Longevity Papers

Biomarkers of ageing serve as important outcome measures in longevity-promoting interventions. However, there is limited consensus on which specific biomarkers are most appropriate for human intervention studies. This work aimed to address this need by establishing an expert consensus on biomarkers of ageing for use in intervention studies via the Delphi method. A three-round Delphi study was conducted using an online platform. In Round 1, expert panel members provided suggestions for candidate biomarkers of ageing. In Rounds 2 and 3, they voted on 500 initial statements (yes/no) relating to 20 biomarkers of ageing. Panel members could abstain from voting on biomarkers outside their expertise. Consensus was reached when there was ≥70% agreement on a statement/biomarker. Of the 460 international panel members invited to participate, 116 completed Round 1, 87 completed Round 2, and 60 completed Round 3. Across the 3 rounds, 14 biomarkers met consensus that spanned physiological (e.g., insulin-like growth factor 1, growth-differentiating factor-15), inflammatory (e.g., high sensitivity c-reactive protein, interleukin-6), functional (e.g., muscle mass, muscle strength, hand grip strength, Timed-Up-and-Go, gait speed, standing balance test, frailty index, cognitive health, blood pressure), and epigenetic (e.g., DNA methylation/epigenetic clocks) domains. Expert consensus identified 14 potential biomarkers of ageing which may be used as outcome measures in intervention studies. Future ageing research should identify which combination of these biomarkers has the greatest utility.

Fatty acid oxidation is of uncertain importance in most stem cells. We show by

Aging and age-related cognitive impairment have emerged as a growing global public health concern and remain no effective preventive strategies. Excessive oxidative stress and neuroinflammation have been proven to contribute to cognitive decline. Vitamin D maintains the redox balance and exerts immunomodulatory effects, but the specific role of vitamin D in aging and age-related cognitive impairment remains elusive. This study explored the neuroprotective effects and the potential molecular mechanisms of 1α,25-Dihydroxyvitamin D3 in the aging model. An aging model was established by the treatment of D-galactose for 14 weeks in Male KM mice. 0.1, 0.5, or 1 μg/kg 1α,25-Dihydroxyvitamin D3 were used in the intervention group for 8 weeks. Cognitive performance was evaluated using the Morris water maze test, and the levels of oxidative stress and neuroinflammation in the hippocampus were further analyzed. D-galactose induced memory impairment, whereas 1α,25-Dihydroxyvitamin D3 intervention prevented cognitive decline, accompanied by a reduction in neuronal apoptosis, an enhancement of synaptic plasticity, and a decrease in Aβ deposition. Meanwhile, 1α,25-Dihydroxyvitamin D3 dramatically attenuated oxidative stress, mitigated microglial cell activation, and ameliorated neuroinflammation by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (AREs) axis and inhibiting the NF-κB signaling pathway. This study provides evidence that 1α,25-Dihydroxyvitamin D3 might be a promising nutritional strategy for preventing cognitive decline in aging, thereby facilitating the clinical application and expanding the insight of vitamin D.

The distribution of time across physical activity, sedentary behaviors, and sleep appears to be essential for the management of obesity. However, the impact of reallocating time among these behaviors, collectively known as 24-h movement behaviors, remains underexplored.

Nicotinamide adenine dinucleotide (NAD

Cellular senescence connects aging and cancer. Cellular senescence is a common program activated by cells in response to various types of stress. During this process, cells lose their proliferative capacity and undergo distinct morphological and metabolic changes. Senescence itself constitutes a tumor suppression mechanism and plays a significant role in organismal aging by promoting chronic inflammation. Additionally, age is one of the major risk factors for developing breast cancer. Therefore, while senescence can suppress tumor development early in life, it can also lead to an aging process that drives the development of age-related pathologies, suggesting an antagonistic pleiotropic effect. In this work, we identified Rian/MEG8 as a potential biomarker connecting aging and breast cancer for the first time. We found that Rian/MEG8 expression decreases with age; however, it is high in mice that age prematurely. We also observed decreased MEG8 expression in breast tumors compared to normal tissue. Furthermore, MEG8 overexpression reduced the proliferative and stemness properties of breast cancer cells both in vitro and in vivo by activating apoptosis. MEG8 could exemplify the antagonistic pleiotropic theory, where senescence is beneficial early in life as a tumor suppression mechanism due to increased MEG8, resulting in fewer breast tumors at an early age. Conversely, this effect could be detrimental later in life due to aging and cancer, when MEG8 is reduced and loses its tumor-suppressive role.

Why people age at different rates is a fundamental, unsolved problem in biology. We created a model that predicts an individuals age from physiological traits that change with age in the large UK Biobank dataset, such as blood pressure, lung function, strength and stimulus- reaction time. The model best predicted a persons age when it heavily-weighted traits that together query multiple organ systems, arguing that most or all physiological systems (lung, heart, brain, etc.) contribute to the global phenotype of chronological age. Differences between calculated "biological" age and chronological age ({Delta}Age) appear to reflect an individuals relative youthfulness, as people predicted to be young for their age had a lower subsequent mortality rate and a higher parental age at death, even though no mortality data were used to calculate {Delta}Age. Remarkably, the effect of each year of physiological {Delta}Age on Gompertz mortality risk was equivalent to that of one chronological year. A Genome-Wide Association Study (GWAS) of {Delta}Age, and analysis of environmental factors associated with {Delta}Age identified known as well as new factors that may influence human aging, including genes involved in synapse biology and a tendency to play computer games. We identify a small number of readily measured physiological traits that together assess a persons biological age and may be used clinically to evaluate therapeutics designed to slow aging and extend healthy life.

Organ function declines with age, and large-scale transcriptomic analyses have highlighted differential aging trajectories across tissues. The mechanism underlying shared and organ-selective functional changes across the lifespan, however, still remains poorly understood. Given the central role of mitochondria in powering cellular processes needed to maintain tissue health, we therefore undertook a systematic assessment of respiratory activity across 33 different tissues in young (2.5 months) and old (20 months) mice of both sexes. Our high-resolution mitochondrial respiration atlas reveals: (1) within any group of mice, mitochondrial activity varies widely across tissues, with the highest values consistently seen in heart, brown fat, and kidney; (2) biological sex is a significant but minor contributor to mitochondrial respiration, and its contributions are tissue-specific, with major differences seen in the pancreas, stomach, and white adipose tissue; (3) age is a dominant factor affecting mitochondrial activity, especially across most brain regions, different fat depots, skeletal muscle groups, eyes, and different regions of the gastrointestinal tract; (4) age effects can be sex- and tissue-specific, with some of the largest effects seen in pancreas, heart, adipose tissue, and skeletal muscle; and (5) while aging alters the functional trajectories of mitochondria in a majority of tissues, some are remarkably resilient to age-induced changes. Altogether, our data provide the most comprehensive compendium of mitochondrial respiration and illuminate functional signatures of aging across diverse tissues and organ systems.

