Longevity Papers

Aging in females predominantly impacts the ovaries before any other organ systems. This phenomenon is closely linked to a gradual depletion of the ovarian follicle reserve and a notable diminishment of oocyte quality. Studies have shown that cellular changes within ovaries can manifest even before the observable depletion of ovarian follicles. To understand the molecular mechanisms underlying these changes, we have conducted a comprehensive analysis of the changes in gene expression in aging mouse ovaries. Using efficient genomics software such as CLC Genomic Workbench, we could detect not only the differentially expressed genes but also delineate the various transcript variants present in the transcriptome of aging ovaries. We verified the results by comparing coding sequences of selected transcripts with the coding sequences of their canonical counterparts from young and aged mice. In general, the analysis methods yielded similar observations. Our findings revealed that traditional gene expression analyses often overlook the differential expression of numerous transcript variants. We identified significant alterations in the expression patterns of alternative transcripts in aging ovaries and found coding sequences that lead to profound functional outcomes. Notably, most of these differentially expressed transcript variants were affected upstream epigenetically and transcriptionally, then generated through alternative splicing events. This suggests that aging may lead to alterations in RNA-binding proteins and spliceosome components, which play a crucial role in mRNA processing within the mouse ovary. Our observations highlight the necessity of focusing on transcript variants and their functions in aging research, as they provide a more nuanced understanding of the biological processes at play.

Theobromine, a commonly consumed dietary alkaloid derived from cocoa, has been linked to extended lifespan in model organisms and to health benefits in humans. We examined associations between circulating theobromine intake, measured using serum metabolomics, and blood-based epigenetic markers of biological ageing in two European human population-based cohorts. Serum theobromine levels were significantly associated with reduced epigenetic age acceleration, as measured by GrimAge (p<2e-7) and DNAmTL (p<0.001) in over 500 individuals from the TwinsUK cohort, and both signals replicated in 1,160 individuals from the KORA cohort (p = 7.2e-08 and p = 0.007, respectively). Sensitivity analyses including covariates of other cocoa and coffee metabolites suggest that the effect is specific to theobromine. Our findings indicate that the reported beneficial links between theobromine intake on health and ageing extend to the molecular epigenetic level in humans.

Intermittent fasting and fasting-refeeding regimens can slow biological aging across taxa. Shifts between fed and fasted states activate ancient nutrient-sensing pathways which alter cellular and epigenetic states to promote longevity. Yet how biological age trajectories progress during fasting-refeeding, and how nutrient-sensing pathways reprogram epigenetic state remain largely unknown. Here we observe increases in predicted biological age of Caenorhabditis elegans during prolonged fasting in adult reproductive diapause, followed by extraordinary reduction of biological age during refeeding. We identify hil-1/H1-0 as an evolutionarily conserved nutrient-regulated linker histone which mediates adaptations to fasting and refeeding downstream of FOXO and TFEB transcription factors. In C. elegans and human cell culture, hil-1/H1-0 upregulation during low-nutrient states promotes long-term survival and subsequent refeeding-induced recovery. Restoration of C. elegans after prolonged fasting is improved by enhancing the natural downregulation of hil-1 specifically during refeeding. Our study identifies HIL-1/H1.0 as part of an ancestral epigenetic switch during fasting-refeeding that reprograms metabolic and cellular states underlying resilience and restoration.

Non-lethal exposure to mitochondrial stress has been shown to have beneficial effects due to activation of signalling pathways, including the mitochondrial unfolded protein response (UPRmt). Activation of UPRmt restores function of the mitochondria and improves general health and longevity in multiple model systems, termed mitohormesis. In C. elegans, mitohormesis can be accomplished by electron transport chain inhibition, decline in mitochondrial translation, decreased mitochondrial import, and numerous other methods that activate UPRmt. However, not all methods that activate UPRmt can promote longevity. These and other studies have started to question whether UPRMT is directly correlated with longevity. Here, we attempt to address this controversy by unravelling the complex molecular regulation of longevity of the nematode under different mitochondrial stressors that induce UPRmt by performing RNA-sequencing to profile transcriptome changes. Using this comprehensive and unbiased approach, we aim to determine whether specific transcriptomic changes can reveal a correlation between UPRmt and longevity. Altogether this study will provide mechanistic insights on mitohormesis and how it correlates with lifespan of C. elegans.

