Longevity Papers

It is widely thought that age-related damage is the single biggest contributing factor to neurodegenerative diseases. However, recent studies are beginning to indicate that many of these diseases may have developmental origins that become unmasked overtime. It has been difficult to prove these developmental origins, as there are still few known links between defective embryonic neurogenesis and progressive neurodegeneration. We have created a constitutive knockout mouse for the N-terminal methyltransferase NRMT1 (Nrmt1-/- mice). Nrmt1-/- mice display phenotypes associated with premature aging. Specifically in the brain, they exhibit age-related striatal and hippocampal degeneration, which is accompanied by impaired short and long-term memory. These phenotypes are preceded by depletion of the postnatal neural stem cell (NSC) pools, which appears to be driven by their premature differentiation and migration. However, this differentiation is often incomplete, as many resulting neurons cannot permanently exit the cell cycle and ultimately undergo apoptosis. Here, we show that the onset of apoptosis corresponds to increased cleavage of p35 into the CDK5 activator p25, which can promote neuroinflammation. Accordingly, Nrmt1-/- brains exhibit an increase in pro-inflammatory cytokine signaling, astrogliosis, complement activation, microgliosis, and markers of a compromised blood brain barrier, all of which indicate an activated neuroimmune response. We also find Nrmt1-/- mice do not activate a corresponding anti-inflammatory response. These data indicate that abnormal neurogenesis can trigger neuroinflammation, which in the absence of compensatory anti-inflammatory signaling, could lead to neuronal apoptosis and progressive neurodegeneration.

Tartrate-resistant acid phosphatase (TRAP/ACP5), primarily known as an osteoclast marker, has emerged as a critical regulator of skeletal integrity, regulating sex-specific bone growth, and bones response to mechanical load in young adult male mice. In this study, we investigated the sex-specific roles of TRAP in bone structure and response to mechanical stimuli in old (19-month-old) wild-type (WT) and TRAP-deficient (TRAP-/-) mice using micro-computed tomography, serum bone turnover markers, in vivo axial mechanical loading, and in vitro mechanotransduction assays. Our findings revealed that TRAP-/- mice of both sexes maintained shorter tibiae than WT mice independent of sex. Notably, male, but not female, TRAP-/- mice have increased trabecular bone volume fraction and cortical bone area compared to WT, indicative of disrupted bone remodelling processes in male mice. Interestingly, TRAP-deficiency substantially impaired the anabolic bone response to mechanical loading, affecting both trabecular and cortical compartments in both sexes, indicating that when challenged, TRAP is important for bone formation also in female mice. Mechanical stimulation in vitro of hematopoietic progenitor cells from WT and TRAP-/- mice revealed that the increased ATP-release in response to mechanical stimulation was only disrupted in male mice, while mechanically induced increase in osteoclast formation was inhibited in TRAP-/- mice of both sexes. These results highlight the importance of TRAP in maintaining trabecular architecture and cortical bone in male mice and underscore its critical function in mediating adaptive responses to mechanical loading of both sexes, during aging. Future investigations should focus on elucidation of TRAP-dependent pathways as potential therapeutic targets to counteract age-related deficits in bone adaptation and remodelling.

The changing demography of human populations has motivated a search for interventions that promote healthy ageing, and especially for evolutionarily-conserved mechanisms that can be studied in lab systems to generate hypotheses about function in humans. Reduced Insulin/IGF signalling (IIS) is leading example, which can extend healthy lifespan in a range of animals; but whether benefits and costs of reduced IIS vary genetically within species is under-studied. This information is critical for any putative translation. Here, in Drosophila, we test for genetic variation in lifespan response to a dominant-negative form of the insulin receptor, along with a metric of fecundity to evaluate corollary fitness costs/benefits. We also partition genetic variation between DNA variants in the nucleus (nDNA) and mitochondrial DNA (mtDNA), in a fully-factorial design that allows us to assess "mito-nuclear" epistasis. We show that reduced IIS can have either beneficial or detrimental effects on lifespan, depending on the combination of mtDNA and nDNA. This suggests that, while insulin signalling has a conserved effect on ageing among species, intraspecific effects can vary genetically, and the combination of mtDNA and nDNA can act as gatekeeper.