We present a novel method for routinely identifying disease resilience associations that offers powerful insights for the discovery of a new class of disease protective targets. We show how this can be used to identify mechanisms in the background of normal cellular biology that work to slow or stop progression of complex, chronic diseases. Actively protective combinatorial analysis identifies combinations of features that contribute to reducing risk of disease in individuals who remain healthy even though their genomic profile suggests that they have high risk of developing disease. These protective signatures can potentially be used to identify novel drug targets, pharmacogenomic and/or therapeutic mRNA opportunities and to better stratify patients by overall disease risk and mechanistic subtype. We describe the method and illustrate how it offers increased power for detecting disease-associated genetic variants relative to traditional methods. We exemplify this by identifying individuals who remain healthy despite possessing several disease signatures associated with increased risk of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or amyotrophic lateral sclerosis (ALS). We then identify combinations of SNP-genotypes significantly associated with reduced disease prevalence in these high-risk protected cohorts. We discuss how actively protective combinatorial analysis generates novel insights into the genetic drivers of established disease biology and detects gene-disease associations missed by standard statistical approaches such as meta-GWAS. The results support the mechanism of action hypotheses identified in our original causative disease analyses. They also illustrate the potential for development of precision medicine approaches that can increase healthspan by reducing the progression of disease.

The development of anti-aging drugs is challenged by both the apparent complexity of the physiological mechanisms involved in aging and the likelihood that many of these mechanisms remain unknown. As a consequence, the development of anti-aging compounds based on the rational targeting of specific pathways has fallen short of the goal. To date, the most impressive compound is rapamycin, a natural bacterial product initially identified as an antifungal, and only subsequently discovered to have anti-aging properties. In this review, we focus on two aminosterols from the dogfish shark, Squalus acanthias, that we discovered initially as broad-spectrum anti-microbial agents. This review is the first to gather together published studies conducted both in vitro and in numerous vertebrate species to demonstrate that these compounds target aging pathways at the cellular level and provide benefits in multiple aging-associated conditions in relevant animal models and in humans. The dogfish aminosterols should be recognized as potential anti-aging drugs.

Sarcopenia frequently occurs with aging and leads to major adverse impacts in elderly individuals. The protective effects of omega-3 polyunsaturated fatty acids against aging-related sarcopenia have been demonstrated; however, the effect and underlying mechanism of EPA or DHA alone remain inconclusive. Hence, the present study was aimed to clarify the differential effects and possible mechanisms of EPA and DHA on aging-related sarcopenia. In this study, two-month-old and eighteen-month-old male C57BL/6J mice were fed with an AIN-93M diet and an AIN-93M diet containing 1% EPA or 1% DHA for 24 weeks, respectively. The results revealed that EPA and DHA supplementation effectively alleviated the decline in grip strength, skeletal muscle mass, and myofiber cross-sectional areas in aged mice, with EPA exhibiting a better effect against aging-related sarcopenia than DHA. The ROS scavenging role of EPA in aged skeletal muscle was also superior to that of DHA. Additionally, EPA showed a stronger role in improving protein turnover and myogenesis in aged skeletal muscle, as evidenced by suppressing the activation of FoxO3a and NF-κB, blunting the expression levels of muscle atrophy markers MAFbx and MuRF1, activating the PI3K/Akt/mTOR signaling pathway, and elevating MyoD expression. Moreover, EPA also revealed a better effect on inhibiting mitochondria- and endoplasmic reticulum stress-mediated apoptosis in aged skeletal muscle. Furthermore, EPA manifested a more pronounced effect on improving mitochondrial damage of aged skeletal muscle than DHA, and the reason might be due to its superior capability of regulating mitochondrial quality control, as clearly shown by enhancing mitochondrial biogenesis through the AMPK/PGC-1α-dependent pathway, restraining the loss of mitochondrial fusion and fission proteins including Opa1, Mfn2, and Fis1, and promoting mitophagy

Work in many systems has shown large-scale changes in gene expression during aging. However, many studies employ just two, arbitrarily-chosen timepoints at which to measure expression, and can only observe an increase or a decrease in expression between young and old animals, failing to capture any dynamic, non-linear changes that occur throughout the aging process. We used RNA sequencing to measure expression in male head tissue at 15 timepoints through the lifespan of an inbred Drosophila melanogaster strain. We detected >6,000 significant, age-related genes, nearly all of which have been seen in previous fly aging expression studies, and which include several known to harbor lifespan-altering mutations. We grouped our gene set into 28 clusters via their temporal expression change, observing a diversity of trajectories; some clusters show a linear change over time, while others show more complex, non-linear patterns. Notably, re-analysis of our dataset comparing the earliest and latest timepoints mimicking a two-timepoint design revealed fewer differentially-expressed genes (around 4,500). Additionally, those genes exhibiting complex expression trajectories in our multi-timepoint analysis were most impacted in this re-analysis; Their identification, and the inferred change in gene expression with age, was often dependent on the timepoints chosen. Informed by our trajectory-based clusters, we executed a series of gene enrichment analyses, identifying enriched functions/pathways in all clusters, including the commonly seen increase in stress- and immune-related gene expression with age. Finally, we developed a pair of accessible shiny apps to enable exploration of our differential expression and gene enrichment results.

We fit ongoing 40+-year mark-recapture databases from the thriving southern right whale (SRW),

Accumulation of DNA damage can accelerate aging through cellular senescence. Previously, we established a Drosophila model to investigate the effects of radiation-induced DNA damage on the intestine. In this model, we examined irradiation-responsive senescence in the fly intestine. Through an unbiased genome-wide association study (GWAS) utilizing 156 strains from the Drosophila Genetic Reference Panel (DGRP), we identified meltrin {beta} (the drosophila orthologue of mammalian ADAM19) as a potential modulator of the senescence-associated secretory phenotype (SASP). Knockdown of meltrin {beta} resulted in reduced gut permeability, DNA damage, and expression of the senescence marker {beta}-galactosidase (SA-{beta}-gal) in the fly gut following irradiation. Additionally, inhibition of ADAM19 in mice using batimastat-94 reduced gut permeability and inflammation in the gut. Our findings extend to human primary fibroblasts, where ADAM19 knockdown or pharmacological inhibition decreased expression of specific SASP factors and SA-{beta}-gal. Furthermore, proteomics analysis of the secretory factor of senescent cells revealed a significant decrease in SASP factors associated with the ADAM19 cleavage site. These data suggest that ADAM19 inhibition could represent a novel senomorphic strategy.