Efficient clearance of central nervous system (CNS) waste proteins and appropriate immune surveillance is essential for brain health. These processes are facilitated by lymphatic networks present in the meninges that drain cerebrospinal fluid (CSF). Age-related impairments to meningeal lymphatic drainage contribute to CNS waste accumulation and immune dysfunction, yet the underlying mechanisms remain poorly understood. Here, we identify extracellular matrix (ECM) remodeling in the aged dura as a key driver of CSF clearance deficits, demonstrating that peri-lymphatic collagen accumulation disrupts lymphatic function. Exploring immune-derived factors contributing to this ECM remodeling, we identify transforming growth factor beta 1 (TGFβ1) as a major regulator using primary human dural fibroblasts. Using a novel mouse model with constitutively active TGFβ receptor 1 (TGFβR1) signaling in dural fibroblasts, we show that excessive peri-lymphatic collagen deposition impairs meningeal lymphatic drainage and alters meningeal immunity. Mechanistically, we reveal that ECM-associated matrix stiffness disrupts lymphatic junction integrity and impairs lymphangiogenesis in human lymphatic endothelial cells. These findings establish dural immune cell and fibroblast-mediated ECM remodeling as a critical regulator of CSF clearance and highlight it as a potential therapeutic target for restoring brain waste clearance in aging.

Nicotinamide adenine dinucleotide (NAD) is a key coenzyme involved in cell metabolism associated with aging, cancer, neurodegenerative diseases and metabolic disorders. We recently showed that NAD

Aging is frequently associated with dysregulated lipid metabolism, while exercise may improve metabolic health, a process in which microRNAs (miRNAs) play a pivotal regulatory role. However, the specific modulation of miRNA expression profiles by different exercise modalities remains poorly characterized. This study aimed to investigate adipose tissue miRNA profiles in aged rats following high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). Eighteen-month-old female rats were divided into three groups (n = 12/group): sedentary (SED), MICT, and HIIT. After 8 weeks of exercise interventions, metabolic outcomes were assessed using Oil Red O staining to quantify intracellular lipid deposition, alongside Western blotting, immunofluorescence, and RT-qPCR to evaluate mRNA and protein expression of adipose tissue markers. Additionally, miRNA sequencing was performed on visceral adipose tissue to identify differentially expressed miRNAs (DEMs), followed by bioinformatic prediction of miRNA-mRNA interactions. Key findings revealed that the HIIT group exhibited more pronounced metabolic benefits compared to MICT, including reduced lipid accumulation (fewer Oil Red O-positive adipocytes) and upregulated expression of lipolytic and autophagy-related proteins (ATGL, HSL, PPAR-γ, ATG3, ATG5, ATG7, ATG12, and ATG16L). miRNA sequencing demonstrated greater divergence in expression profiles between HIIT and SED groups than between MICT and SED groups. KEGG pathway analysis highlighted significant enrichment in the MAPK, PI3K-Akt, and Rap1 signaling pathways. Furthermore, 11 DEMs (e.g., miR-34a, miR-146a) were identified as potential regulators of adipose aging, with hub genes including Shc1, Grb2, Itgb1, Ptpn11, Mapk14, Fyn, Plcg1, Sos1, and Actg1. In conclusion, HIIT significantly ameliorates age-related adipocyte inflammation and metabolic dysfunction. Exercise-induced miRNA reprogramming may alleviate the functional decline of aged adipose tissue, and HIIT-induced miRNA reprogramming is more abundant. The miRNA sequencing data pinpoint critical regulatory genes and pathways, providing novel insights into the molecular mechanisms by which exercise counteracts metabolic abnormalities in aged adipose tissue.

Background and ObjectivesWhile hearing loss is a known risk factor for dementia, the impact of incident hearing loss on subsequent dementia risk remains underexplored. This study examined the association between newly reported hearing loss and dementia risk in U.S. adults, focusing on critical intervention periods for dementia prevention.Research Design and MethodsParticipants from the Health and Retirement Study who reported no hearing loss or hearing aid use in 2010 or 2012 were included. Incident hearing loss and dementia were assessed via self-report and proxy report. Pooled logistic regression models with inverse probability weighting estimated the cumulative incidence of dementia at 2, 4, 6, and 8 years after baseline. Risk ratios (RR) with 95% confidence intervals were calculated from 200 bootstrap samples. Subgroup analyses were conducted by age, sex, and cardiovascular disease (CVD) status.ResultsAmong 13,599 participants, 1125 (8.3%) reported incident hearing loss. Dementia incidence was higher among those with hearing loss (6.6%) compared to those without (4.9%). Starting at 4 years, incident hearing loss was associated with a higher dementia risk, persisting at 8 years (RR = 1.34; 95% CI: 1.05, 1.59). This association was significant among individuals aged 50-64 years and those with CVD.Discussion and ImplicationsIncident hearing loss is associated with a heightened dementia risk, particularly in midlife and among individuals with CVD. Future research should investigate the effectiveness of timely interventions aimed at preventing dementia in individuals with hearing loss.

