Longevity Papers

Obesity is associated with skeletal deterioration and increased fracture risk, but the underlying mechanism is unclear. Herein, it is shown that obese gut microbiota promotes skeletal deterioration by inducing bone marrow macrophages (BMMs) senescence and grancalcin (GCA) secretion. Obese mice and those receiving obese fecal microbiota transplants exhibit increased senescent macrophages and elevated GCA expression in the bone marrow. In a study of 40 participants, it is found that obese patients are associated with higher serum GCA levels. It is further revealed that obese gut-microbiota derived lipopolysaccharides (LPS) stimulate GCA expression in senescent BMMs via activating Toll-like receptor 4 pathway. Mice with depletion of the Gca gene are resistant to the negative effects of obesity and LPS on bone. Moreover, neutralizing antibody against GCA mitigates skeletal deterioration in obese mice and LPS-induced chronic inflammation mouse model. The data suggest that the interaction between gut microbiota and the immune system contributes to obesity-associated skeletal deterioration, and targeting senescent macrophages and GCA shows potential of protecting skeletal health in obese population.

Non-invasive assessment of brain blood vessels with magnetic resonance (MR) imaging provides important information about brain health and aging. Time-of- flight MR angiography (TOF-MRA) in particular is commonly used to assess the morphology of blood vessels, but acquisition of MRA is time-consuming and is not as commonly employed in research studies or in the clinic as the more standard T1- or T2-weighted MR contrasts (T1w/T2w). To enable quantification of brain blood vessel morphology in T1w/T2w images, we trained a neural network model, anat2vessels, on a dataset with paired MR/MRA. The model provides accurate segmentations as assessed in cross-validation on ground truth images, particularly in cases where T2w images are used. In addition, correlation between features that are extracted from model-based vessel segmentations and from ground truth account for as much as 78% of the variance in these features. We further evaluated the model in another dataset that does not include MRA and found that anat2vessels-based vessel morphology features contain information about aging that is not captured by cortical thickness features that are routinely extracted from T1w/T2w images. Moreover, we found that vessel morphology features are associated with individual variability in blood pressure and cognitive abilities. Taken together these results suggest that anat2vessels could be fruitfully applied to a range of existing and new datasets to assess the role of brain blood vessels in aging and brain health. The model is provided as open-source software in https://github.com/nrdg/anat2vessels/.

Aging is accompanied by widespread DNA methylation changes across the genome. While age-related methylation studies typically focus on individual CpGs, cluster analysis provides more robust data and improved interpretation. We characterized age-associated CpG-cluster methylation changes in mouse spleens, peripheral blood mononuclear cells, and livers. We identified a novel signature termed blanket methylations (BMs), fully methylated CpG clusters absent in young tissues but appearing in aged tissues. BM formation was locus- and cell-dependent, with minimal overlap among tissues. Statistical analysis, heterogeneity assessment, and random modeling demonstrated that BMs arise through nonrandom mechanisms and correlate with accelerated aging. Notably, BMs appeared in chronologically young mice with progeroid or disease-driven aging, including in 4-month-old Zmpste24-/- (lifespan ∼5 months) and 3-month-old Huntington's disease model mice (lifespan ∼4 months). The detection of BMs in purified CD4+ T cells demonstrated that their occurrence is intrinsic to aging cells rather than a result of infiltration from other tissues. Further investigation revealed age-related downregulation of zinc-finger-CxxC-domain genes, including Tet1 and Tet3, which protect CpG islands from methylation. Importantly, TET1 or TET3 depletion induced BM formation, linking their loss to age-associated methylation drift. These findings establish BMs as a robust marker of epigenomic aging, providing insight into age-related methylation changes.

Senescence in stem cells and progenitor cells can be particularly detrimental because these cells are essential for tissue renewal and overall organismal homeostasis. In mesenchymal stromal cells (MSCs), which comprise a heterogeneous mix of stem cells, progenitors, fibroblasts, and other stromal cells, senescence poses a significant challenge, as it impairs their ability to support tissue repair and maintenance. This decline in regenerative capacity can contribute to aging-related diseases, impaired wound healing, and degenerative disorders. One hallmark of senescence is resistance to apoptosis, mediated by activation of anti-apoptotic pathways. Consequently, senotherapeutics have emerged as a promising strategy to selectively eliminate senescent cells and promote healthy aging. Plant secondary metabolites, notably polyphenols and terpenes, exhibit diverse effects on living organisms and have served as medicinal agents.