Cellular senescence is a multifaceted process marked by irreversible cell cycle arrest in response to stressors such as DNA damage, oxidative stress, and telomere shortening, leading to significant cellular and mitochondrial alterations. These changes impact mesenchymal stem cell (MSC) function, affecting their differentiation, self-renewal, and regenerative abilities. Senescent MSCs adopt the senescence-associated secretory phenotype (SASP), characterized by the secretion of pro-inflammatory factors that propagate senescence to neighboring cells. Key features of senescent MSCs include altered morphology, reduced proliferative and differentiation capacity, and changes in their secretome. Mitochondrial dysfunction plays a central role in this process, impairing stemness, increasing oxidative stress, and contributing to cellular aging by generating reactive oxygen species (ROS). The chapter provides an overview of various methods to analyze senescent cells, including techniques to detect changes in cell proliferation, DNA damage, apoptosis, and mitochondrial function. It also highlights assays for mitochondrial alterations such as fluorescent staining, membrane potential analysis, and mitophagy evaluation. These tools are essential for understanding the complex mechanisms of cellular senescence and mitochondrial dysfunction, offering insights into aging and potential therapeutic strategies.

Dysregulated Wnt signaling causes age-related characteristics such as oxidative stress, stem cell senescence, and abnormal bone homeostasis. Here we explored whether supplemental n-acetyl-l-cysteine (NAC) recovers the age-associated complications relative to osteoblastic Wntless (Wls) ablation and examined the possible mechanisms therein. For this work, we administered Col2.3-Cre;Wls

An important hallmark of aging is the loss of proteostasis, which can lead to the formation of protein aggregates and mitochondrial dysfunction in neurons. Although it is well known that protein synthesis is finely regulated in the brain, especially at synapses, where mRNAs are locally translated in activity-dependent manner, little is known as to the changes in the synaptic proteome and transcriptome during aging. Therefore, this work aims to elucidate the relationship between transcriptome and proteome at soma and synaptic level during aging. Proteomic and transcriptomic data analysis reveal that, in young animals, proteins and transcripts are correlated and synaptic regulation is driven by changes in the soma. During aging, there is a decoupling between transcripts and proteins and between somatic and synaptic compartments. Furthermore, soma-synapse gradient of ribosomal genes changes upon aging, i.e. ribosomal transcripts are less abundant and ribosomal proteins are more abundant in synaptic compartment of old mice with respect to younglings. Additionally, transcriptomics data highlight a difference in the splicing of certain synaptic mRNA with aging. Taken together, our data provide a valuable resource for the study of the aging synapse.

Cellular senescence is a condition characterized by stable, irreversible cell cycle arrest linked to the aging process. The accumulation of senescent cells in the cardiac muscle can contribute to various cardiovascular diseases (CVD). Telomere shortening, epigenetic modifications, DNA damage, mitochondrial dysfunction, and oxidative stress are known contributors to the onset of cellular senescence in the heart. The link between mitochondrial processes and cellular senescence contributed to the age-related decline in cardiac function. These include changes in mitochondrial functions and behaviours that arise from various factors, including impaired dynamics, dysregulated biogenesis, mitophagy, mitochondrial DNA (mtDNA), reduced respiratory capacity, and mitochondrial structural changes. Thus, regulation of mitochondrial biology has a role in cellular senescence and cardiac function in aging hearts. Targeting senescent cells may provide a novel therapeutic approach for treating and preventing CVD associated with aging. CYP epoxygenases metabolize N-3 and N-6 polyunsaturated fatty acids (PUFA) into epoxylipids that are readily hydrolyzed to diol products by soluble epoxide hydrolase (sEH). Increasing epoxylipids levels or inhibition of sEH has demonstrated protective effects in the aging heart. Evidence suggests they may play a role in cellular senescence by regulating mitochondria, thus reducing adverse effects of aging in the heart. In this review, we discuss how mitochondria induce cellular senescence and how epoxylipids affect the senescence process in the aged heart.

The geroscience hypothesis proposes that underlying biological processes, such as the accumulation of senescent cells, have deleterious effects on multiple tissues and increase the risk of many chronic conditions with aging. Senescent cells produce heterogenous biomarkers, also called senescence-associated secretory phenotype (SASP). Circulating concentrations of senescence biomarkers may reflect an underlying burden of senescent cells in various tissues. Plasma levels of these proteins have been associated with increased mortality and poorer physical function. The associations of them with the incidence of major age-related conditions including heart failure, cardiovascular disease, stroke, and dementia, have not been studied. We measured 35 senescence biomarkers in baseline plasma samples from 1678 participants aged 70-79 years old in the longitudinal Health ABC cohort study. Clinical outcomes were ascertained and validated over an average 11.5 year follow-up. In models adjusted for age, sex, and race, higher levels of most of senescence biomarkers were associated with increased risk of all-cause mortality, mobility limitation, and heart failure. Several were also associated with an increased risk of coronary heart disease, stroke, and dementia. Very few were associated with the risk of cancer. Proteins that were selected by Lasso regression for each outcome that commonly included GDF15 and IL6, significantly improved the prediction of mortality, mobility limitation, and heart failure compared with age, sex, and race alone. These results indicate that levels of senescence biomarkers predict an increased risk of several age-related clinical outcomes and may identify individuals most likely to benefit from senotherapeutics.

Studies using mitophagy reporter mice have established steady-state landscapes of mitochondrial destruction in mammalian tissues, sparking intense interest in basal mitophagy. Yet how basal mitophagy is modified by healthy aging in diverse brain cell types has remained a mystery. We present a comprehensive spatiotemporal analysis of mitophagy and macroautophagy dynamics in the aging mammalian brain, reporting critical region- and cell-specific turnover trajectories in a longitudinal study. We demonstrate that the physiological regulation of mitophagy in the mammalian brain is cell-specific, dynamic and complex. Mitophagy increases significantly in the cerebellum and hippocampus during midlife, while remaining unchanged in the prefrontal cortex (PFC). Conversely, macroautophagy decreases in the hippocampus and PFC, but remains stable in the cerebellum. We also describe emergent lysosomal heterogeneity, with subsets of differential acidified lysosomes accumulating in the aging brain. We further establish midlife as a critical inflection point for autophagy regulation, which may be important for region-specific vulnerability and resilience to aging. By mapping

Autophagy is a vital cellular process responsible for the degradation of proteins, organelles, and other cellular components within lysosomes. In neurons, basal autophagy is indispensable for maintaining cellular homeostasis and protein quality control. Accordingly, lysosomal dysfunction has been proposed to be associated with neurodegeneration, and with Parkinson's disease (PD) in particular. Aging, dopamine metabolism, and PD-linked genetic mutations are thought to impair the autophagic-lysosomal pathway, disrupt cellular proteostasis, and contribute to PD pathogenesis. These alterations represent an opportunity to identify potential new therapeutic targets and disease biomarkers, thus laying the groundwork for the development of novel disease-modifying strategies for PD that are aimed at restoring cellular proteostasis and quality control systems.

