Longevity Papers

Transcription factor-based direct conversion of somatic cells represents an interesting avenue for generating induced neural stem cells (iNSCs) from peripheral blood without transit through a pluripotent stage. While this paradigm has been shown to be associated with epigenetic de-aging, the dynamics of this process have remained unclear. Here, we used overexpression of the two reprogramming factors SOX2 and cMYC to generate iNSC from erythroid progenitors of donors ranging from neonatal to 101 years of age. Using an epigenetic clock algorithm, we corroborated our previous finding that iNSCs generated from aged donors show pronounced epigenetic de-aging, preserving around 13 % and 5 % of the original donor age at low and high passages, respectively. Studying the dynamic of epigenetic de-aging during iNSC conversion across time, we found that this process is largely protracted, continuing for several weeks and even beyond forced neuronal differentiation of iNSCs. Transcriptomic differences between young and old donor-derived iNSCs dissipate with extended time in conversion, too. Concordant with this observation, established iNSC lines lack age-associated cellular hallmarks, similar to induced pluripotent stem cells and their derivatives. Interestingly, time course analysis of DNA methylation and RNA sequencing data revealed that acquisition of a bona fide NSC signature extends greatly beyond the time point when proliferative PAX6-positive iNSCs emerge. The unexpected slow dynamics of these processes makes iNSC conversion an attractive model for dissecting the mechanisms underlying somatic transdifferentiation and de-aging.

As populations age worldwide, understanding the biology of aging and its contribution to disease becomes increasingly important. Cellular senescence, a hallmark of aging, plays a pivotal role in shaping inter-organ communication and systemic health. Once viewed primarily as a local mechanism to prevent the proliferation of damaged cells, senescence is now recognized as a dynamic, multifaceted process that influences physiology across the lifespan. Through senescence-associated secretory phenotype (SASP) proteins and other signaling modalities, including metabolites, extracellular vesicles, immune cells, and neural circuits, senescent cells contribute to both homeostatic regulation and the propagation of chronic inflammation, fibrosis, and age-related disease. These effects are often context-dependent, and senescence in one organ can influence distant tissues, driving asynchronous aging and disease vulnerability. This review examines the mechanisms by which senescent cells facilitate inter-organ communication, including emerging roles for blood-borne factors, immune cell dynamics, and neuroendocrine signals. We highlight illustrative examples of organ crosstalk and emphasize the potential translational relevance of these pathways. We also examine therapeutic strategies aimed at modulating senescence, including senolytics, senomorphics, and interventions targeting specific SASP components, as well as the potential of lifestyle modifications to mitigate biological aging. Understanding senescence and the associated inter-organ communication offers new insights into aging biology and opens promising avenues for addressing age-related diseases in an integrated, organ-spanning framework.

Mitochondrial membrane potential (MMP) is essential for mitochondrial functions, yet current methods for modulating MMP lack precise spatial and temporal control. Here, we present an optogenetic system that enables reversible formation of inter-mitochondrial contacts (mito-contacts) with high spatiotemporal precision. Blue light stimulation induces rapid formation of mito-contacts, which fully dissipate upon cessation of illumination. These light-induced mito-contacts can enhance MMP, leading to increased ATP production under stress conditions. Moreover, in human retinal cells and C. elegans, high MMP induced by mito-contacts alleviates the deleterious effects of prolonged blue light exposure, restoring energy metabolism and extending organismal lifespan. This optogenetic approach provides a powerful tool for modulating MMP and offers potential therapeutic applications for diseases linked to mitochondrial dysfunction.

The aging process markedly amplifies the risk of kidney diseases, whereas kidney dysfunction also accelerates aging. However, the intricate interplay between aging and kidney diseases remains incompletely understood. In this context, we conducted a comprehensive genetic investigation by incorporating multivariate aging indicators and multiple kidney phenotypes. We explored their shared genetic architecture for each trait pair through cross-trait analyses, and two-step mediation analyses were employed to investigate the mediating role of plasma metabolites in causal relationships. Our findings revealed significant negative correlations between healthy aging and kidney diseases, kidney injury, and kidney function decline. We identified 949 pleiotropic single nucleotide polymorphisms, 85 candidate pleiotropic genes, and 8 shared causal genes across tissues, including SH2B3 and MAP2K1 as druggable genes. Notably, mediation analyses highlighted the crucial role of lipoprotein in mediating the detrimental causal effects of kidney diseases on healthy aging. These findings underscore the complex shared genetic etiology and mediators between aging and kidney phenotypes, offering novel insights into their underlying mechanisms and highlighting potential therapeutic strategies.

Obesity triggers chronic low-grade inflammation contributing to cardiovascular and metabolic diseases. Over-release of adipokines and pro-inflammatory mediators by white adipose tissue (WAT) enhances inflammation through a feedforward loop involving endothelial and immune cells, promoting atherosclerosis. Our previous studies showed that in vivo gene transfer of the longevity-associated variant (LAV) of BPIFB4 restores endothelial and cardiac function and reduces systemic inflammation in mouse models. Here we investigated the anti-inflammatory potential of orally administered recombinant rhLAV-BPIFB4 in ApoE-/- mice fed a high-fat diet to elucidate its role in modulating endothelial dysfunction primed by adipose tissue inflammation. We studied

