Longevity Papers

Vascular ageing (VA), characterized by vascular endothelial dysfunction, is a major contributor to age-related chronic conditions. Leucine-rich repeat-containing protein 8A (LRRC8A) is vital in maintaining vascular endothelial function; however, the role of endothelial LRRC8A in VA is undefined. We aimed to investigate the role and mechanism of endothelial LRRC8A in VA.

Approximately 17% of people aged 65 years and older are anemic, and 10% of death certificates report anemia as a secondary cause of death in the US. Nonetheless, anemia remains unexplained in 30-50% of older adults. This unexplained anemia of aging (UAA) is a diagnosis of exclusion. The mechanism, impact, and progression of UAA remain unknown. At older ages, anemia adds to pre-existing co-morbidities with significant adverse health consequences, representing a compelling unmet clinical concern. The National Institute on Aging held a workshop in 2024 to discuss current knowledge and research opportunities. Topics included the epidemiology of anemia at older age, its clinical implications; probable mechanism(s) underlying UAA, ie; low grade inflammation's effects on erythropoiesis; the role of microbiota in iron regulation in bone marrow; the importance of ruling out a diagnosis of leukemic clonal hematopoiesis (CH), which is more prevalent in older age; the role of senescence and aging governing hematopoiesis, and effects of sex hormones on hematopoietic stem cell aging. Understanding the roles of these factors could reduce the proportion of the older anemic population whose anemia remains unexplained and offer insights into new potential diagnostic and intervention strategies. Speakers reviewed previous clinical trials in patients with UAA and CH. They discussed lessons learned, and future research priorities ., including efforts to develop new diagnostic algorithms and potential uses of machine learning.

Astrocyte diversity is currently expanding both between and within specific brain regions. Here, we assessed the spatial distribution and transcriptomic profile of two hippocampal astrocyte subpopulations, defined by combinatorial expression of the cell surface astrocyte markers ACSA-1 or GLAST/SLC1A3, and ACSA-2 or ATP1B2. Fluorescence activated cell sorting and genome-wide transcriptomics by bulk RNAseq uncovered distinct transcriptional signatures of the two astrocyte subsets and highlighted heterogeneous responses during aging. The most abundant ATP1B2/GLAST double-positive astrocytes corresponded to mature glial cells with increased protein glycosylation and stable gene expression patterns. Signatures related to mitochondrial respiration and cholesterol metabolism were induced during aging in ATP1B2 single-positive astrocytes, while cell adhesion genes from the {gamma}-protocadherin cluster were repressed in double-positive astrocytes. Heterochronic co-culture assays with primary neurons show the loss of synaptogenic function of old ATP1B2/GLAST astrocytes. Our results complement previous studies demonstrating the presence of morphological and molecular astrocyte heterogeneity within the hippocampus, and uncover differences among astrocyte subsets in their transcriptomic response to aging.

Cornus officinalis Sieb. et Zucc. (C. officinalis) has been widely utilized as a traditional Chinese medicine and food ingredient in China. C. officinalis polysaccharides (COPs) is one of the key bioactive components of C. officinalis, which has attracted much attention due to their decent pharmacological activities, such as anti-aging, antioxidant, anti-tumor, antidiabetic, neuroprotective effects and anti-atherosclerotic efficacy. COPs can be extracted via diverse methods with the extraction yields ranging from 3.42 % to 30.43 %. Although significant progress has been made in the extraction and purification technologies, the structure-activity relationships between COPs structures and their pharmacological effects remain to be fully elucidated. To address this, the present review systematically summarizes recent advances in COPs research, including extraction methods, purification techniques, structural characteristics, bioactivities, and safety assessment. In addition, the structure-activity relationships of COPs were critically analyzed and their potential applications, current challenges, and future research directions were discussed, which would provide theoretical reference and practical guidance for the follow-up studies.

The pregnane X receptor (Pxr) regulates metabolism and inflammation, but its roles in bone homeostasis remain elusive. This study demonstrates that Pxr deficiency in bones induces osteoporotic phenotypes, with reduced trabecular bone mass, impaired osteogenesis, increased inflammation, and apoptosis. RNA sequencing reveals downregulation of the PI3K/Akt signaling pathway in Pxr-deficient bones, a key pathway linked to cell survival and differentiation. In vitro, primary bone marrow mesenchymal stem cells (BMSCs) with Pxr deficiency exhibited inhibited antioxidant enzyme activity, elevated intracellular reactive oxygen species level, activated pro-inflammatory cytokines, suppressed PI3K/Akt pathway, enhanced apoptosis, and decreased osteogenic differentiation. Conversely, Pxr overexpression in BMSCs from aged mice restores PI3K/Akt activation, mitigates apoptosis, and rescues osteogenic differentiation, with these multidirectional beneficial effects abrogated by a PI3K/Akt inhibitor. Moreover, both genetical overexpression of Pxr and pharmacological activation of Pxr improve bone quality in aged mice. These findings identify Pxr as a key regulator of bone homeostasis via the PI3K/Akt pathway, suggesting Pxr as a potential treatment target for age-related bone loss.

Mitophagy is crucial for the selective autophagic degradation of damaged mitochondria, helping to maintain both mitochondrial and cellular homeostasis. Here, we report a fluoroalkylated polypyridinium that specifically targets mitochondria and exhibits high activity in mitophagy induction. The polymer effectively restores mitochondrial function and alleviates the inflammatory response in foam cells by activating mitophagy, and displays inherent red fluorescence under physiological conditions, allowing for direct tracing of its biodistribution in cells and in vivo. Besides, the polymer nanoparticle shows high serum stability due to the antifouling properties of fluoroalkyl tags. After intravenous administration, the nanoparticle reduces oxidative stress, promotes mitophagy, and decreases cellular senescence in atherosclerotic plaques, contributing to high therapeutic efficacy. This study presents an innovative and effective strategy for the treatment of atherosclerosis and other mitochondrial dysfunction-related inflammatory conditions.

The field of ageing science has gone through remarkable progress in recent decades, yet many fundamental questions remain unanswered or unexplored. Here we present a curated list of 100 open problems in ageing and longevity science. These questions were collected through community engagement and further analysed using Natural Language Processing to assess their prevalence in the literature and to identify both well-established and emerging research gaps. The final list is categorised into different topics, including molecular and cellular mechanisms of ageing, comparative biology and the use of model organisms, biomarkers and the development of therapeutic interventions. Both long-standing questions and more recent and specific questions are featured. Our comprehensive compilation is available to the biogerontology community on our website ( www.longevityknowledge.app ). Overall, this work highlights current key research questions in ageing biology and offers a roadmap for fostering future progress in biogerontology.

