Longevity Papers

Sensorimotor and cognitive abilities undergo substantial changes throughout the human lifespan, but the corresponding changes in the functional properties of cortical networks remain poorly understood. This can be studied using temporal and spatial scales of functional magnetic resonance imaging (fMRI) signals, which provide a robust description of the topological structure and temporal dynamics of neural activity. For example, timescales of resting-state fMRI signals can parsimoniously predict a significant amount of the individual variability in functional connectivity networks identified in adult human brains. In the present study, we quantified and compared temporal and spatial scales in resting-state fMRI data collected from 2,352 subjects between the ages of 5 and 100 in Developmental, Young Adult, and Aging datasets from Human Connectome Project. For most cortical regions, we found that both temporal and spatial scales largely decreased with age across most cortical areas throughout the lifespan, with the visual cortex and the limbic network consistently showing the largest and smallest scales, respectively. For some prefrontal regions, however, these two scales displayed non-monotonic trajectories during adolescence and peaked around the same time during adolescence and decreased throughout the rest of the lifespan. We also found that cortical myelination increased monotonically throughout the lifespan, and its rate of change was significantly correlated with the changes in both temporal and spatial scales across different cortical regions in adulthood. These findings suggest that temporal and spatial scales in fMRI signals, as well as cortical myelination, are closely coordinated during both development and aging.

Ion transport within mitochondria influences their structure, energy production, and cell death regulation. TMBIM5, a conserved calcium/proton exchanger in the inner mitochondrial membrane, contributes to mitochondrial structure, ATP synthesis, and apoptosis regulation. The relationship of TMBIM5 with the mitochondrial calcium uniporter complex formed by MCU, MICU1-3, and EMRE remains undefined. We generated Tmbim5-deficient Drosophila that exhibit disrupted cristae architecture, premature mitochondrial permeability transition pore opening, reduced calcium uptake, and mitochondrial swelling - resulting in impaired mobility and shortened lifespan. Crossing these with flies lacking mitochondrial calcium uniporter complex proteins was generally detrimental, but partial MICU1 depletion ameliorated the Tmbim5-deficiency phenotype. In human cells, MICU1 rescues morphological defects in TMBIM5-knockout mitochondria, while TMBIM5 overexpression exacerbates size reduction in MICU1-knockout mitochondria. Both proteins demonstrated opposing effects on submitochondrial localization and coexisted in the same macromolecular complex. Our findings establish a functional interplay between TMBIM5 and MICU1 in maintaining mitochondrial integrity, with implications for understanding calcium homeostasis mechanisms.

O-GlcNAc transferase (OGT) interacts robustly with all three mammalian TET methylcytosine dioxygenases. Here we show that deletion of the Ogt gene in mouse embryonic stem (mES) cells results in a widespread increase in the TET product 5-hydroxymethylcytosine in both euchromatic and heterochromatic compartments, with a concomitant reduction in the TET substrate 5-methylcytosine at the same genomic regions. mES cells treated with an OGT inhibitor also displayed increased 5-hydroxymethylcytosine, and attenuating the TET1-OGT interaction in mES cells resulted in a genome-wide decrease of 5-methylcytosine, indicating that OGT restrains TET activity and limits inappropriate DNA demethylation in a manner that requires the TET-OGT interaction and the catalytic activity of OGT. DNA hypomethylation in OGT-deficient cells was accompanied by derepression of transposable elements predominantly located in heterochromatin. We suggest that OGT protects the genome against TET-mediated DNA demethylation and loss of heterochromatin integrity, preventing the aberrant increase in transposable element expression noted in cancer, autoimmune-inflammatory diseases, cellular senescence and aging.

Biological aging clocks across organs and omics data, including clinical phenotypes, neuroimaging, proteomics, and epigenetics, have proven instrumental in advancing our understanding of human aging and disease. Here, we expand this aging clock framework to plasma metabolomics by developing 5 organ-specific metabolome-based biological age gaps (MetBAGs) using 107 plasma non-derived metabolites from 274,247 UK Biobank participants. Our multi-organ MetBAGs were trained using Lasso regression and neural networks, achieving a mean absolute error of approximately 6 years (0.25

Chronic heavy alcohol use is a major risk factor for premature aging and age-related diseases. DNA methylation (DNAm)-based epigenetic clocks are novel tools for predicting biological age. However, the newest configurations, causality-enriched epigenetic clocks, have not been assessed in the context of alcohol consumption and alcohol use disorder (AUD).