Low-quality oocytes directly affect fertilization and embryonic development, contributing to infertility in women, while germ cell senescence leads to reduced germ cell numbers and decreased egg quality. Dasatinib and quercetin (D and Q), as senolytic drugs, have been extensively explored in different age-related diseases. However, their effects on in vitro cultured senescent oocytes and the molecular mechanisms underpinning ovarian aging remain elusive. Here, we report that a nano-encapsulated senolytic D + Q cocktail efficiently improves the quality of post-ovulatory aging oocyte in vitro and follicle quantity in ovaries in a cyclophosphamide (Cy)-induced premature ovarian failure (POF) mouse model. Cocktail supplementation to cultured oocytes potently reduces reactive oxygen species (ROS) levels, maintains spindle integrity, decreases fragmented oocyte frequencies, rescues mislocalized cortical granules (CGs) and mitochondrial membrane potential (MMP), and alleviates DNA damage and apoptosis. Importantly, the cocktail effectively ameliorates fertility deficits in the model. Transcriptome analysis shows cocktail administration to fertility-deficient mice not only up-regulates developmental gene expression but also reduces senescence-associated secretory phenotype (SASP) accumulation. Therefore, our nano-encapsulated D + Q cocktail is a promising reagent for assisted reproductive technology and improving reproductive outcomes in POF.

Stem cells play a crucial role in maintaining tissue regenerative capacity and homeostasis. However, mechanisms associated with stem cell senescence require further investigation. In this study, we conducted a proteomic analysis of human dental pulp stem cells (HDPSCs) obtained from individuals of various ages. Our findings showed that the expression of NUP62 was decreased in aged HDPSCs. We discovered that NUP62 alleviated senescence-associated phenotypes and enhanced differentiation potential both in vitro and in vivo. Conversely, the knocking down of NUP62 expression aggravated the senescence-associated phenotypes and impaired the proliferation and migration capacity of HDPSCs. Through RNA-sequence and decoding the epigenomic landscapes remodeled induced by NUP62 overexpression, we found that NUP62 helps alleviate senescence in HDPSCs by enhancing the nuclear transport of the transcription factor E2F1. This, in turn, stimulates the transcription of the epigenetic enzyme NSD2. Finally, the overexpression of NUP62 influences the H3K36me2 and H3K36me3 modifications of anti-aging genes (HMGA1, HMGA2, and SIRT6). Our results demonstrated that NUP62 regulates the fate of HDPSCs via NSD2-dependent epigenetic reprogramming.

T cell aging contributes to the lower vaccine efficacy in older adults, yet the molecular mechanism remains elusive. Here, we show the density of initially responding naïve CD4

Hematopoietic aging is characterized by diminished stem cell regenerative capacity and an increased risk of hematologic dysfunction. We previously identified that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) regulates hematopoietic stem cell activity. Here, we expand on this work and demonstrate that in aged mice, (1) 15-PGDH expression and activity remain conserved in the bone marrow and spleen, suggesting it remains a viable therapeutic target in aging, (2) prolonged PGDH inhibition (PGDHi) significantly increases the frequency and number of phenotypic hematopoietic stem and progenitor cells across multiple compartments, with transcriptional changes indicative of enhanced function, (3) PGDHi-treated bone marrow enhances short-term hematopoietic recovery following transplantation, leading to improved peripheral blood output and accelerated multilineage reconstitution, and (4) PGDHi confers a competitive advantage in primary hematopoietic transplantation while mitigating age-associated myeloid bias in secondary transplants. Notably, these effects occur without perturbing steady-state blood production, suggesting that PGDHi enhances hematopoiesis under regenerative conditions while maintaining homeostasis. Our work identifies PGDHi as a translatable intervention to rejuvenate aged HSCs and mitigate hematopoietic decline.

Telomeric Repeat-Containing RNA (TERRA) is a class of noncoding RNAs (ncRNAs) emanating from telomeres and control telomere dynamics. Recent studies showed that TERRAs influence chromatin structure and gene expression. TERRAs can also play a crucial role in controlling inflammation, oxidative stress, DNA damage, and cellular senescence. This review article discussed the significance of TERRAs in modulating these processes, particularly in CNS. While our understanding of TERRAs largely stems from cancer research, their involvement in these physiologic and pathologic pathways highlights their potential as therapeutic targets for CNS disorders as well.