The effectiveness of the immune system decreases with increasing age. This process is known as immunosenescence. Recent studies showed the influence of aging on neutrophil granulocytes (PMNs) and T-cells, with the extent of the influence appearing to depend on various co-factors (such as the primary diseases of a patient). In this study, the PMNs and T-cells of younger and older adult patients were tested for their immunoreactivity before and after an operation in order to examine the consequences of the aging process on the moderately triggered immune system. Whole blood was taken from young patients (aged 18-65 years) and old patients (> 65 years) before and one day after an operation. Previous illnesses and medication intake were taken from the patient's file. PMNs and T-cells were isolated. Immunoassays, live cell imaging (LCI) and flow cytometric examinations (FACS) were performed in order to assess certain properties of the PMNs (chemotactic migration, ROS production, NET formation, change of surface epitopes), their expression of adhesion molecules as well as their cell viability. In addition, the blood samples were subjected to a laboratory chemical examination. Above all during the initial LCI observation period (< 40 min), the PMNs of old patients covered longer distances than those of young patients. NETosis, ROS production and surface antigen expression were influenced neither by age nor by the surgical procedure. Regardless of age, PMNs´ ROS production started earlier 24 h after the operation compared to the pre OP values. By labeling the translocator protein (TSPO), it was demonstrated that mitochondrial release occurs only during suicidal NETosis. Old patients showed significantly more TSPO-labeled mitrochondria per PMN. The neutrophil-to-lymphocyte ratio (NLR) and the CD4/CD8 ratio were significantly increased in older patients. The share of CD28- and CD8-positive cells was increased in younger patients. All patients showed postoperative leukocytosis caused by an increase in monocytes and PMNs, which was independent of the extent of the trauma. Only young patients showed a postoperative increase in lymphocytes. Old patients had higher IL-6 levels than young patients. The operation did not lead to any increases in the IL-6 and CRP levels. Age influences the function of PMNs and T-cells more strongly than a moderate surgical trauma in combination with anaesthesia. The results advance our understanding of the decreasing effectiveness of the immune system in old age.

Exercise is the primary choice for managing age-related sarcopenia. However, many exercise intervention subtypes are currently used to manage age-related sarcopenia with little published evidence comparing their efficacy, meaning the optimal exercise intervention subtype for sarcopenia remains unclear. We performed a Bayesian network meta-analysis addressing these uncertainties.

The factors influencing hippocampal aging are complex, and it remains challenging to identify effective anti-aging drugs and reveal pharmacological mechanisms. This study investigates the effects of autophagy mediated by the SIRT1/FoxO1 signaling pathway on resveratrol resistance to H

Advancing age is accompanied by an accumulation of senescent T cells that secrete pro-inflammatory senescence-associated secretory phenotype (SASP) molecules. Gut-microbiota-derived signals are increasingly recognised as immunomodulators. In the current study, we demonstrated that ageing and the accumulation of senescent T cells are accompanied by a reduction in microbial-derived short-chain fatty acids (SCFAs). Culturing aged T cells in the presence of butyrate suppresses the induction of a senescence phenotype and inhibits the secretion of pro-inflammatory SASP factors, such as IL6 and IL8. Administration of faecal supernatants from young mice rich in butyrate prevented in vivo accumulation of senescent spleen cells in aged mice. The molecular pathways governing butyrate's senomorphic potential include a reduced expression of DNA damage markers, lower mitochondrial ROS accumulation, and downregulation of mTOR activation, which negatively regulates the transcription factor NFκB. Our findings establish butyrate as a potent senomorphic agent and provide the evidence base for future microbiome restitution intervention trials using butyrate supplements for combating T cell senescence, ultimately reducing inflammation and combating age-related pathologies to extend lifelong health.

Histone H4K16 acetylation (H4K16ac) is a key epigenetic mark essential for chromatin structure and DNA repair, which is substantially reduced in the accelerated aging disorder Hutchinson-Gilford progeria syndrome (HGPS). The specific enzymes governing H4K16ac homeostasis, particularly the deacetylase responsible for its loss in HGPS, remain poorly defined. Here, we sought to identify the enzymes regulating H4K16ac and determine if their inhibition could rescue HGPS-associated cellular defects. Using systematic siRNA screening in HeLa and U2OS cells, we confirmed that KAT8/MOF is the principal H4K16 acetyltransferase. Surprisingly, we identified HDAC2 as the dominant class I histone deacetylase for H4K16ac; knockdown of the highly homologous HDAC1 had no effect. While SIRT1 knockdown also increased H4K16ac, its contribution was minimal in HGPS vascular smooth muscle cells (VSMCs) compared to HDAC2. Crucially, selective pharmacological inhibition of HDAC2, but not SIRT1, robustly restored H4K16ac levels in HGPS VSMCs. This restoration led to a significant rescue of premature aging phenotypes, including improvements in nuclear morphology, preservation of proliferative capacity (Ki67) at late passages, and a significant reduction in cellular senescence. The effects of HDAC2 inhibition on cellular senescence and nuclear morphology suggests that HDAC2-mediated histone deacetylation contributes directly to the pathological features of HGPS, extending the functional impact of HDAC2 inhibition beyond DNA repair defects to fundamental aspects of cellular aging.

This study investigated the relationship between plasma Interleukin-17A (IL-17A) and Interleukin-17F (IL-17F) levels and peripheral arterial disease (PAD), and explored the role of IL-17F in neovascularization in a preclinical PAD model of aged mice. Using an enzyme-linked immunosorbent assay, we found that plasma IL-17A levels were similar in young and aged groups in both PAD patients and mice with hindlimb ischemia. In contrast, IL-17F levels were elevated in the aged group. Spearman correlation analysis showed a positive correlation between IL-17F levels and PAD severity, onset risk, and cardiovascular outcome. Under simulated ischemic conditions, IL-17F induced endothelial cells (ECs) senescence and dysfunction in a dose-dependent manner. In aged male and female mice following left femoral artery ligation, results from Doppler imaging, ischemia and motor scores, and histology indicated that neutralization of IL-17F enhanced blood flow recovery, reduced ischemia scores, improved motor scores, and facilitated muscle regeneration and repair. Micro-CT, whole-mounting, and immunofluorescence staining results showed that neutralization of IL-17F promoted neovascularization and inhibited ischemic hindlimb muscle ECs' senescence and dysfunction. This study reveals for the first time that higher IL-17F levels were positively associated with PAD severity, onset risk, and cardiovascular outcome. Neutralization of IL-17F promoted postischemic neovascularization in aged mice, suggesting it represented a promising therapeutic strategy for elderly PAD patients.