This study aims to determine if neurons derived from induced pluripotent stem cells (iPSCsNs) and directly converted neurons (iNs) from the same source cells exhibit changes in mitochondrial properties related to aging. This research addresses the uncertainty around whether aged iPSCsNs retain aging-associated mitochondrial impairments upon transitioning through pluripotency while direct conversion maintains these impairments. We observe that both aged models exhibit characteristics of aging, such as decreased ATP, mitochondrial membrane potential, respiration, NAD

A coordinated response to stress is crucial for promoting the short- and long-term health of an organism. The perception of stress, frequently through the nervous system, can lead to physiological changes that are fundamental to maintaining homeostasis. Activating the response to low oxygen, or hypoxia, extends healthspan and lifespan in C. elegans. However, despite some positive impacts, negative effects of the hypoxic response in specific tissues prevent translation of their benefits in mammals. Thus, it is imperative to identify which components of this response promote longevity. Here, we interrogate the cell-nonautonomous hypoxic response signaling pathway. We find that HIF-1-mediated signaling in ADF serotonergic neurons is both necessary and sufficient for lifespan extension. Signaling through the serotonin receptor SER-7 in the GABAergic RIS interneurons is necessary in this process. Our findings also highlight the involvement of additional neural signaling molecules, including the neurotransmitters tyramine and GABA, and the neuropeptide NLP-17, in mediating longevity effects. Finally, we demonstrate that oxygen- and carbon-dioxide-sensing neurons act downstream of HIF-1 in this circuit. Together, these insights develop a circuit for how the hypoxic response cell-nonautonomously modulates aging and suggests valuable targets for modulating aging in mammals.

Hutchinson-Gilford progeria syndrome, caused by a mutation in the LMNA gene, leads to increased levels of truncated prelamin A, progerin, in the nuclear membrane. The accumulation of progerin results in defective nuclear morphology and is associated with altered expression of linker of the nucleoskeleton and cytoskeleton complex proteins, which are critical for nuclear signal transduction via molecular coupling between the extranuclear cytoskeleton and lamin-associated nuclear envelope. However, the molecular mechanisms underlying progerin accumulation-induced nuclear deformation and its effects on intranuclear chromosomal organization remain unclear. Here, the spatiotemporal evolution of nuclear wrinkles is analyzed in response to variations in substrate stiffness using a doxycycline-inducible progerin expression system. It is found that cytoskeletal tension regulates the onset of progerin-induced nuclear envelope wrinkling and that the molecular interaction between SUN1 and LMNA controls the actomyosin-dependent attenuation of nuclear tension. Genome-wide analysis of chromatin accessibility and gene expression further suggests that an imbalance in force between the intra- and extranuclear spaces induces nuclear deformation, which specifically regulates progeria-associated gene expression via modification of mechanosensitive signaling pathways. The findings highlight the crucial role of nuclear lamin-cytoskeletal connectivity in bridging nuclear mechanotransduction and the biological aging process.

Collagen, a protein known for its long lifespan, is susceptible to accumulation of advanced glycation end products (AGEs) with age. These AGEs are considered markers that indicate the aging severity and influence the mechanics of tissues, leading to fragile bones and hardened skin. While many cross-linking AGEs have been widely studied for their ability to reduce the elasticity of biological tissues, contributing to skin hardening and fragile bones, through strong covalent bonds, non-cross-linking AGEs, or AGE adducts, are typically investigated as indicators of aging or as signaling factors in pathological conditions. However, recent experimental findings have revealed that the number of AGE adducts in aged bone is comparable to enzymatic cross-links, which are significantly more abundant than cross-linking AGEs. Based on these observations, we consider one of the most abundant AGE adducts - carboxymethyllysine (CML) - and employ molecular dynamics simulations to explore its direct impact on the mechanical and conformational properties of single tropocollagen molecules. Our models demonstrate that tropocollagen peptides, constructed based on sequences experimentally identified with sites of CML modifications in type I collagen derived from human cortical bone, exhibit heterogeneous behaviors under tensile testing. Still, most of these modified peptides display compromised structural stability, reduction in structural strength, and diminished energy dissipation ability when tension is applied. This study highlights the potential impact of non-cross-linking AGEs on collagen behavior at molecular scale and provides insights into the mechanisms underlying these modifications. Gaining a deeper understanding of the role of AGE adducts and their contribution to the aging process may pave the way for future solutions in antiaging research.