The fundamental cause theory posits social factors as causes of disease as they encompass access to important resources such as knowledge, wealth, and social networks. While these social factors have been consistently associated with oral and systemic diseases, causality remains unestablished. Here, we estimated the causal effect of social adversity, comprising low economic and social capital, on the development of (1) oral conditions (OC) and (2) multimorbidity including oral conditions (MIOC) in a cohort of middle-aged and older adults over a 7-y period and assessed whether effects varied by age or gender. We analyzed 2 waves from the Canadian Longitudinal Study on Aging (CLSA) (2011 and 2018). Social adversity comprised low economic (income) and social capital (community participation, social relationships). OC was defined as having 1 or more of poor self-reported oral health, lack of functional dentition (<20 natural teeth), or edentulism. Participants with an OC at baseline were excluded. MIOC was defined as having 2 or more chronic diseases and an OC. Logistic marginal structural models with inverse probability weighting estimated the causal odds ratio (OR) of developing both outcomes, controlling for sociodemographic and behavioral factors. In a total of 23,366 participants, 14% experienced social adversity at baseline, with a prevalence of 17% OC and 7% MIOC at follow-up. Social adversity significantly increased the odds of developing OC (OR = 1.9, 95% confidence interval [CI] 1.7, 2.2) and MIOC (OR = 1.7, 95% CI 1.5, 2.0) at follow-up. The observed effects were strongest in the middle-aged group, with similar odds observed in both men and women. Our findings indicate that social and economic capital are causally linked to the development of OC and MIOC over time. We suggest that policies for healthy aging should prioritize action on social and living conditions.

The hippocampus (HC), a central hub for memory and cognition, exhibits unique metabolic resilience during aging despite widespread brain glucose hypometabolism. Here, we report that aged humans and macaques paradoxically display elevated HC glucose uptake (18F-FDG PET SUVR) alongside strengthened connectivity to sensory-motor and limbic networks-an adaptive rewiring revealed by graph-theoretical metabolic network analysis. Integrated multi-omics profiling identified STT3A (oligosaccharyltransferase) and ALG5 (dolichyl-phosphate β-glucosyltransferase) as key regulators of age-related HC adaptation, with their upregulation in aged macaque hippocampi driving N-glycosylation-dependent metabolic reprogramming. Mechanistically, STT3A/ALG5 silencing in aged rats reduced insulin receptor/AKT1/AS160 phosphorylation, impairing GLUT4 membrane trafficking, while enhancing GLUT3 glycosylation and neuronal glucose uptake. This dual regulation preserved synaptic integrity and spatial memory retrieval despite reduced hippocampal FDG metabolism. Behavioral assays further demonstrated STT3A knockdown-induced motor coordination improvements through GLUT3-mediated metabolic rebalancing. Our findings establish STT3A-ALG5 as a glycosylation checkpoint that sustains HC energy homeostasis via GLUT4-to-GLUT3 substrate switching, positioning 18F-FDG PET as a dynamic biomarker for monitoring HC aging and these glycosyltransferases as therapeutic targets against cognitive decline.

Epitalon, a naturally occurring tetrapeptide, is known for its anti-aging effects on mammalian cells. This happens through the induction of telomerase enzyme activity, resulting in the extension of telomere length. A strong link exists between telomere length and aging-related diseases. Therefore, telomeres are considered to be one of the biomarkers of aging, and increasing or maintaining telomere length may contribute to healthy aging and longevity. Epitalon has been the subject of several anti-aging studies however, quantitative data on the biomolecular pathway leading to telomere length increase, hTERT mRNA expression, telomerase enzyme activity, and ALT activation have not been extensively studied in different cell types. In this article, the breast cancer cell lines 21NT, BT474, and normal epithelial and fibroblast cells were treated with epitalon then DNA, RNA, and proteins were extracted. qPCR and Immunofluorescence analysis demonstrated dose-dependent telomere length extension in normal cells through hTERT and telomerase upregulation. In cancer cells, significant telomere length extension also occurred through ALT (Alternative Lengthening of Telomeres) activation. Only a minor increase in ALT activity was observed in Normal cells, thereby showing that it was specific to cancer cells. Our data suggests that epitalon can extend telomere length in normal healthy mammalian cells through the upregulation of hTERT mRNA expression and telomerase enzyme activity.

Mitochondrial sirtuins regulate metabolism and are emerging drug targets for metabolic and age-related diseases such as cancer, diabetes, and neurodegeneration. Yet, the extent of their functions remain unclear. Here, we uncover a physiological role for the C. elegans mitochondrial sirtuins, sir-2.2 and sir-2.3, in lifespan regulation. Using genetic alleles with deletions that destroy catalytic activity, we demonstrate that sir-2.2 and sir-2.3 mutants live an average of 25% longer than controls when fed the normal lab diet of live E. coli OP50. While decreased consumption of food is a known mechanism for lifespan extension, we did not find evidence of reduced pharyngeal pumping. Interestingly, lifespan extension effected by loss of sir-2.2 or sir-2.3 is sensitive to the diet. The lifespan extension of the sir-2.2 mutants is eliminated and that of sir-2.3 mutants is attenuated when the animals are fed the E. coli strain HT115, which is typically used for RNAi experiments. We used growth ability of the food source and a virulent pathogenic strain to ask if differences in pathogenicity are related to the mechanisms for lifespan extension. sir-2.3 deletion results in lifespan extension in all conditions. However, removing the ability of the food source to grow eliminated the sir-2-mediated effect. We also examine the response of the mutants to oxidative stress, and our results suggest that a hormetic response contributes to lifespan extension in both mutants. Our data suggest that sir-2.2 and sir-2.3 use overlapping yet distinct mechanisms for regulating lifespan.