This study applied multivariate ANOVA to investigate age-related microstructural changes in the brain tissues driven primarily by myelin, iron, and water content, as observed in MRI (semi-)quantitative R1, R2*, MTsat and PD maps. This is effectively a re-analysis of the data analyzed in a univariate way by Callaghan et al., 2014. Voxel-wise analyses were performed on gray matter (GM) and white matter (WM), in addition to region of interest (ROI) analyses. The multivariate approach identified brain regions showing coordinated alterations in multiple tissue properties and demonstrated bidirectional correlations between age and all examined modalities in various brain regions, including the caudate nucleus, putamen, insula, cerebellum, lingual gyri, hippocampus, and olfactory bulb. The multivariate model was more sensitive than univariate analyses, as evidenced by detecting a larger number of significant voxels within clusters in the supplementary motor area, frontal cortex, hippocampus, amygdala, occipital cortex, and cerebellum bilaterally. The examination of normalized, smoothed, and z-transformed maps within the ROIs revealed concurrent age-dependent alterations in myelin, iron, and water content. These findings contribute to our understanding of age-related brain differences and provide insights into the underlying mechanisms of aging. The study emphasizes the importance of multivariate analysis for detecting subtle microstructural changes associated with aging when dealing with multiple quantitative MRI parameter maps.

Environmental stressors and sex-specific life-history strategies synergistically shape senescence patterns in ectotherms, yet their interactive effects on telomere dynamics remain poorly understood. This study investigates how altitude-related environmental factors and sexual dimorphism drive telomere length variation in the montane salamander Pachytriton cheni across an elevational gradient (850-1350 m) in Qingliangfeng Nature Reserve, China. Using qPCR, skeletochronology and physiological assays, we analysed telomere length, age, oxidative damage markers and environmental parameters in 100 individuals. Results revealed a significant positive correlation between altitude and relative telomere length (RTL), with males exhibiting stronger elevational dependence than females. Multivariate models identified divergent environmental effects: higher flow velocity promoted telomere maintenance, whereas elevated water temperature, dissolved oxygen and dietary diversity accelerated attrition. Despite lower mobility, females maintained longer telomeres than males, suggesting sex-specific trade-offs favouring somatic maintenance over reproductive investment. Oxidative damage markers (malondialdehyde and protein carbonyls) were elevated at lower altitudes, aligning with free radical theory predictions. These findings highlight the interplay of environmental stressors (e.g., thermal and oxidative pressures) and sex-driven energy allocation in shaping telomere dynamics. Our work underscores the importance of integrating climate resilience into conservation strategies for high-altitude amphibians, particularly as habitat degradation and climate change threaten montane ecosystems. Our findings on the genotype-environment-sex interactions in P. cheni provide a conceptual framework for predicting how ectotherms may senesce in rapidly changing environments.

Aging induces structural and functional alterations in the kidneys, including changes in renal morphology and progressive decline in renal function. During aging, the gut microbiota undergoes profound shifts in composition and activity, transitioning from predominantly commensal to more pathogenic communities. Renal dysfunction further exacerbates this process by reducing toxin clearance and promoting the accumulation of uremic metabolites, which disrupt gut microbial balance. In turn, gut dysbiosis impairs kidney function, creating a self-perpetuating cycle of microbial imbalance and renal damage. Hence, breaking this vicious cycle of dysbiosis and kidney damage is important. This review sheds light on the bidirectional relationship between gut microbiota and kidney aging. It also highlights the potential of microbiota-targeted interventions to restore microbial balance and delay the onset of age-related issues.

Given that limited research has examined the relationships between lifestyle activities of varying intensities, including moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), and sedentary behavior (SB), and dynapenia, which refers to an age-related decline in muscle function, this study aimed to investigate the longitudinal associations between MVPA, LPA, and SB and the risk of dynapenia among older adults in Taiwan.

Age-related hearing loss (HL) is an increasing contributor to the global burden of disease in aging populations. Its interactions with major chronic diseases remain insufficiently characterized. We analyzed data from the Global Burden of Disease 2021 study for adults aged ≥ 45 years. YLDs for HL, diabetes, cardiovascular diseases (CVD), stroke, and depressive disorders were examined from 1990 to 2021. Data were stratified by age, sex, and region. Multivariate regression models and Pearson correlations were applied to evaluate associations, and a linear forecast projected HL burden to 2030. Visualizations included temporal trends, boxplots, and correlation heatmaps. Between 1990 and 2021, HL YLDs increased from 28.7 million to 67.9 million (+ 136.7%). Diabetes (+ 311.9%), CVD (+ 123.8%), and stroke (+ 112.6%) also rose substantially. Regression analysis indicated significant associations between HL and stroke (β = 1.798, p = 0.0010) and depression (β = 0.218, p < 0.001), whereas diabetes showed no independent effect and CVD displayed a negative relationship (β = -1.374, p = 0.0016). Correlation analyses revealed regional clustering, with HL aligning more closely with stroke than with diabetes or CVD. Forecasting projected HL YLDs to reach 75.6 million by 2030, underscoring its growing impact. HL has become a major global health challenge in aging populations, strongly linked to multimorbidity, particularly stroke and depression. Integrating auditory health into chronic disease frameworks and healthy aging strategies is essential to reduce future disease burden.

Males and females are known to have dramatically different health and lifespan trajectories, but the underlying basis for these differences is only now being fully investigated. In the Caenorhabditis elegans nematode model system, most aging studies have been conducted with hermaphrodites, and little is known about male-specific responses to pro-longevity mutations. Several previous studies have used the auxin-inducible degron system to degrade the insulin-like DAF-2/IGF-1 receptor in hermaphrodites, finding that both ubiquitous and tissue-specific degradation can extend lifespan. Here we show that ubiquitous degradation of DAF-2 in male C. elegans increases median lifespan by more than 440%, one of the longest lifespan extensions by a single intervention to date. Conversely, degrading DAF-2 in the male germline decreased lifespan, opposite of its effect in hermaphrodites. Using male mating and reproductive success as a meaningful ecological and neurophysiological measure of healthspan, we found that ubiquitous degradation of DAF-2 greatly prolongs reproductive health, likely by prolonging function of the male intromittent organ in the tail. This work highlights the importance of studying sex differences in aging and highlights the utility of using C. elegans males to understand the underlying basis of enhanced lifespan and healthspan.

The hippocampus, a brain region critical for memory, undergoes significant age-related changes at both the macroscopic and microstructural levels. This study investigates these changes using high-gradient diffusion MRI (dMRI) data analyzed in an unfolded hippocampal space. We applied the Soma and Neurite Density Imaging (SANDI) model to quantify microstructural alterations in 72 cognitively healthy participants aged 19-85 years, scanned on a 3 T Connectome MRI scanner with a maximum gradient strength of 300 mT/m. By combining SANDI with a super-resolution algorithm and the HippUnfold toolbox, we achieved high spatial fidelity in our analysis. We observed significant age-related reductions in soma fraction and soma radius, particularly in the subiculum and dentate gyrus, alongside increases in extracellular diffusivity and extracellular fraction, indicating a decline in cellular density and structural integrity. These microstructural changes occur alongside macroscopic alterations such as reduced hippocampal volume and cortical thickness, decreased gyrification, and increased curvature in specific subfields. The spatial correlations between microstructural and macroscopic metrics across the unfolded hippocampal space are weak, both in their mean values and in how they change with age. Our findings suggest that SANDI metrics provide sensitive and complementary information to traditional structural measures, offering new insights into the microstructural underpinnings of hippocampal aging. This study highlights the potential of advanced dMRI techniques to detect subtle age-related changes in hippocampal microstructure, which may contribute to our understanding of aging and its impact on memory and cognition.