Developmental time (or time to maturity) strongly correlates with an animal's maximum lifespan, with late-maturing individuals often living longer. However, the genetic mechanisms underlying this phenomenon remain largely unknown. This may be because most previously identified longevity genes regulate growth rate rather than developmental time. To address this gap, we genetically manipulated prothoracicotropic hormone (PTTH), the primary regulator of developmental timing in

Substantial progress in aging research continues to deepen our understanding of the fundamental mechanisms of aging, yet there is a lack of interventions conclusively shown to attenuate the processes of aging in humans. By contrast, replacement interventions such as joint replacements, pacemaker devices and transplant therapies have a long history of restoring function in injury or disease contexts. Here, we consider biological and synthetic replacement-based strategies as aging interventions. We discuss innovations in tissue engineering, such as the use of scaffolds or bioprinting to generate functional tissues, methods for enhancing donor-recipient compatibility through genetic engineering and recent progress in both cell therapies and xenotransplantation strategies. We explore synthetic approaches including prostheses, external devices and brain-machine interfaces. Additionally, we evaluate the evidence from heterochronic parabiosis experiments in mice and donor-recipient age-mismatched transplants to consider whether systemic benefits could result from personalized replacement approaches. Finally, we outline key challenges and future directions required to advance replacement therapies as viable, scalable and ethical interventions for aging.

Polycomb repressive complexes (PRCs) are pivotal epigenetic regulators that preserve cell identity by restricting transcription responses to sub-threshold extracellular signals. Their roles in osteoblast function and bone formation remain unclear. Here in aging osteoblasts, we found marked activation of PRC1.1 complex, with KDM2B acting as a chromatin-binding factor and BCOR and PCGF1 enabling histone H2A monoubiquitylation (H2AK119ub1). Osteoblast-specific Kdm2b inactivation significantly enhances bone remodeling under steady-state conditions and in scenarios of bone loss. This enhancement is attributed to H2AK119ub1 downregulation and subsequent Wnt signaling derepression. Furthermore, we developed a small molecule termed iBP, that specifically inhibits the interaction between BCOR and PCGF1, thereby suppressing PRC1.1 activity. Notably, iBP administration promotes bone formation in mouse models of bone loss. Therefore, our findings identify PRC1.1 as a critical epigenetic brake on bone formation and demonstrate that therapeutic targeting of this complex enhances Wnt pathway activation, offering a promising strategy against skeletal deterioration.

The nucleolus is a membraneless organelle and an excellent stress sensor. Any changes in its architecture or composition lead to nucleolar stress, resulting in cell cycle arrest and interruption of ribosomal activity, critical factors in aging and cancer. In this study, we identified and described the pivotal role of the RNA-binding protein (RBP) HNRNPK in ribosome and nucleolar dynamics. We developed an in vitro model of endogenous HNRNPK overexpression and an in vivo mouse model of ubiquitous HNRNPK overexpression. These models showed disruptions in translation and caused alterations in the nucleolar structure, resulting in p53-dependent nucleolar stress, cell cycle arrest, senescence, and bone marrow failure phenotype, similar to what is observed in patients with ribosomopathies. Together, our findings identify HNRNPK as a master regulator of ribosome biogenesis (RiBi) and nucleolar homeostasis through p53, providing a new perspective on the orchestration of nucleolar integrity, ribosome function and cellular senescence.

Large-scale single-cell atlas efforts have revealed many aging- or disease-associated cell types, yet these populations are often underrepresented in heterogeneous tissues, limiting detailed molecular and dynamic analyses. To address this, we developed EnrichSci - a highly scalable, microfluidics-free platform that combines Hybridization Chain Reaction RNA FISH with combinatorial indexing to profile single-nucleus transcriptomes of targeted cell types with full gene-body coverage. When applied to profile oligodendrocytes in the aging mouse brain, EnrichSci uncovered aging-associated molecular dynamics across distinct oligodendrocyte subtypes, revealing both shared and subtype-specific gene expression changes. Additionally, we identified aging-associated exon-level signatures that are missed by conventional gene-level analyses, highlighting post-transcriptional regulation as a critical dimension of cell-state dynamics in aging. By coupling transcript-guided enrichment with a scalable sequencing workflow, EnrichSci provides a versatile approach to decode dynamic regulatory landscapes in diverse cell types from complex tissues.

Social determinants of health are social factors that affect health and survival. Two of the most powerful social determinants are socioeconomic status (SES) and race/ethnicity; people with lower SES or marginalized race/ethnicity tend to experience earlier onset of aging-related diseases and have shorter lifespans. DNA methylation (DNAm) measures of biological aging, often referred to as epigenetic clocks, are increasingly used to study the social determination of health. However, there are several generations of epigenetic clocks and it remains unclear which are most sensitive to social factors affecting health. Moreover, there is uncertainty about how technical factors, such as the tissue from which DNA is derived or the technology used to measure DNA methylation may affect associations of social determinants with epigenetic clocks. We conducted a pre-registered multi-level meta-analysis of 140 studies, including N = 65,919 participants, encompassing 1,065 effect sizes for associations of SES and racial/ethnic identity with three generations of epigenetic clocks. We found that associations were weakest for the first generation of epigenetic clocks developed to predict age differences between people. Associations were stronger for the second generation of epigenetic clocks developed to predict mortality and health risks. The strongest associations were observed for a third generation of epigenetic clocks, sometimes referred to as epigenetic speedometers, developed to predict the pace of aging. In studies of children, only the speedometers showed significant associations with SES. Effects of sex and technical factors were minimal and there was no evidence of publication bias.