Deciphering the complex interplay between neuronal activity and mitochondrial function is pivotal in understanding brain aging, a multifaceted process marked by declines in synaptic function and mitochondrial performance. Here, we identified an age-dependent coupling between neuronal and synaptic excitation and mitochondrial DNA transcription (E-TC

Climate change introduces greater thermal variability, profoundly affecting ectothermic species whose body temperatures rely heavily on the environment. Understanding the physiological and metabolic responses to such variability is crucial for predicting how these species will cope with changing climates. This study investigates how chronic thermal stress impacts mitochondrial metabolism and physiological parameters in Drosophila melanogaster, hypothesizing that a fluctuating thermal regime (FTR) activates protective mechanisms enhancing stress tolerance and longevity. To test this, Drosophila were exposed to constant 24°C or to an FTR of 24°C/15°C day/night cycle following an initial 5-day period at 24°C. The FTR group exhibited rapid transcript level changes after the first day of FTR, particularly those related to heat shock proteins, mitophagy and regulatory factors, which returned to initial levels after 5 days. Mitochondrial respiration rates initially decreased after 1 and 2 days of FTR, then recovered by Day 5, indicating rapid acclimation. Enhanced antioxidant enzyme activities were observed early in the FTR group, after 1 day for mtSOD and SODcyt+ext and 3 days for both SOD and catalase, followed by a decline by Day 5, suggesting efficient oxidative stress management. The FTR group showed lower CTmax on Day 3, reflecting possible physiological strain at that time point, and complete recovery by Day 5. Longevity increased under FTR, highlighting the activation of protective mechanisms with beneficial long-term effects. These suggest that FTR prompts a temporal succession of rapid physiological adjustments at different levels of organisation, enhancing long-term survival in D. melanogaster.

Mitochondria are versatile and complex organelles that can continuously communicate and interact with the cellular milieu. Deregulated communication between mitochondria and host cells/organelles has significant consequences and is an underlying factor of many pathophysiological conditions, including the process of aging. During aging, mitochondria lose function, and mitocellular communication pathways break down; mitochondrial dysfunction interacts with mitochondrial dyscommunication, forming a vicious circle. Therefore, strategies to protect mitochondrial function and promote effective communication of mitochondria can increase healthy lifespan and longevity, which might be a new treatment paradigm for age-related disorders. In this review, we comprehensively discuss the signal transduction mechanisms of inter- and intracellular mitochondrial communication, as well as the interactions between mitochondrial communication and the hallmarks of aging. This review emphasizes the indispensable position of inter- and intracellular mitochondrial communication in the aging process of organisms, which is crucial as the cellular signaling hubs. In addition, we also specifically focus on the status of mitochondria-targeted interventions to provide potential therapeutic targets for age-related diseases.

Ageing of the endometrium is a critical factor that affects reproductive health, yet its intricate mechanisms remain poorly explored. In this study, we performed transcriptome profiling and experimental verification of endometrium and endometrial organoids from young and advanced age females, to elucidate the underlying mechanisms and to explore novel treatment strategies for endometrial ageing. First, we found that age-associated decline in endometrial functions including fibrosis and diminished receptivity, already exists in reproductive age. Subsequently, based on RNA-seq analysis, we identified several changes in molecular processes affected by age, including fibrosis, imbalanced inflammatory status including Th1 bias in secretory phase, cellular senescence and abnormal signalling transduction in key pathways, with all processes been further validated by molecular experiments. Finally, we uncovered for the first time that PI3K-AKT-FOXO1 signalling pathway is overactivated in ageing endometrium and is closely correlated with fibrosis and impaired receptivity characteristics of ageing endometrium. Blocking or activation of PI3K by LY294002 or 740Y-P could attenuate the effect of ageing or accelerate dysfunction of endometrial organoids. This discovery is expected to bring new breakthroughs for understanding the pathophysiological processes associated with endometrial ageing, as well as treatment strategies to improve reproductive outcomes in women of advanced reproductive age.

Extracellular vesicles (EVs) play crucial roles in aging. In this National Institutes on Aging-funded study, we sought to identify circulating extracellular vesicle (EV) biomarkers indicative of longevity. The plasma EV proteome of 48 older adults (mean age 77.2 ± 1.7 years [range 72-80]; 50% female, 50% Black, 50% < 2-year survival, 50% ≥ 10-year survival) was analyzed by high-resolution mass spectrometry and flow cytometry. The ability of EV peptides to predict longevity was evaluated in discovery (n = 32) and validation (n = 16) datasets with areas under receiver operating characteristic curves (AUCs). Longevity-associated large EV (LEV) plasma subpopulations were mainly related to immune cells (HLA-ABC

Cellular senescence is a pivotal contributor to aging and age-related diseases. The targeted elimination of senescent cells, known as senolysis, has emerged as a promising therapeutic strategy for mitigating these conditions. Glutaminase 1 (GLS1), a key enzyme in the glutaminolysis pathway, has been implicated in various cellular senescence processes. However, its specific role in senescent renal tubular epithelial cells (TECs) remains unclear. This study investigates the role and underlying mechanisms of GLS1 in senescent TECs. Using D-galactose (D-gal)-induced senescence of HK-2 cells, we found that GLS1 inhibition eliminated senescent TECs by promoting excessive mitochondrial permeability transition pore (mPTP) opening. Mechanistically, the excessive mPTP opening is associated with upregulation of mitofusin 1 (MFN1). Inhibition of GLS1 in D-gal-treated HK-2 cells induced a shift in mitochondrial dynamics from fission to fusion, accompanied by a significant increase in MFN1 expression. Knocking down MFN1 reduced the mPTP opening and the expression of mPTP-related genes (PPIF, VDAC and BAX) in cells co-treated with D-gal and the GLS1 inhibitor BPTES. Moreover, treatment of aged mice with BPTES specifically eliminated senescent TECs and ameliorated age-associated kidney disease. These findings reveal that GLS1 inhibition eliminate senescent TECs by promoting excessive mPTP opening, suggesting that targeting GLS1 may be a novel senolytic strategy for alleviating aging-related kidney diseases.

