Longevity Papers

The rapid growth in the global aging population has intensified concerns regarding age-related diseases (ARDs), which pose substantial health and socioeconomic burdens. Current therapeutic strategies, such as small-molecule drugs, primarily target downstream pathophysiological manifestations, including inflammation, fibrosis, and metabolic imbalance, but have limited ability to address the underlying molecular causes of disease. Antisense oligonucleotides (ASOs) are emerging as a promising modality capable of precise, sequence-specific regulation of gene expression at the RNA level, offering the potential to directly modulate disease etiology. This review examines the relationship between major ARD categories and the hallmarks of aging and highlights recent research trends in ASO-based therapeutics. We explore the connections between hallmark aging processes and major ARDs, including neurodegenerative, cardiovascular, metabolic, and musculoskeletal disorders, emphasizing dysregulated genes that contribute to disease progression. Preclinical and clinical studies demonstrate that ASOs can offer targeted intervention against key pathological mechanisms such as protein aggregation, chronic inflammation, metabolic dysfunction, and tissue fibrosis by modulating gene expression. Despite their promise, major challenges remain, including poor tissue-specific delivery, limited penetration into certain tissues, and concerns around long-term safety. Emerging delivery strategies such as ligand conjugates and lipid nanoparticle systems are expanding the therapeutic reach of ASOs. By providing a programmable approach to precisely regulate pathogenic gene expression, ASOs have the potential to redefine the therapeutic landscape for ARDs in an aging society. This review provides an integrated perspective on these advances and their implications for future therapeutic development.

The utility of messenger RNA (mRNA) as a therapeutic modality has been widely demonstrated with the containment of COVID-19, yet the decisions in sequence design in the untranslated regions (UTRs) remain largely unexplored, especially in preclinical models. Here, we focus on the 5' UTR of mRNA and discover sequences that improve therapeutic potential in mouse models of aging and obesity. Bioinformatic analysis of RNA sequencing (RNA-seq), single-cell RNA-seq, ribosome profiling, and crosslinking and immunoprecipitation followed by sequencing data revealed that ribosomal protein (RP) mRNAs are abundant and ubiquitous but undergo distinct translational regulation by LARP1 and LARP4. Of 11 RP mRNAs, we find that the 5' UTRs of RPL18, RPL35, and RPS9 improve the protein output of synthetic mRNAs in human and mouse cells. Investigation of mutant 5' UTRs indicates that this improvement is independent of its terminal oligopyrimidine motif but strong in cells with high levels of reactive oxygen species. In aged mice and mice receiving a high-fat diet, synthetic mRNAs with the 5' UTR of RPS9 resulted in improved protein expression and enhanced humoral immunity through T helper cell 2 cytokines when encoding viral antigens. Altogether, our results highlight the importance of UTR sequence in expanding the therapeutic potential of synthetic mRNAs for aged individuals and those diagnosed with obesity.

Sarcopenia, defined as progressive loss of skeletal muscle mass and function, is a major health issue with economic consequences in aging societies. Physical activity is recognized as preventive, but its long-term impact across different life stages is not well established. This study examined the association between lifetime physical activity and sarcopenia prevalence using nationally representative data from the China Health and Retirement Longitudinal Study (CHARLS).

Hyperbaric oxygen therapy (HBOT) has been proposed as a direct anti-osteoporotic intervention rather than solely an adjunctive therapy. We systematically synthesized preclinical in vivo evidence and underlying mechanisms following PRISMA, with prospective registration (PROSPERO CRD42024525038), by searching PubMed, Embase, Cochrane Library, and Web of Science to November 2025. Of 3281 records, six studies (2016-2025) met inclusion across ovariectomy, hindlimb unloading, spinal cord transection, and D-galactose-induced aging models in Wistar and Sprague-Dawley rats. HBOT protocols most used 2.0-2.2 atm absolute with 85-100 % oxygen for 40-60 min per session. Across studies, HBOT improved bone mineral density and trabecular microarchitecture (e.g., BV/TV, Tb.Th, Tb.N), enhanced biomechanical strength, increased formation markers (e.g., procollagen type I N-terminal propeptide, bone-specific alkaline phosphatase, osteocalcin), and reduced resorption markers (e.g., C-terminal telopeptide of type I collagen, tartrate-resistant acid phosphatase-5b). Mechanistic signals converged on remodeling and vascular-metabolic pathways: modulation of the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) axis; restoration of Wnt/β-catenin signaling with reduced sclerostin; attenuation of oxidative and inflammatory stress (e.g., tumor necrosis factor-α); pro-angiogenic support (vascular endothelial growth factor, basic fibroblast growth factor); and neuropeptide-related effects (calcitonin gene-related peptide). Risk-of-bias profiles were mixed and heterogeneity precluded meta-analysis. Collectively, preclinical data indicate that HBOT mitigates osteoporotic bone loss primarily through coordinated, mechanisms of action that rebalance bone remodeling and improve the osteovascular milieu, while underscoring the need for standardized dosing parameters and rigorously designed human studies powered for clinically meaningful endpoints.

