Longevity Papers

Curcumin, a natural compound found in turmeric, has shown promise in treating brain-related diseases and conditions associated with aging. Curcumin has shown multiple anti-inflammatory and brain-protective effects, but its clinical use is limited by challenges like poor absorption, specificity and delivery to the right tissues. A range of contemporary approaches at the intersection with bioengineering and systems biology are being explored to address these challenges. Data from preclinical and human studies highlight various neuroprotective actions of curcumin, including the inhibition of neuroinflammation, modulation of critical cellular signaling pathways, promotion of neurogenesis, and regulation of dopamine levels. However, curcumin's multifaceted effects - such as its impact on microRNAs and senescence markers - suggest novel therapeutic targets in neurodegeneration. Tetrahydrocurcumin, a primary metabolite of curcumin, also shows potential due to its presence in circulation and its anti-inflammatory properties, although further research is needed to elucidate its neuroprotective mechanisms. Recent advancements in delivery systems, particularly brain-targeting nanocarriers like polymersomes, micelles, and liposomes, have shown promise in enhancing curcumin's bioavailability and therapeutic efficacy in animal models. Furthermore, the exploration of drug-laden scaffolds and dermal delivery may extend the pharmacological applications of curcumin. Studies reviewed here indicate that engineered dermal formulations and devices could serve as viable alternatives for neuroprotective treatments and to manage skin or musculoskeletal inflammation. This work highlights the need for carefully designed, long-term studies to better understand how curcumin and its bioactive metabolites work, their safety, and their effectiveness.

Sensorimotor and cognitive abilities undergo substantial changes throughout the human lifespan, but the corresponding changes in the functional properties of cortical networks remain poorly understood. This can be studied using temporal and spatial scales of functional magnetic resonance imaging (fMRI) signals, which provide a robust description of the topological structure and temporal dynamics of neural activity. For example, timescales of resting-state fMRI signals can parsimoniously predict a significant amount of the individual variability in functional connectivity networks identified in adult human brains. In the present study, we quantified and compared temporal and spatial scales in resting-state fMRI data collected from 2,352 subjects between the ages of 5 and 100 in Developmental, Young Adult, and Aging datasets from Human Connectome Project. For most cortical regions, we found that both temporal and spatial scales largely decreased with age across most cortical areas throughout the lifespan, with the visual cortex and the limbic network consistently showing the largest and smallest scales, respectively. For some prefrontal regions, however, these two scales displayed non-monotonic trajectories during adolescence and peaked around the same time during adolescence and decreased throughout the rest of the lifespan. We also found that cortical myelination increased monotonically throughout the lifespan, and its rate of change was significantly correlated with the changes in both temporal and spatial scales across different cortical regions in adulthood. These findings suggest that temporal and spatial scales in fMRI signals, as well as cortical myelination, are closely coordinated during both development and aging.

Aging affects reproductive capabilities in males through physiological and behavioral alterations, including endocrine changes and decreased libido. In this study, we investigated the influence of intermittent fasting (IF) on these aging-related declines, using male C57BL/6J mice. Our findings revealed that IF significantly preserved reproductive success in aged mice, not by improving traditional reproductive metrics such as sperm quality or endocrine functions but by enhancing mating behavior. This behavioral improvement was attributed to IF's ability to counter age-dependent increases in serotonergic inhibition, primarily through the decreased supply of the serotonin precursor tryptophan from the periphery to the brain. Our research underscores the potential of dietary interventions like IF in mitigating age-associated declines in male reproductive health and suggests a novel approach to managing conditions related to reduced sexual desire, highlighting the complex interplay between diet, metabolism, and reproductive behavior.

Mitochondria play a crucial role in brain homeostasis and changes in mitochondrial bioenergetics are linked to age-related neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. We investigated changes in the activities of the electron transport chain (ETC) complexes in normally aging baboon brains and determined how these changes relate to donor sex, morning cortisol levels, and walking speed. We assessed mitochondrial bioenergetics from archived prefrontal cortex (PFC) tissues from a large cohort (60 individuals) of well-characterized aging baboons (6.6-22.8 years, approximately equivalent to 26.4-91.2 human years). Aging was associated with a decline in mitochondrial ETC complexes in the PFC, which was more pronounced when normalized for citrate synthase activity, suggesting that the decline is predominantly driven by changes in the specific activity of individual complexes rather than global changes in mitochondrial content. When donor sex was used as a covariate, we found that ETC activity was preserved with age in females and declined in males. Males had higher activities of each individual ETC complex and greater lactate dehydrogenase activity at a given age relative to females. Circulating cortisol negatively correlated with walking speed when male and female data were combined. We also observed a robust positive predictive relationship between walking speed and respiration linked to complexes I, III, and IV in males but not in females. This data reveals a link between frailty and PFC bioenergetic function and highlights a potential molecular mechanism for sexual dimorphism in brain resilience.

Skin function depends on a meticulously regulated dynamic interaction of distinct skin compartments such as the epidermis and dermis. Adaptive responses at the molecular and cellular level are essential for these interactions - and if dysregulated - drive skin aging and other pathologies. After defining the role of redox homeodynamics in physiology and aging pathology, we focus on the redox distress-dependent aging of dermal fibroblasts including their progenitors. We here discuss the prime role of senescent fibroblasts in the control of their own endogenous niche and stem cell niches for epidermal stem cells, hair follicle stem cells, adipocyte precursors and muscle stem cells. We here review that redox imbalance induced reduction in Insulin-like Growth Factor-1 drives skin aging by the depletion of stem cell pools. This IGF-1 reduction is mediated via the redox-sensitive transcription factor JunB and also by the redox-dependent changes in sphingolipid-metabolism, among others. In addition, we will discuss the changes in the extracellular matrix of the skin affecting cellular senescence and the skin integrity and function in aging. The aim is a deeper understanding of the two main redox-dependent hubs such as JunB-induced depletion of IGF-1, and the sphingolipid-mediated remodeling of the cell membrane with its impact on IGF-1, fibroblast heterogeneity, function, senescence and plasticity in skin aging.

The recent designation of Cryptococcus neoformans as a critical-priority fungal pathogen by the World Health Organization highlights the imperative need for novel antifungal agents with distinct mechanisms of action. This study elucidates the novel ferroptotic pathway underlying C. neoformans-induced cell death in Caenorhabditis elegans and investigates the therapeutic potential of isobavachalcone (IBC) through comprehensive evaluation of core biochemical markers: total glutathione (GSH), malondialdehyde, ferrous iron content, and lipid reactive oxygen species (ROS). Integrated transcriptomic analysis via RNA-seq and subsequent RT-qPCR validation revealed critical gene expression patterns associated with antiferroptotic regulation. Our findings demonstrate that C. neoformans infection initiates ferroptosis in C. elegans through iron-dependent lipid peroxidation cascades. Remarkably, IBC administration conferred significant protection against fungal-induced ferroptosis by restoring redox homeostasis-evidenced by elevated GSH levels, attenuated ROS accumulation, and decreased ferrous iron content. Mechanistic investigations identified IBC-mediated upregulation of SKN-1 and GSH biosynthesis genes, coupled with suppression of GPX-1 activity. These coordinated effects disrupted the iron-ROS amplification loop through modulation of the GSH-GPX-1 axis, ultimately extending host lifespan in C. neoformans-challenged models. Our results position IBC as a ferroptosis inhibitor with dual antioxidant and iron-chelating properties, offering a therapeutic strategy against cryptococcal infections through targeting of evolutionary conserved cell death pathways.

O-GlcNAc transferase (OGT) interacts robustly with all three mammalian TET methylcytosine dioxygenases. Here we show that deletion of the Ogt gene in mouse embryonic stem (mES) cells results in a widespread increase in the TET product 5-hydroxymethylcytosine in both euchromatic and heterochromatic compartments, with a concomitant reduction in the TET substrate 5-methylcytosine at the same genomic regions. mES cells treated with an OGT inhibitor also displayed increased 5-hydroxymethylcytosine, and attenuating the TET1-OGT interaction in mES cells resulted in a genome-wide decrease of 5-methylcytosine, indicating that OGT restrains TET activity and limits inappropriate DNA demethylation in a manner that requires the TET-OGT interaction and the catalytic activity of OGT. DNA hypomethylation in OGT-deficient cells was accompanied by derepression of transposable elements predominantly located in heterochromatin. We suggest that OGT protects the genome against TET-mediated DNA demethylation and loss of heterochromatin integrity, preventing the aberrant increase in transposable element expression noted in cancer, autoimmune-inflammatory diseases, cellular senescence and aging.