Fish telomere lengths vary significantly across the numerous species, implicating diverse life strategies and environmental adaptations. Zebrafish have telomere dynamics that are comparable to humans and are emerging as a key model in which to unravel the systemic effects of telomere shortening on aging and interorgan communication. Here, we discuss zebrafish telomere biology, focusing on the organismal impact of telomere attrition beyond cellular senescence, with particular emphasis on how telomeric shortening in specific tissues can unleash widespread organ dysfunction and disease. This highlights a novel aspect of tissue communication, whereby telomere shortening in one organ can propagate through biological networks, influencing the aging process systemically. These discoveries position zebrafish as a valuable model for studying the complex interactions between telomeres, aging, and tissue cross talk, providing important insights with direct relevance to human health and longevity.

Extensive accumulation of senescent cells contributes to organismal aging, and slowing down the process of cellular senescence may ameliorate age-related pathologies. Targeted inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) is found to suppress the conversion of cells to senescence. The regulatory-associated protein of mTOR (Raptor), a key component of mTORC1, has been implicated as important in the aging process, and its druggability deserves to be investigated. Due to high efficiency and high convenience in drug construction, siRNA shows great potential in silencing Raptor expression via RNA interfering therapy. Here, we developed a functionalized anti-aging nanoplatform based on tetrahedral DNA nanostructures (TDNs) encapsulating siRNA targeting Raptor for synergistic anti-aging therapy, named siR-TDN

Drugs that eliminate senescent cells, senolytics, can be powerful when combined with prosenescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a pyroptosis-apoptosis-necroptosis (PAN)optosis-like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis. Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death receptor 5 via Jun N-terminal protein kinase (JNK) pathway activation. We show that a combination of a death receptor 5 (DR5) agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent natural killer (NK) and CD8+ T cell-mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine interleukin 18 (IL18).

Unfit cells with defective signalling or gene expression are eliminated through competition with neighbouring cells. However, physiological roles and mechanisms of cell competition in vertebrates remain unclear. In addition, universal mechanisms regulating diverse cell competition are unknown. Using zebrafish imaging, we reveal that cell competition ensures robust patterning of the spinal cord and muscle through elimination of cells with unfit sonic hedgehog activity, driven by cadherin-mediated communication between unfit and neighbouring fit cells and subsequent activation of the Smad-Foxo3-reactive oxygen species axis. We identify Foxo3 as a common marker of loser cells in various types of cell competition in zebrafish and mice. Foxo3-mediated physiological cell competition is required for eliminating various naturally generated unfit cells and for the consequent precise patterning during zebrafish embryogenesis and organogenesis. Given the implication of Foxo3 downregulation in age-related diseases, cell competition may be a defence system to prevent abnormalities throughout development and adult homeostasis.

Cellular senescence (CS) is a hallmark of Alzheimer's disease (AD). However, the mechanisms through which CS contributes to AD pathogenesis remain poorly understood. We found that CS level in AD was higher compared with the healthy control group. Transcriptome-based differential expression analysis identified 113 CS-related genes in blood and 410 in brain tissue as potential candidate genes involved in AD. To further explore the causal role of these genes, an integrative mendelian randomization analysis was conducted, combining AD genome-wide association study summary statistics with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) data from blood samples, which identified five putative AD-causal genes (CENPW, EXOSC9, HSPB11, SLC44A2, and SLFN12) and 18 corresponding DNA methylation probes. Additionally, integrative analysis between eQTLs and mQTLs from blood uncovered two genes and 12 corresponding regulatory elements involved in AD. Furthermore, two genes (CDKN2B and ITGAV) were prioritized as putative causal genes in brain tissue and were validated through in vitro experiments. The multi-omics integration study revealed the potential role and underlying biological mechanisms of CS driven by genetic predisposition in AD. This study contributed to fundamental understanding of CS in AD pathogenesis and facilitated the identification of potential therapeutic targets for AD prevention and treatment.

Calorie restriction (CR) and physical exercise (EX) are well-established interventions known to extend health span and lifespan in animal models. However, their impact on human biological aging remains unclear. With recent advances in omics technologies and biological age (BioAge) metrics, it is now possible to assess the impact of these lifestyle interventions without the need for long-term follow-up. This study compared BioAge biomarkers in 41 middle-aged and older adult long-term CR practitioners, 41 age- and sex-matched endurance athletes (EX), and 35 sedentary controls consuming Western diets (WD), through PhenoAge: a composite score derived from nine blood-biomarkers. Additionally, a subset of participants (12 CR, 11 EX, and 12 WD) underwent multi-omic profiling, including DNA methylation and RNAseq of colon mucosa, blood metabolomics, and stool metagenomics. A group of six young WD subjects (yWD) served as a reference for BioAge calculation using Mahalanobis distance across six omic layers. The results demonstrated consistently lower BioAge biomarkers in both CR and EX groups compared to WD controls across all layers. CR participants exhibited lower BioAge in gut microbiome and blood-derived omics, while EX participants had lower BioAge in colon mucosa-derived epigenetic and transcriptomic markers, suggesting potential tissue-specific effects. Multi-omic pathway enrichment analyses suggested both shared and intervention-specific mechanisms, including oxidative stress and basal transcription as common pathways, with ether lipid metabolism uniquely enriched in CR. Despite limitations due to sample size, these findings contribute to the broader understanding of the potential anti-aging effects of CR and EX, offering promising directions for further research.

In this paper, we advance the network theory of aging and mortality by developing a causal mathematical model for the mortality rate. First, we show that in large networks, where health deficits accumulate at nodes representing health indicators, the modeling of network evolution with Poisson processes is universal and can be derived from fundamental principles. Second, with the help of two simplifying approximations, which we refer to as mean-field assumption and homogeneity assumption, we provide an analytical derivation of Gompertz law under generic and biologically relevant conditions. We identify the parameters in Gompertz law as a function of the parameters driving the evolution of the network, and illustrate our computations with simulations and analytic approximations.

Evidence that life-extending interventions are not uniformly effective across the lifespan calls for an analytic tool that can estimate age-specific treatment effects on mortality hazards. Here we report such a tool, applying it to mouse data from 42 compounds tested in the NIA Interventions Testing Program. This tool identified agents that either reduced (22) or increased (15) mortality hazards or did both (2) in at least one sex, most with marked variation in the duration of efficacy and magnitude of effect size. Only 8 reduced mortality hazards after 90% mortality, when the burden of senescence is the greatest. Sex differences were common. This new analytic tool complements the commonly used log-rank test. It detects more potential life-extending candidates (22 versus 10) and indicates when during the life course they are effective. It also uncovers adverse effects.