Cellular senescence, a hallmark of aging, is characterized by irreversible, permanent cell cycle arrest accompanied by halted proliferation triggered by endogenous or exogenous stimuli. The accumulation of senescent cells in tissues or organs elicits detrimental effects on adjacent normal cells through their pathogenic senescence‑associated secretory phenotype (SASP), driving secondary senescence, disrupting tissue homeostasis and ultimately exacerbating age‑related pathologies such as types of cancer and neurodegenerative disorders. Hepatic disorders constitute a leading cause of global mortality, imposing considerable healthcare burdens. Robust clinical evidence has now demonstrated a strong correlation between cellular senescence and poor clinical outcomes in various hepatopathies. This intricate yet critical signaling network is dynamically regulated in both physiological homeostasis and chronic hepatic inflammatory conditions. Notably, recent years have witnessed extensive research into pharmacological strategies to deplete senescent cells, inhibit SASP, and target other senescence markers across diverse contexts, thereby establishing the field of senotherapeutics. The present review systematically summarized key molecular pathways and biomarkers of hepatic senescence, while outlining the emerging role of cellular senescence in inflammatory liver disorders. It also discussed the therapeutic potential of senescence‑regulating drugs for liver disease, which could alleviate hepatic inflammation and enhance clinical outcomes.

Exposure to low levels of environmental challenges, known as hormetic stress, such as nutrient deprivation and heat shock, fosters subsequent stress resistance and promotes healthy aging in later life. However, specific mechanisms governing transcriptional reprogramming upon hormetic nutrient stress remain elusive. In this study, we identified histone H3 lysine 27 acetylation (H3K27ac) as a crucial driver of transcriptomic adaptation to hormetic fasting. Beyond its immediate function of enhancing lipid catabolism for alternative energy sources, stress-induced H3K27ac activates lifelong antioxidant defenses, thereby reducing reactive oxygen species (ROS) produced by stress-induced fatty acid oxidation and their accumulation during aging. The increase in H3K27ac, mediated by pioneer factor PHA-4/FOXA and cooperating transcription factor NHR-49/HNF4, is crucial for lifespan extension under hermetic nutrient stress in Caenorhabditis elegans. Our findings establish H3K27ac as a key transcriptional switch that bridges nutrient status with transcriptomic reprogramming, underpinning the pro-longevity effects of hormetic fasting through orchestrating lipid catabolism and antioxidative defenses.

While intermittent fasting (IF) promotes longevity in animal models, its systemic effects in humans remain poorly understood. Here, we present a six-month longitudinal IF intervention in 114 women (BMI 25-35) with deep clinical, molecular, and microbiome profiling across >3,400 biospecimens from six tissues. Analyses spanning >2,200 multi-omic features and 11,000 microbial function predictions demonstrate coordinated clinical benefits, including improvements in body composition and cardiorespiratory fitness, and reveal coordinated molecular responses across tissues. Iron metabolism emerged as a central axis: transferrin increased while ferritin, haemoglobin, and erythrocytes decreased, changes that opposed ageing trajectories yet remained within physiological limits. Epithelial DNA methylation biomarkers (cervical, buccal) of cancer risk reduced, while blood clocks were largely unresponsive, underscoring tissue-specificity of the epigenome. Immune profiling uncovered dynamic, partially reversible shifts. Notably, we derived a new immunophenotyping-based ImmuneAge score that increased during fasting and tracked with inflammatory function, while the pro-inflammatory cytokine IL-17A declined selectively in postmenopausal women. Oral microbiota showed rapid restructuring, whereas gut microbiota shifted more subtly toward enhanced metabolic capacity. Together, these data provide unprecedented insight into the systemic and tissue-specific responses to IF in humans and identify iron homeostasis and immune remodelling as candidate mechanisms. Our findings are available through the Lifestyle Atlas (https://eutops.github.io/lifestyle-atlas).