Normative reference charts are widely used in healthcare, especially for assessing the development of individuals by benchmarking anatomic and physiological features against population trajectories across the lifespan. Recent work has extended this concept to gray matter morphology in the brain, but no such reference framework currently exists for white matter (WM) even though WM constitutes the essential substrate for neuronal communication and large-scale network integration. Here, we present the first comprehensive WM brain charts, which describe how microstructural and macrostructural features of WM evolve across the lifespan, by leveraging over 26,199 diffusion MRI scans from 42 harmonized studies. Using generalized additive models for location, scale, and shape (GAMLSS), we estimate age- and sex-stratified trajectories for 72 individual white matter pathways, quantifying both tract-specific microstructural and morphometric features. We demonstrate that these WM brain charts enable four important applications: (1) defining normative trajectories of WM maturation and decline across distinct pathways, (2) identifying previously uncharacterized developmental milestones and spatial gradients of tract maturation, (3) detecting individualized deviations from normative patterns with clinical relevance across multiple neurological disorders, and (4) facilitating standardized, cross-study centile scoring of new datasets. By establishing a unified, interpretable reference framework for WM structure, these brain charts provide a foundational metric for research and clinical neuroscience. The accompanying open-access trajectories, centile scoring tools, and harmonization methods facilitate precise mapping of WM development, aging, and pathology across diverse populations. We release the brain charts and provide an out-of-sample alignment process as a Docker image: https://zenodo.org/records/15367426.

Sulfur mustard (SM), a potent alkylating agent, has been widely used in chemical warfare, causing severe acute and long-term health complications. While its immediate toxic effects are well documented, the late-onset complications remain poorly understood. Chronic exposure to SM has been linked to persistent oxidative stress, inflammation, and genomic instability, contributing to the progression of various diseases, including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and cancer. This review explores the emerging role of telomere biology in the delayed pathophysiology of SM exposure. Evidence suggests that telomere shortening and dysregulation of telomeric repeat-containing RNA (TERRA) may serve as key molecular indicators of SM-induced aging and cellular dysfunction. Furthermore, inflammatory pathways, particularly NF-κB and TGF-β signaling, appear to be closely associated with telomere attrition, perpetuating chronic inflammation and fibrosis. By integrating oxidative stress, inflammation, and telomere dynamics, we propose a novel model linking telomere biology to SM-induced late complications. Understanding these mechanisms could pave the way for targeted therapeutic strategies, including antioxidant and epigenetic interventions, to mitigate long-term effects. Future research should focus on validating telomere-based biomarkers for early detection and exploring novel interventions to alleviate SM-induced chronic health conditions.

Epigenetic aging estimators commonly track chronological and biological aging, quantifying its accumulation (i.e., epigenetic age acceleration) or speed (i.e., epigenetic aging pace). Their scores reflect a combination of inherent biological programming and the impact of environmental factors, which are suggested to vary at different life stages. The transition from adolescence to adulthood is an important period in this regard, marked by an increasing and, then, stabilizing epigenetic aging variance. Whether this pattern arises from environmental influences or genetic factors is still uncertain. This study delves into understanding the genetic and environmental contributions to variance in epigenetic aging across these developmental stages. Using twin modeling, we analyzed four estimators of epigenetic aging, namely Horvath Acceleration, PedBE Acceleration, GrimAge Acceleration, and DunedinPACE, based on saliva samples collected at two timepoints approximately 2.5 years apart from 976 twins of four birth cohorts (aged about 9.5, 15.5, 21.5, and 27.5 years at first and 12, 18, 24, and 30 years at second measurement occasion).