Cell states and biological processes are defined by their epigenetic profiles, distinctive composites of DNA- and histone-based chromatin components. However, the specific histone posttranslational modifications that distinguish cellular senescence and the impact of their distribution on transcription, especially with regard to gene length, have not been fully elucidated. Here, we show that promoter loss of symmetric dimethylated H4R3 (H4R3me

Aging is a heterogeneous process, with organ systems and individuals experiencing variable rates of decline that are not fully reflected by chronological age. This variability contributes to the complexity of system morbidity, which poses increasing challenges for clinical care and biomedical research. In this review, we discuss the heterogeneity of organ and whole-body aging and perspectives on genomics as possible mechanisms that relate to such heterogeneity. We discuss how static genomics, including nuclear genetic variants, and dynamic genetics, such as somatic mutations, epigenetic drifts, and mitochondrial DNA changes might explain the variable rate of aging across organ systems and the whole body. We discuss that the use of metrics that capture heterogeneity in organ and body aging is critical to identify genomic biomarkers of aging, clarifying mechanisms of adaptation versus decline.

Human Umbilical Cord-derived Mesenchymal Stromal Cells (hUC-MSCs) represent a promising candidate for regenerative medicine, though their therapeutic potential is constrained by replicative senescence. Pyrroloquinoline quinone (PQQ), a redox-active coenzyme, has been reported to protect against cellular aging. However, its precise role and mechanism of action in mitigating replicative senescence of hUC-MSCs remain to be elucidated. This study employed an integrated approach of phenotypic screening and transcriptomic profiling to systematically evaluate the anti-senescence effects of PQQ on replicatively senescent hUC-MSCs. Our results indicated that PQQ treatment enhanced proliferative capacity, reduced senescence-associated β-galactosidase (SA-β-gal) activity, and attenuated G1 phase cell cycle arrest. Moreover, PQQ improved mitochondrial membrane potential, reduced intracellular reactive oxygen species (ROS) accumulation, and attenuated telomere attrition. RNA sequencing analysis suggests that PQQ treatment appears to alleviate senescence-related transcriptional features, which is consistent with the observed phenotypic improvements. Gene Set Enrichment Analysis (GSEA) revealed a significant upregulation of pathways governing cell cycle progression and DNA replication following PQQ intervention. Key Driver Analysis (KDA) further identified regulators within these pathways, including PLK1, MCM5, and CDC6. Subsequent qPCR validation showed that the expression of these genes, which are critical for DNA replication initiation and mitotic progression, was downregulated in senescent cells and increased following PQQ treatment. In conclusion, the effect of PQQ on the replicative senescence of hUC-MSCs may be related to the upregulation of genes associated with the cell cycle and DNA replication.

Hematopoietic stem cells (HSCs) reside in the bone marrow in a quiescent state, but can be mobilized into the blood in response to inflammation, cytokine stimulation, nervous activity or hypoxia. Chronic inflammation, a hallmark of aging, accelerates HSC aging by promoting myeloid-biased differentiation and reducing self-renewal capacity, yet the role of mechanical stimulation in regulating these processes remains poorly understood. Here, we found that PIEZO1 senses shear stress in blood flow to induce HSC proliferation and myelopoiesis. We show that shear stress induces PIEZO1-mediated ion currents and Ca

Transposable elements (TEs), once considered "junk" DNA, constitute nearly half of the mammalian genome and can replicate and reposition within the host genome. Advances in omics technologies have improved the capture and annotation of TEs, enabling functional studies. Here, we review TEs classification, structure, regulation, and annotation methods. TEs act as regulatory elements or non-coding RNAs, influencing gene networks and cell fate. While once thought inactive in somatic cells, recent evidence suggests that TEs remain transcriptionally active in various tissues, contributing to function. Focusing on skeletal muscle development, pathological regeneration, and aging, we discuss TEs expression patterns and their potential functional. TEs exhibit stage-specific expression during muscle development and are implicated in muscle-related diseases. Building on the transposon theory of aging, we summarize the increased TEs transcription and chromatin accessibility in aging muscle. Understanding TEs in skeletal muscle biology provides insights into muscle development and age-related functional decline.