Accurate detection of somatic mutations in noncancerous cells is critical for studying somatic mosaicism, a process implicated in aging and multiple chronic diseases. However, single-cell and single-molecule DNA sequencing platforms differ in their error profiles, coverage biases, and sensitivity to specific mutation types, complicating cross-platform comparisons. Here, we present in vitro and in silico benchmarks to quantify true-positive and false-positive rates in single-cell whole-genome sequencing using Single-Cell Multiple Displacement Amplification, and in single-molecule sequencing using Nanorate Sequencing (NS) and whole-genome NS (WGNS). Using standard cell lines, we show that all three methods detect single-nucleotide variants (sSNVs) and small insertions and deletions (sINDELs) with high accuracy, but differ in genomic coverage and susceptibility to artifacts. Method-specific biases influence mutational signatures and hotspot detection. Applying results of the benchmark to IMR-90 fibroblasts, we estimate higher in vitro mutation rates using NS than expected from in vivo data, consistent with potential replication stress and culture-associated DNA damage. Overall, our study highlights the substantial impact of sequencing platform-specific biases on somatic mutation detection and interpretation, and lays the foundation for standardized, cross-platform-comparable analyses of somatic mosaicism in normal human tissues.

Aging of the blood system impacts systemic health and can be traced to hematopoietic stem cells (HSCs). Despite multiple reports on human HSC aging, a unified map detailing their molecular age-related changes is lacking. We developed a consensus map of gene expression in HSCs by integrating seven single-cell datasets. This map revealed previously unappreciated heterogeneity within the HSC population. It also links inflammatory pathway activation (TNF/NF{kappa}B, AP-1) and quiescence within a single gene expression program. This program dominates an inflammatory HSC subpopulation that increases with age, highlighting a potential target for further experimental studies and anti-aging interventions.

Ferroptosis is a newly recognized form of programmed cell death characterized by iron overload-dependent lipid peroxidation. These pathological phenomena are often observed in neurodegenerative diseases. Aging is an irreversible process characterized by the deterioration of tissue and cell function. It has been shown to contribute to neurodegenerative diseases and increase susceptibility to ferroptosis. Therefore, ferroptosis may be involved in the progression of neurodegenerative diseases as a pathogenic factor, and aging is the common catalyst of both processes. The purpose of this review is to elucidate the latest progress on the mechanisms related to ferroptosis in neurodegenerative diseases, including iron overload, lipid peroxidation, antioxidant defense, cell membrane repair, and the regulation of autophagy and transcription factors. We also explored the relationship between ferroptosis and aging and reported that aging can induce ferroptosis by increasing iron overload, enhancing lipid peroxidation, and exacerbating autophagy disorders. Since ferroptosis is a pathogenic factor in neurodegenerative diseases, we screened gene bank databases and found that many genes associated with ferroptosis and neurodegenerative diseases overlap. Additionally, genes related to both the peroxidation pathway and ferroptosis are enriched. Ferroptosis occurs under conditions of age-related iron accumulation and lipid enrichment, as well as due to disorders in autophagy levels and transcription factors. Furthermore, in various neurodegenerative diseases, specific pathological changes or products can also contribute to the occurrence of ferroptosis. Finally, based on animal studies and clinical trials involving ferroptosis inhibitors, physical therapies, stem cell treatments, and exosome therapies in neurodegenerative diseases, it has been found that inhibiting ferroptosis can effectively reverse neurological dysfunction and cognitive impairment associated with these conditions. However, given various limitations, the conclusions of some animal studies and clinical trials have not been ideal, indicating that further large-scale research is necessary. Taken together, ferroptosis induces aging-related neurodegenerative diseases and neuronal cell death, triggering disease onset and progression. Ferroptosis inhibitors, physical therapies, stem cell treatments, and exosome therapies show great potential for inhibiting ferroptosis in neurodegenerative disease.

While certain forms of mitochondrial impairment confer longevity, disease-associated mutations trigger dysfunction and severe pathogenesis. The adaptive pathways that distinguish benefit from pathology remain unclear. Here we reveal that longevity induced by mitochondrial Complex I/nuo-6 mutation in C. elegans is dependent on the endoplasmic reticulum (ER) Ca2+ channel, InsP3R. We find that the InsP3R promotes mitochondrial respiration, but the mitochondrial calcium uniporter is dispensable for both respiration and lifespan extension in Complex I mutants, suggesting InsP3R action is independent of matrix Ca2+ flux. Transcriptomic profiling and imaging reveal a previously unrecognized role for the InsP3R in regulating mitochondrial scaling, where InsP3R impairment results in maladaptive hyper-expansion of dysfunctional mitochondrial networks. We reveal a conserved InsP3R signaling axis through which calmodulin and actomyosin remodeling machineries, including Arp2/3, formin FHOD-1, and MLCK, constrain mitochondrial expansion and promote longevity. Disruption of actin remodeling or autophagy mimics InsP3R loss. Conversely, driving fragmentation ameliorates mitochondrial expansion and rescues longevity, supporting a model in which InsP3R-dependent actin remodeling sustains mitochondrial turnover. These findings establish an inter-organelle signaling axis by which ER calcium release orchestrates mitochondrial-based longevity through cytoskeletal effectors.