Aging is associated with genome-wide changes in DNA methylation in humans, facilitating the development of epigenetic age prediction models. However, these models have been trained primarily on European-ancestry individuals and none account for the impact of methylation quantitative trait loci (meQTL). To address these gaps, we analyze the relationships between age, genotype, and CpG methylation in 3 understudied populations: central African Baka (n = 35), southern African ‡Khomani San (n = 52), and southern African Himba (n = 51). We show that published prediction methods yield higher mean errors in these cohorts compared to European-ancestry individuals and find that unaccounted-for DNA sequence variation may be a significant factor underlying this loss of accuracy. We leverage information about the associations between DNA genotype and CpG methylation to develop an age predictor that is minimally influenced by meQTL and show that this model remains accurate across a broad range of genetic backgrounds. Intriguingly, we also find that the older individuals and those with lower epigenetic age acceleration carry more genetic variants linked to reduced epigenetic age. These findings support the hypothesis that multiple heritable factors collectively influence healthspan and longevity in human populations.

Astrocytes are central to brain homeostasis, supporting neuronal metabolism, synaptic activity, and the blood-brain barrier. With aging, these glial cells undergo molecular and functional changes that weaken support functions and promote neuroinflammation, contributing to neurodegeneration. Yet the systems-level mechanisms of astrocytic aging remain poorly defined in human models. Because aging also heightens risk for cardiovascular disease, cognitive impairment, type 2 diabetes, and systemic inflammation, clarifying shared astrocytic pathways is critical for understanding brain-body crosstalk. Using an in vitro human astrocyte model exposed to sublethal oxidative stress (10 M H2O2), we profiled transcriptomic changes and identified differentially expressed genes across antioxidant defences, proteostasis, transcriptional regulation, vesicular trafficking, and inflammatory signalling. We then performed seven network-prioritization analyses on a curated human protein-protein interactome: one seeded with the astrocyte H2O&2-responsive genes and six with phenotype-associated gene sets (Alzheimer\'s disease, cardiovascular disease, cognitive impairment, type 2 diabetes, oxidative stress, and inflammation). Intersecting the top 5% scoring genes from each run yielded a 127-gene core shared across all seven, enriched for proteostasis, DNA repair, mitochondrial regulation, and telomere and nuclear envelope maintenance. Structure-guided analyses highlighted vulnerable interfaces, including lamin A/C-lamin B1, -actinin-filamins, 14-3-3 dimers, and aminoacyl-tRNA synthetase assemblies, where pathogenic variants are predicted to destabilize or aberrantly stabilize protein interactions. Structure-based interface predictions also highlight potential interactions between APP-VCP/p97 and p53-14-3-3{zeta} that link proteostasis and stress signalling. Together, these findings define a conserved astrocytic vulnerability network that may couple neurodegeneration with cardiovascular disease and nominate structurally testable targets for biomarkers and interventions.

Despite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWH) experience persistent inflammation, immune dysfunction, and premature onset of cardiovascular and aging related comorbidities. To define the underlying mechanisms, we performed longitudinal transcriptomic profiling in peripheral blood mononuclear cells (PBMCs) from a cohort of simian immunodeficiency virus (SIV) infected rhesus macaques spanning four key stages: preinfection, acute infection, short term ART, and long term ART. Bulk RNA sequencing revealed dynamic immune remodeling across infection and treatment. Acute SIV infection induced robust antiviral and inflammatory programs, with upregulation of interferon-stimulated genes (ISGs), IL-27, JAK/STAT, and NFkB signaling, coupled with suppression of T cell and B cell activation pathways. Short term ART effectively reversed these transcriptional perturbations, restoring adaptive immune gene expression and reducing innate antiviral responses to near baseline levels. In contrast, chronic SIV infection on long term ART maintained viral suppression but was characterized by reactivation of innate immune pathways, including TLR2/TLR4/MYD88, NFkB, and inflammasome (NLRP3 or NLRP12, caspase1) signaling, along with sustained macrophage activation, platelet/coagulation signaling, and senescence-associated secretory phenotype. Protein analyses confirmed persistent CASPASE1 and NFkB activation in spleen tissue. Pathologic evaluation of a carotid artery from an SIV infected, long term ART treated macaque revealed macrophages in plaques with p21 expressing; senescent cells with intraluminal thrombus formation, recapitulating key features of HIV associated atherogenesis. Together, these findings demonstrate that while ART normalizes acute infection induced immune dysregulation, chronic SIV infection sustains a chronic, macrophage and TLR driven inflammatory state linked to vascular injury and aging process regardless of long term suppression of viremia. Targeting inflammasome, NFkB, and senescence pathways may mitigate nonAIDS comorbidities in PLWH.

The skin is one of the earliest organs in the human body to exhibit signs of aging, with photoaging mainly caused by chronic ultraviolet (UV) exposure and recognized as a major form of extrinsic aging. Small extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hucMSC-sEVs) have been shown to delay skin aging by upregulating pregnancy zone protein (PZP), which modulates inflammatory responses, oxidative stress, and extracellular matrix remodeling. However, the core regulatory network underlying these effects remains unclear. Focusing on PZP, this study integrated bioinformatics to identify GATA2 as a potential upstream transcriptional regulator and GRP75 as a possible downstream target, indicating a GATA2/PZP/GRP75 signaling axis that may regulate photoaging. ChIP assays and dual-luciferase reporter analyses confirmed that GATA2 binds to the promoter region of PZP and upregulates its transcription. Knockdown and overexpression experiments further demonstrated that GATA2 suppresses or promotes PZP expression, thereby significantly influencing the senescence phenotype of dermal fibroblasts under UV irradiation. In addition, protein docking, co-immunoprecipitation (CoIP), and immunofluorescence colocalization assays validated the interaction between PZP and GRP75. PZP alleviates mitochondrial calcium overload and dysfunction by inhibiting the abnormal elevation of GRP75, thus delaying photoaging. These findings offer novel insights and targets for skin-aging intervention.

​​ Immune function decline (immunosenescence) accelerates systemic aging and adversely impacts cognitive function. Antioxidants may mitigate these effects; however, the role of ascorbic acid (AA), a key antioxidant, in counteracting immunosenescence and enhancing cognition remains inadequately explored.