Glycation is a class of modifications arising from non-enzymatic reactions of reducing sugars with proteins, lipids, and/or DNA, generating advanced glycation end-products (AGEs). AGEs are linked to many age-related comorbidities. In response to HIV-1 infection, activated T-cells and macrophages shift their predominate metabolism from oxidative phosphorylation to glycolysis. Increased glycolytic flux enhances AGE formation, which may increase age-related comorbidities. In this prospective, multicenter cohort study of antiretroviral therapy treated people with HIV, we explored predictive associations by baseline plasma AGE concentrations and their corresponding detoxification metabolites, with incident comorbidities and mortality. AGEs included dicarbonyl sugars: 3-deoxyglucosone, glyoxal, and methylglyoxal. Methylglyoxal-derived metabolites included carboxyethyl-arginine, carboxyethyl-lysine, and methylglyoxal hydroimidazolone-1. Detoxification metabolites included reduced and oxidized glutathione, and the glyoxalase cycle products lactoyl-glutathione and lactoyl-Lysine modified proteins. Plasma was collected at study entry, in the fasting state, and assayed by liquid chromatography-mass spectroscopy. Incident clinical outcomes included diabetes, chronic kidney disease, hypertension, neurocognitive impairment, peripheral neuropathy, frailty, fractures, recurrent falls, and all-cause mortality. Among 376 participants, higher baseline plasma concentrations of methylglyoxal derived AGEs predicted increased risks of diabetes, chronic kidney disease, and recurrent falls, while higher 3-deoxyglucosone predicted an increased risk of peripheral neuropathy. By contrast, higher baseline concentrations of reduced or oxidized glutathione, lactoyl-glutathione, and/or lactoyl-Lysine modified proteins predicted lower risks of diabetes, neurocognitive impairment, frailty, fractures, recurrent falls, and all-cause mortality. These findings support growing experimental evidence of the potential to mitigate age-related declines by interventions that reduce glycation or increase glutathione.

Peripheral arterial disease is a common vascular disease in the elderly. Therapeutic revascularization, including angiogenic and arteriogenic therapy, is a promising treatment approach for peripheral arterial disease. However, the progress of clinical trials is not ideal, possibly due to insufficiency of preclinical models, such as not taking into account the effect of aging on vascular regeneration. Macrophages are crucial in angiogenesis and arteriogenesis. The aging microenvironment typically makes recruited monocytes and macrophages more susceptible to senescence. However, the feature of macrophages in ischemic hindlimb muscle of old individuals and their underlying role remains unclear. In this study, we reveal that macrophages of ischemic skeletal muscle in old mice are more senescent and proinflammatory. By transplanting macrophages into mice following hindlimb ischemia, we find senescent macrophages inhibit revascularization. Mechanistically, these senescent macrophages induce endothelial dysfunction via increasing vascular endothelial growth factor A-165B (VEGF-A165B) expression and secretion, and eventually impair revascularization. Notably, plasma VEGF-A165B levels are elevated in old patients with PAD and positively associated with a lower ankle brachial index (ABI). Our study suggests that targeting the senescent macrophages presents an avenue to improve age-related revascularization damage.

Machine learning has emerged as a valuable tool in precision medicine and aging research. Here, we introduce the autonomic age gap, a novel metric quantifying the individual deviation between machine-learning-estimated biological age and chronological age, based on autonomic nervous system function. We collected high-resolution electrocardiograms and continuous blood pressure recordings at rest from 1,012 healthy individuals. From these signals, 29 autonomic indices were extracted, encompassing time-, frequency-, and symbol-domain heart rate variability, cardiovascular coupling, pulse wave dynamics, and QT interval features. Based on those parameters, a Gaussian process regression model was trained on 879 participants to estimate chronological age referred to as autonomic age. The model was used to estimate the deviation from expected healthy aging, the autonomic age gap, in an independent validation set and two test sets stratified by cardiovascular risk (CVR) using the Framingham. The was evaluated via the autonomic age gap. High CVR individuals had a significantly increased autonomic age gap of 9.7 years compared to the low CVR group and the validation set. In contrast, the low CVR group had a negative age gap of -2.2 years on average. Predictions in the validation sample closely matched calendar age with a deviation below 0.5 years. Additionally, in the high-risk group, the slope of predicted versus actual age suggested accelerated physiological aging. These findings highlight the autonomic age gap as a sensitive and interpretable marker of cardiovascular risk and aging, offering potential clinical utility for early risk detection and longitudinal health monitoring.