Aging-related cognitive decline is a major concern in aging societies. Theobromine (TB), a cacao-derived methylxanthine, exerts neuroprotective effects through anti-inflammatory, antioxidant, and neurotrophic mechanisms; however, its efficacy in aging models remains unclear. This study investigated the mechanisms underlying neuroprotective effects of chronic TB administration in senescence-accelerated mouse prone 8 (SAMP8), a model of age-related memory impairment. SAMP8 and SAMR1 mice were fed either a control diet or a diet supplemented with 0.05% TB for 50 d. Cognitive performance was evaluated by the novel object recognition (NOR) test. Neurotrophic factors (BDNF and NT-3), synaptic proteins (PSD95 and synaptophysin), and plasticity-related signaling molecules (phosphorylated CREB and TrkB) were analyzed in the prefrontal cortex and hippocampus. Inflammatory cytokines, lipid peroxides, and antioxidant enzymes were quantified. Molecular docking was used to assess TB's interaction with phosphodiesterase (PDE) enzymes. TB improved short-term memory in SAMP8, increasing discrimination index in the NOR test. This was accompanied by increased BDNF, NT-3, PSD95, and synaptophysin levels and enhanced CREB and TrkB phosphorylation. Furthermore, TB lowered the levels of pro-inflammatory cytokines (IL-1β, TNF-α) and phosphorylated NF-κB, reduced lipid peroxidation, and increased the levels of antioxidant markers (HO-1, GSH). These effects were minimal in SAMR1. No adverse effects on body weight or blood parameters were observed. Molecular docking indicated that TB binds to PDE enzymes with weaker inhibitory activity than selective inhibitors. TB enhances short-term memory and synaptic function in aged mice via neurotrophic, antioxidant, and anti-inflammatory mechanisms, supporting its potential as a safe dietary intervention for age-related cognitive decline.

Despite being a common environmental heavy metal, copper is an essential trace element for organisms, playing a vital role in the assembly and function of the mitochondrial respiratory chain. However, excessive copper exposure induces significant biological toxicity. Copper overload can lead to mitochondrial dysfunction, growth inhibition, and cytotoxicity, but its impact on lifespan and the underlying mechanism remains largely unexplored. Caenorhabditis elegans, characterized by a short life cycle, transparency, and high genetic homology (60-80 %) with humans, serves as an ideal model for researching the homeostasis and toxicity of metal ions. In this study, we utilized CuCl

The human gut microbiome (GM) is increasingly recognized as one of the main systems influencing the aging trajectory. Age-related dysbiosis, with imbalance between symbionts and pathobionts, can in fact fuel chronic inflammation (inflammaging) and promote frailty. In older individuals, GM composition is characterized by marked inter-individual variability and consistently influenced by environmental exposures. Studies conducted in animals and closed human communities suggest that social contacts are associated with horizontal transmission of commensal bacteria, enhancing biodiversity and preventing dysbiosis. Recent studies also suggest transmission of intestinal commensal bacteria from animals to humans sharing the same household. Bacterial populations residing on environmental surfaces may also have an influence on GM composition. In this framework, impoverishment of social relationships in older individuals may not be only associated with cognitive and emotional disengagement, but also with unfavorable changes in GM composition, driven by isolation and top-down neuromodulation of intestinal function. In fact, studies conducted during forced social distancing in the COVID-19 pandemic suggest GM changes pointing towards dysbiosis. Therefore, the detrimental consequences of social isolation for health outcomes of older individuals, including frailty progression towards disability, could be at least partly mediated by GM dysbiosis. Conversely, interventions aimed at restoring sociality, including animal-assisted activities, could expose older individuals to a range of novel bacterial species helping to counteract GM dysbiosis. This perspective article critically discusses the concept of social microbiome, its possible relevance for maintenance of good health in human beings, and its implications for the care of older patients.

Aging is characterized by systemic inflammation and progressive cognitive decline, yet the molecular pathways linking peripheral aging signals to central nervous system dysfunction remain elusive. Here, we identify plasma extracellular vesicle (EV)-derived long interspersed nuclear element-1 (LINE-1) RNA as a potent systemic aging factor mediating neuroinflammation and cognitive impairment in humans and mice. Plasma EV LINE-1 RNA levels markedly increase with age and strongly correlate with established brain aging biomarkers, including neurofilament light chain (NFL). Utilizing mouse models, we demonstrate that EVs from aged individuals penetrate the blood-brain barrier, deliver LINE-1 RNA to microglia, and initiate cGAS-STING signaling, leading to pronounced neuroinflammation, neuronal damage, and impaired cognition. Pharmacological blockade of LINE-1 reverse transcription by 3TC or inhibition of STING signaling with H151 significantly ameliorates these age-associated deficits. Notably, aged peripheral tissues, especially brain and lung, emerge as primary sources of pro-aging EVs enriched with LINE-1 RNA, revealing a novel mechanism of inter-organ communication in aging. Our findings position EV-derived LINE-1 RNA and its downstream cGAS-STING pathway as critical systemic drivers of brain aging, presenting promising therapeutic targets for mitigating cognitive decline and age-related neurodegenerative diseases.