Molecular aging clocks estimate biological age from molecular biomarkers and often outperform chronological age in predicting health outcomes. Types include epigenetic, transcriptomic, proteomic, and metabolomic clocks. NMR-based metabolomic clocks provide a non-invasive, high-throughput platform to assess metabolic health. We summarize key NMR-based models and present a new approach that combines high predictive accuracy with clinical interpretability, identifying disease-specific metabolic distortions and supporting risk stratification and early detection of accelerated aging.

The sustained production of blood and immune cells is driven by a pool of hematopoietic stem cells (HSCs) and their offspring. Due to the intrinsic heterogeneity of HSCs, the composition of emergent clones changes over time, leading to a reduced clonality in aging mice and humans. Theoretical analyses suggest that clonal conversion rates and clonal complexity depend not only on HSC heterogeneity, but also on additional stress conditions. These insights are particularly relevant in the context of stem cell transplantations, which still remain the only curative option for many hematologic diseases, increasingly considered viable for elderly individuals. However, age-related clonal changes post-transplantation are not well understood. To address this, we conducted a barcode-based assessment of clonality to investigate post-transplantation changes in both homo- and hetero-chronic settings, combined with low- and high-intensity pre-conditioned recipients. A robust and polyclonal engraftment was observed across all groups, but with distinct differences in barcode diversity. In particular, transplanted aged HSCs showed no changes in clonality, regardless of recipient age or pre-conditioning. Young HSCs transplanted into severely pre-conditioned old hosts as well as under reduced pre-conditioning, allowed for full lymphoid reconstitution, but showed substantial differences in clonality. Also, myeloid lineage bias, a hallmark of aged HSCs, was confirmed at a clonal level across all experimental groups. Overall, we found that aged HSCs generally maintain clonal diversity similar to young HSCs, but notable differences emerge under hetero-chronic conditions and varying pre-conditioning regimens. These findings challenge current paradigms and underscore the complex interactions between aging and transplantation conditions.

Aging Clock models have emerged as a crucial tool for measuring biological age, with significant implications for anti-aging interventions and disease risk assessment. However, human aging clock models that offer single-cell resolution and account for cell and tissue heterogeneities remain underdeveloped. This study introduces scAgeClock, a novel gated multi-head attention (GMA) neural network-based single-cell aging clock model. Leveraging a large-scale dataset of over 16 million single-cell transcriptome profiles from more than 40 human tissues and 400 cell types, scAgeClock demonstrates improved age prediction accuracy compared to baseline methods. Notably, the mean absolute error for the best-performing cell type is remarkably low at 2 years. Feature importance analysis reveals enrichment of aging clock genes related to ribosome, translation, defense response, viral life cycle, programmed cell death, and COVID-19 disease. A novel metric, the Aging Deviation Index (ADI) proposed by this study, revealed deceleration of ages in cells with higher differentiation potencies and tumor cells in higher phases or under metastasis, while acceleration of ages was observed in skin cells. Furthermore, scAgeClock is publicly available to facilitate future research and potential implementations.

The regulation of cellular metabolism and growth in response to nutrient availability is crucial for cell survival and can significantly impact on lifespan. Central to this regulation is a class of transporters that sense and transport specific nutrients and transduce the signal downstream to control genes responsible for growth and survival. In this study, we identified SUL1, a plasma membrane transporter responsible for regulating the entry of extracellular sulfate in

Research methods for the investigation of the biology of aging have often implicitly generalized strain-specific results. Dietary interventions, such as caloric restriction and periodic fasting, have been shown to enhance metabolic health and extend lifespan in preclinical models. However, inter-individual variation in physiological responses to these interventions, which affects their safety and efficacy when translated to humans, remains poorly understood despite being observed in multiple studies. In this study, we implemented intermittent fasting (IF) for two days per week in 10 inbred strains (n = 800 mice) from the Collaborative Cross (CC). The CC is a multiparent recombinant inbred strain panel that offers a diverse collection of reproducible models to study the genetic control of heterogeneous intervention responses. We conducted longitudinal phenotyping to characterize hundreds of traits, including lifespan, in the CC mice. We demonstrate that sex and genetic background induce variable responses to intermittent fasting across multiple physiological outcomes, including metabolic, hematologic, and immunologic health. Effects of IF on lifespan were sex-specific and variable across genetic backgrounds. Thus we establish that response to IF is genetically determined in an animal model with physiological features similar to humans. We compared our findings in the CC with those from a parallel study of Diversity Outbred (DO) mice, highlighting common predictors of health and lifespan, as well as key differences between the genetically diverse inbred and outbred models. These findings underscore the importance of genetic factors in dietary intervention responses, offering valuable insights for translating intermittent fasting benefits to human health and longevity.