Age-related hearing loss (HL) and sarcopenia (ARS) are prevalent geriatric syndromes sharing common risk factors. This study aimed to identify shared biomarkers and elucidate convergent pathogenic mechanisms. Transcriptomic datasets were obtained from public database. Differential expression analysis was performed, followed by enrichment analysis. Hub genes were identified via LASSO regression, SVM-RFE, and random forest algorithms. Diagnostic performance was evaluated using receiver operating characteristic curve analysis across 6 independent cohorts. Comprehensive integrative analysis revealed distinct yet overlapping molecular signatures between HL and ARS. In HL, 11 upregulated and 16 downregulated genes were shared between 2 diseases, and complement and coagulation cascades, Toll-like receptor signaling, efferocytosis, as well as immune response processes were found to be associated with these genes. Machine learning identified 10 hub genes (AIMP2, JUN, SEMA5A, RASL12, GUSB, C1QA, GYPC, IRF7, C1QB, SERPING1) as shared biomarkers. Notably, these genes demonstrated robust diagnostic utility: individual genes exhibited area under the curve (AUC) values > 0.7 in most cohorts. Although the combined 10-gene model achieved AUC = 1 in several cohorts, these results should be interpreted with caution due to the limited sample sizes in some datasets (e.g., GSE6045, n = 3 per group), which may inflate performance metrics. Permutation tests confirmed that the AUC values were significantly better than chance in several cohorts (P < .05). This study pioneers a machine-learning framework to uncover shared molecular drivers of HL and ARS, identifying 10 hub genes as promising diagnostic biomarkers.

Biological aging remains a central focus of research, from the scale of sub-cellular processes to whole-organism tissue morphology and function. In this work, we developed a novel and quantitatively interpretable method for the prediction of variables, such as age, from tomographic medical images. The method uses supervoxels (whose granularity is selected by the user), standardized through inter-subject image registration, and tissue-specific feature extractions from each supervoxel to convert all image data collected into a set of well-defined imaging biomarkers. We applied the method to age prediction, using linear modelling and whole-body water-fat MRI data of 38,235 subjects (age span = 45 - 82 years) in the multicentre UK Biobank study, resulting in predictions representing morphological age (MA). We observed state-of-the-art whole-body age prediction performance on a held-out test set with a mean absolute error of 1.951/2.057 years, and R2 of 0.884/0.892 for females/males, respectively. The method was observed to outperform both previously reported CNN-based results from the UK Biobank, and predictions from explicit biomarkers, from a multi-organ/tissue segmentation approach, in a direct comparison. The image-based interpretability of the model allowed for detailed and tissue-specific analysis of the utilized body-wide associations with age. Important regions for the predictions included volumes of the aorta, regional muscle, bone marrow, and adipose tissue depots, and lean tissue fat content. The predicted MAs were of clinical relevance as they were significantly related to both type 2 diabetes and all-cause mortality. A key finding was an accuracy/utility trade-off where the more parsimonious models showed lower CA predictive performance but higher clinical relevance and interpretability. The proposed method facilitates automated image-to-biomarker conversions and predictions based on subsets of anatomies, tissues, and image features, for potential application in numerous future medical studies. Code is shared at github.com/Radiological-Image-Analysis-Group-UU/ukbb_age_prediction.

T cell metabolism constitutes a pivotal regulator of cellular states and disease progression. At the cellular level, the metabolic status of T cells directly governs their function and fate determination. Senescent T cells, for instance, exhibit fundamentally distinct metabolic signatures compared to effector T subsets, underscoring metabolic reprogramming as a critical mechanistic driver of T cell senescence. In pathological contexts, aberrant metabolic rewiring in T cells disrupts differentiation, function, and cellular survival, thereby contributing to disease onset and progression. Notably, the pathological accumulation of senescent T cells observed across chronic inflammatory and autoimmune diseases positions metabolism-driven T cell senescence as a key nexus linking metabolic dysregulation to clinical manifestations. Consequently, targeted modulation of T cell metabolism offers a dual therapeutic potential: direct intervention in cellular states (e.g., delaying senescent phenotypes) and synergistic amelioration of disease pathology through functional immune restoration. This Review summarizes the fundamental principles of T cell metabolic reprogramming, its causative role in propelling T cell senescence, and the dynamic interplay between metabolic dysfunction, T cell senescence, and disease pathogenesis. We specifically dissect these relationships in two immunologically divergent conditions-systemic lupus erythematosus (SLE, exemplifying hyperactive autoimmunity) and chronic infection (Chronic HIV infection, reflecting immune exhaustion)-to establish a mechanistic framework for developing metabolism-targeted immunotherapeutics that precisely restore T cell efficacy.

Cellular senescence is a well-established tumor-suppressive cell cycle arrest program. However, chronic inflammation through the senescence-associated secretory phenotype (SASP) can alternatively drive immune suppression and cancer progression. Using prostate cancer patient samples and murine models, we find p16+ and p21+ senescent cells accumulate throughout malignant progression and associate with immune suppression. Single cell sequencing revealed p16 and p21 mark distinct epithelial and stromal senescent populations, with p21+ non-tumor cells expressing the highest SASP. p21+ stromal cell removal blocked the SASP to reverse immune suppression and slow tumor growth. Senolytic BCL-xL inhibitor treatment could clear p21+ stromal senescent cells, reactivating anti-tumor CD8+ T cell immunity and inhibiting prostate tumor progression in mice. Suppression of BCL-xL or p21 also potentiated anti-PD-1 ICB in preclinical prostate cancer models. Our findings demonstrate that targeting p21+ senescent stromal populations can yield therapeutic benefits in advanced prostate cancer through activating anti-tumor immunity and enhancing immunotherapy outcomes.