Aging is associated with the decline of many bodily functions including motor coordination. Aging-related impairment in motor coordination can result in falls, which reduce independence, health span, and quality of life in the elderly. To study the neural mechanisms that underlie this decline, we studied aged mice and observed a progressive decline in motor coordination on multiple motor coordination assays. The cerebellum is critically involved in motor coordination and balance, and cerebellar Purkinje cells play an important role in modulating motor output and coordinated movements. Purkinje cells fire high-frequency and high-regularity action potentials in healthy young adult mice. We wondered whether this firing remained stable across lifespan in aging mice. We performed juxtacellular recordings from Purkinje cells in acute cerebellar slices and observed a reduction in the rate of firing in aged animals without changes in firing regularity. To understand whether reduced Purkinje cell firing rate caused impaired motor performance in aged mice, we used chemogenetics to modulate Purkinje cell firing. Reducing Purkinje cell firing rates in young mice impaired motor performance, while elevating Purkinje cell firing rates in aged mice improved motor performance. Our results suggest that Purkinje cell firing rate impacts motor coordination and that the aging-related reduction of Purkinje cell firing rate that we observed contributes to impaired motor coordination and could contribute to declining health span and quality of life in the elderly.

Trimethylstannyl chloride (TMT) exhibits multiorgan toxicity and is widely used as a plastic heat stabilizer. Selenium is an essential trace element for humans, and its deficiency can cause renal tissue damage in both humans and animals. This study reveals a geographic co-occurrence between selenium deficiency and TMT exposure. Transcriptomic analysis indicates that selenium deficiency is closely associated with ribosomal damage, inflammation, and aging processes following TMT exposure. Pathological analysis of broiler kidneys revealed tubular injury and inflammatory cell infiltration. Downregulation of AMPK/SIRT3 expression, coupled with ROS production disrupting the antioxidant system, activated ribosomal stress responses. This triggered significant inflammation and accelerated the aging processes. In vitro experiments demonstrated that adding ROS inhibitors (NAC) and SIRT3 activators (2-APQC) significantly downregulated the expression levels of inflammation- and aging-related genes. In summary, -SE and TMT induce renal aging through multiple mechanisms involving the AMPK/SIRT3 signaling pathway and ribosomal stress.

Alterations in mitochondrial DNA (mtDNA) have been associated with worse cognitive abilities in older adults and premature epigenetic aging in young adulthood. However, it is not clear how mitochondrial dysfunction affects brain function in young adulthood and whether cognition-related networks might be most affected. We tested whether mtDNA functional impact (FI) score might map onto specific patterns of between-network functional connectivity in young adults from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC). We also tested whether these relationships might be mediated by accelerated epigenetic aging, calculated using Horvath's epigenetic clock, CheekAge clock, and AltumAge clock. General connectivity method was used as a reliable marker of individual differences in brain function. We showed that a greater mtDNA FI score was associated with lower connectivity between the dorsal attention and language networks (beta = -0.41, p = 0.0007, AdjR

Calorie restriction (CR) extends maximal lifespan and maintains cellular homeostasis in various animal models. We have previously shown that CR induces a global reduction of protein fractional synthesis rates (FSRs) across the hepatic proteome in mice, but the timing and regulatory mechanisms remain unclear. Nitric oxide (NO), a bioactive molecule upregulated during CR, is a potential regulator of protein synthesis. To explore the role of NO in hepatic proteome fluxes during CR, we used in vivo deuterium labeling from heavy water and liquid chromatography/mass spectrometry-based (LC/MS-based) flux proteomics in WT and NO-deficient (NO-) mice. We observed a transition to reduced global protein FSRs that occurred rapidly between days 25 and 30 of CR. NO deficiency, whether genetic or pharmacological, disrupted the slowing of proteome-wide fluxes and the beneficial effects on body composition and physiology. Administering the NO donor molsidomine restored the reduction in hepatic FSRs in NO- mice. Furthermore, inhibiting NO pharmacologically, whether starting on day 1, day 14, or day 24 of CR, mitigated the reduction in hepatic protein FSRs at day 32, highlighting NO's critical role during the transition period. These results underscore the importance of NO in CR-induced changes in proteostasis and suggest NO as a potential CR-mimetic target, while offering a specific time window for identifying other signals and testing therapeutic interventions.

Age-related muscle dysfunction is a major contributor to disability, frailty, and poor clinical outcomes in older adults. Skeletal Muscle Function Deficit (SMFD) framework integrates multiple domains as: muscle mass, muscle density, strength, and power to capture a broader spectrum of age-related muscle dysfunction. The primary aims of these analyses are to develop and validate a composite SMFD score and evaluate its association with key geriatric outcome. This study used data from the InCHIANTI follow-up study, involving an initial cohort of 1035 older participants, with a total of 3196 assessments. The SMFD score was computed by assigning quintile-based values of muscle area, density, strength, and lower limb power. Associations with adverse health outcomes, and major chronic diseases were analyzed using mixed-effects models. The SMFD score declined over time from baseline to the third follow-up was: β ± SE:-0.64 ± 0.12 (p-value < 0.001), β ± SE:-1.94 ± 0.13 (p-value < 0.001), and β ± SE:-4.43 ± 0.14 (p-value < 0.001), respectively, and was associated with: BADL (OR = 0.57; 95 %CI: 0.46-0.69), IADL (OR = 0.70; 95 %CI: 0.66-0.75), poor physical performance (SPPB < 7) (OR = 0.68; 95 %CI: 0.64-0.73), Fried's frailty phenotype (OR = 0.72; 95 % CI: 0.68-0.76), hospitalization (OR = 0.96; 95 %CI: 0.93-0.99), and falls' number (OR = 0.96; 95 %CI: 0.92-0.99). Whereas higher SMFD scores were negatively associated with Parkinson's disease, stroke, and hip osteoarthritis. The SMFD score is a valid, multidimensional measure that predicts adverse outcomes in older adults. It holds promise for use in clinical assessment, risk stratification, and targeted interventions.