Long Interspersed Nuclear Elements-1 (LINE-1 or L1) make up approximately 21% of the human genome, with some L1 loci containing intact open reading frames (ORFs) that facilitate retrotransposition. Because retrotransposition can have deleterious effects leading to mutations and genomic instability, L1 activity is typically suppressed in somatic cells through transcriptional and post-transcriptional mechanisms. However, L1 elements are derepressed in senescent cells causing age-associated inflammation. Despite the recognition of L1 activity as a hallmark of aging, the underlying molecular mechanisms governing L1 derepression in these cells are not fully understood. In this study, we employed high throughput sequencing datasets and validated our findings through independent experiments to investigate the regulation of L1 elements in senescent cells. Our results reveal that both replicative and oncogene-induced senescence are associated with reduced expression of the cytidine deaminase APOBEC3B, a known suppressor of L1 retrotransposition. Consequently, senescent cells exhibited diminished levels of C-to-U editing of full-length L1 elements. Moreover, Ribo-seq profiling indicated that progression to senescence is not only associated with increased L1 transcription, but also translation of L1 ORFs. In summary, our results suggest that the depletion of APOBEC3B contributes to enhanced activity of L1 in senescent cells and promotion of L1-induced DNA damage and aging.

Osteoporosis, a significant age-related disease, is marked by diminished bone density and an elevated risk of fractures, representing a considerable global health challenge. Bone marrow mesenchymal stem cells (BMSCs) are essential in maintaining bone integrity through their differentiation into osteoblasts, which are crucial for bone formation. Nevertheless, the aging of BMSCs diminishes their regenerative abilities and intensifies inflammation, thereby playing a critical role in osteoporosis pathogenesis. This review explores the intricate mechanisms of BMSC senescence and its influence on osteoporosis, detailing cellular and molecular markers, such as oxidative stress, the senescence-associated secretory phenotype (SASP), and pivotal signaling pathways, including P53, PI3K/mTOR, and autophagy. We assess current interventions aimed at reducing BMSC senescence, with an emphasis on pharmacological methods like melatonin and antioxidants, alongside nonpharmacological strategies, such as exercise and dietary supplementation with omega-3 fatty acids. Furthermore, the challenges and limitations of translating these strategies into clinical applications are addressed, highlighting the necessity for personalized medicine to accommodate treatment outcome variability. Future research directions should focus on emerging therapeutic targets and novel interventions, such as gene editing technologies and advanced tissue engineering techniques. By integrating these strategies, this review endeavors to enhance the understanding and treatment of osteoporosis, emphasizing the critical need to target BMSC senescence to develop effective therapies.

An anticipated health boost from the increasing educational attainment of the US population has not materialized, with life expectancy and healthy longevity both stagnating over the past decade. We seek to understand how changes in the level of educational attainment across successive birth cohorts in the US have impacted disability-free life expectancy (DFLE) among older Americans. We analyzed data from the US Health and Retirement Study spanning 2000 to 2020, focusing on four ten-year birth cohorts. We then decomposed changes in population-level expectancies into contributions from shifts in educational composition, health status at midlife, and health and mortality transitions at older ages across different educational groups. DFLE increased notably for females but not for males, with disabled life expectancy (DLE) remaining stable. Shifts in educational composition primarily drove increases in DFLE and total life expectancy. However, deteriorating midlife health among those without a high school diploma reduced DFLE for this group, which tempered overall population-level gains. Health and mortality transitions among the less educated contributed to increased DLE. Our findings show that educational attainment is a major structural factor influencing US population health. Expanding access to higher education and reducing education inequality will play a significant role in future changes to healthy longevity.

Mammalian aging is reportedly driven by the loss of epigenetic information; however, its impact on skeletal muscle aging remains unclear. This study shows that aging mouse skeletal muscle exhibits increased DNA methylation, and overexpression of DNA methyltransferase 3a (Dnmt3a) induces an aging-like phenotype. Muscle-specific Dnmt3a overexpression leads to an increase in central nucleus-positive myofibers, predominantly in fast-twitch fibers, a shift toward slow-twitch fibers, elevated inflammatory and senescence markers, mitochondrial OXPHOS complex I reduction, and decreased basal autophagy. Dnmt3a overexpression resulted in reduced muscle mass and strength and impaired endurance exercise capacity with age, accompanied by an enhanced inflammatory signature. In addition, Dnmt3a overexpression reduced not only sensitivity to starvation-induced muscle atrophy but also the restorability from muscle atrophy. These findings suggest that increased DNA methylation disrupts skeletal muscle homeostasis, promotes an aging-like phenotype, and reduces muscle metabolic elasticity.

By eliciting lung necrosis, which enhances aerosol transmission, Mycobacterium tuberculosis (Mtb) sustains its long-term survival as a human pathogen. In studying the human-like necrotic granuloma lesions characteristic of Mtb-infected B6.Sst1S mice, we found that lung myeloid cells display elevated senescence markers- cell cycle arrest proteins p21 and p16, the DNA damage marker {gamma}H2A.X, senescence-associated {beta}-Galactosidase activity, and senescence-associated secretory phenotype (SASP). These markers were also elevated in Mtb-infected aged wild type (WT) mice but not in young WT mice. Global transcriptomics data revealed activation of pro-survival (PI3K, MAPK) and anti-apoptotic pathways in Mtb-infected B6.Sst1S macrophages. As senescent cells are long-lived, non-dividing cells that release tissue-damaging SASP, we treated Mtb-infected mice with a cocktail of three senolytic drugs (dasatinib, quercetin, and fisetin) designed to kill senescent cells. Senolytic drug treatment prolonged survival and reduced Mtb lung counts in B6.Sst1S and aged WT mice to a greater degree than young WT mice and concomitantly reduced lung senescence markers. These findings indicate that (1) Mtb infection may induce lung myeloid cells to enter a senescent state and that these cells play a causal role in disease progression, and (2) Senolytics merit consideration for human clinical trials against tuberculosis (TB).