While circadian rhythm disruption may promote neurodegenerative disease, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types remains unknown. Here we used a translating ribosome affinity purification to identify the circadian translatomes of astrocytes, microglia and bulk tissue in healthy mouse cortex and in the settings of amyloid-β plaque pathology or aging. We show that glial circadian translatomes are highly cell-type-specific and exhibit profound, context-dependent reprogramming in response to amyloid pathology or aging. Transcripts involved in glial reactivity, immunometabolism and proteostasis, as well as nearly half of all Alzheimer's disease risk genes, displayed circadian oscillations, many of which were altered by pathology. Microglial oxidative stress and amyloid phagocytosis showed temporal variation in gene expression and function. Thus, circadian rhythms in gene expression are cell-dependent and context dependent, and provide important insights into glial function in health, Alzheimer's disease and aging.

Investigating the interplay between mitochondrial DNA (mtDNA) variations and epigenetic aging metrics may elucidate biological mechanisms associated with age-related diseases. We estimated epigenetic age acceleration (EAA) metrics from DNA methylation data and derived mtDNA metrics, including heteroplasmic variants and mtDNA copy number (mtDNA CN) from whole genome sequencing. Linear regressions and meta-analyses were conducted to assess associations between EAA and mtDNA metrics, adjusting for chronological age, self-identified sex, and other covariates in 6,316 participants (58% female, 41% non-White Americans). Mediation analysis was conducted to examine whether EAA mediated the relationship between mtDNA CN and metabolic traits. A higher burden of rare heteroplasmic variants was associated with accelerations of first-generation EAA metrics, while a lower level mtDNA CN was associated with accelerations of second- and third-generation EAA metrics. For example, one standard deviation (SD) higher MSS, a score based on the predicted functions of rare heteroplasmic variants, was associated with a 0.22-year higher EAA by the Hannum method (p = 1.3E-6) among all participants, while one SD lower mtDNA CN was associated with higher DunedinPACE (β = -0.005, p = 6.0E-4). No significant association was observed between the heteroplasmy burden of common variants and EAAs. Furthermore, we observed DunedinPACE mediated 11.1% and 10.8% of the associations of mtDNA CN with obesity and T2DM in older FHS participants, respectively. Our analysis indicated that higher levels of heteroplasmy burden of rare variants and lower mtDNA CN were associated with accelerated epigenetic aging, and these associations showed stronger magnitudes among older participants.

Aging is a process characterized by the progressive decline in physiological function and increased susceptibility to disease. Many cellular functions, including unfolded protein responses (UPR, an endoplasmic reticulum (ER) stress coping mechanism), Ca2+ signaling, cellular signaling and inflammatory responses are affected by aging. These significantly impact Ca2+ handling by cardiac cells and the architecture of cardiomyocytes, leading to impaired contractility, and increased risk of arrhythmias. Cellular Ca2+ homeostasis and the UPR are interdependent, therefore, understanding and influencing these key cellular pathways should provide new therapeutic strategies for managing age-related cardiac diseases. Modulating Ca2+ handling and cellular stress pathways presents distinctive approaches to preventing molecular alterations linked to aging, while providing opportunities to reduce molecular damage and promote the effectiveness of cellular repair processes.

With the increasing proportion of elderly individuals, understanding biological mechanisms of aging is critical. Retinal vascular complexity, measured as fractal dimension (

Osteoporosis is a chronic age-related condition in which imbalanced activities between bone-forming osteoblasts and bone-resorbing osteoclasts lead to the progressive loss of bone volume and quality. While drugs that target osteoclastic activity have been developed, there remains a lack of efficient therapies that increase osteoblast number and function in aging bones. Here, we investigated if Activin, known to increase in the circulation with age, plays a primary role in bone loss associated with aging. We showed that, in mouse femurs, levels of Activin signaling progressively increased with age and strongly correlated with the loss of trabecular bone. Furthermore, mice lacking the type I receptor for Activin, namely Alk4, in osteoblast progenitors (Alk4 cKO mice) had increased trabecular bone acquisition, osteoblast number, and bone formation rate. In addition, Alk4 cKO male mice were protected against early age-related trabecular bone loss observed at 1 year of age. These results indicate that Activin signaling inhibits bone formation and osteoblast activity and is likely associated with osteoporosis. To further test this, we injected 2-year-old male mice with a ligand trap (Alk4-Fc) to capture circulating Activin. Alk4-Fc protected against loss of trabecular bone in femurs and L5 vertebrae. Interestingly, Alk4-Fc also prevented a decrease in muscle mass in gastrocnemius, quadriceps, and triceps suggesting that circulating Activins also play a role in sarcopenia. In summary, our preclinical mouse models reveal that circulating Activins play a primary role in age-related bone loss and can be efficiently targeted to alleviate osteoporosis and sarcopenia in aging mice.