Aging leads to progressive decline in the functions of cells, tissues, and organs, severely affecting muscle performance and overall health, highlighting the urgent need for effective therapeutic agents. This study investigated the antiaging properties of tricin, a flavonoid abundant in grains, using biological models, including human fibroblasts,

Aging results from the gradual accumulation of molecular damage as a result of cellular processes and is characterized by impaired functions, most notably an age-related decline in ATP production. However, the causal relationship between cellular ATP homeostasis and aging has not been established. In this study, we employed a nucleotide transporter from a eukaryotic intracellular parasite to directly alter ATP levels in budding yeast cells and exchange it with the extracellular milieu. We found that ATP depletion significantly shortens lifespan, whereas supplementation of the medium with ATP fully restores it. Analysis of gene expression showed inhibition of catabolic processes suggesting that increased ATP suppresses glucose metabolism. Our results also showed that ATP supplementation leads to lifespan extension. Overall, our study revealed the direct impact of cellular ATP homeostasis on the regulation of lifespan. This work offers new insights into the bioenergetic control of aging and positions energy metabolism as a promising target for longevity interventions.

Per- and polyfluoroalkyl substances (PFASs) can impact various systems in the human body. However, their influence on biological aging remains unclear. This study aims to investigate the association between PFASs exposure and biological aging based on data from 9756 participants in the China National Human Biomonitoring Program and assesses the potential moderating effect of Dietary Diversity Score (DDS). Biological age indexes were calculated using the Klemera-Doubal method (KDM) and Mahalanobis distance (MD). The DDS was calculated based on the consumption frequency of 13 food groups over the past 12 months. Most PFASs showed positive associations with KDM-age acceleration (KDM-AA), while no statistically significant associations were observed with MD. The dose-response relationships of PFASs with KDM-AA and MD were steeper at low concentrations of PFASs, and then the slope appeared flat at higher concentrations. The weighted quantile sum revealed positive mixture effects of PFASs on biological aging. PFHpS and PFNA were both major contributors to KDM-AA and MD. DDS appeared to potentially modify the association between PFASs and biological aging. Our findings demonstrate that PFASs were significantly associated with accelerated biological aging, whereas higher DDS mitigates these adverse effects, highlighting the importance of this preventive measure.

Environmental enrichment (EE) represents a robust experimental framework exploring the intricate interplay between genes and the environment in shaping brain development and function. EE is recognized as a non-invasive intervention, easily translatable to elderly human cohorts, and extrapolated from research on animal aging models. Age is the most important risk factor for ischemic stroke. Research indicates that EE, characterized by increased sensory, cognitive, and social stimulation, leads to structural changes in the brain, such as enhanced dendritic complexity and synaptic density, particularly in the hippocampus and cortex. Tailored EE interventions for elderly stroke survivors include cognitively stimulating activities and participation in social groups. These interventions enhance cognitive function and support recovery by promoting neural repair. Additionally, EE helps to mitigate sensory deficits commonly observed in older adults, ultimately improving mental performance and quality of life. EE has shown promise in preventing relapse, enhancing attention, reducing anxiety, forestalling age-related DNA methylation alterations, and amplifying neurogenesis through heightened neural progenitor cell (NPC) populations. Aligning preclinical studies with clinical trials can enhance neurorehabilitation conditions for stroke patients, thereby optimizing the environments in which they recover. This can be achieved through the concerted efforts of multidisciplinary teams working collaboratively. This review explores how EE specifically impacts the aging brain and ischemic stroke, a major age-related neurological disorder with global health implications. The potential of enviro-mimetics and relevant clinical studies on EE's effects on ischemic stroke survivors are discussed. This review enhances our understanding of the effects of EE on aging and ischemic stroke, motivating further research aimed at refining strategies for stroke management and recovery.

Mitochondrial quality control (MQC) is a critical mechanism for maintaining mitochondrial function and cellular metabolic homeostasis, playing an essential role in the self-renewal, differentiation, and long-term stability of hematopoietic stem cells (HSCs). Recent research highlights the central importance of MQC in HSC biology, particularly the roles of mitophagy, mitochondrial biogenesis, fission, fusion and mitochondrial transfer in regulating HSC function. Mitophagy ensures the removal of damaged mitochondria, maintaining low levels of reactive oxygen species (ROS) in HSCs, thereby preventing premature aging and functional decline. Concurrently, mitochondrial biogenesis adjusts key metabolic regulators such as mitochondrial transcription factor A (TFAM) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) to meet environmental demands, ensuring the metabolic needs of HSCs are met. Additionally, mitochondrial transfer, as an essential form of intercellular material exchange, facilitates the transfer of functional mitochondria from bone marrow stromal cells to HSCs, contributing to damage repair and metabolic support. Although existing studies have revealed the significance of MQC in maintaining HSC function, the precise molecular mechanisms and interactions among different regulatory pathways remain to be fully elucidated. Furthermore, the potential role of MQC dysfunction in hematopoietic disorders, including its involvement in disease progression and therapeutic resistance, is not yet fully understood. This review discusses the molecular mechanisms of MQC in HSCs, its functions under physiological and pathological conditions, and its potential therapeutic applications. By summarizing the current progress in this field, we aim to provide insights for further research and the development of innovative treatment strategies.