Small non-coding RNAs (sncRNAs), particularly microRNAs (miRNAs), play an important role in transcriptome regulation by binding to mRNAs and post-transcriptionally inhibiting protein production. This regulation occurs in both physiological and pathological conditions, where the expression of many miRNAs is altered. Previous reports by our group and others have demonstrated that miRNA expression is also altered during aging. However, most studies have analyzed human peripheral blood samples or brain samples from animal models, leaving a gap in knowledge regarding miRNA expression in the human brain. In this work, we analyzed the expression of sncRNAs from coronal sections of human hippocampal samples, a tissue with a high vulnerability to deleterious conditions such as aging. Samples from young (n = 5, 27-49 years old), old (n = 8, 58-88 years old), and centenarian (n = 3, 97, 99, and 100 years old) individuals were included. Our results reveal that sncRNAs, particularly miRNAs, are differentially expressed (DE) in the human hippocampus with aging. Besides, miRNA-mediated regulatory networks revealed significant interactions with mRNAs deregulated in the same hippocampal samples. Surprisingly, 80% of DE mRNA in the centenarian vs. old comparison are regulated by hsa-miR-192-5p and hsa-miR-3135b. Additionally, validated hsa-miR-6826-5p, hsa-let-7b-3p, hsa-miR-7846, and hsa-miR-451a emerged as promising miRNAs that are deregulated with aging and should be further investigated.

Chaperone-mediated autophagy (CMA) is the lysosomal degradation of individually selected proteins, independent of vesicle fusion. CMA is a central part of the proteostasis network in vertebrate cells. However, CMA is also a negative regulator of anabolism, and it degrades enzymes required for glycolysis,

Targeting senescent cells and the factors that accelerate this pathological state has recently emerged as a novel field in medicinal chemistry. As attention shifts to synthetic substances, studies on natural agents are often overlooked. In this paper, we present a detailed computational modeling study that encompasses quantum mechanics and molecular dynamics to elucidate the senotherapeutic activity of fisetin. The mitochondrial environment, serving as a proxy for senescence, received special attention. Throughout the study, fisetin's outstanding geroprotective properties-exhibiting significant potential against •OOH, O2•-, and •OH radicals, surpassing those of Trolox or ascorbate-were identified. Furthermore, fisetin demonstrated a high capacity to restore oxidatively damaged biomolecules to their pristine forms, thereby renewing the functionality of proteins and amino acids. The senolytic properties were examined in terms of Bcl-2 and Bcl-xL inhibition. The results indicated that fisetin not only binds effectively to these proteins but also, with appropriate modifications, may exhibit specific selectivity toward either target. This study highlights fisetin's remarkable activity in these areas and provides a molecular description of the underlying processes, paving the way for future research.

Chronic inflammation is a hallmark of aging and contributes to many age-associated diseases. Metabolic intervention is a strategy to modulate inflammation. However, the connection between inflammation and metabolism during aging remains poorly understood. A mechanism driving chronic inflammation involves cytoplasmic chromatin fragments (CCFs), which appear in senescent cells and aged tissues, activating the cGAS-STING pathway. The size of the CCFs exceeds the capacity of the nuclear pore complex, raising the question of how chromatin fragments enter the cytoplasm. Here, we report that chromatin fragments exit the nucleus via nuclear egress, a membrane trafficking process at the nuclear envelope that shuttles large complexes from the nucleus to the cytoplasm. Inactivating critical nuclear egress ESCRT-III or Torsin proteins results in accumulation of chromatin fragments at the nuclear membrane, thereby impairing the activation of cGAS-STING and senescence-associated inflammation. Notably, nuclear egress of CCFs is inhibited by glucose limitation or metformin treatment. This is due to AMPK phosphorylation and autophagic degradation of the ESCRT-III component, ALIX. Metformin treatment in naturally aged mice downregulates ALIX protein and blocks cGAS activation and chronic inflammation in the small intestine. Together, our study defines a central mechanism linking nutrient sensing and chronic inflammation, two distinct hallmarks of aging, and suggests a new approach to suppress age-associated inflammation by targeting the nuclear egress of chromatin fragments.

Mesenchymal stem/stromal cells (MSCs) are becoming increasingly important for biomedical applications, such as cell therapy, disease modeling, and drug screening. At the same time, long-term cultivation, which is necessary to prepare a sufficient amount of cellular material for therapeutic and research purposes, is accompanied by the development of replicative senescence. Partial reprogramming emerged as a novel method that shows promising results in the rejuvenation of cells in vitro and in vivo; however, it has not yet been applied for human MSCs that have undergone replicative senescence in culture. In the present study, we subjected senescent human endometrial MSCs to partial reprogramming using Sendai virus vectors containing genes encoding Yamanaka transcription factors Oct4, Sox2, Klf4, and c-Myc. Characterization of the MSCs 5 days after transduction showed the loss of key markers of senescence: the youthful morphology was restored, the expression of senescent-associated β-galactosidase and the number of double-strand DNA breaks decreased, proliferation was activated, and the DNA damage response was enhanced. Further, using an in vitro wound-healing assay, we demonstrated that conditioned medium from partially reprogrammed MSCs showed higher therapeutic activity than that from senescent cells. However, a biosafety test revealed the presence of viral components in conditioned medium, which caused the agglutination of erythrocytes. Collectively, our data suggest that partial reprogramming is a potentially effective strategy for the rejuvenation of cultured MSCs in late passages but requires the use of virus-free protocols, such as chemical reprogramming.

Estimators of biological age hold promise for use in preventive medicine, for early detection of chronic conditions, and for monitoring the effectiveness of interventions aimed at improving population health. Among the promising biomarkers in this field are DNA methylation-based biomarkers, commonly referred to as epigenetic clocks. This review provides a survey of these clocks, with an emphasis on second-generation clocks that predict human morbidity and mortality. It explores the validity of epigenetic clocks when considering factors such as race, sex differences, lifestyle, and environmental influences. Furthermore, the review addresses the current challenges and limitations in this research area.