Epigenetic inheritance alerts naïve descendants to prepare for stresses that could still be present, whereas distant descendants return to a basal state after several generations without stress. However, organisms are frequently exposed to stresses successively across generations. We found that parental hypoxia exposure increased P0 longevity, caused intergenerational lipid reduction, and elicited transgenerational fertility reduction that was dependent on generationally transmitted small RNAs. Here, we find that

Living animals reach their end-of-life through a stereotypic set of fascinating but poorly understood processes. The discovery, first in flies and later in nematodes and zebrafish, of the "Smurf phenotype" has provided a valuable tool to investigate ageing and its associated physiological changes. Using the Smurfs, we have shown an evolutionarily conserved end-of-life transition across Drosophilids, nematodes, and zebrafish. This tool has been key to identify the discontinuous nature of ageing and predict impending death from natural causes as well as from environmental stresses. This phenotype led us to propose a two-phase perspective of ageing: a first phase where individuals are apparently healthy and have low risk of mortality, but show an age-dependent and increasing risk of entering a second phase, marked by more pronounced hallmarks of ageing and a markedly increased risk of death. Here, we test whether these two consecutive phases of ageing separated by the Smurf transition are a conserved feature of ageing in the mammals using Mus musculus as a model. We performed a longitudinal longevity study using both males and females from two different mouse genetic backgrounds and by integrating physiological, metabolic, and molecular measurements with the life history of approximately 150 mice. We show the existence of a phenotypic signature typical of the last phase of life, observable at any chronological age. Validating the two-phase ageing model in a mammalian organism allows better characterization of the high risk of imminent death and would extend its implications to a broader range of species for ageing research. The Stage 1 version of this Registered Report was submitted on 19th January 2022.

This study investigated the relationship between estimated glucose disposal rate (eGDR), aging acceleration (AgeAccel), and mortality in adults diagnosed with cardiovascular-kidney-metabolic (CKM) stages 1 to 4.

Cysteine sulfenylation (Cys-SOH) is a transient redox-sensitive post-translational modification that regulates protein activity and cellular stress responses, yet its in vivo dynamics remain difficult to capture due to short half-life and low abundance. Here, we report the design and application of BTD-Az, a cell-permeable probe that incorporates an azide handle into the benzothiazine scaffold, enabling rapid bioorthogonal labeling of Cys-SOH both in vivo and in vitro, followed by efficient enrichment through strain-promoted azide-alkyne cycloaddition. This approach streamlines the detection and analysis of Cys-SOH with exceptional specificity and convenience. BTD-Az exhibited negligible cytotoxicity, efficiently enriched sulfenylated proteins in vitro, and achieved direct in vivo labeling in mouse tissues through SPAAC-mediated pull-down. Coupling BTD-Az with 4D-DIA proteomics allowed global sulfenylome profiling, revealing >5000 labeled proteins across tissues. As a proof-of-concept biological application, we applied BTD-Az to aging cartilage and identified 95 proteins with differential sulfenylation, including the mitochondrial enzyme IDH2, whose Cys-SOH modification promoted proteasomal degradation and exacerbated redox imbalance. Collectively, this study establishes BTD-Az as a robust chemical tool for in vivo sulfenylation profiling, providing a broadly applicable platform for redox proteomics and the discovery of redox-sensitive regulatory mechanisms in health and disease.

Introduction Pathogenic variants in PKP2 are the most common cause of familial arrhythmogenic right ventricular cardiomyopathy (ARVC). Objective To test whether PKP2 deficiency only in cardiomyocytes is sufficient to provoke premature aging and pro-inflammatory senescence in non-myocytes, cardiac resident cells. Methods We studied mice with cardiomyocyte-specific, tamoxifen-activated loss of PKP2 (PKP2cKO) using conventional and multiplex imaging, cytokine arrays, epigenetic clocks, spatial transcriptomics, expansion and structured illumination microscopy, and correlative data analysis. We examined non-myocytes and cardiomyocytes for premature aging and senescence. Results We observed senescence-associated heterochromatin foci (SAHFs) and p21 staining in non-myocytes. Cytokines in media of non-myocyte cells were consistent with senescence-associated secretory phenotype (SASP). Epigenetic clocks identified premature aging. Multiplex immunohistochemistry showed non-myocyte cells in niches, intermingled with cardiomyocytes. Spatial transcriptomics showed over-representation of SASP-related transcripts, predominantly in myocyte-rich areas of the left ventricle. SAHFs, p21 staining and increased epigenetic age were not found in cardiomyocytes from PKP2cKO hearts, though we observed structural features associated to premature aging. Cross-reference analysis showed correlation between the PKP2cKO cardiac proteome and that of mice 5 or 6 times their chronological age, as well as transcriptional signatures of neurodegenerative diseases. Conclusion Loss of PKP2 expression only in adult cardiac myocytes is sufficient to induce pro-inflammatory senescence in non-myocytes, and overall premature cardiac aging. This is the first study to intersect cellular senescence and premature aging in desmosomal arrhythmogenic cardiomyopathies. We speculate that cell-agnostic molecular signatures, biomarkers, and pharmacology of senescence and of neurodegenerative diseases may be relevant to diagnose or treat PKP2-ARVC.

Inclusions of -Synuclein (Syn) characterize multiple age-related neurodegenerative diseases, including Parkinson's disease (PD) and Multiple System Atrophy (MSA). While interactions between Syn and lipids are known to contribute to Syn pathobiology, the precise cellular mechanisms that link lipids to Syn toxicity have yet to be elucidated. Through lipidomic profiling of Caenorhabditis elegans, we found that Syn progressively alters lipid metabolism in aging worms. Syn strongly reduces overall content of triacylglycerols (TAG) and disrupts the structure of lipid droplets (LD). These pathological changes depend on Syn's properties to condensate and form inclusions. Apart from lowering TAG levels, Syn also increases the proportion of long-chain unsaturated fatty acids (LCUFAs). Consequently, genetic inhibition of LCUFA biosynthesis alleviates Syn-induced loss of C. elegans motility. Strikingly, bypassing lipid metabolic defects by supplementing Medium Chain Fatty Acids (MCFAs) restores the Syn-impaired mitochondrial response and rescues motility. These results link Syn condensation to impaired TAG metabolism, which reduces mitochondrial function and enhances overall toxicity. Together with the finding that plasma TAGs are lowered in Parkinson patient cohorts, these results suggest that restoring TAG metabolism could alleviate Syn-induced toxicity in Parkinson's and other age-related synucleinopathies.