Epigenetic modifications, including histone post-translational modifications, are central drivers of age-associated structural and functional changes in the genome, influencing gene expression and cellular resilience. Our objective was to determine the effects of inhibiting histone deacetylases (HDACs) and the histone methyltransferase SETDB1 on lifespan, reproduction, and stress response in the rotifer Brachionus manjavacas, a model organism for aging studies. We exposed rotifers to three pharmaceutical compounds, including the HDAC inhibitors {beta}-hydroxybutyrate and sodium butyrate and the SETDB1 inhibitor mithramycin A. We quantified changes in the global histone modification levels by immunoblotting, and measured lifespan, reproduction, and heat stress resistance in the drug-treated rotifers relative to a control. Global histone acetylation levels increase with {beta}-hydroxybutyrate and sodium butyrate treatments. Histone 3 K9 trimethylation (H3K9me3) levels were reduced by treatment with mithramycin A. {beta}-hydroxybutyrate significantly extended lifespan without significantly modifying heat stress resistance. In contrast, mithramycin A increased lifespan and enhanced heat stress tolerance, demonstrating a dual protective effect. Sodium butyrate specifically improved heat stress resistance without affecting overall lifespan. Importantly, none of the three treatments had a significant impact on lifetime reproduction. These findings provide insights into the role of histone modifications in aging and suggest potential interventions targeting epigenetic marks to promote longevity and resilience.

Maternal iron deficiency (ID) disrupts maternal and offspring health by impairing iron status and antioxidant defenses. Rapamycin is known to promote autophagy, enhance antioxidant activity, and extend lifespan. This study investigates the intergenerational effects of post-deficiency dietary interventions using normal and rapamycin-treated diets on Drosophila melanogaster. Female flies (F0) were subjected to an iron-deficient diet for 14 days, followed by a 30-day recovery period on either a normal diet or a rapamycin-supplemented diet. Some F0 females were subsequently mated with normal males to produce F1 offspring. Physiological, biochemical, and gene expression analyses were conducted on F0 flies post-chelation and post-intervention. Post-eclosion evaluations, including a 60-day survival study, were performed on both generations. In F0 females, iron chelation significantly reduced (p < 0.0001) body weight, iron levels, and antioxidant enzyme activity, while increasing glutathione (GSH) levels. Gene expression analysis revealed significant changes (p < 0.05) in iron storage (Fer1HCH), autophagy (ATG1), and telomere-related genes (dHeT-A, dTahre, dTart). While a normal diet partially restored iron levels and survival, the rapamycin-treated diet improved antioxidant defenses but had mixed effects on survival and gene expression. In the F1 generation, male and female offspring from mothers on a normal diet exhibited reduced and increased iron levels, respectively, alongside improved median survival. Rapamycin increased body weight and iron levels in female offspring but reduced their median survival. Post-deficiency dietary interventions significantly shape antioxidant responses and survival in both iron-deficient mothers and their offspring. While normal diets support recovery of iron status, rapamycin enhances antioxidant defenses but compromises survival, particularly in female offspring.

Since the discovery that ageing is a modifiable process in animal models, significant advancements in geroscience have led to the emergence of the field of Precision Geromedicine, which aims to optimise health and healthspan by targeting ageing-related processes. Ageing-related diseases (ARDs), accounting for 80% of Singapore's disease burden in 2019, are on the rise as the nation approaches the "super-aged" status by 2030. In response, Singapore is reshaping its healthcare system to focus on healthy ageing, as seen in the launch of the Healthier SG initiative in 2023, which empowers citizens to manage their health proactively with support from over 1800 private general practices. Additionally, Singapore is investing in geroscience to build the foundations of Precision Geromedicine, aiming to integrate gerodiagnostics and gerotherapeutics into clinical practice. Leveraging its robust healthcare system, digital infrastructure, and socio-political stability, Singapore is well-positioned to become a model for addressing ARDs amidst global demographic shifts.

Aging manifests as the progressive declines of homeostatic resilience and repair mechanisms, marked by dysregulations across systems and increasing individual heterogeneity. However, the breadth of measures of homeostatic dysregulation remains underexplored. Here, we introduce DISCO as a novel measure of homeostatic dysregulation, integrating clinical, proteomics, metabolomics, and microbiomes data. DISCO demonstrated moderate correlation with chronological age but robustly predicted mortality, frailty, and chronic disease risk, outperforming Mahalanobis distance in health outcome prediction, comparable to the best epigenetic clocks. Organ/tissue-specific DISCO analysis revealed limited organ-disease specificity, suggesting systemic rather than localized dysregulation drives health decline. Network analysis identified aging-associated proteins as central hubs strongly linked to DISCO scores; further, organ-level DISCO metrics most predictive of age and outcomes were also central within biological networks. Collectively, DISCO emerges as a validated measure of whole-body homeostatic dysregulation, providing a tool for aging risk stratification and insights into systemic aging mechanisms.