Cellular senescence is the basic unit of organismal aging, a complicated biological process involving several cell types and tissues. It is also an important mechanism by which the body responds to damage and potential carcinogenesis. However, excessive or abnormal cellular senescence can lead to tissue functional degradation and the occurrence of diseases. In recent years, the role of epigenetic modifications in cellular senescence has received extensive attention. Lactylation, a novel post-translational modification derived from lactate, has recently gained significant attention as a key factor in cellular metabolism and epigenetic regulation, gradually demonstrating its importance in the regulation of cellular senescence. This review emphasizes the bidirectional causal relationship between lactylation and cellular senescence, highlighting its potential as a therapeutic target for aging-related diseases.

Metabolic dysregulation represents one of the major driving forces in aging. Although multiple genetic and pharmacological manipulations are known to extend longevity in model organisms, aging is a complex trait, and targeting one's own genes may be insufficient to prevent age-dependent deterioration. An alternative strategy could be to use enzymes from other species to reverse age-associated metabolic changes. In this review, we discuss a set of enzymes from lower organisms that have been shown to affect various metabolic parameters linked to age-related processes. These enzymes include modulators of steady-state levels of amino acids (METase, ASNase, and ADI), NADPH/NADP

Aging is accompanied by considerable changes in the gut microbiome, yet the molecular mechanisms driving aging and the role of the microbiome remain unclear. Here we combined metagenomics, transcriptomics and metabolomics from aging mice with metabolic modelling to characterize host-microbiome interactions during aging. Reconstructing integrated metabolic models of host and 181 mouse gut microorganisms, we show a complex dependency of host metabolism on known and previously undescribed microbial interactions. We observed a pronounced reduction in metabolic activity within the aging microbiome accompanied by reduced beneficial interactions between bacterial species. These changes coincided with increased systemic inflammation and the downregulation of essential host pathways, particularly in nucleotide metabolism, predicted to rely on the microbiota and critical for preserving intestinal barrier function, cellular replication and homeostasis. Our results elucidate microbiome-host interactions that potentially influence host aging processes. These pathways could serve as future targets for the development of microbiome-based anti-aging therapies.

The long-term impact of early-life varicella infection on chronic disease risk remains understudied. In this UK Biobank analysis, we found that documented early-life varicella infection was associated with significantly reduced risks of multiple chronic diseases, with the strongest protective associations for neurodegenerative conditions (Alzheimer's disease: HR = 0.23, Parkinson's disease: HR = 0.46). These inverse associations were consistently stronger in women, increased with age, and remarkably, appeared to outweigh the effects of socioeconomic deprivation on disease risk. Mendelian randomization analyses supported causality for several outcomes. Prior varicella infection was further associated with favorable baseline health profiles, including lower BMI, improved lung function, and reduced inflammatory markers. Our findings suggest that early-life varicella infection may confer long-term protection against chronic diseases through persistent modulation of immune and inflammatory pathways, challenging simplified views of infections as uniformly harmful and highlighting the complex, time-dependent interactions between infectious exposures and chronic disease risk across the lifespan.

Aging, the decline in physiological function over time, is marked by the intracellular accumulation of damaged components. It can be attributed to a trade-off between the investment into organismal maintenance and the production of high-quality offspring, where the parent accumulates damage over time and retains it upon reproduction, while the offspring is rejuvenated. Asymmetric damage partitioning has been observed even in simple unicellular organisms, such as Escherichia coli bacteria, that retain aggregates of misfolded proteins during cell division. However, recent studies presented conflicting evidence on the effect of protein aggregates on fitness, ranging from detrimental effects on cell growth to enhanced stress survival. Here, we show that the decisive factor driving growth decline in E. coli is not the presence of a protein aggregate, but the proportion of the intracellular space occupied by it. By following single-cell E. coli lineages expressing fluorescently labeled DnaK chaperones, we quantified damage accumulation and partitioning across generations in microfluidic devices. Our results suggest that the aggregation of damaged proteins allows cells to keep damage separate from vital processes and compensate for the lost intracellular space by growing to larger sizes. This process results in morphologically asymmetric divisions, a finding that counters the long-assumed symmetry of E. coli cell division. In line with other recent evidence, our findings point to a more complex role of protein aggregation, with implications for our understanding of the cellular mechanisms underlying aging as well as its evolutionary origins.