Frailty and sarcopenia are age-related conditions linked to mitochondrial dysfunction, but their causal mechanisms remain poorly defined. This study aimed to identify mitochondrial-related genes causally associated with frailty and sarcopenia using comprehensive multi-omics approaches.

Collagen, the most abundant protein in the mammalian extracellular matrix, is critical for skin structure and function, with Type I and Type III collagens being particularly important. Collagen degradation in skin is accelerated by aging and UV exposure, leading to structural and functional impairments. Exogenous collagen supplementation has been shown to restore skin structure and function. Traditional collagen extraction from animal tissues is limited by safety and quality concerns, while recombinant human collagen offers improved safety but faces challenges in solubility and production. This study aimed to construct a chimeric collagen derived from both Type I and Type III collagens and achieve its soluble expression in E. coli. Through translational pausing technology, a recombinant chimeric human collagen containing functional domains of both collagen types was successfully constructed and expressed with a yield of 1.36 g/L. A cysteine-rich C-propeptide domain was fused to enhance assembly and stability. The "dual-function" collagen significantly promoted fibroblast proliferation, migration, and adhesion, while stimulating endogenous Type I and Type III collagen production. Using the C. elegans model, the recombinant protein extended lifespan and enhanced oxidative aging resistance. Skin imaging confirmed its penetration into the dermis, and human skin efficacy tests demonstrated its ability to reduce periorbital wrinkles and crow's feet. This recombinant "dual" human collagen promotes endogenous collagen synthesis, accelerates skin repair, reduces aging signs, and shows no observed side effects, offering promising potential for anti-aging applications.

Skeletal muscle atrophy occurs in several diseases and is associated with chronic stress. Studies indicate that glucocorticoid receptor signalling is the major pathway that mediates stress-induced muscle degeneration. Although the glucocorticoid signalling pathway is relatively well characterized, there is a need to identify modulators of this pathway that may be useful for drug targeting. SIRT2 is a mammalian Sirtuin known to mediate the longevity benefits of calorie restriction and exercise. Currently, the role of SIRT2 in regulating stress-induced skeletal muscle atrophy is unclear. We found that SIRT2 is a critical regulator of muscle homeostasis and is required to protect against stress-induced muscle atrophy. SIRT2 levels are reduced during glucocorticoid-induced muscle atrophy. SIRT2 deficient mice are susceptible to glucocorticoid-induced muscle atrophy, while muscle-specific SIRT2-transgenic mice exhibit improved muscle function and are protected from glucocorticoid-induced atrophy. Mechanistically, SIRT2 binds and deacetylates critical residues in the DNA-binding domain of GR and negatively affects GR activity. Our findings suggest that SIRT2 activation may protect against glucocorticoid-induced skeletal muscle atrophy.

Tissue structure and molecular circuitry in the colon can be profoundly impacted by systemic age-related effects but many of the underlying molecular cues remain unclear. Here, we build a cellular and spatial atlas of the colon across three anatomical regions and 11 age groups, encompassing ~1,500 mouse gut tissues profiled by spatial transcriptomics and ~400,000 single nucleus RNA-sequencing profiles. We develop a computational framework, cSplotch, which learns a hierarchical Bayesian model of spatially resolved cellular expression associated with age, tissue region and sex by leveraging histological features to share information across tissue samples and data modalities. Using this model, we identify cellular and molecular gradients along the adult colonic tract and across the main crypt axis and multicellular programs associated with aging in the large intestine. Our multimodal framework for the investigation of cell and tissue organization can aid in the understanding of cellular roles in tissue-level pathology.

Age is the predominant risk factor for late-onset Alzheimer's disease, and interventions that reduce biological age may be therapeutic. We previously reported that bezisterim, a novel anti-inflammatory insulin sensitizer, modulated epigenetic age acceleration (EAA) in a randomized, placebo-controlled, 7-month Alzheimer's disease trial. Building on prior evidence linking bezisterim-induced EAA changes to improved cognitive and functional outcomes, we conducted integrative analyses to elucidate underlying molecular mechanisms. Bezisterim significantly reduced EAA across 12 independent biological clocks, reinforcing its impact on validated aging biomarkers, and identifying targets predominantly involved in inflammation and cognition, including transcriptional regulators that orchestrate broader gene networks. Genome-wide methylation profiling revealed 2,154 genes with significant differential promoter methylation between bezisterim and placebo groups. Treatment increased promoter methylation - suggesting transcriptional repression - in 433 genes known to be associated with aging and disease processes, including microglial neuroinflammation, pro-inflammatory kinase activity, cognitive decline, lipid metabolism, and transcriptional regulation. Conversely, treatment-decreased methylation of 15 genes potentially improved autophagy, and increased anti-inflammatory phosphatases and macrophage polarization. Analyses were conducted to search for correlations between promoter methylation and the 31 previous clinical measures in bezisterim and placebo subjects. Significant correlations (72 bezisterim, 13 placebo) suggest that methylation differences contribute to observed clinical differences. The majority of the correlations in bezisterim subjects were associated with neurologic and metabolic improvements, and 12 of 72 were correlated with 2-5 clinical measures each, potentially emphasizing their contribution to clinical benefit. Bezisterim appears to exert pleiotropic effects through coordinated modulation of aging-related epigenetic programs, potentially counteracting neurodegenerative processes at the intersection of inflammation, metabolism, and transcriptional control.