The first generation who engaged with digital technologies has reached the age where risks of dementia emerge. Has technological exposure helped or harmed cognition in digital pioneers? The digital dementia hypothesis predicts that a lifetime of technology exposure worsens cognitive abilities. An alternative hypothesis is that such exposures lead to technological reserve, wherein digital technologies promote behaviours that preserve cognition. We tested these hypotheses in a meta-analysis and systematic review of studies published in Medline, PsycInfo, CINAHL, Science Direct, Scopus, Cochrane Library, ProQuest and Web of Science. Studies were included if they were observational or cohort studies focused on general digital technology use in older adults (over age 50) and included either a cognitive or dementia diagnosis outcome. We identified 136 papers that met inclusion criteria, of which 57 were compatible with odds ratio or hazard ratio meta-analysis. These studies included 411,430 adults (baseline age M = 68.7 years; 53.5% female) from cross-sectional and longitudinal observational studies (range: 1-18 years, M = 6.2 years). Use of digital technologies was associated with reduced risk of cognitive impairment (OR = 0.42, 95% CI 0.35-0.52) and reduced time-dependent rates of cognitive decline (HR = 0.74, 95% CI 0.66-0.84). Effects remained significant when accounting for demographic, socioeconomic, health and cognitive reserve proxies. All studies were evaluated for quality on the basis of a standardized checklist; the primary outcomes replicated when limiting analyses to the highest-quality studies. Additional work is needed to test bidirectional causal interpretations, understand mechanisms that underpin technological reserve, and identify how types and timings of technology exposures influence cognitive health.

In this study, we investigated the contribution of rare coding variants to human longevity by analyzing whole exome sequencing data from 1245 German long-lived individuals (LLI) and 4105 geographically matched younger controls. We identified novel exome-wide significant associations at both the single-variant and gene level, with a significant over-representation of genes involved in mechanistic target of rapamycin (mTOR) signaling. As such, three rare single variants in the mTOR-pathway genes RPS6, FLCN, and SIK3 were enriched in LLI. Additionally, RWDD1 emerged as a strong candidate gene for longevity, with LLI exhibiting a statistically significant burden of rare missense variants in this gene. Other associations involved PRAC2, SLC16 A6, FOCAD, IHH, MESD, HOXA4, and DNAJB13. Furthermore, we observed an enrichment of protein-truncating variants in the genes ASXL1 and TET2 amongst LLI, likely as a result of clonal haematopoiesis. The study emphasizes the role of rare variants in human longevity, particularly through mTOR signaling.

Somatic genetic variation (SOGV), accumulating during an organism's lifetime, was traditionally viewed as detrimental rather than adaptive due to links with cancer and senescence. However, in modular organisms like corals, deleterious mutations can be purged at the cellular or polyp level, while adaptive mutations may rise in frequency as polyps create genetically distinct modules. Quantifying the somatic genetic landscape in corals is necessary to understand the role these mutations may have in coral and clonal animal development and evolution. Here, we catalog somatic genetic variation in eight Acropora palmata colonies from Curacao. Whole genomes were sequenced (70-100x depth), documenting mutation variant allele frequency shifts as genets aged. Large numbers of SOGVs were observed in six- to ten-year-old colonies, and inferred mutation rates were used to age a genet of uncertain age to almost a century old. Although mutations were not fixed at the polyp or branch levels, i.e. they always displayed frequencies <0.5 as expected at mutating homozygous sites, their allele frequencies followed a power-law distribution, similar to aging human tissues. No signs of positive selection were found; instead SOGVs in the colony of uncertain age were under purifying selection. In one colony, mutations in 28 samples from along a branch were analyzed using a SNP microarray. Contrary to expectations, genetic and physical distances were unrelated. This observation together with the observed lack of fixation may be explained by a large stem cell population, the de-differentiation or dormancy of stem cells, the contribution of strong purifying selection, or a combination of the previously mentioned. Our findings provide a neutral framework against which to test for module-level selection of genetic variation in corals, explore the relationship between physical and genetic distance within a colony, and apply a somatic genetic clock to colonies of Acropora palmata. This work provides necessary fundamental insights into the landscape of somatic mutations in reef-building coral, highlighting the importance of studying these mutations as they may contribute to genetic diversity and adaptability in colonial animals.