Cancer risk increases with age, and cellular senescence may be a major contributor to cellular carcinogenesis. Enormous efforts have been made to investigate the interrelation between aging and tumors, but little is known about the comparative features of normal aging, cellular senescence, and cancer at single-cell resolution. By integrating analyses of genomics, epigenomics, and bulk and single-cell transcriptomics, we revealed a directionally opposite transcriptional profile between cellular senescence and tumorigenesis at the single-cell level, which may be affected by epigenomic regulations. A total of 648 aging-dependent senescence-associated coregulated modules (SACMs), disproportionately affecting the reproductive systems of both females and males, were initially defined across 17 tissues. Single-cell analysis revealed that aging primarily affects endothelial cells, followed by T cells, epithelial cells, macrophages, and fibroblasts. Opposite directions of change in gene expression between aging and cancer can commonly be observed in endothelial, fibroblast, and epithelial cells, which may prompt the opposing patterns of gene expression between tissue aging and epithelial carcinoma at the bulk level. A similar pattern of expression can be observed in immune cells, which are characterized by decreased self-renewal with aging, but this pattern is reversed in epithelial carcinoma. Our study highlighted the role of senescence as a natural barrier against tumor formation and supported the idea that aging-related systemic environment changes create a protumorigenic milieu.

The circadian rhythm is a key biological mechanism that aligns organisms' physiological processes with Earth's 24-h light-dark cycle, crucial for cellular and tissue homeostasis. Disruption of this system is linked to accelerated aging and age-related diseases. Central to circadian regulation is the CLOCK protein, which controls gene transcription related to tissue homeostasis, cellular senescence, and DNA repair. Research reveals CLOCK's dual role: in normal cells, it supports rejuvenation by activating DNA repair factors like XPA and modulating metabolism; in tumor cells, CLOCK signaling is often hijacked by oncogenic drivers like c-MYC and Pdia3, which inhibit telomere shortening / cellular senescence, thereby fostering uncontrolled proliferation and tumorigenesis. Additionally, gut microbiota-derived aryl hydrocarbon receptor (AhR) signals can disrupt the CLOCK-BMAL1 complex, affecting circadian rhythms. CLOCK also interacts with mTOR and NF-κB pathways to regulate autophagy and mitigate harmful secretions impacting tissue function. This review examines the molecular links between CLOCK and cellular senescence, drawing from animal and human studies, to highlight CLOCK's role in aging and its potential as a target for anti-aging therapies.

The microstructural architecture of white matter supporting information flow across local circuits and large-scale networks changes throughout the lifespan. However, the genetic and cellular factors underlying age-related variations in white matter microstructure have yet to be established. Here, we examined the genetic associates of individual differences in diffusion-based measures of white matter in a population-based cohort (N=29,862) from the UK Biobank. Estimates of heritability from Genome-Wide Association Study (GWAS) data revealed that genetic factors are linked to population variability in 96.1% of 432 tract microstructural measures. The presence of shared genetic influences was observed to be greater within, relative to between, broad tract classes (commissural, association, projection, and complex cerebellar). Age associations with microstructural changes were estimated across diffusivity measures, with association class tracts showing the greatest vulnerability to age-related decline in older adults. Analyses of imputed cellular associates of age-related changes in white matter revealed a preferential relationship with cell gene markers of oligodendrocytes and other glial cell types, with sparse relationships observed for inhibitory and excitatory cells. These data indicate that white matter tract microstructure is shaped by genetic factors and suggest a role for glial cell-related transcripts in late-life changes in the structural wiring properties of the human brain.

Aging is widely regarded as an irreversible arrest of cellular growth and proliferation, often accompanied by systemic metabolic organ abnormalities, ultimately reducing quality of life and increasing mortality in the elderly. Multi-organ transcriptomic analyses suggest that adipose tissue is among the earliest organs to respond to aging, characterized by changes in fat content and redistribution of adipose tissue, decline in thermogenic adipose function, reduced proliferation and differentiation capacity of adipose progenitor and stem cells, accumulation of senescent cells, and immunosenescence. These alterations may act synergistically and play a role in abnormalities in metabolic organs including the cardiovascular, liver, skeletal muscle, and brain. Studies have demonstrated that exercise ameliorates the effects of adipose tissue aging on metabolic organ abnormalities by inhibiting inflammation, reducing the accumulation of ectopic lipids, enhancing the browning of white adipose tissue and thermogenesis in brown adipose tissue, improving lipid metabolism, regulating the secretion of adipokines, and mitigating immunosenescence. This review summarizes the main characteristics of adipose tissue aging, the effects of adipose tissue aging on metabolic organ abnormalities, and the potential mechanisms by which exercise ameliorates the effects of adipose tissue aging on metabolic organ abnormalities. It provides theoretical support for basic and clinical research on exercise-based prevention and treatment of aging-related diseases.