6-Shogaol is a natural dietary phenolic extensively rich in edible and medicinal plants such as Zingiber officinale Roscoe and Brassica spp., utilized as tumor inhibitor and a promising anti-aging drug. Our previous study has revealed that 6-shogaol significantly prolonged healthy life of C. elegans. However, the interactions of 6-shogaol with the microbiota, gut and brain during natural aging process remain largely unexplored.

Reproduction affects lifespan and fat metabolism across species, suggesting a shared regulatory axis. In Caenorhabditis elegans, ablation of germline stem cells leads to extended lifespan and increased fat storage. While many studies focus on germline-less glp-1(e2144) mutants, the hermaphroditic germline of C. elegans provides an excellent opportunity to study how distinct germline anomalies affect lifespan and fat metabolism. We compare metabolomic, transcriptomic, and genetic pathway differences among three sterile mutants: germline-less glp-1, feminized fem-3, and masculinized mog-3. All three accumulate excess fat and share expression changes in stress response and metabolism genes. However, glp-1 mutants exhibit the most robust lifespan extension, fem-3 mutants live longer only at certain temperatures, and mog-3 mutants are markedly short-lived. The extended lifespan in fem-3 mutants require daf-16/FOXO, as in glp-1 mutants. In contrast, daf-16 is dispensable for the already shortened lifespan of mog-3 mutants. Interestingly, mog-3 partially mimics male/mating-induced demise, offering a simplified model to study metabolic and reproductive trade-offs underlying this phenomenon. Our data indicate that disrupting specific germ cell populations leads to distinct and complex physiological and longevity outcomes. These findings highlight the importance of investigating sex-dependent differences and underlying mechanisms to fully understand and potentially modulate these relationships.

Although research on ageing has largely concentrated on understanding the fundamental biology of the ageing process and devising pharmaceutical interventions in order to slow it down, increasing evidence has underscored the crucial role of environmental inputs across the life course and across generations, in shaping both individual and intergenerational trajectories of age-related health. These include nutrition, air pollution, social deprivation, lifestyle factors, climate change and exposure to environmental toxins, including microplastics and nanoplastics. The development of the concept of the exposome of ageing and the emergence of the new field of 'exposomics' have identified a blind spot, in particular, for geroscience. The impact of the exposome affecting human 'healthspan' (i.e., years lived in good health), extending across generations, is significant and yet under-explored in research. As such, it is under-appreciated that the declining health of the planet will have intergenerational ripple effects, epigenetically priming adverse health in future generations. We discuss the capacity to manipulate our exposome to mitigate against such effects, by addressing root causes, rather than symptoms, of both physiological and planetary dysregulation, dysfunction and decay. We propose a systems-based framework that reconnects research on ageing with exposomics and planetary ecology, creating a new field of 'ecological or exposome pharmacology', harnessing the activity of Nrf2 as a senotherapeutic intervention to improve trans- and intergenerational physiology in the face of declining planetary health.

Our understanding of aging has grown through the study of systems biology, including single-cell analysis, proteomics and metabolomics. Studies in lab organisms in controlled environments, while powerful and complex, fall short of capturing the breadth of genetic and environmental variation in nature. Thus, there is now a major effort in geroscience to identify aging biomarkers that might be applied across the diversity of humans and other free-living species. To meet this challenge, the Dog Aging Project (DAP) aims to identify cross-sectional and longitudinal patterns of aging in complex systems, and how these are shaped by the diversity of genetic and environmental variation among companion dogs. Here we surveyed the plasma metabolome from the first year of sampling of the Precision Cohort of the DAP. By incorporating extensive metadata and whole genome sequencing, we overcome the limitations inherent in breed-based estimates of genetic effects, and probe the physiological basis of the age-related metabolome. We identified effects of age on approximately 36% of measured metabolites. We also discovered a novel biomarker of age in the post-translationally modified amino acids (ptmAAs). The ptmAAs, which are generated by protein hydrolysis, covaried both with age and with other biomarkers of amino acid metabolism, and in a way that was robust to diet. Clinical measures of kidney function mediated about half of the age effect on ptmAA levels. This work identifies ptmAAs as robust indicators of age in dogs, and points to kidney function as a physiological mediator of age-associated variation in the plasma metabolome.

Aging biomarkers play a vital role in understanding longevity, with the potential to improve clinical decisions and interventions. Existing aging clocks typically use blood, vitals, or imaging collected in a clinical setting. Wearables, in contrast, can make frequent and inexpensive measurements throughout daily living. Here we develop PpgAge, an aging clock using photoplethysmography at the wrist from a consumer wearable. Using the Apple Heart & Movement Study (n = 213,593 participants; >149 million participant-days), our observational analysis shows that this non-invasive and passively collected aging clock accurately predicts chronological age and captures signs of healthy aging. Participants with an elevated PpgAge gap (i.e., predicted age greater than chronological age) have significantly higher diagnosis rates of heart disease, heart failure, and diabetes. Elevated PpgAge gap is also a significant predictor of incident heart disease events (and new diagnoses) when controlling for relevant risk factors. PpgAge also associates with behavior, including smoking, exercise, and sleep. Longitudinally, PpgAge exhibits a sharp increase during pregnancy and concurrent with certain types of cardiac events.