Klotho, a protein primarily expressed in the kidneys and brain, plays a critical role in aging, vascular health, and various metabolic processes. Lower serum Klotho levels have been associated with several chronic diseases, including cardiovascular disease, diabetes, and kidney disease. Although the role of Klotho in platelet regulation remains underexplored, thrombocytosis may be influenced by Klotho levels. Investigating this relationship could offer new insights into thrombocytosis pathogenesis. This study aimed to examine the relationship between serum Klotho levels and thrombocytosis in a U.S. cohort. We hypothesized that lower Klotho levels would be associated with an increased risk of thrombocytosis, potentially providing a novel perspective on thrombocytosis regulation. We conducted a cross-sectional analysis of data from 12,700 participants in the NHANES 2007-2016 cohort. Multivariate logistic regression models were used to assess the association between serum Klotho levels and thrombocytosis, adjusting for relevant covariates. Of the 12,700 participants, 86 had thrombocytosis. The thrombocytosis group had significantly lower mean serum Klotho levels compared to the non-thrombocytosis group (p < 0.01). After adjusting for confounders, an inverse association between serum Klotho levels and thrombocytosis was observed (odds ratio 0.89, 95% CI 0.82-0.97, p = 0.007). Compared to the lowest Klotho quartile (≤ 700.7 pg/ml), the adjusted odds ratios for thrombocytosis in the second (700.8-915.3 pg/ml) and third (≥ 915.4 pg/ml) quartiles were 0.6 (95% CI: 0.36-1.01, p = 0.055) and 0.49 (95% CI: 0.29-0.84, p = 0.01), respectively. Our findings suggest an inverse correlation between serum Klotho levels and thrombocytosis in adults aged 40 and older. These results highlight the potential role of Klotho in thrombocytosis regulation, and future longitudinal studies are needed to establish causality and explore the underlying mechanisms.

Biological processes are often spatially regulated, ensuring molecular and cellular events occur in their most strategically advantageous locations. Cellular senescence, marked by cell cycle arrest and hypersecretion, is recognized as an important part of physiological processes like development and healing, but it also contributes to aging and disease. However, the spatial distribution of senescent cells and its physiological and pathological impact remain unclear. Here we compile evidence on senescent cell localization in development, healing, and aging. We emphasize the significance of their spatial patterns and speculate on the effects of disrupted spatial positioning of senescence in relation to pathologies. To summarize the specific spatial functions of senescent cells, we propose to refer to them as 'barrier' and 'conductor' functions. The 'barrier' function of senescent cells, due to their altered morphology and apoptosis resistance, separates tissues and builds a border between two environments. The conductor function, with the secretion of signaling factors, influences the surrounding area and stimulates migration, differentiation, or proliferation, among other processes. Overall, this Review explores the spatial patterning of cellular senescence in biological processes, highlighting its dual roles as 'barrier' and 'conductor' functions, and examines the implications of senescent cell distribution in development, healing, aging, and disease.

The impact of dietary patterns on health and lifespan is well-established, yet the effects of meal timing on the aging process and risk of premature death remain unclear. This study aimed to investigate the association between the difference in energy and macronutrient intake at dinner versus breakfast and the risk of premature mortality and biological aging.

Biological aging clocks across organs and omics data, including clinical phenotypes, neuroimaging, proteomics, and epigenetics, have proven instrumental in advancing our understanding of human aging and disease. Here, we expand this aging clock framework to plasma metabolomics by developing 5 organ-specific metabolome-based biological age gaps (MetBAGs) using 107 plasma non-derived metabolites from 274,247 UK Biobank participants. Our multi-organ MetBAGs were trained using Lasso regression and neural networks, achieving a mean absolute error of approximately 6 years (0.25

Pulmonary fibrosis is an incurable disease that manifests with advanced age. Yet, how hematopoietic aging influences immune responses and fibrosis progression remains unclear. Using heterochronic bone marrow transplant mouse models, we found that an aged bone marrow exacerbates lung fibrosis irrespective of lung tissue age. Upon lung injury, there was an increased accumulation of monocyte-derived alveolar macrophages (Mo-AMs) driven by cell-intrinsic hematopoietic aging. These Mo-AMs exhibited an enhanced profibrotic profile and stalled maturation into a homeostatic, tissue-resident phenotype. This delay was shaped by cell-extrinsic environmental signals such as reduced pulmonary interleukin-10 (IL-10), perpetuating a profibrotic macrophage state. We identified regulatory T cells (T

Efforts to increase health span bring to light the necessity of constructing biological age (BA) for measuring aging. However, universally adaptive BA needs further investigation, especially among the Chinese population. Therefore, this study aimed to construct BA using routine clinical markers for the Chinese population. Included were two Chinese prospective cohorts, the Kailuan Study I (n = 83,571) for developing BA and the Kailuan Study II (n = 21,229) for validation. Leveraging baseline age-related clinical markers, we developed phenotypic BA (Pheno-Age) using Levine's methods and Klemera-Doubal BA (KDM-Age) using KDM methods and calculated the residuals of regressions of the two BA measured at baseline and during follow-up on chronological age, namely BA acceleration. The predictive performance of baseline, cumulative average, and updated BAs on mortality was evaluated using the area under the curve (AUC) and calibration plots. COX regressions were used to estimate hazard rations (HRs) and 95% confidence intervals (CIs) for the BA acceleration and risk of mortality. During 1,443,857 person-years of follow-up, 12,679 deaths were recorded in the two cohorts. Baseline Pheno-Age and KDM-Age produced desirable predictions for mortality in both the Kailuan Study I (AUC, 0.810 and 0.806, respectively) and the Kailuan Study II (AUC, 0.867 and 0.819, respectively). Calibration plots showed reasonable agreement between predicted and observed probabilities. The pooled multivariable-adjusted HRs (95% CIs) for per standard deviation increment of baseline Pheno-Age acceleration and mortality was 1.24 (1.18, 1.30), and for KDM-Age acceleration was 1.16 (1.10, 1.21). Similar predictive performance and association were observed when using cumulative average or updated BA. The associations were stronger in the adults aged ≤60 years, smokers, and drinkers, relative to their counterparts (P for interaction <0.05 for all). Pheno-Age and KDM-Age, developed and validated in the two large prospective cohorts, could predict mortality, independent of chronological age and other potential confounders, in Chinese populations.

Inexorable high serum phosphate levels in chronic kidney disease (CKD) patients deteriorate the functionality of the musculoskeletal, renal, and cardiovascular systems, thereby contributing to increased morbidity and mortality. Higher phosphate balance has also been correlated with increased mortality rates in individuals with normal renal function, independent of other comorbidities. Clinical and epidemiological studies of CKD patients and healthy subjects, alongside evidence of accelerated aging in murine models induced by excessive phosphate loading, indicate that phosphate toxicity is a driver of premature aging and age-related organ damage.

The anti-ageing response of Dietary Restriction (DR) is thought to be an ancient mechanistic response, reasoning from its phenotypic conservation in a wide range of organisms. However, DR is implemented using different diets and methods across species, and evidence for conservation at the mechanistic level remains limited. Here we tested the longevity and fecundity response to DR across eight different species of Drosophila using the same diets in a reaction norm framework. We confirm that DR is phenotypically conserved across Drosophila. Next, we used comparative transcriptomics across six species and found strongly concordant differential expression in response to DR (rs > 0.28, < 0.72, P < 0.0001). We studied the evolutionary history of the top concordantly differentially expressed orthologous genes and identified that the large majority of these genes are young genes and are Diptera specific. Our results indicate that large parts of the DR response are likely to be taxonomic specific, suggesting that the genetic basis of DR is not widely conserved. To validate this hypothesis we tested whether the 15 most conserved genes that change in transcription in response to DR using conditional in vivo RNAi. Surprisingly, we found that 12 out of 15 genes tested had a lifespan phenotype, with 9 extending lifespan. Five of these genes are related to cysteine metabolism implicating it in the mechanisms of DR, further suggesting physiological compensation to DR is ubiquitous and providing a possible biomedical target. Our findings suggest that while large parts of the DR response are taxonomically specific, some core mechanisms are conserved across divergent species. The comparative approaches we used here hold promise to identify shared mechanisms relevant to our own species and therefore ultimately anti-ageing interventions.