Cellular senescence, characterized by a permanent state of cell cycle arrest and a secretory phenotype contributing to inflammation and tissue deterioration, has emerged as a target for age-related interventions. Accumulation of senescent cells is closely linked with intervertebral disc (IVD) degeneration, a prevalent age-dependent chronic disorder causing low back pain. Previous studies have highlighted that platelet-derived growth factor (PDGF) mitigated IVD degeneration through anti-apoptosis, anti-inflammation, and pro-anabolism. However, its impact on IVD cell senescence remains elusive. In this study, human NP and AF cells derived from aged, degenerated IVDs were treated with recombinant human (rh) PDGF-AB/BB for 5 days and changes of transcriptome profiling were examined through mRNA sequencing. NP and AF cells demonstrated similar but distinct responses to the treatment. However, the effects of PDGF-AB and BB on human IVD cells were comparable. Specifically, PDGF-AB/BB treatment resulted in downregulation of gene clusters related to neurogenesis and response to mechanical stimulus in AF cells while the downregulated genes in NP cells were mainly associated with metabolic pathways. In both NP and AF cells, PDGF-AB and BB treatment upregulated the expression of genes involved in cell cycle regulation, mesenchymal cell differentiation, and response to reduced oxygen levels, while downregulating the expression of genes related to senescence associated phenotype, including oxidative stress, reactive oxygen species (ROS), and mitochondria dysfunction. Network analysis revealed that PDGFRA and IL6 were the top hub genes in treated NP cells. Furthermore, in irradiation-induced senescent NP cells, PDGFRA gene expression was significantly reduced compared to non-irradiated cells. However, rhPDGF-AB/BB treatment increased PDGFRA expression and mitigated the senescence progression through increased cell population in the S phase, reduced SA-{beta}-Gal activity, and decreased expression of senescence related regulators including P21, P16, IL6, and NF-{kappa}B. Our findings reveal a novel anti-senescence role of PDGF in the IVD, making it a promising potential candidate to delay aging-induced IVD degeneration.

Bisphosphonates (BPs) have been the major class of medicines used to treat disorders of excessive bone loss for over five decades. Recently it has been recognized that BPs may also have additional significant beneficial extra-skeletal effects. These include a reduction of all-cause mortality and of conditions commonly linked to ageing, such as cancer and cardiovascular disease. Here we show that bisphosphonates co-localize with lysosomal and endosomal organelles in non-skeletal cells and stimulate cell growth at low doses. In vivo spatial transcriptomic analysis revealed differentially expressed senescence markers in multiple organs of aged BP-treated mice, and a shift in cellular composition toward those of young counterparts. Similarly, a 5000-plex plasma proteome analysis from osteopenic patients before and after BP-treatment showed significant alterations in ~400 proteins including GTPase regulators and markers of senescence, autophagy, apoptosis, and inflammatory responses. Furthermore, treatment with BPs protected against the onset of senescence in vitro. Proteome-wide target deconvolution using 2D thermal profiling revealed novel BP-binding targets (PHB2, ASAH1), and combined with RNA- and ATAC-seq of BP-treated cells and patient data, suggests downstream regulation of the MEF2A transcription factor within the heart. Collectively, these results indicate how BPs may beneficially modify the human plasma proteome, and directly impact multiple non-skeletal cell types through previously unidentified proteins, thereby influencing a range of pathways related to senescence and ageing.

In light of increasing attention being paid to aging research globally, the accumulation of aging hallmarks and their corresponding targeting therapeutics have been substantially revealed. However, uncovering the genuine drivers within epigenetic alterations that lead to aging remains a formidable challenge. In this study, we identified tRNASec(NCA) as the most severely damaged tRNA species in the kidneys of naturally aged mice. This damage not only dysregulated selenoproteins with anti-aging effects, but also generates a 5\'-tRNA fragment cleaved at the 34th position, which accumulates in an age-dependent manner. Mechanistically, the 5\'-tRNASec(NCA) half interacts and activates Toll-like receptor 7, thereby triggering innate immune responses and promoting cellular senescence in both mice and human cells. Moreover, in a naturally aged mice model, administration of an antisense oligonucleotide (ASO) targeting the 5\'-tRNASec(NCA) half remarkably ameliorates aging markers, enhances telomere length, and extends healthspan and lifespan. In addition, ASO-5\'-tRNASec(NCA) half plays another role in directly targeting and downregulating BCAT1 via the RNAi pathway to intervene in the senescence process. Our findings underscore tRNA damage as a novel aging hallmark, and targeting the damage-induced products presents a novel strategy for aging intervention, thus expanding our knowledge of the aging process.

People living with HIV (PLWH) exhibit accelerated aging, characterized by systemic inflammation, termed "inflammaging." While T-cell expansion is prevalent in PLWH, its connection to inflammaging remains unclear. In this study, we analyzed the TCRβ repertoire of 257 healthy controls (HC) and 228 PLWH, revealing pronounced T cell clonal expansion in PLWH. The expansion was only partially reversed following antiretroviral therapy (ART) and closely associated with ART duration, CD4+ T and CD8+ T cell counts and the CD4/CD8 ratio. TCR-based age modeling showed a continuous accelerated trajectory of aging in PLWH, especially in younger individuals, in stark contrast to the nonlinear aging acceleration pattern seen in HC. Furthermore, using single-cell RNA combined TCR sequencing and in vitro experiments, we identified GNLY+CD8+ T cells as the primary population driving clonal expansion and maintenance in PLWH. These cells are characterized by high cytotoxicity and low exhaustion and are activated by interleukin-15 (IL-15) in vitro. Notably, GNLY+CD8+ T cells predominantly express the pro-inflammatory 15 kDa form of granulysin(GNLY). The supernatant from IL-15-stimulated CD8+ T cells induces monocytes to secrete inflammatory factors and disrupts the integrity of intestinal epithelial cells, which can be partially restored by the anti-GNLY antibodies. These findings identify GNLY+CD8+ T cells as the central drivers of persistent clonal expansion, highlighting their crucial role for mitigating inflammaging in PLWH.