Age is a risk factor for aortic aneurysm (AA), and different segments of the aorta exhibit varying susceptibilities to aneurysm. The specific factors that contribute to the higher incidence of AA and its complications with aging remain unclear. Matrix metalloproteinases (MMPs) are elevated in AA. However, the connection between aging, aortic MMP activity, and the increased prevalence of AA and its complications has not been systematically evaluated. This study leveraged MMP-targeted molecular imaging to investigate how aging affects aortic MMP expression and activity, as well as aneurysm development and survival. MethodsAA development and animal survival were monitored for 28 days after Angiotensin (Ang)-II infusion in 8-10-week-old (young) and >51-week-old (old) Apoe-/- mice. Aortic MMP activation was quantified by PET/CT using an MMP-targeted tracer, 64Cu-RYM2, at baseline and 1 week after Ang II infusion. MMP activity and expression were quantified by tissue zymography and quantitative reverse transcription polymerase chain reaction, and compared between different segments of the aorta in young and old animals, and before and after Ang II infusion. ResultsOld animals survival to 28 days was significantly lower than that of young Ang-II-infused Apoe-/- mice (P < 0.05). 64Cu-RYM2 PET/CT showed significantly higher aortic MMP activation before and 1 week after Ang-II infusion in old compared to young Apoe-/-mice. The 64Cu-RYM2 signal was significantly higher in animals that did not survive 28 days than those that did (P < 0.01). MMP activity significantly increased by 4 days after Ang-II infusion, when dissection was found in a subset of Apoe-/- mice; and was significantly higher in the dissected, compared to adjacent, apparently normal, segments of the aorta. MMP activity was also significantly higher in the ascending thoracic aorta of untreated young and old mice, as well as of Ang-II-treated Apoe-/-mice (which was associated with significantly higher Mmp2 gene expression), and of old wild-type mice. ConclusionAging is associated with increased MMP activity along the aorta and worse AA survival. MMP-targeted molecular imaging can inform the aneurysm survival prospects. Selective MMP inhibitors and tracers may help prevent and track aneurysm growth, dissection, and rupture.

Maintaining cardiovascular health (CVH) is essential for preventing cardiovascular disease (CVD).

Aging involves widespread metabolic dysregulation, including a decline in total nicotinamide adenine dinucleotide (NAD) levels. While NAD precursor supplementation elevates total NAD levels, it does not reveal tissue-specific effects of an altered NADH [reduced form of NAD

The ovarian aging can lead to infertility, increase risk of diabetes, heart disease, and other serious problems. Ferroptosis is involved in the aging of various tissues. However, the mechanism underlying the role of ferroptosis in natural ovarian aging remains unclear. Here, we revealed the role of ferroptosis in ovarian aging and explore the intervention strategies for ovarian aging. Transcriptome data suggested that ferroptosis may be involved in ovarian aging. Through iron ion detection, Prussian blue staining, immunohistochemistry (IHC) staining and western blot (WB), we further confirmed that ferroptosis occurs in aging ovaries. Meanwhile, Acyl-CoA synthetase long-chain family member 4 (Acsl4) is highly expressed in senescent ovaries. We also found that the ferroptosis inhibitor Deferoxamine (DFO), Ferrostatin-1 (Fer-1) or the Acsl4 inhibitor Rosiglitazone (Rosi) inhibited ovarian aging and granulosa cell damage in vivo and in vitro. Further mechanistic studies have shown that Myeloid ectopic viral integration site 2 (Meis2) could cooperate with specificity protein 1 (SP1) to promote transcription of Acsl4 gene. Acetyl-proteomic analysis demonstrated that the acetylation level of K401 residue in Acsl4 (Acsl4-K401) was significantly reduced, and retinoblastoma binding protein 7 (Rbbp7) was identified via immunoprecipitation-mass spectrometry (IP-MS) as a direct mediator of Acsl4 deacetylation. Deacetylation of Acsl4-K401 can increase enzyme activity by promoting ATP binding. In conclusion, the increased expression level and the decreased acetylation level of Acsl4 protein promote ferroptosis, which in turn induces ovarian aging. Inhibiting ferroptosis or Acsl4 can alleviate ovarian aging. Our research has revealed a new mechanism of ovarian aging and provided potential new targets for alleviating it.