To investigate the effect of pyrroloquinoline quinone (PQQ) on skin aging in the Bmi-1 KO mice and its underlying mechanisms, we administered a normal diet to both Wild type mice (WT) and Bmi-1 KO mice, while supplementing the diet of Bmi-1 KO mice with PQQ (PQQ+Bmi-1 KO). Subsequently, we compared the thickness of the skin epidermis, dermis, pilosebaceous unit and collagen ratio using HE staining and Masson's trichrome. Additionally, immunohistochemical staining, Western blotting and electron microscopy were applied across all three groups. The results revealed that Bmi-1 KO mice exhibited premature aging phenotypes compared to the WT group; however, PQQ administration effectively delayed premature aging in Bmi-1 KO mice. Furthermore, reduced epidermal thickness, dermal thickness, pilosebaceous units count as well as collagen ratio were observed in Bmi-1 KO mice. Moreover, the PCNA positive cell percentage also decreased in Bmi-1 KO mice. Conversely, treatment with PQQ significantly increased epidermal thickness, dermal thickness, pilosebaceous unit count, collagen ratio and PCNA positive cell percentage when compared to Bmi-1 KO mice. In order to further investigate the anti-aging mechanism of PQQ, experiments have revealed that PQQ effectively suppressed the expression of cell cycle proteins p16, p19, and p53 in Bmi-1 KO mice. In addition, autophagy-related experiments demonstrated that compared to the WT group, Bmi-1 KO mice exhibited an increased number of autophagosomes along with decreased expression of Beclin-1 and LC3Ⅱ/LC3Ⅰratio, and increased expression of p62. However, supplementation with PQQ resulted in a reduction in the number of autophagosomes while increasing the expression of Beclin-1 and LC3Ⅱ/LC3Ⅰratio and decreasing the expression of p62. This study provides evidence that downregulation of Bmi-1 promotes skin aging, whereas PQQ delays skin aging in Bmi-1 KO mice by promoting cell proliferation, inhibiting the expression of p16, p19 and p53 and enhancing autophagy levels.

Naked mole-rats have exceptionally long lifespans and reproduce eusocially, with a single female, the queen, producing all offspring. Other eusocial species, such as bees, ants, and termites, also have long lifespans relative to their solitary kin. We propose that eusociality drives the evolution of longevity through three mechanisms: first, individuals in eusocial populations tend to be older than in non-eusocial populations, and thus genes favoring survival at later ages are more strongly selected; second, slower growth in eusocial populations reduces early mortality from resource scarcity, making longevity more important. Finally, the fitness benefits of long lifespan are stronger when the population\'s reproductive success rests on the survival of a single individual. Non-eusocial species reproducing in ways that partly access these benefits also have relatively long lifespans. We demonstrate these three mechanisms using mathematical models and computer simulations, highlighting longevity as an evolvable, selectable trait. Our results echo conclusions from Life History Theory but cast them in a new light.

Metabolic-inflammatory states are central to multiorgan mechanisms of aging, but precise functional biomarkers of physiological aging remain less clear.

We revisit much-investigated relationships between schooling and health, focusing on schooling impacts on cognitive abilities at older ages using the Harmonized Cognition Assessment Protocol in the Health and Retirement Study (HRS) and a bounding approach that requires relatively weak assumptions. Our estimated upper bounds on the population average effects indicate potentially large causal effects of increasing schooling from primary to secondary. Yet, these upper bounds are smaller than many estimates from studies of causal schooling impacts on cognition using compulsory schooling laws. We also cannot rule out small and null effects at this margin. However, we find evidence for positive causal effects on cognition of increasing schooling from secondary to tertiary. We replicate findings from the HRS using data on older adults from the Midlife in United States Development Study Cognitive Project. We further explore possible mechanisms behind the schooling effect (e.g., health, socioeconomic status, occupation, and spousal schooling), finding suggestive evidence of effects through such mechanisms.

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Collagen loss is one of the major contributor to signs of skin aging such as dryness, roughness, and wrinkle formation, which is closely linked to a decline in the amount of proline produced in mitochondria. Melatonin has been shown to improve several clinical signs of skin aging, while the mechanism is unclear. In our study, we found that mitophagy, proline synthesis key enzyme NADK2 and proline and collagen levels were significantly reduced, while oxidative stress levels increased in aging skin, and melatonin supplementation could effectively up-regulate mitophagy level and restore proline synthesis and further improved skin aging. However, proline supplementation could also exert an anti-aging effect, while it had no effect on the mitochondrial dysfunction. Moreover, our study indicated that melatonin enters the cell by binding to the MT1 receptor and then enters the mitochondria via the PEPT1 transporter to exert its mitochondrial protective effects. This study helps to elucidate the mechanism of mitochondrial dysfunction-induced skin aging, and provides new theoretical guidance for revealing the mechanism of skin aging and rationally utilizing endocrine hormones to improve skin aging, which has a broad application prospect.

Aging is a degenerative process. Therefore, the background of our study is to evaluate the effects of boron, one of the important underground resources in Türkiye, on aging and related diseases. This study aimed to assess the antioxidant effect and the cognitive functions of boric acid (BA) in a D-galactose (D-gal)-induced aging model.

Senescence associated secretory phenotype (SASP) contributes to age-related pathology, however the role of SASP in Chronic Kidney Disease (CKD) is unclear. Here, we employ a variety of omic techniques to show that senescence signatures can separate CKD patients into distinct senescence endotypes (Sendotype).

Aging is accompanied by considerable changes in the gut microbiome, yet the molecular mechanisms driving aging and the role of the microbiome remain unclear. Here we combined metagenomics, transcriptomics and metabolomics from aging mice with metabolic modelling to characterize host-microbiome interactions during aging. Reconstructing integrated metabolic models of host and 181 mouse gut microorganisms, we show a complex dependency of host metabolism on known and previously undescribed microbial interactions. We observed a pronounced reduction in metabolic activity within the aging microbiome accompanied by reduced beneficial interactions between bacterial species. These changes coincided with increased systemic inflammation and the downregulation of essential host pathways, particularly in nucleotide metabolism, predicted to rely on the microbiota and critical for preserving intestinal barrier function, cellular replication and homeostasis. Our results elucidate microbiome-host interactions that potentially influence host aging processes. These pathways could serve as future targets for the development of microbiome-based anti-aging therapies.

The capacity of the central nervous system for structural plasticity and regeneration is commonly believed to show a decreasing progression from "small and simple" brains to the larger, more complex brains of mammals. However, recent findings revealed that some forms of neural plasticity can show a reverse trend. Although plasticity is a well-preserved, transversal feature across the animal world, a variety of cell populations and mechanisms seem to have evolved to enable structural modifications to take place in widely different brains, likely as adaptations to selective pressures. Increasing evidence now indicates that a trade-off has occurred between regenerative (mostly stem cell-driven) plasticity and developmental (mostly juvenile) remodeling, with the latter primarily aimed not at brain repair but rather at "sculpting" the neural circuits based on experience. In particular, an evolutionary trade-off has occurred between neurogenic processes intended to support the possibility of recruiting new neurons throughout life and the different ways of obtaining new neurons, and between the different brain locations in which plasticity occurs. This review first briefly surveys the different types of plasticity and the complexity of their possible outcomes and then focuses on recent findings showing that the mammalian brain has a stem cell-independent integration of new neurons into pre-existing (mature) neural circuits. This process is still largely unknown but involves neuronal cells that have been blocked in arrested maturation since their embryonic origin (also termed "immature" or "dormant" neurons). These cells can then restart maturation throughout the animal's lifespan to become functional neurons in brain regions, such as the cerebral cortex and amygdala, that are relevant to high-order cognition and emotions. Unlike stem cell-driven postnatal/adult neurogenesis, which significantly decreases from small-brained, short-living species to large-brained ones, immature neurons are particularly abundant in large-brained, long-living mammals, including humans. The immature neural cell populations hosted in these complex brains are an interesting example of an "enlarged road" in the phylogenetic trend of plastic potential decreases commonly observed in the animal world. The topic of dormant neurons that covary with brain size and gyrencephaly represents a prospective turning point in the field of neuroplasticity, with important translational outcomes. These cells can represent a reservoir of undifferentiated neurons, potentially granting plasticity within the high-order circuits subserving the most sophisticated cognitive skills that are important in the growing brains of young, healthy individuals and are frequently affected by debilitating neurodevelopmental and degenerative disorders.