Ultraviolet-B (UVB) radiation exacerbates oxidative stress, accelerating collagen degradation and skin aging. While collagen and its hydrolysates offer therapeutic potential, medical apparatus and instruments call for high quality and traceability. Here we investigated the synergistic effects of collagen and collagen peptides derived from Shad (Alosa sapidissima) scales against UVB-induced skin damage. Collagen was extracted and peptides were obtained through enzymatic hydrolysis. Structural characterization confirmed collagen's triple helix and peptide fragments. In vitro assays demonstrated concentration-dependent antioxidant activity: collagen peptides (5%-10%) and collagen (0.5%-1%) exhibited potent DPPH/ABTS⁺ radical scavenging, with their combination outperforming individual components. In UVB-irradiated mice, topical application of the collagen-peptide mixture significantly reduced epidermal thickening, suppressed ROS production, and enhanced SOD activity. Histological analysis revealed mitigated wrinkle formation and improved dermal blood flow. The mixture also formed stable hydrogels, enhancing bioavailability. These findings highlight the dual mechanism of collagen (structural support) and peptides (antioxidant/moisturizing effects), offering a promising strategy for combating photoaging. This study provides foundational insights for developing marine collagen-based dermatological therapies.

Aging is a complex process that frequently includes cognitive decline with memory loss. In the hippocampus, the number of somatostatin-positive (Sst

It is known that the senescence-associated secretory phenotype (SASP) can promote senescence of surrounding normal cells. However, SASP signaling during senescence of mesenchymal stromal cells (MSCs) has not yet been fully studied. We determined the pattern of secreted proteins specific to MSCs under stress-induced senescence. Using chromatography-mass spectrometry, proteins specific to the secretome of senescent or "young" cells were identified. The secretome of senescent cells contains proteins both associated with senescence (LOXL2, CCL2, PLAT, SERPINE2, etc.) and important for reducing the impact of these processes, in particular, proteins responsible for inhibition of oxidative stress (MIF, PRDX5, GSTM2), detoxification of methylglyoxal (GLO1), and suppression of inflammatory reactions (GAS6, GSTM2). The obtained results indicate the complex etiology of aging and the ambiguity of the function of SASP within the paracrine induction of aging of neighboring cells.

Aging disrupts physiological homeostasis, impairing thermoregulation, metabolism, and water balance, but the underlying neural mechanisms remain unclear. Here, we identify arginine vasopressin (AVP) neurons in the supraoptic nucleus (SON) of the hypothalamus as a critical driver of these changes. Using single-nucleus RNA-sequencing of the anterior hypothalamus in young and aged mice, we found Avp to be one of the most upregulated neuronal transcripts with age. Aged SON-AVP neurons displayed enlarged size and heightened excitability, features consistent with hyperactivity. Functionally, chemogenetic activation of SON-AVP neurons in young mice reproduced aging-associated phenotypes including hypothermia, reduced energy expenditure, and suppressed water intake. Conversely, knockdown of Avp in the SON of aged mice restored water balance, partially improved thermoregulation and systemic metabolism. Pharmacological inhibition of AVP receptors revealed that neuroendocrine release of AVP drives homeostatic deficits, with distinct roles for V1A and V2 receptors. Senolytic drug treatment improved systemic metabolism and reduced inflammaging but does not rescue hypothalamic AVP dysfunction, underscoring a brain autonomous mechanism of age-related physiological failure. Together, our findings establish SON-AVP neuronal hyperactivity as a driver of impaired homeostasis with age and suggest that targeted modulation of neuroendocrine AVP signaling may offer a therapeutic strategy to alleviate age-associated water balance defects.

The Asian Working Group for Sarcopenia (AWGS) presents an updated 2025 consensus reframing sarcopenia management through a life-course approach to muscle health promotion. While aligning with the Global Leadership Initiative in Sarcopenia (GLIS), this update provides healthcare providers with Asia-specific guidance. The consensus introduces three key refinements: first, expanding sarcopenia diagnosis to middle-aged adults (50‒64 years) with validated diagnostic thresholds; second, simplifying the diagnostic algorithm to require only concurrent low muscle mass and strength, with physical performance as an outcome measure; and third, introducing an enhanced muscle health framework recognizing skeletal muscle as vital for healthy longevity, emphasizing cross-talk with brain, bone, adipose tissue and immune systems. This framework leverages the World Health Organization's Integrated Care for Older People (ICOPE) implementation for enhanced case-finding through natural overlap between muscle health and ICOPE's intrinsic capacity domains. The consensus provides evidence-based recommendations for multimodal interventions that combine resistance exercise with nutritional supplementation, representing advancement toward proactive muscle health promotion and establishing a framework for reducing age-related decline in Asian populations.

Age-related protein aggregation drives senile osteoporosis. Aberrant tRNA modifications exacerbate the progression, yet mechanisms linking these to bone loss remain unclear. In this study, we identify Nsun2 (m5C methyltransferase) as key regulator: age-dependent Nsun2 downregulation in BMSCs reduces m5C levels of tRNAs, destabilizing tRNAs and impairing translation efficiency of specific transcripts. This directly disrupts the protein synthesis of molecular chaperone and pro-osteogenic factors, accelerating misfolded protein aggregates and activating unfolded protein response, inducing BMSCs senescence and impairing osteogenesis. Mice specifically depleted of Nsun2 exhibited reduced bone mass, whereas mice overexpressing Nsun2 alleviated age-associated bone loss. Notably, the exacerbated protein aggregation and bone mass loss in Nsun2-deficient mice were ameliorated following treatment with the molecular chaperone activator-ML346. Remarkably, ML346 administration proved sufficient to reverse age-related functional deficits in aged mice. Overall, our findings demonstrate that aberrant tRNA-m5C modification alters protein synthesis and induces proteostasis collapse, which constitute a novel contributor to the pathogenesis of senile osteoporosis. Additionally, reduction of protein aggregation through the activation of molecular chaperones presents a promising therapeutic strategy for this disease.

Yeast replicative lifespan is a crucial part of aging research, yet its quantification remains labor-intensive and time-consuming, particularly when using time-lapse imaging and microfluidics. Manual counting methods for cell division events are prone to bias and inefficiency, while existing automated approaches often require extensive annotated datasets. These limitations hinder the adaptability of such tools across different microfluidic setups. To address these challenges, we propose a versatile image analysis approach that accurately detects yeast cell division events. To reduce the burden of requiring a large cell division annotated dataset, we pretrained a Masked Auto-Encoder on large-scale segmented yeast cell images. This substantially reduced the annotated data needed to train the transformer model for detecting cellular division events. Additionally, the model is trained directly on budding event detection, circumventing reliance on arbitrary heuristics, such as changes in cell area. By leveraging self-supervised pretraining, we reduced the training data requirement to fewer than 50 mother cells (~1,000 divisions), representing a >5-fold reduction compared to prior methods while maintaining comparable accuracy.

Hematopoiesis changes over the lifetime to adapt to the physiology of development, maturation, and aging. Temporal changes in hematopoiesis parallel age-dependent incidences of certain blood diseases. Several heterochronic regulators of hematopoiesis have been identified, but how the master transcription factor (TF) circuitry of definitive hematopoietic stem cells (HSCs) adapts to changes in physiology over the lifespan is unknown. Here, we show that programmed upregulation of expression of the ETS family TF Erg during prenatal to adult maturation is evolutionarily conserved and required for implementation of adult patterns of HSC self-renewal and myeloid, erythroid, and lymphoid differentiation. Erg deficiency maintains fetal transcriptional and epigenetic programs in adulthood, and persistent juvenile phenotypes in Erg haploinsufficient mice are at least in part dependent on deregulation of the fetal-biased factor Hmga2. Overall, we identify a mechanism whereby master HSC TF networks are rewired to specify stage-specific hematopoiesis, a finding directly relevant to age-biased blood diseases.