Genome wide association studies have identified multiple loci that mediate the risk of developing late-onset Alzheimer\'s Disease (LOAD). The gene WW-domain containing oxidoreductase (WWOX) has been identified in recent LOAD risk meta-analyses, yet its function in the brain is poorly understood. Using Drosophila, we discovered that knockdown of the highly conserved Wwox gene impacts longevity and sleep, having roles in both neuronal and glial subtypes. In an amyloid beta 42 (A{beta}42) transgenic model of AD, RNAi- mediated knockdown of Wwox significantly decreased both lifespan and locomotion whilst elevating soluble A{beta}42. Transcriptomic and metabolomic analyses revealed that these effects were accompanied by elevated lactate dehydrogenase (Ldh) mRNA and lactate levels, downstream of an increase in the key unfolded protein response protein Atf4. Strikingly, we found that upregulation of Wwox in the A{beta}42 model through CRISPR activation significantly reduced amyloid load, improved longevity and locomotion. Multi-omics analysis revealed Wwox upregulation partially reversed several key A{beta}42-induced transcriptional pathways in the brain and reduced levels of L-methionine and associated enzymes. These findings support a role for reduced WWOX levels in the genetic risk of developing LOAD via pyruvate metabolism and point towards WWOX activation as a protective therapeutic strategy.

Age-related white matter (WM) microstructure maturation and decline occur throughout the human lifespan, complementing the process of gray matter development and degeneration. Here, we create normative lifespan reference curves for global and regional WM microstructure by harmonizing diffusion MRI (dMRI)-derived data from ten public datasets (N = 40,898 subjects; age: 3-95 years; 47.6% male). We tested three harmonization methods on regional diffusion tensor imaging (DTI) based fractional anisotropy (FA), a metric of WM microstructure, extracted using the ENIGMA-DTI pipeline. ComBat-GAM harmonization provided multi-study trajectories most consistent with known WM maturation peaks. Lifespan FA reference curves were validated with test-retest data and used to assess the effect of the ApoE4 risk factor for dementia in WM across the lifespan. We found significant associations between ApoE4 and FA in WM regions associated with neurodegenerative disease even in healthy individuals across the lifespan, with regional age-by-genotype interactions. Our lifespan reference curves and tools to harmonize new dMRI data to the curves are publicly available as eHarmonize ( https://github.com/ahzhu/eharmonize ).

Background The Cambridge Centre for Ageing and Neuroscience (Cam-CAN) started in 2010 to study the effect of healthy adult ageing on cognition and the brain in a population-derived sample. The study design and protocol for Phases 1-3 of Cam-CAN were detailed in Shafto et al. (2014); this paper outlines the design and protocol of Phases 4-5, which enable longitudinal investigation of cognitive and brain ageing over approximately 12 years. More details about the Cam-CAN project can be found here: www.cam-can.org. Methods/Design Phase 4 was an at-home assessment of cognition, demographics and lifestyle, performed approximately 6 years after Phase 1 (baseline assessment), for which all people from Phase 1 were invited. Phase 5 combined repeated online cognitive, demographics and lifestyle assessment, followed by in-lab attendance for MRI and MEG brain scanning, approximately 12 years after Phase 1, for which all people from Phase 2 (baseline brain assessment) were invited. Demographics, lifestyle and cognitive data are therefore now available for three timepoints, and MRI and MEG brain data for two timepoints. Discussion The Cam-CAN study offers deep and wide phenotyping of neurocognitive health across the adult lifespan (18-96). These rich data will allow researchers to address questions like: why do some people maintain their cognitive abilities better than others, in terms of their brain structure or function, their lifestyle and/or their genetics? Given the shifting demographics towards old age in most countries, this knowledge will be important to help people function independently for longer, reducing both individual and societal burden.

Aging is associated with the accumulation of senescent cells, which are triggered by tissue injury response and often escape clearance by the immune system. The specific traits and diversity of these cells in aged tissues, along with their effects on the tissue microenvironment, remain largely unexplored. Despite the advances in single-cell and spatial omics technologies to understand complex tissue architecture, senescent cell populations are often neglected in general analysis pipelines due to their scarcity and the technical bias in current omics toolkits. Here we used the physical properties of tissue to enrich the age-associated fibrotic niche and subjected them to single-cell RNA sequencing and single-nuclei ATAC sequencing (ATAC-seq) analysis and named this method fibrotic niche enrichment sequencing (FiNi-seq). Fibrotic niche of the tissue was selectively enriched based on its resistance to enzymatic digestion, enabling quasi-spatial analysis. We profiled young and old livers of male mice using FiNi-seq, discovered Wif1- and Smoc1-producing mesenchymal cell populations showing senescent phenotypes, and investigated the early immune responses within this fibrotic niche. Finally, FiNi-ATAC-seq revealed age-associated epigenetic changes enriched in fibrotic niche cells. Thus, our quasi-spatial, single-cell profiling method allows the detailed analysis of initial aging microenvironments, providing potential therapeutic targets for aging prevention.