SIRT6 is a protein deacylase, deacetylase, and mono-ADP-ribosylase (mADPr) regulating biological pathways important for longevity including DNA repair and silencing of LINE1 retrotransposons. SIRT6 knockout mice die by 30 days of age, whereas SIRT6 overexpression increases lifespan in male mice. Finding safe pharmacological activators of SIRT6 would have clinical benefits. Fucoidan, a polysaccharide purified from brown seaweed, has been identified as an activator of SIRT6 deacetylation activity. Here, we show that fucoidan also activates SIRT6 mADPr activity, which was shown to be elevated in certain human centenarians. Administering fucoidan to aged mice led to a significant increase in median lifespan in male mice. Both male and female mice demonstrated a marked reduction in frailty and epigenetic age. Fucoidan-treated mice showed repression of LINE1 elements suggesting that the beneficial effects of fucoidan are mediated, at least in part, by SIRT6. As brown seaweed rich in fucoidan is a popular food item in South Korea and Japan, countries with the highest life expectancy, we propose that fucoidan supplementation should be explored as a safe strategy for activating SIRT6 and improving human healthspan and lifespan.

Aging is reflected by genome-wide DNA methylation changes, which form the basis of epigenetic clocks, but it is largely unclear how these epigenetic modifications are regulated and whether they directly affect the aging process. In this study, we performed epigenetic editing at age-associated CpG sites to explore the consequences of interfering with epigenetic clocks. CRISPR-guided editing targeted at individual age-related CpGs evoked genome-wide bystander effects, which were highly reproducible and enriched at other age-associated regions. 4C-sequencing at age-associated sites revealed increased interactions with bystander modifications and other age-related CpGs. Subsequently, we multiplexed epigenetic editing in human T cells and mesenchymal stromal cells at five genomic regions that become either hypermethylated or hypomethylated upon aging. While targeted methylation seemed more stable at age-hypermethylated sites, both approaches induced bystander modifications at CpGs with the highest correlations with chronological age. Notably, these effects were simultaneously observed at CpGs that gain and lose methylation with age. Our results demonstrate that epigenetic editing can extensively modulate the epigenetic aging network and interfere with epigenetic clocks.

As the global population ages, it is critical to identify diets that, beyond preventing noncommunicable diseases, optimally promote healthy aging. Here, using longitudinal questionnaire data from the Nurses' Health Study (1986-2016) and the Health Professionals Follow-Up Study (1986-2016), we examined the association of long-term adherence to eight dietary patterns and ultraprocessed food consumption with healthy aging, as assessed according to measures of cognitive, physical and mental health, as well as living to 70 years of age free of chronic diseases. After up to 30 years of follow-up, 9,771 (9.3%) of 105,015 participants (66% women, mean age = 53 years (s.d. = 8)) achieved healthy aging. For each dietary pattern, higher adherence was associated with greater odds of healthy aging and its domains. The odds ratios for the highest quintile versus the lowest ranged from 1.45 (95% confidence interval (CI) = 1.35-1.57; healthful plant-based diet) to 1.86 (95% CI = 1.71-2.01; Alternative Healthy Eating Index). When the age threshold for healthy aging was shifted to 75 years, the Alternative Healthy Eating Index diet showed the strongest association with healthy aging, with an odds ratio of 2.24 (95% CI = 2.01-2.50). Higher intakes of fruits, vegetables, whole grains, unsaturated fats, nuts, legumes and low-fat dairy products were linked to greater odds of healthy aging, whereas higher intakes of trans fats, sodium, sugary beverages and red or processed meats (or both) were inversely associated. Our findings suggest that dietary patterns rich in plant-based foods, with moderate inclusion of healthy animal-based foods, may enhance overall healthy aging, guiding future dietary guidelines.