The female longevity advantage (averaging 4 to 6 years globally) stems from reduced susceptibility to inflammaging, the chronic, low-grade inflammation driving age-related diseases like fibrosis and cardiovascular decline [10]. Interleukin 11 (IL-11), a gp130-family cytokine, has emerged as a pivotal inflammaging mediator: Its genetic or pharmacological inhibition extends mouse median lifespan by 22.5% in males and 25% in females, with enhanced healthspan benefits in the latter [20-29]. Here, we propose that estrogen\'s direct suppression of IL-11 transcription via estrogen receptor-alpha (ERalpha)-mediated interference with NF-kappa B/AP-1 on the IL-11 promoter in osteoblasts, fibroblasts, and endothelial cells establishes a premenopausal \"hormonal firewall\" against IL-11-driven senescence and multi-organ fibrosis [0-9]. In contrast, testosterone exhibits neutral or permissive effects, correlating with elevated IL-11 in hyperandrogenic states like polycystic ovary syndrome (PCOS) [30-40]. To test this, we developed an ordinary differential equation (ODE) model integrating IL-11 dynamics with upstream triggers (e.g., Ang II, c-Myc/miR-23 derepression) and suppressors (SIRT1 deacetylates IL-11 promoter histones; p53 represses IL-11/c-Myc; NRF2 quenches NF-kappa B) [10, 12]. In persistent inflammaging simulations (impaired degradation, k_deg=0.1), high estrogen (1.0 arbitrary units) reduced steady-state IL-11 by 63% (179.96 to 65.77 at t=20 days), cascading to 40-50% lower STAT3/NF-kappa B activation and triad cytokines (TNF-alpha/IL-6/IL-1beta). [11,13]. Synergy with high SIRT1/p53/NRF2 amplified suppression to [~]74% for IL-11 [16,17]. Post-menopausal estrogen decline erodes this buffer, but cumulative pre-menopausal protection persists, explaining sustained sex gaps post-65. [32,34]. This framework predicts estrogen replacement therapy (HRT) could mitigate inflammaging equitably, narrowing longevity disparities. [35]. Validation via sex-stratified IL-11 cohorts and HRT-fibrosis trials is warranted, positioning IL-11 as a sex-specific therapeutic nexus.

Understanding the genetic and epigenetic regulation of mitochondrial DNA (mtDNA) is essential for elucidating mechanisms of aging and disease. Long-read sequencing can span the entire mitochondrial genome and directly capture base-modification signals, yet analytical tools for such data remain limited. We developed Himito, a graph-based toolkit for analyzing mitochondrial genome using long reads. Himito filters reads originating from nuclear mitochondrial insertions (NUMTs), constructs a sequence graph to represent mtDNA diversity, assembles primary haplotypes, calls variants, and analyzes 5-methylcytosine (5mC) modifications within a unified framework. Benchmarking on high-quality reference datasets shows Himito achieves superior performance in assembly and variant calling compared with existing tools. Applied to the All of Us (AoU) v8 dataset, Himito identified pathogenic mtDNA variants, revealed population-scale haplogroup diversity, and uncovered age-related genetic and epigenetic patterns. These results demonstrate that long-read sequencing, combined with graph-based analysis, enables integrated characterization of mitochondrial genomic and epigenomic variation. Himito is available at https://github.com/broadinstitute/Himito.

Lipid-droplet (LD) accumulation emerges in microglia and neurons with age. Because neither cell type is specialized for lipid storage, LDs are linked to dysfunction. The upstream drivers of LD formation and their effects on neighboring cells remain unclear. Here, we identify a mitochondrial-iron axis that promotes LD formation in aging microglia via reactive oxygen species (ROS), which secondarily reshapes neuronal iron handling. LD-enriched microglia show reduced mitochondrial mass and increased labile iron, ROS, and lipid peroxidation. Chelating labile iron or scavenging ROS suppresses LD formation. Conditioned media from iron-stressed microglia alter neuronal iron homeostasis, indicating transcellular coupling. In primary neurons, iron overload increases LDs and activates coordinated iron, ROS, and lipogenesis programs, whereas antioxidant treatment attenuates iron-driven LD accumulation. Together, these findings position iron overload as an upstream regulator of ROS-dependent LD biogenesis in microglia and neurons and reveal a microglia

A mechanistic network of ovarian aging, highlighting mitochondrial dysfunction as a central hub interconnected with genetic, metabolic, and inflammatory pathways.

Metabolic diseases, including obesity, Type 2 diabetes (T2D), and metabolic syndrome, are increasingly prevalent worldwide, driven by sedentary lifestyles, aging populations, and complex genetic and environmental factors. Traditionally understood as disorders of glucose and lipid metabolism, a growing body of evidence now implicates cellular senescence as a central, age-related contributor to metabolic dysfunction. Senescent cells (SCs) accumulate in key metabolic tissues where they disrupt tissue function through the senescence-associated secretory phenotype (SASP), a pro-inflammatory and fibrogenic secretome. SASP factors exacerbate insulin resistance, chronic inflammation, and tissue remodeling, advancing the progression and complications of metabolic diseases. These insights have catalyzed the development of senotherapeutics, a class of interventions that includes senolytics (to eliminate SCs), senomorphics (to suppress SASP), and senosensitizers (to render resistant SCs more vulnerable to clearance). Although preclinical studies show promise, translation into clinical practice faces significant challenges, including identifying reliable biomarkers, understanding SC heterogeneity, and optimizing treatment timing and safety. As research advances, senotherapeutics may offer a transformative approach not only to managing metabolic diseases but also to mitigating associated comorbidities. The recognition that antidiabetic agents already in clinical use can modulate key features of senescence highlights a unique translational opportunity, suggesting that prevention of age-related metabolic disorders may be achievable with therapies already available in routine clinical practice. Medicine is poised to enter a new era in which targeting cellular senescence could fundamentally reshape the prevention and treatment of age-related metabolic disorders, offering the potential for improved healthspan and reduced disease burden across the lifespan.