Although the brain's structural and functional alterations with age are individually well documented, how differences in cognitive abilities emerge from variations in the underlying spatio-temporal patterns of regional brain activity is largely unknown. Patterns of increased synchronization between brain regions are taken as enhanced cognitive integration, while decreased synchronization is indicative of cognitive segregation. The ability to dynamically switch between different levels of integration and segregation across different cognitive systems is believed to be crucial for overall cognitive performance. Building on a recently proposed cognitively informed, synchronization-based framework, we study here age-related variations in dynamical flexibility between segregation and integration, as captured by changes in the variable patterns of partial synchronization or chimera states. Leveraging personalized brain network models based on large-scale, multisite datasets of cross-sectional healthy cohorts, we systematically show how regional brain stimulation produces distinct patterns of synchronization. We find that chimera states play a crucial role in regulating the balance between cognitive integration and segregation as the brain ages, providing new insights into the mechanisms underlying cognitive decline and preservation in aging. Whereas the emergent synchronization behavior of brain regions belonging to the same cognitive system often show the same aging trends, different cognitive systems can demonstrate distinct trends. This supports the idea that aging affects cognitive systems differently and that understanding this variability is essential for a more comprehensive view of neuro-cognitive aging. At the same time, dynamical flexibility increases in the oldest age groups across most cognitive systems. This may reflect compensatory mechanisms to counteract age-related cognitive declines and points towards a phenomenon of dedifferentiation. Yet, the multiplicity of behaviors highlights that whereas dedifferentiation emerges in certain cognitive systems, differentiation can also occur in others. This illustrates that these processes, though seemingly oppositional, can coexist and unfold in parallel across different cognitive systems.

The sex chromosome aneuploidies Turner syndrome (45,X; TS) and Klinefelter syndrome (47,XXY; KS) are associated with aging-related comorbidities, reduced life expectancy and genome-wide DNA methylation changes. This indicates that biological aging, reflecting physiological function rather than chronological age, is increased in both syndromes. To investigate whether DNA methylation patterns linked to physiological decline could contribute to the comorbidity patterns and reduced lifespan in TS and KS, we applied so-called epigenetic clocks to DNA methylation data from cohorts of TS (n = 57) compared to female controls (n = 33) and KS (n = 65) compared to male controls (n = 63). Additionally, we evaluated correlations between epigenetic age and clinical variables, aiming to identify clinical aging markers in TS and KS.

Aging is the foremost risk factor for metabolic syndrome and atherosclerosis, which is a principal cause of cardiovascular diseases (CVDs). Vascular endothelial cells (ECs), which line the vascular intima, play a central role in maintaining vascular homeostasis. Their dysfunction, marked by impaired barrier function, inflammation, and metabolic dysregulation, constitutes an early and pivotal event in atherogenesis. As key sensors of hemodynamic forces, ECs are constantly exposed to blood flow-induced shear stress, which exert divergent effects on metabolism depending on the flow pattern. Laminar flow with relatively high shear stress (LS), as a critical atheroprotective factor, maintains EC quiescence and promotes anti-inflammatory responses and antioxidant defense, whereas disturbed flow with low and oscillatory shear stress (OS), induces the athero-susceptible signaling network to activate glycolysis and inflammation in ECs. While genetic, epigenetic, and molecular signaling mechanisms in EC physiology and pathophysiology have been extensively explored, the crucial role of EC metabolism in EC dysfunction and atherogenesis remains largely understudied. By serving as precursors, intermediates, and end products of cellular processes, metabolites offer a dynamic snapshot of endothelial metabolic states under both physiological and pathophysiological conditions. With aging, ECs undergo profound metabolic reprogramming, including disrupted glycolysis, mitochondrial dysfunction, and altered redox homeostasis. In healthy vasculature, ECs maintain quiescence and metabolic homeostasis, primarily relying on glycolysis for energy. With aging, the gradual accumulation of atherosclerotic risk factors, including oxidative stress, inflammation, dyslipidemia, and hyperglycemia, drives metabolic reprogramming in ECs, particularly in regions exposed to disturbed flow with OS, ultimately leading to EC dysfunction and atherosclerosis. This review summarizes recent advances in age-related metabolic reprogramming in ECs and its contribution to atherosclerosis, particularly focusing on the dysregulation of glycolysis, fatty acid metabolism, amino acid metabolism, and mitochondrial respiration induced by age and fluid shear stress. This review also outlines recent methodologies for profiling EC metabolism, and discusses potential therapeutic applications of targeting EC metabolism to prevent or delay the development of atherosclerosis.