Recent influenza vaccine formulations have improved the magnitude of B-cell antibody responses in older adults; however, older adults remain significantly at risk for severe influenza-related illness. Although antibodies are an important metric of vaccine effectiveness, they only represent one aspect of the immune response. In this study, we combined in vitro and ex vivo assays with human samples to investigate B, CD4+ T, and myeloid cell responses to influenza vaccine antigens. We found that older adults mounted equivalent antibody titers to younger adults but had fewer influenza-specific CD4+ T cells and reduced antiviral-associated T helper cell populations. Single-cell transcriptomics revealed that older adults had attenuated interferon transcriptional signatures in T helper and myeloid cell subsets. These data suggest that with aging, transcriptional programming alterations in myeloid cells contribute to reduced antiviral T cell responses, and formulating vaccines tailored to myeloid responses is necessary to improve outcomes in older adults.

Renal epithelial cell senescence and kidney aging have become the focus of scientific investigation. However, how epigenetic regulation in these processes remains elusive. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, regulates trimethylation of histone H3 at lysine 27 (H3K27me3) and plays an important role in renal pathophysiology. In this study, we show that the expression of EZH2 is decreased in naturally aged and irradiation (IR)-induced mouse kidneys, as well as in IR-induced human renal cortical tubular epithelial (RCTE) cells through proteasome-mediated degradation. Inhibition of EZH2 with its specific inhibitor 3-DZNeP promotes tubular cell senescence and kidney aging characterized by an increase in the expression of senescence markers, including p16 and p21, in mouse kidneys and in IR-induced RCTE cells. We show that EZH2 represses the transcription of p16 through trimethylation of H3K27me3, which directly binds to the promoter of p16. EZH2 represses the transcription of p21 through directly binding to the promoter of p21, and this process is involved in its interaction with p53 and its phosphorylation by ataxia-telangiectasia mutated (ATM), a critical protein involved in the cellular response to DNA damage. Inhibition of ATM with its inhibitor decreased the phosphorylation of EZH2 and the binding of EZH2 to the promoter of p21 in IR-treated RCTE cells in a p53-dependent manner. This study suggests that EZH2 plays a critical role in preventing kidney aging and DNA-damage-induced renal tubular cellular senescence, in which senescence and kidney aging also result in the destabilization of EZH2, forming a negative feedback loop.

Biological age refers to a person\'s overall health in aging, as distinct from their chronological age. Diverse measures of biological age, referred to as clocks, have been developed in recent years and enable risk assessments, and an estimation of the efficacy of longevity interventions in animals and humans. While most clocks are trained to predict chronological age, clocks have been developed to predict more complex composite biological age outcomes, at least in humans. These composite outcomes can be made up of a combination of phenotypic data, chronological age, and disease or mortality risk. Here, we develop the first such composite biological age measure for mice: the mouse phenotypic age model (Mouse PhenoAge). This outcome is based on frailty measures, complete blood counts, and mortality risk in a longitudinally assessed cohort of male and female C57BL/6 mice. We then develop clocks to predict Mouse PhenoAge, based on multi-omic models using metabolomic and DNA methylation data. Our models accurately predict Mouse PhenoAge, and residuals of the models are associated with remaining lifespan, even for mice of the same chronological age. These methods offer novel ways to accurately predict mortality in laboratory mice thus reducing the need for lengthy and costly survival studies.

With parental age rising around the globe, an increased understanding of the impact on health and longevity is needed. Here, we report how the continuous selection of the last progeny during the Caenorhabditis elegans reproductive span results in a diminishment of multiple age-related health measures. After more than fifty generations of late selection, progeny displayed diminished resistance to acute oxidative stress, disrupted partitioning of stored lipids, reduced movement capacity, and an overall shortening of lifespan. In contrast, starvation resistance was improved and late selection had negligible effects on developmental timing and total reproductive output that suggests a reduction in lifespan health to preserve reproductive capacity. The phenotypes of late selection are reminiscent of animals with activation of the cytoprotective transcription factor SKN-1 but are unlikely a result of a spontaneous genetic mutation. These findings suggest the existence of a homeostatic mechanism for bookmarking the temporal boundaries of the parental reproductive span that reshapes the way we think about parental age influencing offspring fitness.