Ames dwarf mice (df/df) live 50% longer than normal littermates due to a genetic defect in growth hormone (GH) signaling. The enhanced longevity of Ames dwarfs has been studied extensively in an endocrinological context of cellular metabolism and increased resistance to oxidative stress (Bartke. World J Mens Health 37(1):19, 8; Bartke 2; BartkeJ Am Aging Assoc 23(4):219, 10; Bartke. World J Mens Health 39(3):454-465, 11; Brown-Borg et al. Nature 384(6604):33-33, 1; Masternak et al. 2018). However, the skeletal muscle system is relatively unexplored, the quality of which dictates metabolic homeostasis, permits movement and exercise, and exerts paracrine effects on other organs (Delmonico and Beck Am J Lifestyle Med 11(2):167-181, 25; Evans et al. GeroScience 46(1):183, 26; Kim and Kim. Endocrinol Metab (Seoul) 35(1):1-6, 15; Masternak et al. 2018). Here, we characterize the fitness capacity and skeletal muscle morphology of Ames mice to determine if previously established longevous effects of GH deficiency extend to skeletal muscle tissue. Mutually exclusive, age-matched cohorts of male Ames mice and wildtype controls performed grip strength, rotarod, and endurance running experiments over 6 months. The largest difference in physical performance was observed in endurance running capacity, where dwarf mice outperformed wildtype controls increasingly with age. Tibialis anterior (TA) muscles were evaluated for myofiber size, quality, and environment. Ames mice show reduced myofiber cross-sectional area (CSA) paired with increased myofibers per muscle. Dwarf myofiber populations are less heterogenous in size and seemingly resist sarcopenia, as skeletal muscle from aged individuals shows youthful morphological resemblance in mean myofiber CSA, size frequency distribution, and presence of fibrotic tissue. Declines in fitness performance and myofiber integrity were observable in age-matched wildtype controls. Utilizing an established longevity model to investigate skeletal muscle function and morphology is a novel approach to gaining insight into the seemingly inverse relationship between GH signaling and mammalian longevity.

This study aims to investigate the effects of long-term aerobic exercise on liver health in aging rats. As age increases, the continuous accumulation of endogenous reactive oxygen species (ROS) damages hepatocytes, leading to liver function decline and the development of diseases such as cirrhosis and liver cancer. Using an 18-month-old rat model, we implemented an eight-month aerobic exercise regimen to systematically evaluate its hepatoprotective effects. The results showed that aerobic exercise effectively reduced oxidative stress and inflammation levels in liver tissue, decreased the expression of cell cycle regulator P53 and inflammatory regulator NF-κB protein, upregulated NRF2 protein expression, improved mitochondrial function, and inhibited the progression of ferroptosis. These beneficial effects were achieved through the upregulation of miR-21 and miR-224 expression induced by exercise. These microRNAs inhibit the translation of MAP2K3 and MAPK14, thereby suppressing the activation of the P38 MAPK pathway. We further found that inhibiting P38 MAPK can enhance cellular antioxidant and anti-inflammatory capabilities, reversing hepatocyte damage caused by hydrogen peroxide. These results demonstrate that long-term aerobic exercise can reprogram aging-related oxidative stress and metabolic pathology by regulating miRNAs and the P38 MAPK pathway, thereby helping to prevent age-related liver diseases.

Aging, the decline in physiological function over time, is marked by the intracellular accumulation of damaged components. It can be attributed to a trade-off between the investment into organismal maintenance and the production of high-quality offspring, where the parent accumulates damage over time and retains it upon reproduction, while the offspring is rejuvenated. Asymmetric damage partitioning has been observed even in simple unicellular organisms, such as Escherichia coli bacteria, that retain aggregates of misfolded proteins during cell division. However, recent studies presented conflicting evidence on the effect of protein aggregates on fitness, ranging from detrimental effects on cell growth to enhanced stress survival. Here, we show that the decisive factor driving growth decline in E. coli is not the presence of a protein aggregate, but the proportion of the intracellular space occupied by it. By following single-cell E. coli lineages expressing fluorescently labeled DnaK chaperones, we quantified damage accumulation and partitioning across generations in microfluidic devices. Our results suggest that the aggregation of damaged proteins allows cells to keep damage separate from vital processes and compensate for the lost intracellular space by growing to larger sizes. This process results in morphologically asymmetric divisions, a finding that counters the long-assumed symmetry of E. coli cell division. In line with other recent evidence, our findings point to a more complex role of protein aggregation, with implications for our understanding of the cellular mechanisms underlying aging as well as its evolutionary origins.

Cellular senescence, characterized by a permanent state of cell cycle arrest and a secretory phenotype contributing to inflammation and tissue deterioration, has emerged as a target for age-related interventions. Accumulation of senescent cells is closely linked with intervertebral disc (IVD) degeneration, a prevalent age-dependent chronic disorder causing low back pain. Previous studies have highlighted that platelet-derived growth factor (PDGF) mitigated IVD degeneration through anti-apoptosis, anti-inflammation, and pro-anabolism. However, its impact on IVD cell senescence remains elusive. In this study, human NP and AF cells derived from aged, degenerated IVDs were treated with recombinant human (rh) PDGF-AB/BB for 5 days and changes of transcriptome profiling were examined through mRNA sequencing. NP and AF cells demonstrated similar but distinct responses to the treatment. However, the effects of PDGF-AB and BB on human IVD cells were comparable. Specifically, PDGF-AB/BB treatment resulted in downregulation of gene clusters related to neurogenesis and response to mechanical stimulus in AF cells while the downregulated genes in NP cells were mainly associated with metabolic pathways. In both NP and AF cells, PDGF-AB and BB treatment upregulated the expression of genes involved in cell cycle regulation, mesenchymal cell differentiation, and response to reduced oxygen levels, while downregulating the expression of genes related to senescence associated phenotype, including oxidative stress, reactive oxygen species (ROS), and mitochondria dysfunction. Network analysis revealed that PDGFRA and IL6 were the top hub genes in treated NP cells. Furthermore, in irradiation-induced senescent NP cells, PDGFRA gene expression was significantly reduced compared to non-irradiated cells. However, rhPDGF-AB/BB treatment increased PDGFRA expression and mitigated the senescence progression through increased cell population in the S phase, reduced SA-{beta}-Gal activity, and decreased expression of senescence related regulators including P21, P16, IL6, and NF-{kappa}B. Our findings reveal a novel anti-senescence role of PDGF in the IVD, making it a promising potential candidate to delay aging-induced IVD degeneration.

This study evaluates the miRNA-mRNA regulatory networks that potentially influence the senescence mechanisms of bone marrow mesenchymal stem cells (BMSCs) in age-related osteoporosis (ARO). By identifying these networks, the study aims to offer new molecular markers and therapeutic targets for ARO.

Samul-tang (SM) is a traditional prescription widely used in clinical practice for the management of gynecological diseases, especially for menstrual regulation and infertility treatment. We previously reported its efficacy in increasing mature oocyte production and improving ovarian reserves, potentially regulated by rat sarcoma virus (Ras) signaling in the ovaries of aged mice. Although the main ingredients of SM are known, the bioactive compounds responsible for protecting ovarian function during aging remain unidentified. This study aimed to identify the active compounds that significantly contribute to the therapeutic potential of SM against age-related decline in ovarian function. The combination of butylphthalide and oleanolic acid improved mature oocyte production similar to that in SM-administered aged mice. Subsequently, we identified butylphthalide as an active compound that mimicked SM's effect on enhancing ovarian reserve. This study introduces a novel strategy for identifying active compounds in multi-component herbal medicines by evaluating compound combinations in an in vivo model, offering promising therapeutic avenues for age-related female infertility through targeted gene expression modulation.

This study introduces the concept of cumulative social advantage as a hierarchical construct encompassing multiple aspects of social connection, including religious, psychosocial, familial, and emotional dimensions. Using data from the Midlife Development in the United States-II (

Aging is frequently characterized by an inadequate primary vaccine response, likely due to immunosenescence and inflamm-aging, a low-level, chronic inflammatory state. Both aspects increase the susceptibility of older adults to viral and bacterial infections, resulting in a higher frequency and severity of infectious diseases. In this preliminary study, a cohort of 52 individuals was recruited and divided into two groups: young (age range 21-35) and older adults (> 60 years old). Peripheral blood mononuclear cells (PBMCs) were collected before (time 0, T0) and after (time 1, T1) the immunization with a tetravalent influenza vaccine. Then, T cell immunophenotyping analysis was conducted to investigate how aging and influenza vaccination influence T cell responses. Additionally, the anti-inflammatory and antioxidant effects of oleuropein (OLE), a secoiridoid extracted from extra virgin olive oil, alone or in combination with BIRB 796, a potent inhibitor of p38 MAPK, were explored to enhancing the impact of influenza virus on T cell activation, aiming to identify potential alternatives or complementary strategies to improve traditional flu-vaccine formulations. Statistically significant observations were noted for a decrement in CD8 + T naïve and an increase of effector memory between the young and older adults after flu-vaccination. Moreover, preliminary findings indicate anti-inflammatory and antioxidant properties of OLE and BIRB 796 on T cell responses, particularly regarding Reactive Oxygen Species/Reactive Nitrogen Species modulation, with a trend toward the decrease of pro-inflammatory cytokines (i.e., Interferon-γ (INF-γ), Tumor Necrosis Factor-α (TNF-α)), αalthough without statistical significance.