Progressive loss of vascular smooth muscle cells (VSMCs) is the pathophysiological basis for aortic aneurysm and dissection (AAD), a life-threatening disease, but the underlying mechanisms are largely unknown. Sirtuin 6 (SIRT6), a class III histone deacetylase, is critical for maintenance of VSMC homeostasis and prevention of vascular remodeling-related diseases. In this study, we investigated the role of VSMC SIRT6 in AAD and the molecular mechanism. We showed that the expression levels of SIRT6 were significantly reduced in VSMCs of the thoracic aorta in AAD patients. We constructed a VSMC-specific Sirt6 deficient mouse line and found that loss of Sirt6 in VSMCs dramatically accelerated angiotensin II (Ang II)-induced AAD formation and rupture, even without an Apoe-deficient background. In human aortic smooth muscle cells (HASMCs), knockdown of SIRT6 led to mitochondrial dysfunction and accelerated VSMC senescence. We revealed that SIRT6 bound to and deacetylated NRF2, a key transcription factor for mitochondrial biogenesis. However, Sirt6 deficiency inhibited NRF2 and reduced mRNAs encoding mitochondrial complex proteins. Notably, MDL-811, a newly developed small-molecule SIRT6 agonist, effectively reversed Ang II-induced mitochondrial dysfunction in HASMCs. In a BAPN-induced TAAD mouse model, administration of MDL-811 (20 mg/kg, i.p., every other day for 28 d) effectively mitigated AAD progression and reduced mortality. These results suggest that SIRT6 plays a protective role against AAD development, and targeting SIRT6 with small-molecule activators such as MDL-811 could represent a promising therapeutic strategy for AAD.

Proper control of mTOR (mechanistic/mammalian target of rapamycin) signaling is relevant for health, disease and ageing. Information from intra- and extra-cellular signaling cues is transmitted to mTOR through an intricate signaling network that impinges on the Rag and Rheb GTPases to regulate its localization and activity. Interestingly, although mTOR is a heavily ubiquitinated protein, the role of this post-translational modification (PTM) in regulating its activation status remains poorly understood. Here, through an unbiased RNAi screen, we identified the tumor suppressor CYLD deubiquitinase (DUB) as a direct negative regulator of both mTORC1 and mTORC2 activities. Mechanistically, CYLD interacts with mTOR and removes non-degradative, K63-linked ubiquitin (Ub) chains from multiple of its residues. Consequently, CYLD loss-of-function cells are characterized by mTORC1/2 hyperactivation, elevated rates of protein synthesis, increased cell size, and resistance to serum-starvation-induced activation of cell death pathways. Moreover, silencing of cyld-1, the C. elegans CYLD ortholog, fully reverses the extended lifespan of low-TORC1-activity mutant worms. Finally, we find that inactivation of CYLD is associated with hyperactivation of mTORC1 also in skin biopsies from CYLD cutaneous syndrome (CCS) patients. In sum, our findings highlight CYLD as a sentinel of mTOR hyperactivation via direct control of its ubiquitination, and suggest that dysregulated mTOR activity may contribute to the development and progression of CCS tumors.

Osteoarthritis is a prevalent joint disease in the aging population. The hallmark of osteoarthritis is the degeneration of the joint cartilage, characterized by changes in chondrocytes including mitochondrial dysfunction. However, the precise mechanisms of how this affects chondrocyte homeostasis and whether such processes can be explored as therapeutic targets for osteoarthritis remain unclear. Here, we show that impaired mitochondrial function and disrupted cartilage matrix metabolism due to loss of mitofusin-2 (MFN2) expression in chondrocytes leads to the development of osteoarthritis. Sirtuin-3 (SIRT3), a key regulator of mitochondrial function, plays a critical role in modulating MFN2 to restore mitochondrial dynamics, reduce fragmentation, and preserve mitochondrial function in chondrocytes. Specifically, SIRT3 directly deacetylates and indirectly deubiquitinates MFN2, preventing its degradation. MFN2-mediated mitochondrial-endoplasmic reticulum (ER) junctions support cellular homeostasis, alleviate ER stress, and maintain mitochondrial calcium ion balance, which collectively mitigate chondrocyte senescence. Extracellular vesicles engineered with MFN2 mRNA effectively prevented cartilage degeneration and restored mobility in osteoarthritic mice. These findings suggest that targeting MFN2 is a promising strategy to prevent cartilage degeneration and alleviate progression of osteoarthritis.