Experimental evolution studies that feature selection on life-history characters are a proven approach for studying the evolution of aging and variation in rates of senescence. Recently, the incorporation of genomic and transcriptomic approaches into this framework has led to the identification of hundreds of genes associated with different aging patterns. However, our understanding of the specific molecular mechanisms underlying these aging patterns remains limited. Here, we incorporated extensive metabolomic profiling into this framework to generate mechanistic insights into aging patterns in Drosophila melanogaster. Specifically, we characterized metabolomic change over adult lifespan in populations of D. melanogaster where selection for early reproduction has led to an accelerated aging phenotype relative to their controls. Using these data we: i) evaluated evolutionary repeatability across the metabolome; ii) assessed the value of the metabolome as a predictor of "biological age" in this system; and iii) identified specific metabolites associated with accelerated aging. Generally, our findings suggest that selection for early reproduction resulted in highly repeatable alterations to the metabolome and the metabolome itself is a reliable predictor of "biological age". Specifically, we find clusters of metabolites that are associated with the different rates of senescence observed between our accelerated aging population and their controls, adding new insights into the metabolites that may be driving the accelerated aging phenotype.

Retrotransposable elements (RTEs) have been implicated in the pathogenesis of several age-associated diseases. Although model systems indicate that age- and sex-dependent loss of heterochromatin increases RTE expression, data from large human studies are lacking. Here we assessed the expression levels of 795 blood RTE subfamilies in 2467 participants of the population-based Rhineland Study. We found that the expression of more than 98% of RTE subfamilies increased with both chronological and biological age. Moreover, the expression of heterochromatin regulators involved in RTE silencing was negatively related to the expression of 690 RTE subfamilies. Finally, we observed sex differences in 42 RTE subfamilies, with higher expression in men. The genes mapped to sex-related RTEs were enriched in immune response-related pathways. Importantly, we validated our key findings in an independent population-based cohort. Our findings indicate that RTEs and their repressors are markers of aging and that their dysregulation is linked to inflammation, especially in men.

Maintaining genomic stability is essential for detecting DNA damage and activating appropriate responses such as repair, apoptosis, or senescence, primarily mediated by the ATM-p53 axis. ATM is the main sensor of double-strand breaks, and once activated, it will either promote the repair of damaged DNA or eliminate the damaged cells through apoptosis. ATM and p53 mutations upset this equilibrium to cause genomic instability, therapy resistance, and tumor progression in the context of cancer. Oncogene-induced senescence is bypassed by ATM inactivation, which allows cells to progress to become tumors, and p53 mutations allow for uncontrolled proliferation and sensitivity to apoptosis. In addition, persistent ATM signaling can trigger a SASP, which paradoxically further enhances an inflammatory tumor microenvironment and contributes to aging-related diseases and cancer progression. Chemical small molecule p53 activators (PRIMA-1, Nutlin-3) and ATM inhibitors (AZD0156, M4076) sensitize cancer to DNA damaging therapy in cells and nude mice without p53. It remains to be seen whether ATM loss results in ATM/p53 signaling that is always detrimental to tumor proliferation or has context-dependent effects since ATM loss can also promote p53-dependent tumor suppression through senescence and apoptosis in specific cancer types. In this review, we consolidate state-of-the-art findings on ATM and p53 coordination in the processes involved in DNA repair, apoptosis, and senescence to show how ATM and p53 dual involvement in tumor suppression and cancer progression is occurring. It also focuses on therapeutic approaches targeting these pathways to benefit from senescence and intimidating cancer treatment outcomes.

Despite significant advances in aging research, translating these findings into clinical practice remains a challenge. Aging is a complex, multifactorial process shaped by many factors including genetic, metabolic, and environmental factors. While medical advancements have extended lifespan, healthspan remains constrained by cellular senescence, telomere attrition, and systemic inflammation-core hallmarks of biological aging. However, emerging evidence suggests that telomere dynamic is not inevitable but can be influenced by oxidative stress, lifestyle choices, and metabolic regulation. This review examines how telomere-based biomarkers and metabolic interventions can drive personalized longevity medicine, enabling targeted strategies to delay aging. Furthermore, it highlights the integration of geroscience into clinical practice-integrated longevity medicine leveraging biomarker tracking, metabolic therapies, and preventive interventions-to redefine aging as a modifiable process, ultimately extending both lifespan and healthspan.

Aging research is often framed within pluralistic frameworks that emphasize cellular and molecular damage processes. Among the most influential are Strategies for Engineered Negligible Senescence (SENS), which aims to counteract biological decline through targeted damage repair, and the Hallmarks of Aging (HoA), which seeks to identify fundamental mechanisms underlying this process. Both proposals, although diverse, significantly influence contemporary approaches to the challenges posed by aging. However, despite extensive discussion, we contend that key conceptual and methodological aspects remain insufficiently explored. This paper seeks to advance the debate by critically analyzing and comparing their foundational goals, theoretical premises, and research frameworks. Specifically, we examine their definitions of aging, perspectives on health and disease, approaches to scientific evidence and causal interventions, and communications strategies. In doing so, we aim to contribute to a deeper understanding and more nuanced assessment of both SENS and the HoA.