Ankle proprioception and attentional resources are crucial for maintaining balance and safely driving. However, research exploring the age-related integrity of ankle proprioception has yielded conflicting results, while the attentional demand of proprioceptive processing in seniors remains underexplored. We investigated how aging affects the interaction between proprioception and attention in healthy sedentary adults using a novel dual-task paradigm. Sedentary old and young adults performed an ipsilateral proprioceptive-matching task with a long target encoding time and a cognitive-attentional subtraction task. These tasks were performed alone (single-task) or simultaneously (dual-task). Older adults showed significantly lower ankle proprioceptive accuracy and consistency in dorsiflexion compared to young adults under the single-task condition. Hence, the matching inaccuracies of seniors were more pronounced relative to young adults, when performing the proprioceptive and cognitive-attentional tasks simultaneously. Importantly, both age groups demonstrated similar cognitive performance in the single-task. However, while younger adults maintained their performance during dual-tasking, seniors showed markedly lower cognitive-attentional scores in the dual compared to the single-task condition. Thus, their dual-task costs were higher than those of young adults. Our findings of impaired ankle proprioception in sedentary older adults in the single-task underline the importance of controlling participants' physical lifestyles and demonstrate that this novel paradigm is highly sensitive to age-related proprioceptive changes. Furthermore, the substantial decline in both proprioceptive and cognitive performance during dual-tasking suggests that sedentary older adults mobilize increasingly large cognitive-attentional resources to process proprioception. This dual-task paradigm may serve as a useful biomarker to predict falls and driving accidents in older populations.

Bisphosphonates (BPs) have been the major class of medicines used to treat disorders of excessive bone loss for over five decades. Recently it has been recognized that BPs may also have additional significant beneficial extra-skeletal effects. These include a reduction of all-cause mortality and of conditions commonly linked to ageing, such as cancer and cardiovascular disease. Here we show that bisphosphonates co-localize with lysosomal and endosomal organelles in non-skeletal cells and stimulate cell growth at low doses. In vivo spatial transcriptomic analysis revealed differentially expressed senescence markers in multiple organs of aged BP-treated mice, and a shift in cellular composition toward those of young counterparts. Similarly, a 5000-plex plasma proteome analysis from osteopenic patients before and after BP-treatment showed significant alterations in ~400 proteins including GTPase regulators and markers of senescence, autophagy, apoptosis, and inflammatory responses. Furthermore, treatment with BPs protected against the onset of senescence in vitro. Proteome-wide target deconvolution using 2D thermal profiling revealed novel BP-binding targets (PHB2, ASAH1), and combined with RNA- and ATAC-seq of BP-treated cells and patient data, suggests downstream regulation of the MEF2A transcription factor within the heart. Collectively, these results indicate how BPs may beneficially modify the human plasma proteome, and directly impact multiple non-skeletal cell types through previously unidentified proteins, thereby influencing a range of pathways related to senescence and ageing.

In light of increasing attention being paid to aging research globally, the accumulation of aging hallmarks and their corresponding targeting therapeutics have been substantially revealed. However, uncovering the genuine drivers within epigenetic alterations that lead to aging remains a formidable challenge. In this study, we identified tRNASec(NCA) as the most severely damaged tRNA species in the kidneys of naturally aged mice. This damage not only dysregulated selenoproteins with anti-aging effects, but also generates a 5\'-tRNA fragment cleaved at the 34th position, which accumulates in an age-dependent manner. Mechanistically, the 5\'-tRNASec(NCA) half interacts and activates Toll-like receptor 7, thereby triggering innate immune responses and promoting cellular senescence in both mice and human cells. Moreover, in a naturally aged mice model, administration of an antisense oligonucleotide (ASO) targeting the 5\'-tRNASec(NCA) half remarkably ameliorates aging markers, enhances telomere length, and extends healthspan and lifespan. In addition, ASO-5\'-tRNASec(NCA) half plays another role in directly targeting and downregulating BCAT1 via the RNAi pathway to intervene in the senescence process. Our findings underscore tRNA damage as a novel aging hallmark, and targeting the damage-induced products presents a novel strategy for aging intervention, thus expanding our knowledge of the aging process.

People living with HIV (PLWH) exhibit accelerated aging, characterized by systemic inflammation, termed "inflammaging." While T-cell expansion is prevalent in PLWH, its connection to inflammaging remains unclear. In this study, we analyzed the TCRβ repertoire of 257 healthy controls (HC) and 228 PLWH, revealing pronounced T cell clonal expansion in PLWH. The expansion was only partially reversed following antiretroviral therapy (ART) and closely associated with ART duration, CD4+ T and CD8+ T cell counts and the CD4/CD8 ratio. TCR-based age modeling showed a continuous accelerated trajectory of aging in PLWH, especially in younger individuals, in stark contrast to the nonlinear aging acceleration pattern seen in HC. Furthermore, using single-cell RNA combined TCR sequencing and in vitro experiments, we identified GNLY+CD8+ T cells as the primary population driving clonal expansion and maintenance in PLWH. These cells are characterized by high cytotoxicity and low exhaustion and are activated by interleukin-15 (IL-15) in vitro. Notably, GNLY+CD8+ T cells predominantly express the pro-inflammatory 15 kDa form of granulysin(GNLY). The supernatant from IL-15-stimulated CD8+ T cells induces monocytes to secrete inflammatory factors and disrupts the integrity of intestinal epithelial cells, which can be partially restored by the anti-GNLY antibodies. These findings identify GNLY+CD8+ T cells as the central drivers of persistent clonal expansion, highlighting their crucial role for mitigating inflammaging in PLWH.

The innate immune signaling network follows a canonical format for signal transmission. The innate immune pathway is crucial for defense against pathogens, yet its mechanistic crosstalk with aging processes remains largely unexplored. Retinoic acid-inducible gene-I (RIG-I), a key mediator of antiviral immunity within this pathway, has an enigmatic role in stem cell senescence. Our study reveals that RIG-I levels increase in human genetic and physiological cellular aging models, and its accumulation drives cellular senescence. Conversely, CRISPR/Cas9-mediated RIG-I deletion or pharmacological inhibition in human mesenchymal stem cells (hMSCs) confers resistance to senescence. Mechanistically, RIG-I binds to endogenous mRNAs, with CDKN1A mRNA being a prominent target. Specifically, RIG-I stabilizes CDKN1A mRNA, resulting in elevated CDKN1A transcript levels and increased p21

SIRT6 is a protein deacylase, deacetylase, and mono-ADP-ribosylase (mADPr) regulating biological pathways important for longevity including DNA repair and silencing of LINE1 retrotransposons. SIRT6 knockout mice die by 30 days of age, whereas SIRT6 overexpression increases lifespan in male mice. Finding safe pharmacological activators of SIRT6 would have clinical benefits. Fucoidan, a polysaccharide purified from brown seaweed, has been identified as an activator of SIRT6 deacetylation activity. Here, we show that fucoidan also activates SIRT6 mADPr activity, which was shown to be elevated in certain human centenarians. Administering fucoidan to aged mice led to a significant increase in median lifespan in male mice. Both male and female mice demonstrated a marked reduction in frailty and epigenetic age. Fucoidan-treated mice showed repression of LINE1 elements suggesting that the beneficial effects of fucoidan are mediated, at least in part, by SIRT6. As brown seaweed rich in fucoidan is a popular food item in South Korea and Japan, countries with the highest life expectancy, we propose that fucoidan supplementation should be explored as a safe strategy for activating SIRT6 and improving human healthspan and lifespan.

Aging is associated with fat atrophy and fibrosis with loss of adipocyte differentiation from preadipocytes. New approaches to this loss involve agents that can renew the proliferative and differentiative capacities of preadipocytes with the aim of creating new healthy adipose tissue that secrete adipokines that positively impact on skin health.