Autophagy, a critical intracellular degradation and recycling pathway mediated by lysosomes, is essential for maintaining cellular homeostasis through the quality control of proteins and organelles. Our research focused on the role of proximal tubular autophagy in the pathophysiology of aging, obesity, and diabetes. Using a novel method to monitor autophagic flux in kidney tissue, we revealed that age-associated high basal autophagy supports mitochondrial quality control and delays kidney aging. However, an impaired ability to upregulate autophagy under additional stress accelerates kidney aging. In obesity induced by a high-fat diet, lysosomal dysfunction disrupts autophagy, leading to renal lipotoxicity. Although autophagy is initially activated to repair organelle membranes and maintain proximal tubular cell integrity, this demand overwhelms lysosomes, resulting in "autophagic stagnation" characterized by phospholipid accumulation. Similar lysosomal phospholipid accumulation was observed in renal biopsies from elderly and obese patients. We identified TFEB-mediated lysosomal exocytosis as a mechanism to alleviate lipotoxicity by expelling accumulated phospholipids. Therapeutically, interventions such as the SGLT2 inhibitor empagliflozin and eicosapentaenoic acid restore lysosomal function and autophagic activity. Based on these findings, we propose a novel disease concept, "Obesity-Related Proximal Tubulopathy." This study underscores autophagic stagnation as a key driver of kidney disease progression in aging and obesity, offering insights into the pathophysiology of kidney diseases and providing a foundation for targeted therapeutic strategies.

The functional significance of long non-coding RNAs (lncRNAs) remains a subject of debate, largely due to the complexity and cost associated with their validation experiments. However, emerging evidence suggests that pseudogenes, once viewed as genomic relics, may contribute to the origin of functional lncRNA genes. In this study spanning eight species, we systematically identified pseudogene-associated lncRNA genes using our PacBio long-read sequencing data and published RNA-seq data. Our investigation revealed that pseudogene-associated lncRNA genes exhibit heightened functional attributes compared to their non-pseudogene-associated counterparts. Notably, these pseudogene-associated lncRNAs show protein-binding proficiency, positioning them as potent regulators of gene expression. In particular, pseudogene-associated sense lncRNAs retain protein-binding capabilities inherited from parent genes of pseudogenes, thereby demonstrating greater protein-binding proficiency. Through detailed functional characterization, we elucidated the unique advantages and conserved roles of pseudogene-associated lncRNA genes, particularly in the context of gene expression regulation and DNA repair. Leveraging cross-species expression profiling, we demonstrated the prominent contribution of pseudogene-associated lncRNA genes to aging-related transcriptome changes across nine human tissues and eight mouse tissues. Overall, our findings demonstrate enhanced functional attributes of pseudogene-associated lncRNA genes and shed light on their conserved and close association with aging.

The incidence of intracranial aneurysms (IAs) is markedly elevated in postmenopausal women compared to men and premenopausal women, a disparity historically linked to declining estrogen levels. Emerging evidence, however, suggests that the expression and functional roles of estrogen receptors (ERs), including ERα, ERβ, and GPER1, in vascular tissues may implicate estrogen-independent pathways in vascular aging and related pathologies. An integrative bioinformatics approach, combining three IA datasets (GSE75436, GSE122897, GSE54083) and two vascular endothelial cell senescence (VECS) datasets (GSE214476, GSE102397) from the Gene Expression Omnibus (GEO) database, was employed to investigate this hypothesis and define shared molecular mechanisms. This cross-disease differential expression analysis identified 452 significantly downregulated genes, suggesting conserved pathogenic pathways in IA and VECS. Among ERs, GPER1 was uniquely downregulated in both conditions. Subsequent weighted gene co-expression network analysis and subsequent module clustering revealed ACACB as a hub gene co-expressed with GPER1 and inversely correlated with IA and VECS progression. In vitro validation confirmed that GPER1 expression was reduced during VECS and that GPER1 silencing decreased ACACB expression and accelerated endothelial senescence, supporting its estrogen-independent role in vascular homeostasis. Computational pharmacological screening further identified PD0325901, SCH772984, and selumetinib as potential therapeutic agents targeting both GPER1 and ACACB, offering a dual-pathway therapeutic strategy. The identification of GPER1 and ACACB as potential target genes associated with IA and VECS provides a framework for developing therapies that circumvent hormone dependency, addressing an unmet need in the treatment of IA and age-related vascular pathologies.

Aging is a major risk factor for the development of cardiovascular diseases (CVD), leading to specific alterations in the heart and vasculature. Besides, the mechanisms and intracellular pathways of aging and the factors affecting it are still not completely clear. Age-related complications such as oxidative stress, decreased autophagy, mitochondrial dysfunction, inflammatory responses, and cardiac dysfunction are associated with relative Klotho deficiency. Klotho, an anti-aging protein, with anti-oxidative and anti-inflammatory properties, has been shown to modulate calcium regulation and autophagy. It also protects against endothelial dysfunction by increasing nitric oxide production. Furthermore, emerging research has revealed that klotho significantly impacts vascular smooth muscle cells (VSMC) energetics and survival. This article has focused on recent advances in using Klotho in age-related CVD and summarizes the pre-clinical evidence supporting this approach. Based on the research, Klotho could provide more therapeutic options for ameliorating aging-related CVD.