The theory of complexity in aging indicates that the complexity of sensor-derived physiological and behavioral signals reflects an older adult's adaptive capacity and, in turn, their frailty. Smart homes with ambient sensors offer a unique opportunity to longitudinally explore the complexity of older adults' indoor movement in a real-world setting. Here, we introduce a computational method to estimate behavior complexity from sensor data. We further conduct a multiple-methods case series to explore the relationship between entropy-measured smart home data complexity and older adult frailty.

Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) was the first randomized controlled trial of calorie restriction (CR) on biomarkers of aging and cardiometabolic health in humans without obesity.

Defective nucleocytoplasmic transport (NCT) has emerged as a contributing factor in the pathogenesis of neurodegenerative diseases and aging. Valosin-containing protein (VCP) is an AAA+ATPase required for disassembly of protein complexes, and mutations in VCP cause neurodegenerative and neuromuscular diseases. We find that VCP is required for quality control of nuclear pore complexes (NPCs) by extracting selected nucleoporins from NPCs for proteasome-mediated degradation. Pathogenic VCP variants cause a reduction in nucleoporins in Drosophila, induced pluripotent stem cell (iPSC)-derived motor neurons, and muscle biopsies from patients, indicating a dominant gain-of-function mechanism. Mechanistically, disease-associated mutations in VCP result in increased recruitment to NPCs through interactions with Ufd1-Npl4, leading to the removal of a subset of nucleoporins from NPCs and disrupting NCT. These findings show that the VCP-Ufd1-Npl4 pathway regulates NPC quality control and that disease-associated variants aberrantly activate the VCP-Ufd1-Npl4 complex to degrade NPCs and disrupt NCT.

Metabolic syndrome (MetS) increases with age. Epigenetic alterations reflect lifelong biological and environmental influences on aging. MetS may contribute to epigenetic age acceleration (EAA) through inflammation and oxidative stress, while elevated EAA may, in turn, exacerbate metabolic dysfunction, but long-term evidence for this bidirectional association is limited.

Aging is characterized by progressive degenerative changes in tissue organization and function, some of which increase the probability of mortality. Major goals of aging research are to elucidate the series of events that cause degenerative changes, and to identify environmental, pharmacological, and genetic factors that influence these changes; this information might lead to new strategies to extend health span and lifespan. Mechanistic studies of aging depend on accurate and precise descriptions of age-related changes, since these descriptions define the aging phenotype. Here, we review studies that describe age-related changes in C. elegans, including measurements of integrated functions such as behavior and reproduction, microscopic analyses of tissue organization, and biochemical studies of macromolecules. We discuss studies that analyze the relationships between different age-related changes. We consider the results in light of mechanistic and evolutionary theories of aging. Together, these studies provide fundamental insights into aging in C. elegans that may be relevant to aging in other animals.

Skeletal muscle is fundamental to human health, serving as the primary effector of movement and a central regulator of systemic metabolism. Age-related declines in muscle mass and mitochondrial function contribute to frailty, metabolic dysfunction, and loss of independence in older adults. While these changes are often attributed to reduced physical activity, chronic inflammation, and impaired regenerative capacity, emerging evidence implicates environmental and metabolic sensing pathways in muscle degeneration. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor best known for mediating responses to environmental pollutants such as dioxins, has recently been recognized as a key regulator of endogenous metabolic and redox processes. AHR activation occurs not only through xenobiotic exposure but also via endogenous ligands derived from tryptophan metabolism-including kynurenine and indole derivatives-whose levels rise in aging, chronic kidney disease (CKD), and other pollutant exposures. Sustained AHR activation in skeletal muscle has been shown to impair mitochondrial oxidative phosphorylation, promote proteolysis, and disrupt neuromuscular junction integrity, linking AHR signaling to muscle pathology. Experimental studies in rodent models demonstrate that pharmacologic or genetic inhibition of AHR can preserve muscle mass, mitochondrial function, and regenerative capacity. This review summarizes the molecular biology of the AHR, its emerging roles in skeletal muscle physiology and pathology, and the growing experimental toolkit for interrogating its function. Understanding how AHR signaling integrates environmental, metabolic, and aging cues may reveal new therapeutic opportunities to preserve skeletal muscle health and physical function across the lifespan.