Autoimmune diseases (AIDs) are a group of disorders in which the immune system mistakenly attacks the body's own tissues, characterized by the loss of tolerance to self-antigens and destruction of tissues. Aging is a natural process of physiological decline that also alters the immune system, a condition known as immunosenescence. During immunosenescence, the immune system undergoes various changes, including modifications and antigenicity of self-antigens, abnormalities in the quantity, phenotype, and function of lymphocytes and antibodies, as well as a narrowing of the B and T cell receptor repertoire, changes that may increase susceptibility to AIDs. Additionally, senescent immune cells and the senescence-associated secretory phenotype (SASP) contribute to target organ involvement in AIDs, exacerbating chronic inflammation and tissue damage. Mitochondrial dysfunction and metabolic imbalances in AIDs lead to the accumulation of senescent cells, which act as upstream drivers of immunosenescence. In this review, we summarize the bidirectional relationship between AIDs and immunosenescence, as well as its potential mechanisms. Therapeutic approaches targeting immunosenescence in AIDs remain at an early stage. Strategies aimed at resetting or reversing the aging immune system are expected to become a novel direction in the future.

Sarcopenia is the progressive loss of muscle mass and strength that can adversely affect an individual's health and quality of life. The objective of this study was to evaluate the effectiveness of a combined nutritional and exercise intervention among older adults who were at risk of sarcopenia.

Aging is reflected by genome-wide DNA methylation changes, which form the basis of epigenetic clocks, but it is largely unclear how these epigenetic modifications are regulated and whether they directly affect the aging process. In this study, we performed epigenetic editing at age-associated CpG sites to explore the consequences of interfering with epigenetic clocks. CRISPR-guided editing targeted at individual age-related CpGs evoked genome-wide bystander effects, which were highly reproducible and enriched at other age-associated regions. 4C-sequencing at age-associated sites revealed increased interactions with bystander modifications and other age-related CpGs. Subsequently, we multiplexed epigenetic editing in human T cells and mesenchymal stromal cells at five genomic regions that become either hypermethylated or hypomethylated upon aging. While targeted methylation seemed more stable at age-hypermethylated sites, both approaches induced bystander modifications at CpGs with the highest correlations with chronological age. Notably, these effects were simultaneously observed at CpGs that gain and lose methylation with age. Our results demonstrate that epigenetic editing can extensively modulate the epigenetic aging network and interfere with epigenetic clocks.

Long-lived mammals are reported to have rare or considerably fewer instances of spontaneous tumors, suggesting they might have evolved specific or convergent mechanisms of cancer resistance to extend lifespan; however, the underlying mechanisms remain insufficiently explored. Here, we conducted comparative analysis across 60 mammalian genomes to investigate the genomic features associated with natural cancer resistance. We identified 296 strongly selected genes unique to long-lived species and associated with immune response, DNA repair, and cancer, which might contribute to cancer resistance and lifespan extension in long-lived species. Further, 229 convergent cancer-related genes were detected in the four extremely long-lived species and in-vitro assays confirmed a convergent mutation of LZTS1, shared by bowhead whales and naked mole rats, could suppress cancer development. Importantly, 16 genes were significantly related to both body weight and cancer, defined as candidate genes of Peto's paradox. Of them, the YAP1 gene, harboring the A214S mutation, was identified as a key gene that upregulated tumor suppression genes by localizing to the cytoplasm, which might prohibit cancer development in the large and long-lived cetaceans. These findings provide novel insights into the molecular mechanisms underlying natural cancer resistance in long-lived mammals and the biological basis of Peto's paradox.

Mitochondrial dysfunction is an irrefutable hallmark of cellular senescence and aging. The dysfunction is marked by increased mitochondrial volume and reduced function, typified by low Adenosine Triphosphate (ATP) production and higher Reactive Oxygen Species (ROS) generation. Over the years, this dysfunction has been linked to Electron Transport Chain (ETC) malfunction and low NAD levels, augmented by poor mitophagy. However, the genetic regulation of mitochondrial dysfunction is still not clear. Here, using several senescence models, the first report on the role of the downregulation of a mitochondrial protein, Translocase of Inner Mitochondrial Membrane 50 (TIMM50), in senescence is presented. The downregulation of TIMM50 is also sufficient for triggering senescence through impaired mitochondrial function, characterized using a variety of mitochondrial function assessment assays. Reduced levels of TIMM50 initiated all the hallmarks of senescence, and overexpression significantly slowed senescence onset in response to an external trigger. The pathway analysis revealed that TIMM50 loss is mediated by the sirtuin1-dependent downregulation of CCAAT enhancer binding protein alpha (CEBPα), a transcription activator for TIMM50 expression. To establish the translational value of the observation, screening several potential anti-aging compounds revealed TIMM50 stabilizing and senescence-delaying effects only for verapamil and mitochondrial ROS quencher, Mito (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO), both known anti-aging entities. Overall, TIMM50 is identified as the key mitochondrial protein whose downregulation is a critical step in initiating cellular senescence.

Caloric restriction is associated with slow aging in model organisms. Additionally, some drugs have also been shown to slow aging in rodents. To better understand metabolic mechanisms that are involved in increased lifespan, we analyzed metabolomic differences in six organs of 12-month-old mice using five interventions leading to extended longevity, specifically caloric restriction, 17-α estradiol, and caloric restriction mimetics rapamycin, canagliflozin, and acarbose. These interventions generally have a stronger effect in males than in females. Using Jonckheere's trend test to associate increased average lifespans with metabolic changes for each sex, we found sexual dimorphism in metabolism of plasma, liver, gastrocnemius muscle, kidney, and inguinal fat. Plasma showed the strongest trend of differentially expressed compounds, highlighting potential benefits of plasma in tracking healthy aging. Using chemical set enrichment analysis, we found that the majority of these affected compounds were lipids, particularly in male tissues, in addition to significant differences in trends for amino acids, which were particularly apparent in the kidney. We also found strong metabolomic effects in adipose tissues. Inguinal fat exhibited surprising increases in neutral lipids with polyunsaturated side chains in male mice. In female mice, gonadal fat showed trends proportional to lifespan extension effect across multiple lipid classes, particularly phospholipids. Interestingly, for most tissues, we found similar changes induced by lifespan-extending interventions to metabolomic differences between untreated 12-month-old mice and 4-month-old mice. This finding implies that lifespan-extending treatments tend to reverse metabolic phenotypes to a biologically younger stage.

The chronological lifespan of Saccharomyces cerevisiae has been pivotal in advancing our understanding of aging in eukaryotic cells. However, gaining a genome-wide perspective of this trait remains challenging due to substantial discrepancies observed across large-scale gene-deletion screens. In this study, we performed a meta-analysis to compile a ranked catalog of key processes and regulators driving chronological longevity in yeast, ensuring their robustness across diverse experimental setups. These consistent chronological aging factors were enriched in genes associated with yeast replicative lifespan and orthologs implicated in aging across other model organisms. Functional analysis revealed that the downstream cellular mechanisms underlying chronological longevity in yeast align with well-established, universal hallmarks of aging, underscoring the potential of the yeast chronological aging model to investigate conserved aging processes. Additionally, we identified transcriptional regulators associated with these consistent genetic factors, uncovering potential global and local modulators of chronological aging. Among these, Tec1, a key regulator of the filamentous growth pathway, emerged as a central hub connected to multiple aging pathways. To further elucidate the functional role of this regulator, we conducted a high-resolution lifespan-epistasis screen, demonstrating that TEC1 and mitochondrial machinery promote chronological longevity in parallel, compensating for each other\'s impaired functions. Our findings provide an integrated view of the core genetic and functional landscape underlying aging in yeast cells.

During aging, adipose tissue within the bone marrow expands while the trabecular red marrow contracts. The impact of these changes on blood cell formation remains unclear. To address this question, we performed single-cell and single-nuclei transcriptomic analysis on adipose-rich yellow bone marrow (BMY) and adipose-poor trabecular red marrow (BMR) from human subjects undergoing lower limb amputations. Surprisingly, we discovered two distinct hematopoietic niches, in which BMY contains a higher number of monocytes and progenitor cells expressing genes associated with inflammation. To further investigate these niches, we developed an in-vitro organoid system that maintains features of the human bone marrow. We find cells from BMY are distinct in their expression of the leptin receptor, and respond to leptin stimulation with enhanced proliferation, leading to increased monocyte production. These findings suggest that the age-associated expansion of bone marrow adipose tissue drives a pro-inflammatory state by stimulating monocyte production from a spatially distinct, leptin-responsive hematopoietic stem/progenitor cell population.