The maintenance of epigenetic landscapes (EL) requires the precise regulation of chromatin-modifying enzymes (ChME). Competition for ChME can lead to degradation of ELs, triggering large-scale changes in the cell fate information contained in EL. Predicting impending epigenetic tipping points (ETP) by identifying early warning signals (EWS) may help to anticipate the onset of cell identity loss during aging and cancer. We have developed a general mathematical framework that incorporates different connectivity patterns generated by the 3D chromatin folding structure to analyze competition-induced ETP in large EL. This framework allows us to measure the sensitivity and robustness of ETP to the availability of metabolic cofactors and to identify potential EWS. Using a dimension reduction method, we derived coarse-grained (CG) equations for the collective observables associated with chromatin modifications. Analysis of the CG system allows the prediction of global transitions that shape the large-scale features of EL, accurately reproduce the corresponding microscopic benchmarks, and reveal the existence of tipping points under conditions of ChME competition. We applied the CG method to predict ETP under different connectivity patterns, including heterogeneous profiles such as those found in Hi-C data. Although a robustness measure for stable EL was derived from the CG dynamics in bistable regimes, sensitivity analysis revealed that metabolic cofactors have the greatest impact on EL robustness. In particular, we identified the metabolic cofactors SAM and acetyl-CoA as potential EWS for the catastrophic loss of hyperacetylated EL induced by ChME competition. The ability to predict global ETP can facilitate the discovery of predictive biomarkers and inform metabolic interventions aimed at limiting and reversing pathological cell fate decisions.

As humans age, some experience cognitive impairment while others do not. When impairment does occur, it is not expressed uniformly across cognitive domains and varies in severity across individuals. Translationally relevant model systems are critical for understanding the neurobiological drivers of this variability, which is essential to uncovering the mechanisms underlying the brain's susceptibility to the effects of aging. As such, non-human primates (NHPs) are particularly important due to shared behavioral, neuroanatomical, and age-related neuropathological features with humans. For many decades, macaque monkeys have served as the primary NHP model for studying the neurobiology of cognitive aging. More recently, the common marmoset has emerged as an advantageous model for this work due to its short lifespan that facilitates longitudinal studies. Despite their growing popularity as a model, whether marmosets exhibit patterns of age-related cognitive impairment comparable to those observed in macaques and humans remains unexplored. To address this major limitation for the development and evaluation of the marmoset as a model of cognitive aging, we directly compared working memory ability as a function of age in macaques and marmosets on the identical task. We also implemented varying delays to further tax working memory capacity. Our findings demonstrate that marmosets and macaques exhibit remarkably similar age-related working memory deficits, with macaques performing better than marmosets on longer delays. These results highlight the similarities and differences between the two most commonly used NHP models and support the value of the marmoset as a model for cognitive aging research within the neuroscience community.

Osteoarthritis (OA), is the most common age-induced degenerative joint disease. It is associated with synovial inflammation, subchondral bone remodeling and cartilage degradation. One of the significant emerging causes of OA progression is senescent cell accumulation within the joint compartment during lifespan. Currently, there are no therapeutic approaches nor stratification tools that rely on the senescence burden in OA. In this study, we identified the b-series ganglioside 3 (GD3) as new senescent cell surface marker associated with OA. Joint RNA sequencing analysis revealed an increase expression of the GD3 synthase, ST8SIA1 in cartilage, synovial tissue, and subchondral bone marrow from OA patients compared to healthy donors. Moreover, we revealed a strong correlative association between the expression of ST8SIA1 and GD3 production with senescence hallmarks in an in vitro-induced 3D organotypic OA cartilage model but also with cartilage histological grading scores in human and preclinical murine OA joints. Anti-GD3 cell sorting showed that GD3-positive human OA chondrocytes or human OA synoviocytes are enriched in senescence and SASP markers compared to GD3-negative counterparts confirming that GD3 is a cell surface marker linked to the senescence stage. Intra-articular anti-GD3 antibody delivery in experimental OA model, reduced local expression of senescence and OA markers in association with a protection against OA-induced subchondral bone remodeling. Our research demonstrates a compelling linkage between ST8SIA1 gene, GD3 and senescence in OA pathology, revealing knowledge and perspectives for a better understanding and anti-senescence treatment of OA pathogenesis.

Hematopoietic stem cells (HSCs) exhibit significant age-related phenotypic and functional alterations. Although single-cell technologies have elucidated age-related compositional changes, prospective identification of aging-associated HSC subsets has remained challenging. In this study, utilizing Clusterin (Clu)-GFP reporter mice, we demonstrated that Clu expression faithfully marks age-associated myeloid/platelet-biased HSCs throughout life. Clu-GFP expression clearly segregates a novel age-associated HSC subset that overlaps with but is distinct from those previously identified using antibodies against aging maker proteins or reporter systems of aged HSC signature genes. Clu-positive (Clu+) HSCs emerge as a minor population in the fetus and progressively expand with age. Clu+ HSCs display not only an increased propensity for myeloid/platelet-biased differentiation but also a unique behaviour in the BM, favouring self-renewal over differentiation into downstream progenitors. In contrast, Clu-negative (Clu-) HSCs exhibit lineage-balanced differentiation, which predominates in the HSC pool during development but becomes underrepresented as aging progresses. Both subsets maintain long-term self-renewal capabilities even in aged mice but contribute differently to hematopoiesis. The predominant expansion of Clu+ HSCs largely drives the age-related changes observed in the HSC pool. Conversely, Clu- HSCs preserve youthful functionality and molecular characteristics into old age. Consequently, progressive changes in the balance between Clu+ and Clu- HSC subsets account for HSC aging. Our findings establish Clu as a novel marker for identifying aging-associated changes in HSCs and provide a new approach that enables lifelong tracking of the HSC aging process.