Skin aging is a multifactorial biological process driven by the cumulative effects of oxidative stress, chronic low-grade inflammation, and progressive deterioration of barrier function. Among its pivotal regulatory nodes, the Vitamin D-Vitamin D receptor (VDR) signaling axis acts as an integrative hub that senses and coordinates photic, redox, and metabolic cues to regulate immune homeostasis and structural integrity, thereby shaping the skin's defensive and reparative capacity throughout aging. Disruption of this axis amplifies inflammaging, accelerates dermal and epidermal structural decline, and compromises cutaneous resilience against environmental insults. Phenotypic shifts in keratinocytes, melanocytes, Langerhans cells, and T lymphocytes during aging are tightly linked to VDR-governed transcriptional programs and pathway crosstalk. Mechanistically, Nrf2-mediated antioxidant networks, Wnt/β-catenin and NF-κB signal interplay, stabilization of E-cadherin/β-catenin complexes, lipid metabolic remodeling, and reprogramming of immune tolerance collectively constitute the molecular basis through which Vitamin D mitigates skin aging. This review systematically delineates the critical role of the VDR axis in the onset and progression of skin aging and proposes its repositioning as a programmable molecular node for intervention, aiming to modulate inflammaging and maintain barrier homeostasis to slow the structural and functional decline of aging skin.

Magnesium's (Mg) role in brain aging is under-studied. We examined associations of dietary and serum Mg with MRI and cognitive measures in a cohort with >10 y follow-up.

Physical activity (PA) is a key strategy in preventing and treating metabolic syndrome (MetS). The purpose is to investigate the associations of leisure-time PA (LTPA) trajectories across adulthood and current PA with MetS at age 61.

Long duration spaceflight is associated with neurological symptoms in astronauts, yet the underlying molecular mechanisms remain unclear. Using human brain organoids cultured aboard the International Space Station, we analyzed three independent spaceflights to demonstrate that exposure to the space environment triggers Space Induced Neural Senescence (SINS), characterized by chromatin remodeling, mitochondrial dysfunction, and activation of viral-like transcriptional programs in the absence of infection. Multiomics analyses identified upregulation of endogenous LINE-1 (L1) retroelements, whose activity was markedly enhanced in organoids lacking MECP2, a known L1 repressor implicated in Rett syndrome. The resulting accumulation of cytoplasmic L1 DNA elicited an IL6 mediated inflammatory and neurotoxic response, which was reversed by reverse transcriptase inhibitors (RTi) such as lamivudine or stavudine. Parallel preclinical experiments in Mecp2-deficient mice confirmed that RTi treatment restored neuronal morphology, synaptogenesis, function, cognition, and survival. These findings reveal that the space environment reactivates dormant genomic retroelements, providing an unexpected mechanistic insight into astronaut neurobiology and identifying a potential therapeutic strategy for both space-induced and terrestrial neurological conditions. Our pioneering study demonstrates the value of space-enabling research in accelerating drug discovery and the treatment of diseases on Earth.

Female reproductive aging is accompanied by a sharp increase in egg aneuploidy rates. Premature loss of chromosome cohesion proteins and early separation of chromosomes are thought to cause high aneuploidy rates during maternal aging. However, because cohesion loss occurs gradually throughout a woman's reproductive lifespan, and because cytoskeletal defects alone can lead to chromosomal abnormalities, the main causes of the rapid rise in aneuploidy at older reproductive ages are still unclear. In this study, we created a versatile and tunable cohesion manipulation system that enables rapid, dose-dependent degradation of the meiotic cohesin REC8 in live mouse oocytes. By coupling this system with quantitative high-resolution live imaging, we directly observed cohesion protein behavior during meiosis and tested the longstanding threshold model of aneuploidy development. Our results show that premature sister chromatid separation sharply increases only when REC8 levels drop below a critical threshold, supporting the idea of a nonlinear, vulnerability-triggering cohesion limit. We also used our system to examine how other age-related issues, such as cytoskeletal disruption and partial centromere dysfunction, can exacerbate chromatid separation in the context of weakened cohesion. This work provides a tractable oocyte platform for modeling and dissecting the multifactorial mechanisms driving female reproductive age-related egg aneuploidy.

The corpus callosum (CC) is the major tract connecting the two hemispheres in placental mammals and diffusion-weighted (DWI) MRI has revealed the meso/macroscopic organization of human CC and its organization of connectivity with the cortex. Here, we applied longitudinal DWI probabilistic tractography to study the CC fibers of mice across the adult lifespan. Our results reveal that connections of eight cortical areas can be delineated within the CC. The mouse CC organization aligns with the human topographical organization with frontal areas occupying the genus and parieto-occipital the posterior splenium region. A further regional analysis of passage fields showed stable field sizes in many of the studied areas over time. In contrast, several areas of the mouse default mode network and motor cortical regions show a decline in size with advancing age. Our analysis also identifies sex differences in the CC with female mice showing a larger orbitofrontal commissural connection. In summary, we confirm a mammalian-like organization of the CC in mice. Furthermore, we confirm an aging-related decline in the integrity of mouse white matter that aligns with previous findings in humans, thus opening up the possibility for future developmental in vivo studies across the entire lifespan using a mouse model.

Aging is a predominant risk factor for heart disease. Aging heart reveals low-grade chronic inflammation, cell apoptosis, cardiac fibrosis, and increased vulnerability to ischemic injury. The underlying molecular mechanisms responsible for cardiac aging and its susceptibility to injury are not fully understood. Although literature reports a role for mitochondrial Arginase 2 (ARG2) in heart failure, contradictory results are reported. How ARG2 participates in cardiac aging is still unknown. In this study, we demonstrate that

Numerous epidemiological studies have found that tea consumption has an anti-aging and preventive effect on age-related diseases. The question of which tea possesses the most potent anti-aging properties and the underlying mechanisms of these effects remains largely obscure.

The term sarcopenia was introduced to describe the age-related decline in muscle mass, but current definitions also include measures of muscle strength and function. Menopause increases sarcopenia risk and may exacerbate the adverse effects of physical inactivity. Exercise training is a potent stimulus to restore muscle health, and nutritional supplementation can further improve the outcomes. The purposes of this study were to examine the changes in a set of sarcopenia-related phenotypes induced by a 14-day step-reduction period followed by a 12-week exercise training programme, with or without fortified milk supplementation in healthy 40-60-year-old females, and to determine whether menopausal status interacted with these changes.

Wheat germ-derived bioactive peptides have attracted substantial attention for their antioxidant and immunomodulatory properties. However, their potential roles and mechanisms in mitigating osteoporosis remain unclear. This study investigated the antiosteoporotic effects of RPPSFF (RPP), a bioactive peptide isolated from wheat germ, and elucidated its molecular mechanism in maintaining bone homeostasis. Using a mouse model of D-galactose-induced aging and an MC3T3-E1 osteoblast model of senescence, we found that RPP significantly enhanced osteogenesis, inhibited bone resorption, and improved systemic antioxidant capacity and bone microarchitecture. Mechanistic analysis through siRNA-mediated gene silencing, pull-down assay, and molecular docking revealed that RPP directly binds to the transcription factor YY1, thereby activating the AMPK/SIRT1 signaling pathway. These findings indicate that RPP modulates oxidative stress and bone metabolism through the YY1/AMPK/SIRT1 pathway, providing a basis for the development of peptide-based nutritional interventions for age-related osteoporosis.