Mitochondrial (mt)ROS, insufficient NAD+, and cellular senescence all contribute to the decrease in bone formation with aging. ROS can cause senescence and decrease NAD+, but it remains unknown whether these mechanisms mediate the effects of ROS in vivo. Here, we generated mice lacking the mitochondrial antioxidant enzyme Sod2 in osteoblast lineage cells targeted by Osx1-Cre and showed that Sod2{Delta}Osx1 mice had low bone mass. Osteoblastic cells from these mice had impaired mitochondrial respiration and attenuated NAD+ levels. Administration of an NAD+ precursor improved mitochondrial function in vitro but failed to rescue the low bone mass of Sod2{Delta}Osx1 mice. Single-cell RNA-sequencing of bone mesenchymal cells indicated that ROS had no significant effects on markers of senescence but disrupted parathyroid hormone signaling, iron metabolism, and proteostasis. Our data supports the rationale that treatment combinations aimed at decreasing mtROS and senescent cells and increasing NAD+ should confer additive effects in delaying age-associated osteoporosis.

Aging is one of the main challenges facing modern society. Understanding the cellular processes that occur in the later stages of life is essential to address age-related diseases. Although aging is a global process that affects the entire body, the brain is one of the most sensitive organs and is affected by numerous degenerative diseases. In this study, we investigate cell types and genes that are particularly sensitive to the aging process. To this end, we performed a time-course single-cell RNAseq experiment series in the brain of the killifish, the vertebrate model with the shortest lifespan, which makes it an excellent model for aging studies. Our analysis reveals that non-glial progenitor cells are among those populations that change the most between young and old animals. Furthermore, we identify specialized stromal clusters that seem to support a primitive hematopoietic program in the brain, which is active only during the embryonic stages in other vertebrate species. Our results show that the expression of embryonic genes in the adult brain appears to be a general feature in killifish, and that several cell populations in the adult killifish brain show a higher level of similarity to the zebrafish embryonic populations than to adult ones. Our study suggests that adult killifish maintain a neotenic gene expression status in the brain that may help in sustaining their characteristic high proliferation and metabolic rates, as well as combat the detrimental effects of this high metabolism on cells, especially at advanced ages.

Cell senescence (CS) is a key aging process that leads to irreversible cell cycle arrest and an altered secretory phenotype. In skeletal muscle (SkM), the accumulation of senescent cells contributes to sarcopenia. Despite exercise being a known intervention for maintaining SkM function and metabolic health, its effects on CS remain poorly understood.

Osteoarthritis (OA), is the most common age-induced degenerative joint disease. It is associated with synovial inflammation, subchondral bone remodeling and cartilage degradation. One of the significant emerging causes of OA progression is senescent cell accumulation within the joint compartment during lifespan. Currently, there are no therapeutic approaches nor stratification tools that rely on the senescence burden in OA. In this study, we identified the b-series ganglioside 3 (GD3) as new senescent cell surface marker associated with OA. Joint RNA sequencing analysis revealed an increase expression of the GD3 synthase, ST8SIA1 in cartilage, synovial tissue, and subchondral bone marrow from OA patients compared to healthy donors. Moreover, we revealed a strong correlative association between the expression of ST8SIA1 and GD3 production with senescence hallmarks in an in vitro-induced 3D organotypic OA cartilage model but also with cartilage histological grading scores in human and preclinical murine OA joints. Anti-GD3 cell sorting showed that GD3-positive human OA chondrocytes or human OA synoviocytes are enriched in senescence and SASP markers compared to GD3-negative counterparts confirming that GD3 is a cell surface marker linked to the senescence stage. Intra-articular anti-GD3 antibody delivery in experimental OA model, reduced local expression of senescence and OA markers in association with a protection against OA-induced subchondral bone remodeling. Our research demonstrates a compelling linkage between ST8SIA1 gene, GD3 and senescence in OA pathology, revealing knowledge and perspectives for a better understanding and anti-senescence treatment of OA pathogenesis.

Hematopoietic stem cells (HSCs) exhibit significant age-related phenotypic and functional alterations. Although single-cell technologies have elucidated age-related compositional changes, prospective identification of aging-associated HSC subsets has remained challenging. In this study, utilizing Clusterin (Clu)-GFP reporter mice, we demonstrated that Clu expression faithfully marks age-associated myeloid/platelet-biased HSCs throughout life. Clu-GFP expression clearly segregates a novel age-associated HSC subset that overlaps with but is distinct from those previously identified using antibodies against aging maker proteins or reporter systems of aged HSC signature genes. Clu-positive (Clu+) HSCs emerge as a minor population in the fetus and progressively expand with age. Clu+ HSCs display not only an increased propensity for myeloid/platelet-biased differentiation but also a unique behaviour in the BM, favouring self-renewal over differentiation into downstream progenitors. In contrast, Clu-negative (Clu-) HSCs exhibit lineage-balanced differentiation, which predominates in the HSC pool during development but becomes underrepresented as aging progresses. Both subsets maintain long-term self-renewal capabilities even in aged mice but contribute differently to hematopoiesis. The predominant expansion of Clu+ HSCs largely drives the age-related changes observed in the HSC pool. Conversely, Clu- HSCs preserve youthful functionality and molecular characteristics into old age. Consequently, progressive changes in the balance between Clu+ and Clu- HSC subsets account for HSC aging. Our findings establish Clu as a novel marker for identifying aging-associated changes in HSCs and provide a new approach that enables lifelong tracking of the HSC aging process.

Global aging raises concerns about cognitive health, metabolic disorders, and sarcopenia. Prevention of reversible decline and diseases in middle-aged individuals is essential for promoting healthy aging. We hypothesize that changes in body composition, specifically muscle mass and visceral fat, and metabolic indices are associated with accelerated brain aging. To explore these relationships, we employed a brain age model to investigate the links between the brain age gap (BAG), body composition, and metabolic markers.

As skin ages, its structure and function undergo significant transformations driven by complex cellular and molecular processes. In this study, we explore these changes using the axolotl, an amphibian model known for its transparent skin, allowing detailed observation of both epidermal and dermal layers. We found that axolotl skin, composed of an epidermis and a collagen-rich dermis with three distinct layers (stratum baladachinum, spongiosum, and compactum), shows clear age-related alterations. These changes include reduced fibroblast numbers, altered lattice-patterned cell morphology, disruption of the lattice patterned collagen fiber pattern, thickening the stratum spongiosum, and thinning of the stratum compactum. Notably, fibroblasts, which play a crucial role in collagen braiding, displayed diminished functionality in older axolotls. This study highlights how aging affects both the structural integrity of dermal collagen and cellular dynamics. Given the similarity between axolotl and mammalian skin, these findings may provide valuable insights into the mechanisms of skin aging and potential avenues for anti-aging therapies. This research offers a foundation for future studies aimed at understanding skin aging and regeneration.

Handgrip strength is a vital marker of muscle function and predictor of health outcomes in older adults. This study investigated the relationship between the muscle-to-fat ratio and 3-year decrease in handgrip strength in community-dwelling adults aged ≥50 years.

Recent research has shifted the focus from the genetic code of DNA to its structural variations, which significantly impact cancer, genetic diseases, and gene regulation. Structural changes, such as the transition from B-DNA to A-DNA, influence DNA stability and flexibility and are affected by factors like DNA methylation and sugar puckering. This study is the first to investigate the relationship between DNA conformational changes and lifespan in two rodent species. The analysis focused on long-lived Nannospalax xanthodon and shorter-lived Rattus rattus, utilizing infrared spectroscopy and principal component analysis (PCA) to examine liver DNA. Results indicated that transition from B-form to A- and Z-forms were more prevalent in N. xanthodon than in R. rattus. However, the dominant DNA conformations in both species are in B-form. Additionally, N-type sugar puckers (C3-endo conformation), associated with these DNA forms, were more prominent in N. xanthodon. In contrast, S-type sugar puckers (C2-endo conformation), characteristic of B-DNA, were found at lower levels in N. xanthodon. Furthermore, the variations in methylation-specific structural modifications of nucleobases were quantitatively assessed among these species. The study proposes a significant connection between the long lifespan of N. xanthodon, which live underground, and their unique DNA structure, offering insights into how different DNA forms, as well as the conformations of their backbone and sugar-base components, may affect longevity, highlighting potential research avenues regarding the biomolecular aspects of aging.