Longitudinal studies now document how leukocyte telomere attrition and epigenetic aging may be accelerated in people with HIV (PWH), in particular, around the time of HIV acquisition, during primary HIV infection, and during untreated chronic HIV infection. Whether chronic low-level inflammation and epigenetic aging go hand in hand or may be partially independent continues to be investigated in PWH and other settings. Epigenetic age acceleration (EAA) in PWH has now clearly been shown to be potentially reversible during successful antiretroviral therapy (ART). These studies point to how the beneficial effects of modern ART also include EAA-decelerating effects that seem large enough to regard ART as a kind of epigenetic rejuvenation therapy. Progress in the field has been limited in part due to the high cost of assessing EAA based on DNA methylation measures ("epigenetic clocks"). Demonstration of the clinical relevance of EAA and its reversion by ART will depend on large studies associating EAA with cardiovascular events and other adverse aging-associated endpoints in PWH.

Organismal aging has been associated with diverse metabolic and functional changes across tissues. Within the immune system, key features of physiological hematopoietic cell aging include increased fat deposition in the bone marrow, impaired hematopoietic stem and progenitor cell (HSPC) function, and a propensity towards myeloid differentiation. This shift in lineage bias can lead to pre-malignant bone marrow conditions such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenias of undetermined significance (CCUS), frequently setting the stage for subsequent development of age-related cancers in myeloid or lymphoid lineages. Human aging has also been associated with diverse lipid alterations across tissues, such as decreased phospholipid membrane fluidity that arises as a result of increased saturated fatty acid (FA) accumulation and a decay in n-3 polyunsaturated fatty acid (PUFA) species by the age of 80 years, however the extent to which impaired FA metabolism contributes to hematopoietic aging is less clear. Here, comprehensive multi-omics analyses uncovered a role for a key PUFA biosynthesis gene, ELOVL2, in mouse and human immune cell aging. Whole transcriptome RNA-sequencing studies and complementary flow cytometric analyses of bone marrow from aged Elovl2 mutant (enzyme-deficient) mice compared with age-matched controls revealed global downregulation in lymphoid cell markers and expression of genes involved specifically in B cell development. These studies unveiled CD79B, a vital molecular regulator of lymphoid progenitor development from the pro-B to pre-B cell stage, as a putative surface biomarker whose loss is associated with accelerated immune aging. The lipidome of mutant versus wild-type mice also displayed significant changes in the biophysical properties of cellular membranes. To investigate the relevance of these finding to human bone marrow aging, analyses of a single cell RNA-seq dataset of human HSPCs across the spectrum of human development and aging uncovered a rare subpopulation (< 7%) of CD34

Physical activity (PA) is one of the most fundamental of all traits in the animal kingdom, has pervasive health benefits, and is genetically influenced. Using data from the Million Veteran Program (MVP), we conducted genetic analyses of leisure, work, and home-time PA. For leisure, for individuals of European (EUR) ancestry, n=189,812 and SNP-based heritability (h2)=0.083+/-0.005; for African ancestry, n=27,044; h2= 0.034+/-0.017; and for Latin-American ancestry, n=10,263; h2= 0.083+/-0.036. EUR and cross-ancestry meta-analyses with UK Biobank identified 67 and 70 lead variants. Leisure-time PA was genetically distinct from PA at home or work, with the latter two showing less health benefit on pathologies and lifespan. Mendelian randomization analyses showed protective effects of leisure-time PA on cardiovascular and respiratory system diseases, metabolic traits, aging, and other traits, and there was protective role of leisure-time PA against COVID-19 hospitalization ({beta}=-0.067+/-0.016; p-value=2.8x10-5). These findings provide new insights into the biology of PA, showing the causal health benefits of leisure-time PA.