Oxidative stress is increasingly recognized as a key pathological driver of skeletal degeneration in diabetes, aging, trauma, and other orthopedic disorders, where excessive reactive oxygen species (ROS) compromise osteoblast and bone marrow mesenchymal stem cell (BMSC) function while promoting osteoclast activity. Natural polyphenols such as baicalein (BA) exhibit potent antioxidant effects but are hindered by poor solubility and limited stability. Here, we report a series of BA-X self-assembled nanoparticles, in which X represents osteogenic metal ions including Mg

Loneliness is associated with age-related health issues through its impact on the brain and body. The brain's allostatic interoceptive system (AIS) consists of regions that predictively regulate bodily functions in reaction to affectively or socially salient situations. We hypothesized that loneliness would interact with age to exacerbate normative age-related differences in the static (ie, average) and dynamic (ie, time-varying) functional connectivity of the AIS during socially salient scenarios. Participants (N=73) rated their loneliness and underwent functional magnetic resonance imaging (fMRI) during a task involving socially neutral, pleasant, and unpleasant conditions. Static and dynamic functional connectivity of the AIS were each quantified using participation coefficient (PC) and within-module degree (WD), which are graph-theoretical metrics indicating integration of the AIS with the rest of the brain and coherence within itself, respectively. Static AIS PC was positively associated with age across conditions. In the socially pleasant condition, static AIS WD decreased with increasing age, but only for those with high loneliness. In both the pleasant and unpleasant conditions, dynamic PC and WD showed steeper negative associations with age in individuals with higher loneliness. Overall, loneliness may exacerbate age-related differences in brain systems that are essential for physiological regulation and responding to social cues.

Hematopoietic stem/progenitor cells (HSPC) aging has long been associated with myeloid skewing, reduced clonal output, and impaired regenerative capacity, but quantitative immunophenotypic and functional analysis across the human lifespan has been lacking. Here, we provide a comprehensive phenotypic, transcriptional, and functional dissection of human hematopoiesis from youth to advanced age. Although primitive hematopoietic stem cell (HSC) numbers were stable during aging, overall cellularity declined, especially for erythroid and lymphoid lineages. HSPCs from older individuals exhibited repopulating frequencies comparable with those from younger donors in both primary and secondary xenografts; however, aged HSCs displayed impaired differentiation, chromatin and cell cycle dysregulation, and poor tolerance to activation-induced proliferative stress, resulting in DNA damage and senescence-like features after xenotransplantation. Importantly, imposing proliferative stress on young human HSPCs in vivo recapitulated key aging-associated phenotypic and functional declines. Together, our findings identify dysregulated activation responses as a defining feature of HSPC aging and establish proliferative stress-based xenotransplantation models as powerful platforms for investigating age-related hematopoietic dysfunctions.

In Caenorhabditis elegans, 40 insulin-like peptides (ILPs) interact with DAF-2, the sole insulin/IGF receptor, to regulate lifespan and stress responses via the FOXO transcription factor DAF-16. By examining worms deficient in the ILP member INS-7 under glucose-present and glucose-absent conditions, we uncovered a previously unrecognized DAF-2-AKT/SGK signaling output that drives reversible growth arrest specifically under glucose-present conditions, while allowing normal development in the absence of glucose, in a manner independent of DAF-16. Through genetic screening, we identified lon-1, transcriptionally downregulated by TGF-β/BMP signaling, as a potential suppressor of this arrest. The ins-7; lon-1 double mutants fully regained normal growth under glucose conditions, suggesting that LON-1 may act as a downstream effector linking insulin/IGF activity to growth regulation. We propose a model in which INS-7 antagonizes DAF-2 signaling in a glucose-dependent manner, thereby influencing LON-1-mediated developmental processes. These findings point to a DAF-16-independent branch of insulin signaling and raise the possibility of crosstalk with TGF-β/BMP pathways, offering new perspectives on hormonal regulation of nutrient-driven growth.