Objectives: Biological age may better capture differences in disease course among people with multiple sclerosis (PwMS) of identical chronological age. We investigated biological age acceleration through metabolomic age (mAge) in PwMS and its association with social determinants of health (SDoH) measured by the area deprivation index (ADI). Methods: mAge was calculated for three cohorts: 323 PwMS and 66 healthy controls (HCs); 102 HCs and 72 DMT-naive PwMS; and 64 HCs and 67 pediatric-onset MS/clinically isolated syndrome patients, using an aging clock derived from 11,977 healthy adults. mAge acceleration, the difference between mAge and chronological age, was compared between groups using generalized linear and mixed-effects models, and its association with ADI was assessed via linear regression. Results: Cross-sectionally, PwMS had higher age acceleration than HCs: 9.77 years in adult PwMS (95% CI:6.57- 12.97, p=5.3e-09), 4.90 years in adult DMT -ve PwMS (95% CI:0.85-9.01, p=0.02), and 6.98 years (95% CI:1.58-12.39, p=0.01) in pediatric-onset PwMS. Longitudinally, PwMS aged 1.19 mAge years per chronological year (95% CI:0.18, 2.20; p=0.02), faster than HCs. In PwMS, a 10-percentile increase in ADI was associated with a 0.63-year (95% CI:0.10- 1.18; p=0.02) increase in age acceleration. Discussion: We demonstrated accelerated mAge in adult and pediatric-onset PwMS and its association with social disadvantage.

Objectives. Resting-state functional connectivity (rsFC) is a highly dynamic process that varies across different times of the day within each individual. Although this variability was long considered to be noise, recent evidence suggests it may allow for an optimal adaptation to changes in the environment. However, the way rsFC is shaped on a circadian scale and its association with cognition are still unclear. Methods. We analyzed data from 90 late-middle-age participants from the Cognitive Fitness in Aging study (61 women; 50-69y). Participants completed five electroencephalographic (EEG) recordings of spontaneous resting-state activity spread over 20h of prolonged wakefulness. Using a temporal multilayer network approach, we characterized the diurnal variations of the dynamic recruitment and integration of resting-state brain networks. We focused on the theta and gamma frequency bands within the default mode network (DMN), central executive network (CEN), and salience network (SN). Additionally, we investigated the relationship recruitment and integration of these network with baseline cognitive performance and at 7-year longitudinal follow-up, as well as with positron emission tomography (PET) early neuropathological markers of Alzheimer disease such as B-amyloid and tau/neuroinflammation. Results. Diurnal changes in theta and gamma dynamics were associated with distinct cognitive aspects. Specifically, higher baseline memory performance was associated with higher theta dynamic integration of the SN and the CEN, as well as higher theta dynamic recruitment of the DMN. Moreover, lower longitudinal memory decline at 7-year was associated with higher theta dynamic integration of the SN, CEN, and DMN. In contrast, higher gamma diurnal dynamic integration of the SN and the CEN was associated with lower executive and attentional performance, as well as higher early B-amyloid accumulation, at baseline. Discussion. These findings suggest that maintaining a balance between network flexibility and stability throughout the diurnal phase of the circadian cycle may play a crucial role in cognitive aging, with stable theta-band connectivity supporting memory, whereas excessive gamma-band stability in the SN and CEN may contribute to executive decline and early amyloid accumulation. These insights highlight the importance of considering time-of-day in brain rsFC studies, calling for a temporal multilayer approach to capture these dynamic patterns more effectively.

Background The glymphatic system plays a crucial role in clearing metabolic waste from the brain, facilitating waste exchange between cerebrospinal fluid and interstitial fluid, and supporting brain homeostasis. However, quantifying glymphatic function has been challenging. The Diffusion Tensor Imaging Along the Perivascular Space (DTI-ALPS) method offers a non-invasive approach to assess glymphatic function by calculating an index that reflects fluid mobility within the brain. This study aimed to identify genetic variants associated with the ALPS index and explore its relationships with metabolic, immune, cognitive, and health-related phenotypes. Methods Data from 43,823 participants in the UK Biobank were analyzed. After rigorous quality control, 36,997 individuals with valid bilateral ALPS indices were included. A genome-wide association study (GWAS) was conducted to identify genetic loci linked to the ALPS index. The study also explored correlations between the ALPS index and various non-imaging traits, including cognitive performance, blood pressure, and lifestyle factors. Statistical analyses included GWAS, gene enrichment analysis, polygenic risk score validation, Cox regression, and Mendelian randomization. Results The GWAS identified 14 independent loci, encompassing 3,814 single-nucleotide polymorphisms, associated with white matter integrity, brain volume, fiber tract connectivity, inflammation, and metabolism. Key candidate genes, such as GNA12, SERPIND1, and MAPT, were linked to vascular function and neurodegenerative diseases. Enrichment analysis revealed significant roles for neuronal development, signal transduction, and metabolic pathways. The ALPS index showed significant associations with non-imaging phenotypes: higher indices correlated with better physical exercise, cognitive performance, and lower metabolic risks, while negative associations were found with smoking and excessive computer use. Polygenic risk scores confirmed these associations. Further analyses suggested that higher ALPS indices may protect against Alzheimer's disease and multiple sclerosis. Conclusions This study represents the largest genome-wide analysis of the ALPS index to date, revealing key genetic variants that influence glymphatic function and their potential role in neurological health. The ALPS index may serve as a promising biomarker for neurodegenerative disease risk and offers new avenues for therapeutic interventions aimed at improving glymphatic clearance.

Inferring chronological age from magnetic resonance imaging (MRI) brain data has become a valuable tool for the early detection of neurodegenerative diseases. We present a method inspired by cosmological techniques for analyzing galaxy surveys, utilizing higher-order summary statistics with multivariate two- and three-point analyses in 3D Fourier space. This method identifies outliers while offering physiological interpretability, allowing the detection of scales where brain anatomy differs across age groups and providing insights into brain aging processes. Similarly to the evolution of cosmic structures, the brain structure also evolves naturally but displays contrasting behaviors at different scales. On larger scales, structure loss occurs with age, possibly due to ventricular expansion, while smaller scales show increased structure, likely related to decreased cortical thickness and gray/white matter volume. Using MRI data from the OASIS-3 database for the complete sample of 864 sessions (reduced sample: 827 sessions), our method predicts chronological age with a Mean Absolute Error (MAE) of ~3.8 years (~3.6 years) for individuals aged ~40-100 (50-85), while providing information as a function of scale. A neural density posterior estimation shows that the 1-sigma uncertainty for each individual varies between ~3 and 7 years, suggesting that, beyond sample variance, complex genetic or lifestyle-related factors may influence brain aging. Applying this method to an independent database, Cam-CAN, validates our analysis, yielding a MAE of ~3.4 for the age range from 18 to 88 years. This work demonstrates the utility of interdisciplinary research, bridging cosmological methods and neuroscience.

In normal aging, little is known in human and animal models about functional changes to glutamate neuronal systems that may contribute to age-related cognitive differences. The present studies investigated glutamate neuronal signaling in the hippocampus (dentate gyrus) and frontal cortex (infralimbic) of young adult (3-8 months), middle-aged (10-13 months), and aged (15-27 months) male and female C57BL/6 mice using microelectrode electrode array (MEA) recording technology to measure second-by-second resting levels of glutamate in anesthetized mice. Glutamate regulation was investigated in vivo by inhibiting the uptake of glutamate by local application of the competitive non-transportable blocker of excitatory amino acid transporters DL-threo-beta-benzyloxyaspartate (TBOA). Resting levels of glutamate and TBOA-induced changes in extracellular glutamate concentration were reliably measured in the hippocampus and frontal cortex of young adult, middle-aged, and aged mice and were seen to significantly increase in aging in the hippocampus. In the frontal cortex we observed an increase only in the middle-aged animals. TBOA produced robust changes in extracellular glutamate in the hippocampus and frontal cortex which showed significant changes in the kinetics of the signals in the middle-aged mice. Interestingly, the variance of the resting glutamate levels in the hippocampus of aged female mice was greater than in aged male mice, supporting a possible age-related gender difference in glutamate function. Taken together, these data support that glutamate signaling in the hippocampus and frontal cortex of aged mice is affected in normal aging with changes in glial regulation of glutamate uptake observed from the TBOA effects in the middle-aged mice.

Reduced oocyte quality is a key factor in age-related fertility decline, and there are no effective treatments available. The secretome of mesenchymal stem cells (MSC-sec) contains various bioactive factors and has the potential to improve oocyte quality. This study aimed to investigate the effective component and molecular mechanism of MSC-sec involved in improving oocyte quality from aged mice and humans.

The potential impacts of drug-induced modulation of mitochondrial function in humans remain unclear despite the high prevalence of "mito-modulatory" medication use among older adults. While these medications, such as statins and metformin, have undergone extensive characterization of their effects on mitochondrial function in vitro, the effects in humans are far more complex and poorly understood.