The traditional Chinese herbal medicine Panax ginseng can optimize physical health and is anticipated to be a valuable resource for investigating anti-aging therapies. This study investigated the anti-aging effects of red ginseng aqueous extract (RG) and white ginseng aqueous extract (WG). Network pharmacology forecasted that the key mechanisms of anti-aging in white and red ginseng were the PI3K-Akt and IIS signaling pathways. Experiments conducted on Caenorhabditis elegans (C. elegans) showed that 5 mg/mL WG and RG notably prolonged lifespan and improved stress resistance. The qPCR analysis revealed that changes in upstream genes activated downstream genes in the IIS pathway. Furthermore, forward and reverse validation indicated that WG and RG acted through the IIS pathway in promoting longevity. RG exhibited superior anti-aging effects compared to WG at the same concentration. This might be attributed to the fact that RG contained more reducing sugars, polyphenols, melanoidins, total saponin content and especially the conversion of ginsenosides. Molecular docking showed that ginsenosides interacted with the key protein DAF-2, with ginsenosides Rg3, Rg5, Rh4, Rf, and Rc binding more strongly than ginsenosides Rb1, Rb2, and Rd. Overall, RG possessed different active ingredients compared to WG and showed superior results in improving aging in C. elegans.

Objective To estimate the proportions of Alzheimer's disease (AD) and all-cause dementia burden attributable to the common risk alleles {varepsilon}3 and {varepsilon}4 in the APOE gene Design Genetic association analyses in three independent cohort studies and one case-control study Settings National cohorts in the UK and Finland (UK Biobank, FinnGen); a pre-intervention cohort of participants in the A4 Study, a multi-national randomised clinical trial; AD case-control samples from the Alzheimer's Disease Genomics Consortium (ADGC) in the U.S. Participants Cohorts aged [≥]60 years in UK Biobank (n=171,128) and FinnGen (n=279,036). Cognitively normal trial recruits with baseline neuroimaging aged 65 to 85 years in A4 (n=4,415). Deceased AD cases and controls in ADGC (mean age ~ 82 years; n=5,007) Main outcomes Clinically diagnosed AD and all-cause dementia, principally or exclusively ascertained through health record linkages (UK Biobank, FinnGen); Cerebral amyloidosis ascertained through Positron Emission Tomography neuroimaging (A4); AD neuropathologically confirmed at autopsy (ADGC). Results In UKB, 73.9% (95% confidence interval: 37.3% to 89.0%) of AD and 37.8% (9.1% to 57.4%) of all-cause dementia were attributable to a combination of {varepsilon}3 and {varepsilon}4 carriage. In FinnGen, estimates were 64.4% (45.1% to 76.6%) for AD and 42.4% (25.0% to 55.4%) for all-cause dementia. In the A4 study, 85.1% (19.2% to 93.9%) of cerebral amyloidosis was attributable to {varepsilon}3 and {varepsilon}4. In the ADGC data, 92.7% (81.4% to 96.5%) of neuropathologically confirmed AD was attributable to {varepsilon}3 and {varepsilon}4, with {varepsilon}4 accounting for 56.9% (36.0% to 63.0%) and {varepsilon}3 for 35.8% (22.1% to 58.3%). Conclusions Without the strong risk-increasing effects of both APOE {varepsilon}3 and {varepsilon}4, most AD would not occur. Apolipoprotein E (apoE) predominates late-onset AD's causes. Research into apoE should be prioritised given its major potential as a target for AD prevention and treatment.

Mitochondrial dysfunction has been implicated in a broad range of age-related pathologies and has been proposed as a causative factor in Alzheimer's disease (AD). Analysis of post-mortem brains from AD patients showed increased levels of Voltage-dependent anion-selective channel 1 (VDAC1) in the dystrophic neurites surrounding amyloid-β (Aβ) deposits, suggesting a direct association between VDAC1 and mitochondrial toxicity. VDAC1 is the most abundant pore-forming protein of the outer mitochondrial membrane and, as a channel, it plays a pivotal role in regulating cellular bioenergetics, allowing the continuous exchange of ions and metabolites (ATP/ADP, Krebs cycle intermediates) between cytosol and mitochondria. In light of this evidence, we looked into the effects of Aβ oligomers on VDAC1 functions through electrophysiological and respirometric techniques. Our findings indicate that Aβ oligomers significantly modify the conductance, voltage dependency, and kinetic features of VDAC1, as well as its slight selectivity for anions, leading to a marked preference for cations. Given that VDAC1 is mainly involved in the trafficking of charged molecules in and out of mitochondria, a general reduction of cell viability and mitochondrial respiration was detected in neuroblastoma cells and primary cortical neurons exposed to Aβ oligomers. Interestingly, the toxic effect mediated by Aβ oligomers was counteracted by the use of NHK1, a small synthetic, cell-penetrating peptide that binds and modulates VDAC1. On these results, VDAC1 emerges as a crucial molecule in mitochondrial dysfunction in AD and as a promising pharmacological target for the development of new therapeutic avenues for this devastating neurodegenerative disease still without a cure.