged microglia to regulatory signals could reflect a restriction in the mechanisms underlying their homeostatic and reactive states. The spectrum of functions, required to respond to life-long needs for brain maintenance and in response to disease, would progressively narrow, preventing microglia from maintaining their protective functions.

The MetaboHealth score is a highly informative health indicator in ageing studies and yet contains only a small number of metabolites. Here we estimate the heritability of the score in 726 monozygotic (MZ) and 450 dizygotic (DZ) twin pairs, and test for association with plasma proteins by comparing extreme scoring individuals selected from two large population cohorts -the Leiden Longevity Study (LLS) and the Rotterdam Study (RS) and discordant monozygotic twin pairs from the Netherlands Twin Register (NTR). The heritability for the MetaboHealth score was estimated at 40%. In 50 high and 50 low scoring MetaboHealth groups from LLS and RS, we uncovered significant differences in plasma proteins, notably in 3 (out of 15) cytokines (GDF15, IL6, and MIG), and 106 proteins (out of 289) as determined by Mass Spectrometry based proteomics analysis. A high MetaboHealth score associated with an increased level for 42 serum proteins, predominantly linked to inflammation and immune response, including CRP and HPT. A low score associated with decreased levels of 71 proteins enriched in high-density lipoprotein (HDL) remodeling and cholesterol transport pathways, featuring proteins such as APOA1, APOA2, APOA4, and TETN. In MZ twins selected for maximal discordance within a pair we found 68 serum proteins associated with the MetaboHealth score indicating that a minor part of the associations observed in LLS and RS is likely explained by genetic influences. Taken together, our study sheds light on the intricate interplay between MetaboHealth, plasma proteins, cytokines, and genetic influences, paving the way for future investigations aimed at optimizing this mortality risk indicator.

The chronic inflammation present in aged individuals is generally depicted as a detrimental player for longevity. Here, it is discussed several beneficial effects associated with the cytokines that are chronically elevated in inflammaging. These cytokines, such as IL-1β, type I interferons, IL-6 and TNF positively regulate macroautophagy, mitochondrial function, anti-tumor immune responses and skeletal muscle biogenesis, possibly contributing to longevity. On the other side, the detrimental and antagonistic role of these cytokines including the induction of sarcopenia, tissue damage and promotion of tumorigenesis are also discussed, underscoring the dichotomy associated with inflammaging and its players. In addition, it is discussed the role of the anti-inflammatory cytokine IL-10 and other cytokines that affect aging in a more linear way, such as IL-11, which promotes senescence, and IL-4 and IL-15, which promotes longevity. It is also discussed more specific regulators of aging that are downstream cytokines-mediated signaling.

Aging is a social problem that people pay particular attention to. Oxidative stress is closely related to aging. Natural polysaccharides have numerous biological activities, and they show good application prospect in preventing oxidative stress and aging prospects. Herein, morphological analysis, molecular weight analysis, monosaccharide composition, methylation analysis, and NMR spectrum analysis were used to characterize the structure of ZJP-04M, an isolated homogeneous polysaccharide from the Ziziphus jujuba fruit. Results indicated that in ZJP-04M, the trunk chain was formed through the alternately connected homogalacturonan skeleton and rhamnogalacturonan-I domain and the branch chain was formed by arabinan and arabinogalactan. After feeding the polysaccharide to Caenorhabditis elegans, ZJP-04M was found to exert a certain paraquet-induced protective effect on the oxidative damage. Under normal conditions, ZJP-04M could significantly prolong the lifespan of C. elegans but exhibited no obvious effect on its reproductive capacity. We futher confirmed that ZJP-04M can play an antiaging role by regulating DAF-16. Based on these results, ZJP-04M can be used in antioxidation and antiaging applications.

Cellular senescence, recognized as a key hallmark of aging, leads to the accumulation of senescent cells in various tissues over time. While the detrimental effects of these cells on age-related pathological conditions are well-documented, there is still limited information about how senescent cells are distributed in normal tissues of both young and aged organs. Our research indicates that fully senescent p16

Platelets are important players in hemostasis. Alterations in platelet number and/or function lead to life-threatening conditions like thrombosis, myocardial infarction and stroke. During aging, changes at the cellular, organ and systemic level occur that affect platelet counts, platelet functionality, the expression of platelet surface receptors, clearance markers as well as their interactions with immune cells. Understanding how these changes influence platelets can help to prevent the alterations of hemostasis and thrombosis we observe in the elderly. In this review, we highlight the respective changes at important sites of the platelet life cycle: bone marrow, liver and spleen, but also show how alterations in immunity contribute. We point out the necessity for further research on age-related systemic alterations in these systems and their interplay with platelets to better understand the complex processes that cause alterations in the platelet life cycle during aging.

The therapeutic effectiveness of dental pulp stem cells (DPSCs) is limited. Sirtuin 7 (SIRT7) has been reported to be associated with a variety of age-related diseases. We aimed to identify the regulatory role of SIRT7 in DPSC senescence and investigate the underlying mechanism. DPSCs were isolated from healthy adults, the stem markers were verified by flow cytomerty analysis. Replicative senescence was induced in DPSCs by serial passage and cells were analyzed at PD16 and 54. DPSC senescence was evaluated by observing senescence-associated β-galactosidase (SA-β-gal) and telomerase reverse transcriptase (TERT) activity. Meanwhile, the markers of senescence levels were monitored by western blotting assay. SIRT7 protein was pulled-down, and the binding relationship between SIRT7 and ROCK1 was verified by immunoprecipitation and western blotting methods. Replicative senescence was induced in DPSCs at PD54. The number of SA-β-gal stained DPSCs significantly increased in the PD54 group while the level of TERT activity was decreased. The cyclin-dependent kinase inhibitors p53, p21, and p16, which are markers of senescence, were markedly up-regulated at PD54. SIRT7 was also found to be lowly expressed at PD54. Inhibition of SIRT7 significantly accelerated the senescence of DPSCs. Moreover, SIRT7 can bind with ROCK1, and SIRT7 could lead to ROCK1 desuccinylation at K520. Inhibited ROCK1 significantly reversed the effects of SIRT7 knockdown on regulating DPSCs senescence. Our results demonstrate that the SIRT7/ROCK1 axis plays a key role in the regulation of DPSC senescence and provide a candidate target to improve the functional and therapeutic potential of DPSCs.

Frailty is one of the most common and challenging consequences of aging, which negatively affects older adults, their families, and society. Caffeine has been shown to be associated with a reduced risk of frailty by observational studies, yet its causal relationship with frailty remains to be tested using more robust methods.

This study investigated the effects of different doses of vitamin E on oxidative stress, cognitive function, and gene expression in aged mice. A total of 32 male mice, aged 12 months, were divided into a control group and three treatment groups. These groups received varying daily doses of vitamin E for a period of 28 days. The results showed significant improvements in cognitive function, specifically in working memory and spatial learning, in the groups that received vitamin E (100, 200, or 400 mg/kg) compared to the control group. The markers of oxidative stress and antioxidant enzyme activities also demonstrated improvements, with higher doses of vitamin E showing greater effects. The analysis of gene expression revealed increased expression of SIRT1, Nrf2, and Calstabin2, particularly at higher doses of vitamin E. These findings suggest that vitamin E supplementation may help counteract age-related cellular changes. The study concludes that vitamin E supplementation can reduce oxidative stress, enhance cognitive function, and affect genetic markers of aging in mice, which may have therapeutic benefits in addressing age-related cognitive decline and oxidative damage. Further research is necessary to investigate the clinical implications of these findings in humans.