Mitochondrial dysfunction and declining energy production are hallmarks of aging, yet we lack a comprehensive systems-level view of ATP synthase (Complex V) activity across tissues, sex, and age. To overcome this, we leveraged a recently developed method to directly quantify complex V hydrolytic activity at scale in 32 tissues from young (10 weeks) and old (80 weeks) male and female mice. Our high-resolution atlas reveals several notable findings: 1) complex V activity differs markedly across tissues, with the highest levels seen in contractile organs such as the heart and striated muscles (quadriceps, hamstring, diaphragm, tongue); 2) sex influences complex V activity in a tissue-specific manner, with significant differences seen in the heart, liver, fat depots, pancreas, spleen, tongue, and cortex; 3) aging has a much larger impact than sex on complex V activity, with a greater number of age-dependent changes seen across tissues; 4) the directionality and magnitude of change in complex V activity across sex and age is variable and tissue dependent; 5) the expression of complex V related genes in human and mouse tissues across age shows only partial concordance with complex V activity, suggesting functional modulation by posttranscriptional mechanisms. This compendium of ATP synthase activity highlights organ-level variations in the mode and tempo of aging, affording an unprecedented view of the shared and divergent changes in ATP synthase function across sex and organ systems. Our data provide a valuable reference for comparative studies of mitochondrial adaptations across space and time, and in pathophysiological contexts.

Photonics and Optoelectronics are becoming increasingly important for use in implantable devices. In animal trials, although not desirable, failure can lead to the direct replacement of either the component or the test subject. In human implementations, however, the longevity of implantable devices typically needs to exceed 5 years and, in some cases, decades. Traditional hermetic metal packages, per definition, are impervious to water vapour. However, such packaging is unsuitable for structures which are millimetre sized or less. Brain probes encompassing optical micro-emitters must, therefore, use protective passivation/encapsulation layers such as silicon oxynitrides/silicone. However, such protection is prone to electrolytic failure driven by the LED-driving voltages. In this paper, we describe an electrical driving methodology which can improve device lifetime of encapsulated devices by balancing time-averaged electric fields to zero. We have tested the method on commercial optrodes to demonstrate platform independence. We show that, with this method, the time to failure can be increased by over two orders of magnitude.

Traumatic brain injury (TBI) affects millions of people globally each year, yet effective treatments remain limited. A major challenge is the complexity of cellular and molecular responses to brain injury, many of which overlap with those seen in aging. A key hallmark of aging is nucleolar enlargement in brain and other tissues, reflecting increased ribosome biogenesis. Nucleolar size is regulated by the target of rapamycin (TOR) signaling pathway, which during aging is aberrantly activated. Inhibiting TOR reduces nucleolar size and extends lifespan in several model organisms. Using a Drosophila melanogaster model of closed-head TBI, we investigated whether injury influences nucleolar dynamics. Immunofluorescence microscopy of fibrillarin, a major nucleolar protein, revealed that brains of young, injured flies had substantially larger nucleoli than uninjured controls within one day of injury. Over the following weeks, the difference gradually diminished as nucleolar size increased in uninjured flies, eventually matching that of injured flies, which remained relatively stable. Additionally, heterogeneity in nucleolar size across cells became more pronounced with injury and aging. Finally, injury of older flies resulted in little or no nucleolar enlargement and even shrinkage within a few days of injury. These results suggest that TBI and aging converge on shared mechanisms that regulate nucleolar size, which may reach a maximal limit through either process. Consistent with this, mortality at 24 hours post-injury in young flies was significantly reduced by pharmacological inhibition of TOR with rapamycin or RapaLink-1, indicating that nucleolar enlargement contributes to TBI-induced damage. Overall, our results suggest that TBI accelerates the aging-associated increase in nucleolar size, implicating elevated ribosome biogenesis in TBI pathogenesis and highlighting TOR inhibition as a promising therapeutic approach.

Cellular quiescence is a metabolically active, non-proliferative state critical for tissue maintenance and regenerative capacity, with broad implications for aging and age-related diseases. In Caenorhabditis elegans, L1 developmental arrest upon hatching in the absence of food provides a robust in vivo model to study quiescence. Here, we investigate the roles of the transcription factors HLH-30/TFEB and DAF-16/FOXO during L1 arrest. We show that HLH-30 and DAF-16 collaborate to ensure survival under starvation, with reciprocal regulation of their subcellular localization and transcriptional activity. HLH-30 exerts broad transcriptional control during L1 arrest, modulating genes involved in chromosome organization and cell cycle progression. Profiling of chromatin spatial distribution reveals that HLH-30 is required for fasting-induced 3D chromatin reorganization. Loss of HLH-30 disrupts seam cell cycle arrest and leads to overactivation of the pioneer transcription factor BLMP-1, leading to premature initiation of developmental programs under starvation. Our findings uncover previously unrecognized functions of HLH-30 in genome architecture and quiescence regulation, highlighting conserved mechanisms of transcriptional control during nutrient deprivation with implications for aging and disease.

Skeletal muscle regeneration is critically shaped by lipid remodeling, yet regulatory mechanisms involved remain unexplored. We identify MBOAT2, a lysophospholipid acyltransferase highly induced in activated satellite cells, as a key enzyme that limits the amounts of polyunsaturated fatty acids (PUFAs) in phosphatidylcholine (PC). Lipidomic profiling reveals a characteristic PC signature which is high in monounsaturated fatty acids (MUFAs) and low in PUFAs in dystrophic, injured, and neonatal muscle, paralleling elevated Mboat2 expression. Given the susceptibility of PUFAs to oxidative damage and the emerging role of lipid peroxidation in driving muscle atrophy during denervation, disuse, and aging, MBOAT2-mediated enrichment of MUFA-PC may represent a protective and pro-regenerative lipid environment. Loss- and gain-of-function approaches confirm that MBOAT2 remodels PC and promotes myogenic repair. Our findings uncover a lipid remodeling circuit in muscle stem cells that buffers oxidative stress and highlight that MBOAT2 may improve regenerative capacity in muscular dystrophy, sarcopenia, and other muscle-wasting conditions.

Higher cardiorespiratory fitness is associated with reduced type 2 diabetes mellitus (T2D) risk, but the underlying mechanisms remain incompletely understood. We investigated whether biological aging mediates the association between maximal oxygen uptake (VO

Energy deficit is a potent physiological stressor that has shaped human evolution and can improve lifespan and healthspan in a wide range of species. Preserving locomotive capacity was likely essential for survival during the human hunter-gatherer period but surprisingly little is known about the molecular effects of energy deficit on human skeletal muscle, which is a key tissue for locomotion and metabolic health. Here we show that after a 5-day 78% reduction in energy availability with concomitant aerobic exercise in healthy men there was a profound modulation of skeletal muscle phenotype alongside increases in fat oxidation at rest and during exercise and a 2.1 ± 0.8 kg loss of fat free mass and 0.8 ± 0.6 kg of fat mass. We used stable isotope (D