Telomeres are DNA-protein structures that primarily protect chromosomes and serve multiple functions of gene regulation. When cells divide, telomeres shorten and their main repair system in ectotherms - telomerase - replaces lost nucleotide complexes ((T2AG3)n in vertebrates). It remains a challenge to experimentally investigate resource requirements for telomere maintenance and its effects on lifespan-reproductive tradeoffs in the wild. In sand lizards (Lacerta agilis), we show that higher female investments into reproduction results in corresponding shortening of telomeres and that males have less frequent and less profound telomere shortening than females; a contributing factor to this may be males' higher telomerase levels. To manipulate resource access for telomere maintenance, we exploit a pseudo-experimental opportunity to analyze 'onboard' resources long-term using lizards that drop their tails with fat and nutrient deposits when attacked by predators. Females with less resources due to regrown tails less often and less profoundly elongate telomeres. Adult lizards with the most TL elongation live the longest, females with the highest lifetime reproductive success shorten telomeres the most, whereas males with the most telomere elongation have the highest lifetime reproductive success. This suggests ongoing evolution of resource-constrained telomere maintenance.

Mosaic loss of Y chromosome (mLOY) is an acquired condition wherein a sizeable proportion of an organ's cells have lost their Y. Large-scale cohort studies have shown that mLOY is age-dependent and a strong risk factor for all-cause mortality and adverse outcomes of age-related diseases. Emerging multi-omics approaches that combine gene expression, epigenetic and mutational profiling of human LOY cell populations at single-cell levels, and contemporary work in in vitro cell and preclinical mouse models have provided important clues into how mLOY mechanistically contributes to disease onset and progression. Despite these advances, what has been missing is a system-level insight into mLOY. By integrating the most recent advances in wide-ranging aspects of mLOY research, we summarize a unified model to understanding the cause and consequence of mLOY at the molecular, cellular, and organismal levels. This model, referred to as the "Unstable Y Cascade model," states that (i) the rise and expansion of LOY result from interaction by the inherently unstable Y, germline genetic and epigenetic variants, and numerous cell-intrinsic and external factors; (ii) LOY initiates genomic, epigenomic, and transcriptomic alterations in X and autosomes, thereafter induces a cascade of tissue-specific cellular alterations that contribute locally to the onset and progression of diseases; and (iii) LOY cells exert paracrine effects to non-LOY cells, thereby amplifying LOY-associated pathological signaling cascades to remote non-LOY cells. This new model has implications in the development of therapeutic interventions that could prevent or delay age-related diseases via mitigating mLOY burden.

Age-dependent changes in DNA methylation allow chronological and biological age inference, but the underlying mechanisms remain unclear. Using ultra-deep sequencing of >300 blood samples from healthy individuals, we show that age-dependent DNA methylation changes are regional and occur at multiple adjacent CpG sites, either stochastically or in a coordinated block-like manner. Deep learning analysis of single-molecule patterns in two genomic loci achieved accurate age prediction with a median error of 1.46-1.7 years on held-out human blood samples, dramatically improving current epigenetic clocks. Factors such as gender, BMI, smoking and other measures of biological aging do not affect chronological age inference. Longitudinal 10-year samples revealed that early deviations from epigenetic age are maintained throughout life and subsequent changes faithfully record time. Lastly, the model inferred chronological age from as few as 50 DNA molecules, suggesting that age is encoded by individual cells. Overall, DNA methylation changes in clustered CpG sites illuminate the principles of time measurement by cells and tissues, and facilitate medical and forensic applications.

The critical role of some RAB family members in oocyte meiosis has been extensively studied, but their role in oocyte aging remains poorly understood. Here, we report that the vesicle trafficking regulator, RAB9 GTPase, is essential for oocyte meiosis and aging in humans and mice. RAB9 was mainly located at the meiotic spindle periphery and cortex during oocyte meiosis. In humans and mice, we found that the RAB9 protein level were significantly increased in old oocytes. Age-related accumulation of RAB9 inhibits first polar body extrusion and reduces the developmental potential of oocytes. Further studies showed that increased Rab9 disrupts spindle formation and chromosome alignment. In addition, Rab9 overexpression disrupts the actin cap formation and reduces the cortical actin levels. Mechanically, Rab9-OE increases ROS levels, decreases mitochondrial membrane potential, ATP content and the mtDNA/nDNA ratio. Further studies showed that Rab9-OE activates the PINK1-PARKIN mitophagy pathway. Importantly, we found that reducing RAB9 protein expression in old oocytes could partially improve the rate of old oocyte maturation, ameliorate the accumulation of age-related ROS levels and spindle abnormalities, and partially rescue ATP levels, mtDNA/nDNA ratio, and PINK1 and PARKIN expression. In conclusion, our results suggest that RAB9 is required to maintain the balance between mitochondrial function and meiosis, and that reducing RAB9 expression is a potential strategy to ameliorate age-related deterioration of oocyte quality.

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

Within a species, larger individuals often have shorter lives and higher rates of age-related disease. Despite this well-known link, we still know little about underlying age-related epigenetic differences, which could help us better understand inter-individual variation in aging and the etiology, onset, and progression of age-associated disease. Dogs exhibit this negative correlation between size, health, and longevity and thus represent an excellent system in which to test the underlying mechanisms. Here, we quantified genome-wide DNA methylation in a cohort of 864 dogs in the Dog Aging Project. Age strongly patterned the dog epigenome, with the majority (66% of age-associated loci) of regions associating age-related loss of methylation. These age effects were non-randomly distributed in the genome and differed depending on genomic context. We found the LINE1 (long interspersed elements) class of TEs (transposable elements) were the most frequently hypomethylated with age (FDR < 0.05, 40% of all LINE1 regions). This LINE1 pattern differed in magnitude across breeds of different sizes- the largest dogs lost 0.26% more LINE1 methylation per year than the smallest dogs. This suggests that epigenetic regulation of TEs, particularly LINE1s, may contribute to accelerated age and disease phenotypes within a species. Since our study focused on the methylome of immune cells, we looked at LINE1 methylation changes in golden retrievers, a breed highly susceptible to hematopoietic cancers, and found they have accelerated age-related LINE1 hypomethylation compared to other breeds. We also found many of the LINE1s hypomethylated with age are located on the X chromosome and are, when considering X chromosome inactivation, counter-intuitively more methylated in males. These results have revealed the demethylation of LINE1 transposons as a potential driver of inter-species, demographic-dependent aging variation. Statements and declarationsNone. No competing interests.