Chronic hypertension with aging induces significant alterations in the structure and function of brain parenchyma and memory dysfunction. While therapeutic control of hypertension reduces risk, the functional changes in neural circuitry that underlie memory deficits are unknown. Identifying possible early onset changes in the hippocampal trisynaptic circuit (HTC) may reveal opportunities for therapeutic intervention. A large-scale clinical study revealed a direct relationship between reduced prospective memory score and reduced hippocampal functional connectivity in subjects with a history of chronic hypertension. Here, we report a potential mechanistic linkage between hypertension/aging and hippocampal neural circuitry dysfunction. We used chronically implanted multi-electrode silicon probes in awake freely behaving rats to monitor synchronous high frequency oscillations (at 140-200 Hz or the "ripple band") in the HTC CA1 subregion. This hippocampal subregion is known to participate in memory consolidation, in part via HTC ripples. The nootropic drug, α5IA, that inhibits α5GABA-A receptors, was administered orally, under conditions for target engagement, and ripple amplitude measured within subject in awake resting Sprague-Dawley (SD) rats. Significant HTC and memory dysfunction was observed in aged-hypertensive SD rats. The results reveal an hypertension/age-associated anomaly in ripple band activity in SD males, characterized by reductions in mean peak ripple amplitude and in the ability of α5IA to potentiate peak ripple amplitude, without effect upon ripple frequency or duration. Thus, the population of large peak amplitude sharp wave ripples is reduced and becomes insensitive to potentiation by α5IA. Having identified a specific change in peak ripple amplitude that is resistant to potentiation by α5IA, a nootropic probe-drug, this finding could lead to nuanced circuitry level approach for the treatment of memory dysfunction with aging and hypertension.

A distinguishing feature of older mesenchymal stem cells (MSCs) from bone marrow (BM) is the transition in their differentiation capabilities from osteoblasts to adipocytes. However, the mechanisms underlying these cellular events during the aging process remain unclear. We identified Angiopoietin-like protein 8 (ANGPTL8), a newly found adipokine implicated in lipid metabolism, that influences the fate of MSCs in BM during skeletal aging. Our studies revealed that ANGPTL8 steered MSCs towards adipogenic differentiation, overshadowing osteoblastogenesis. Mice with overexpressed ANGPTL8 exhibited reduced bone mass and increased bone marrow adiposity, while those with transgenic depletion of ANGPTL8 showed lowered bone loss and less accumulation of bone marrow fat. ANGPTL8 influenced the bone marrow niche of MSCs by inhibiting the Wnt/β-catenin signaling pathway. Partial inhibition of PPARγ rescued some aspects of the phenotype in MSCs with ANGPTL8 overexpression. Furthermore, treatment with Angptl8-Antisense Oligonucleotide (Angptl8-ASO) improved the phenotype of aging mice. The research proposes that ANGPTL8 is a critical regulator of senesence-related changes in the BM niche and the cell fate switch of MSCs.

Telomere damage can lead to senescence, aging and aging-related disorders, and cancer. Previously, we reported that cell-free chromatin particles (cfChPs) that circulate in human blood can readily enter healthy cells and damage their DNA. Herein, we show that dsDNA breaks inflicted by cfChPs selectively target telomeres, with the resulting DNA damage remaining unrepaired over time, whereas dsDNA breaks inflicted by γ-rays are not specific to telomeres and have a faster repair kinetics. We propose that cfChPs that are released from the billions of dying cells to enter the blood circulation are natural DNA damaging agents with a unique mechanism of action.

Aging alters cardiac resilience to anesthetic and surgical stress, yet the molecular basis of these effects remains poorly understood. To define age-dependent cardiac transcriptional responses to isoflurane exposure and operative (ISO/OP) stress, we analyzed gene expression profiles across young adult (3m), late middle-aged (17m), and geriatric mice (27m) following short-term 2 h ISO/OP exposure. At 24 h after cessation, all age groups exhibited distinct cardiac transcriptional signatures separating ISO/OP from sham controls. In young adult hearts, transcriptional alterations 24 hours after cessation of ISO/OP were characterized by dysregulation of small molecule catabolic processes, fatty acid metabolism, disruptions to protein processing in endoplasmic reticulum and cytoskeletal organization. Late middle-aged mice displayed amplified perturbations in lipid metabolism alongside suppression of muscle system and calcium signaling pathways, while old mice showed robust activation of PPAR and AMPK signaling and downregulation of genes governing contractility and morphogenesis. In contrast, geriatric mice showed upregulation of fatty acid metabolic pathways, robust activation of PPAR and AMPK signaling, coupled with suppression of muscle differentiation and actin organization following ISO exposure, indicating a maladaptive metabolic reprogramming. Overlapping DEGs across all age groups converged on pathways regulating oxidative stress, Ca2+; handling, hypertrophy, and energy metabolism, suggesting a conserved but age-intensified cardiac stress response. Longitudinal profiling in aged mice revealed persistent transcriptomic remodeling five weeks after stress. Crucially, this remodeling was observed even after ISO exposure alone, indicating that general anesthesia is a primary driver of this long-term effect. This persistent signature was marked by mitochondrial dysfunction and dysregulation of genes associated with diabetic cardiomyopathy, extracellular matrix integrity, and neurodegenerative signaling. Together, these findings identify isoflurane exposure as a potent inducer of persistent, age-dependent metabolic and structural reprogramming in the heart, implicating impaired lipid utilization and mitochondrial homeostasis as central mechanisms linking the perioperative period, and specifically anesthetic exposure, to long-term cardiovascular vulnerability.