Objectives: Biological age may better capture differences in disease course among people with multiple sclerosis (PwMS) of identical chronological age. We investigated biological age acceleration through metabolomic age (mAge) in PwMS and its association with social determinants of health (SDoH) measured by the area deprivation index (ADI). Methods: mAge was calculated for three cohorts: 323 PwMS and 66 healthy controls (HCs); 102 HCs and 72 DMT-naive PwMS; and 64 HCs and 67 pediatric-onset MS/clinically isolated syndrome patients, using an aging clock derived from 11,977 healthy adults. mAge acceleration, the difference between mAge and chronological age, was compared between groups using generalized linear and mixed-effects models, and its association with ADI was assessed via linear regression. Results: Cross-sectionally, PwMS had higher age acceleration than HCs: 9.77 years in adult PwMS (95% CI:6.57- 12.97, p=5.3e-09), 4.90 years in adult DMT -ve PwMS (95% CI:0.85-9.01, p=0.02), and 6.98 years (95% CI:1.58-12.39, p=0.01) in pediatric-onset PwMS. Longitudinally, PwMS aged 1.19 mAge years per chronological year (95% CI:0.18, 2.20; p=0.02), faster than HCs. In PwMS, a 10-percentile increase in ADI was associated with a 0.63-year (95% CI:0.10- 1.18; p=0.02) increase in age acceleration. Discussion: We demonstrated accelerated mAge in adult and pediatric-onset PwMS and its association with social disadvantage.

Ageing is often accompanied by cognitive decline and an increased risk of dementia. Exercise is a powerful tool for slowing brain ageing and enhancing cognitive function, as well as alleviating depression, improving sleep, and promoting overall well-being. The connection between exercise and healthy brain ageing is particularly intriguing, with exercise-induced pathways playing key roles. This review explores the link between exercise and brain health, focusing on how skeletal muscle influences the brain through muscle-brain crosstalk. We examine the interaction between the brain with well-known myokines, including brain-derived neurotrophic factor, macrophage colony-stimulating factor, vascular endothelial growth factor and cathepsin B. Neuroinflammation accumulates in the ageing brain and leads to cognitive decline, impaired motor skills and increased susceptibility to neurodegenerative diseases. Finally, we examine the evidence on the effects of exercise on neuronal myelination in the central nervous system, a crucial factor in maintaining brain health throughout the lifespan.

Notch signaling plays a pivotal role in regulating satellite cell (SC) behavior during skeletal muscle development, homeostasis, and repair. While well-characterized in mouse models, the impact of Notch signaling in human muscle tissues remains largely underexplored. Here, a 3D tissue-engineered model of human skeletal muscle ("myobundles") is utilized as an in vitro platform for temporal control and studies of Notch singaling. Myofiber-specific overexpression of the Notch ligand, DLL1, early in myobundle differentiation increases the abundance of 3D SCs and shifts their phenotype to a more quiescent-like state, along with decreasing muscle mass and function. In contrast, myofiber-specific DLL1 overexpression after one week of myobundle differentiation does not affect 3D SC abundance or muscle function, but increases transcriptomic markers of SC quiescence, confirming the temporal dependence of SC activation and self-renewal on Notch signaling activity. Finally, for the first time these studies show that even after a transient, myofiber-specific upregulation of Notch signaling in myobundles, 3D SCs expanded from these tissues can re-form functional "secondary" myobundles containing an amplified SC pool. Future studies in the described human myobundle platform are expected to aid the development of novel Notch-targeted therapies for muscular dystrophies and aging.

Genomic stability, encompassing DNA damage and repair mechanisms, plays a pivotal role in the onset of diseases and the aging process. The stability of DNA is intricately linked to the chemical and mechanical forces exerted on chromatin, particularly within lamina-associated domains (LADs). Mechanical stress can induce DNA damage through the deformation and rupture of the nuclear envelope, leading to DNA bending and cleavage. However, DNA can evade such mechanical stress-induced damage by relocating away from the nuclear membrane, a process facilitated by the depletion of H3K9me3-marked heterochromatin and its cleavage from the lamina. When DNA double-stranded breaks occur, they prompt the rapid recruitment of Lamin B1 and the deposition of H3K9me3. Despite these insights, the precise mechanisms underlying DNA damage and repair under mechanical stress remain unclear. In this review, we explore the interplay between mechanical forces and the nuclear envelope in the context of DNA damage, elucidate the molecular pathways through which DNA escapes force-induced damage, and discuss the corresponding repair strategies involving the nuclear cytoskeleton. By summarizing the mechanisms of force-induced DNA damage and repair, we aim to underscore the potential for developing targeted therapeutic strategies to bolster genomic stability and alleviate the impacts of aging and disease.