Aflatoxin B1 (AFB1), a known human carcinogen, represents the most toxic aflatoxin metabolite. Exposure to AFB1 causes increased oxidative stress and immunotoxicity, which are important factors contributing to aging. However, the role of AFB1-induced toxicity in altered innate immunity and aging remains largely unclear. The nematode Caenorhabditis elegans is a suitable model organism for studying aging and toxicology due to its well-studied molecular mechanisms and short life cycle. Effects of AFB1 at 1, 2.5, and 5 μM (312, 781, and 1561 μg/L) on growth, reproduction, and lifespan were examined. The Pseudomonas aeruginosa PA14 slow-killing assay was performed to investigate innate immunity, followed by studying the possible mechanisms using transgenic strains and qPCR analysis. The results showed that early life long-term AFB1 exposure (2.5 and 5 μM) delayed development, reduced reproduction, and shortened lifespan in C. elegans. Furthermore, in aged worms, AFB1 exposure caused a dose-dependent decrease in survival of C. elegans against P. aeruginosa PA14 infection. At adulthood day 4 in the presence of live Escherichia coli OP50, AFB1 (2.5 μM) significantly increased lipofuscin levels (a hallmark of aging) compared to adult day 0, whereas no increase in lipofuscin was observed in nematodes (adulthood day 4) fed with dead E. coli OP50. Additionally, the increased lipofuscin was abolished in the skn-1 mutant with either live or dead E. coli OP50. Furthermore, AFB1 suppressed intestinal SKN-1::GFP translocation. Two-way ANOVA analysis revealed that the activity of E. coli OP50 and AFB1 interactively affected the expression of genes: skn-1, gst-4, hsp-16.1, hsp-16.49, and hsp-70. Our findings highlight the role of AFB1-induced toxicity in altered innate immunity and aging through the involvement of the transcription factor SKN-1/Nrf2.

Primary age-related tauopathy (PART) and Alzheimers disease (AD) share hippocampal phospho-tau (p-tau) pathology but differ in p-tau extent and {beta}-amyloid presence. As a result, PART uniquely enables investigation of amyloid-independent p-tau mechanisms during brain aging. We conducted an epigenome-wide association (EWAS) study of PART, nominating 13 new and robust p-tau/methylation associations. We then jointly analyzed PART and AD epigenomes to develop novel epigenetic clocks, "TauAge", that predict p-tau severity in region-specific, age-, and {beta}-amyloid-independent manners. Integrative transcriptomic analyses revealed that genes involved in synaptic transmission are related to hippocampal p-tau severity in both PART and AD, while neuroinflammatory genes are related to frontal cortex p-tau severity in AD only. Further, a machine learning classifier trained on PART-vs-AD epigenetic differences stratifies an independent cohort of neuropathologically indeterminate cases into pathological subgroups with disparity in cognitive impairment. Together, these findings demonstrate the brain epigenomes substantial role in linking tau pathology to cognitive outcomes in aging and AD.

With the rapid development of immunological techniques in recent years, our understanding of immune senescence has gradually deepened, but the role of immune senescence in cancer biology remains incompletely elucidated. Understanding these mechanisms and interactions is crucial for the development of tumor biology. This review examines five key areas: the classification and main features of immune senescence, factors influencing immune cell senescence in cancer, the reciprocal causal cycle between immune senescence and malignancy, and the potential of immune senescence as a target for cancer immunotherapy.

The mitochondrial genome (mtDNA) is an important source of inherited extranuclear variation. Clonal increases in mtDNA mutation heteroplasmy have been implicated in aging and disease, although the impact of this shift on cell function is challenging to assess. Reprogramming to pluripotency affects mtDNA mutation heteroplasmy. We reprogrammed three human fibroblast lines with known heteroplasmy for deleterious mtDNA point or deletion mutations. Quantification of mutation heteroplasmy in the resulting 76 induced pluripotent stem cell (iPSC) clones yielded a bimodal distribution, creating three sets of clones with high levels or absent mutation heteroplasmy with matched nuclear genomes. iPSC clones with elevated deletion mutation heteroplasmy show altered growth dynamics, which persist in iPSC-derived progenitor cells. We identify transcriptomic and metabolic shifts consistent with increased investment in neutral lipid synthesis as well as increased epigenetic age in high mtDNA deletion mutation iPSC, consistent with changes occurring in cellular aging. Together, these data demonstrate that high mtDNA mutation heteroplasmy induces changes occurring in cellular aging.

The Retinoblastoma (RB) protein is crucial for regulating gene transcription and chromatin remodeling, impacting cell cycle progression, cellular senescence, and tumorigenesis. Cellular senescence, characterized by irreversible growth arrest and phenotypic alterations, serves as a vital barrier against tumor progression and age-related diseases. RB is crucial in mediating senescence and tumor suppression by modulating the RB-E2F pathway and cross talking with other key senescence effectors such as p53 and p16

Microbial infectivity increases with rising environmental temperature, heightening the risk of infection to host organisms. The host's basal immunity is activated accordingly to mitigate upcoming pathogenic threats; still, how animals sense temperature elevation to adjust their preventive immune response remains elusive. This study reports that high temperature enhances innate immunity differently from pathogen infection. Unlike pathogen invasion requiring the mitochondrial unfolded protein response (UPR), high temperature engages the endoplasmic reticulum (ER) UPR to trigger the innate immune response. Furthermore, chronic activation of the XBP-1 UPR branch represses nucleolar ribosome biogenesis, a highly energy-consuming process, leading to lipid accumulation. The subsequent increase in oleic acid promotes the activation of the PMK-1 immune pathway. Additionally, ribosome biogenesis was identified as a regulator of longevity, wherein its impact is dependent on lipid metabolism and innate immunity. Collectively, our findings reveal the crucial role of ER-nucleolus crosstalk in shaping preventive immune responses and lifespan regulation.

To unravel the causes and effects of aging we can monitor the time-evolution of the aging process and learn how it is structured by genetic and environmental variation before ultimately testing theories about the causal drivers of aging. Diverse Outbred (DO) mice provide widespread, yet controlled, genetic variation generating considerable variation in mouse lifespan - here, we explore the relationship between DO mouse aging and lifespan. We profiled the plasma multiome of 110 DO mice at three ages using liquid chromatography - mass spectrometry (LC-MS)-based metabolomics and lipidomics and proteomics. Individual mice varied more than two-fold in natural lifespan. The combination of known age and resulting lifespan allows us to evaluate alternative models of how molecules were related to chronological age and lifespan. The majority of the aging multiome shifts with chronological age highlighting the accelerating chemical stress of aging. In contrast, proteomic pathways encompassing both well-appreciated aspects of aging biology, such as dysregulation of proteostasis and inflammation, as well as lesser appreciated changes such as through toll-like receptor signaling, shift primarily with fraction of life lived (the ratio of chronological age to lifespan). This measure, which approximates biological age, varies greatly across DO mice creating a global disconnect between chronological and biological age. By sampling mice near their natural death we were able to detect loss-of-homeostasis signatures involving focal dysregulation of proteolysis and the secreted phosphoproteome which may be points-of-failure in DO aging. These events are succeeded by massive changes in the multiome in mices final three weeks as widespread cell death reshapes the plasma of near-death mice.