INTRODUCTION: While changes associated with age-related diseases, like oxidative stress, begin in midlife, most aging studies focused on older individuals. Our study assessed in vivo brain metabolites in healthy adults, including the understudied middle-age group. METHODS: 7T magnetic resonance spectroscopy data were acquired from 87 healthy adults (45 women) aged 20-79 years. Levels of eight metabolites were measured in posterior cingulate cortex (PCC) and centrum semiovale white matter (CSWM). RESULTS: With increasing age, we found (a) lower glutathione and glutamate, and higher myo-inositol in PCC, and (b) lower N-acetylaspartate and glutamate, and higher N-acetylaspartyl glutamate, myo-inositol, and total creatine in CSWM. Notably, these changes started in midlife and were largely driven by age-related changes in women. DISCUSSION: Overall, we found evidence that (a) oxidative stress, (b) neuroinflammation, and (c) neuronal loss begin in midlife of healthy adults. Targeting these mechanisms in midlife may slow brain aging and reduce the risks of developing age-related diseases.

Female reproductive aging is the earliest manifestation of aging in humans, with fertility declining due to reduced oocyte quality well before menopause. Menopause marks the definitive end of reproductive potential and the onset of increased risk for multiple age-related, chronic diseases. Emerging evidence links reproductive disorders, from infertility to widespread gynecological conditions such as polycystic ovarian syndrome, with elevated risks of premature morbidity and mortality. Indeed, it is increasingly evident that even normal reproductive transitions such as puberty, pregnancy, and menopause, act as physiological inflection points that shape long-term systemic health. Yet, fertility continues to be viewed primarily through the prism of procreation, with limited knowledge of the underlying biological mechanisms and scarce clinical focus on its broader health implications. Recent discoveries elucidating the genetic basis of reproductive traits combined with advances in our understanding of fundamental aging mechanisms offer a compelling framework to address these persistent knowledge gaps with far-reaching public-health consequences. This review synthesizes the current knowledge on how reproductive aging, normal reproductive phases and major reproductive dysfunctions influence long-term health trajectories and argues for a shift toward integrated, lifespan-based approaches to reproductive health in research and clinical care.

The advent of in vivo reprogramming through transient expression of the Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC) holds strong promise for regenerative medicine, despite ongoing concerns about safety and clinical applicability. This review synthesizes recent advances in in vivo reprogramming, focusing on its potential to restore regenerative competence and promote rejuvenation across diverse tissues, including the retina, skeletal muscle, heart, liver, brain, and intestine. We highlight mechanistic parallels and distinctions between injury-induced dedifferentiation and OSKM-mediated reprogramming, emphasizing the roles of dedifferentiation, transient regenerative progenitors, and epigenetic remodeling. Critical safety considerations-such as teratoma formation, organ failure, and loss of cell identity-are discussed alongside strategies designed to mitigate these risks, like cyclic induction and targeted delivery. Finally, we briefly note the growing translational interest in this field, alongside directing readers to recent reviews for detailed coverage of biotech initiatives. Collectively, this work underscores the transformative potential of in vivo reprogramming for both tissue regeneration and rejuvenation, while stressing the importance of precise spatiotemporal control for its safe clinical application.

Ageing is marked by widespread cortical changes, but the molecular underpinning and network connectivity shaping this variability remain poorly understood. We analysed structural MRI from 952 adults aged 18--94 using morphometric similarity networks, subtype/stage inference, and cortical transcriptomics. Based on intra-network connectivity within three major cortical networks and their associations with longevity genes, two robust subtypes emerged. The normative-ageing subtype (metabolic-immune) showed connectivity profiles consistent with typical age-related decline and was enriched for genes involved in metabolism, insulin signalling, and immune regulation. The compensatory subtype (stress-repair) displayed more preserved intra-network connectivity and was linked to stress-response, DNA repair, and proteostasis genes. Although the two subtypes overlap in oxidative stress and neurodegeneration pathways, their distinct molecular signatures capture biologically meaningful differences in cortical ageing. By integrating network-based morphometry with transcriptomics, we establish a novel framework to distinguishes normative decline from compensatory adaptation in ageing profiles to provide biologically informed markers of brain ageing.

Although Ubc9-mediated SUMOylation are recognized to regulate the multiple aspects of hepatic biological processes, its impact on hepatic senescence and metabolic dysfunction-associated steatotic liver disease (MASLD), however, is yet to be fully addressed. Herein noted an age-dependent decrease of hepatic Ubc9 expression is first noted along with an escalated decrease of protein SUMOylation, which is coupled with enhanced senescent marker expressions both in humans and mice. Interestingly, Ubc9 is dispensable for liver development at the embryonic stage. However, Ubc9 deficiency in hepatocytes rendered mice with an exacerbated hepatic aging phenotype and more susceptible to fatty liver disease and steatohepatitis following the challenge of a methionine- and choline-deficient (MCD)-diet. Ii is further demonstrated that nuclear ribosomal protein L3 (RPL3) interacts with DExD/H-box (DDX/DHX) helicases (DHX9), which then recruits RNA polymerase II to the p16 promoter to transcribe its expression, thereby exacerbating the hepatocyte aging process. However, Ubc9-mediated SUMOylation prevents RPL3 nuclear translocation, by which it represses the expression of senescent markers such as p16 to attenuate the hepatic aging process. Together, the study highlights that Ubc9-mediated SUMOylation of RPL3 could be an unappreciated mechanism against hepatic aging in clinical settings.