IntroductionPositron emission tomography (PET) myocardial flow reserve (MFR) is a robust indicator of coronary vascular health and a strong predictor of cardiovascular risk. Clinical guidelines typically use fixed MFR thresholds (e.g., <2.0) to stratify risk, yet this approach overlooks individual variation, particularly by age and sex. We aimed to establish age- and sex-adjusted MFR percentiles and to evaluate their prognostic and predictive performance for cardiovascular risk assessment, in comparison with conventional fixed-threshold MFR approach. MethodsUsing data from the REFINE PET registry (24,820 patients from 12 sites), we measured PET MFR and derived age- and sex-adjusted MFR reference percentiles using quantile regression in patients without known coronary artery disease. All patients were categorized into percentile-based quartile groups. The primary outcome for prognostic and prediction analyses was major adverse cardiovascular events (MACE), defined as all-cause mortality, myocardial infarction, or heart-failure hospitalization. Time-to-event associations were evaluated using covariate-adjusted survival models, with cumulative incidence and hazard ratios (HR) estimated at 1 and 5 years in the derivation dataset, an independent but similar validation dataset A, and a high-risk validation dataset B. Predictive performance for MACE was assessed using discrimination, calibration, and reclassification metrics, comparing percentile-based models with models using a fixed MFR threshold (<2.0). ResultsAmong participants (mean age 66.5 years; median follow-up 3.6 years), age- and sex-adjusted MFR quartile groups were strong independent predictors of MACE, with adjusted HR increasing stepwise across quartile groups at both early and later follow-up. At 1 year, HR (95% CI) comparing the lowest to the highest quartile group were 4.06 (3.41-4.82) in the derivation cohort, 3.31 (2.32-4.71) in validation cohort A, and 2.35 (2.05-2.70) in validation cohort B. At 5 years, the corresponding HR were 2.18 (1.86-2.56), 1.77 (1.31-2.40), and 1.59 (1.36-1.86). Percentile-based models demonstrated consistently higher discrimination, better calibration, and greater net reclassification for MACE at both time points compared with fixed-threshold MFR models. Although 67.2% of patients had preserved MFR (>2.0), cardiovascular risk increased steadily across MFR percentiles even within this range. ConclusionAge- and sex-adjusted MFR percentiles provide a reliable, clinically actionable measure of vascular health, improving cardiovascular risk stratification by better capturing age- and sex-related heterogeneity in vascular risk. Compared with traditional fixed-threshold approaches, MFR percentiles demonstrate improved predictive performance for cardiovascular risk assessment across diverse patient populations. CLINICAL PERSPECTIVEO_ST_ABSWhat is new?C_ST_ABSO_LIIn a large, multinational real-world registry of more than 24,000 patients undergoing PET MPI, we derived age- and sex-adjusted myocardial flow reserve (MFR) percentiles, establishing a lifespan-based reference framework with age-specific reference values. C_LIO_LIAge- and sex-adjusted MFR percentiles showed a strong, graded association with 1- and 5-year cardiovascular risk and demonstrated improved prognostic and predictive performance compared with fixed MFR thresholds and models without MFR across independent derivation and validation datasets, including a higher-risk cohort. C_LIO_LILower adjusted MFR percentiles were consistently associated with higher risk of major adverse cardiovascular events, including all-cause mortality, myocardial infarction, and heart-failure hospitalization. C_LI What are the clinical implications?O_LIAge- and sex-adjusted MFR percentiles provide a personalized, dynamic measure of coronary vascular health that improves cardiovascular risk stratification by accounting for age- and sex-related heterogeneity. C_LIO_LIA percentile-based approach may help clinicians better identify patients at elevated cardiovascular risk who may warrant closer monitoring or intensified preventive strategies, while avoiding unnecessary intervention in lower-risk individuals. C_LIO_LIBy integrating macrovascular and microvascular dysfunction, age- and sex-adjusted MFR percentiles offer a clinically interpretable marker of vascular aging that may inform future research on aging biomarkers, novel therapeutics and cardiovascular risk assessment across the spectrum of atherosclerotic and microvascular disease. C_LI

Background: Tissue inhibitor of metalloproteinases 2 (TIMP2) has been shown to revitalize aspects of synaptic plasticity and hippocampus-dependent cognition in aged mice. We examined TIMP2's relevance in human brain aging and tested whether TIMP2 may be modifiable via known pro-plasticity behaviors in humans and mice. Methods: Plasma TIMP2 levels were quantified via SomaScan in three independent human cohorts, including two cross-sectional (UCSF: n=83; Stanford: n=31) and one with longitudinal measurement (ROSMAP: n=213). We examined associations of plasma TIMP2 with cognitive performance, brain volumes, and engagement in neuroprotective lifestyle behaviors, including objectively measured physical activity (UCSF) and a multi-domain lifestyle composite (ROSMAP). We used mouse models to directly test effects of environmental enrichment on (1) plasma TIMP2 levels and (2) hippocampal neurogenesis in wildtype versus TIMP2 knockout mice. Results: Higher plasma TIMP2 associated with better global cognition and larger brain volumes across human cohorts. Longitudinal decreases in plasma TIMP2 associated with steeper cognitive decline. Physical activity positively associated with plasma TIMP2 cross-sectionally, and longitudinal changes in multi-domain lifestyle factors positively associated with change in TIMP2 levels over time in humans. Mice exposed to an enriched environment for 3 weeks exhibited elevated plasma TIMP2 levels. While wildtype mice exposed to enrichment exhibited elevated adult hippocampal neurogenesis, this effect was lost in mice in which TIMP2 had been deleted. Conclusions: TIMP2 demonstrates clinical relevance for brain aging in humans and may represent a mechanism through which lifestyle behaviors confer neuroprotection. Further examination of TIMP2 as a potential therapeutic target for prevention of cognitive decline is warranted.

Ovarian aging reduces oocyte quality and is a major limiting factor in assisted reproductive technologies (ART) such as IVF and ICSI. This review highlights the role of follicular fluid (FF) as a mirror of the oocyte microenvironment and summarizes molecular alterations linked to aging and ovarian dysfunction. We focus on metabolites, proteins, microRNAs, and exosomes within FF that influence oocyte quality and reproductive outcomes, aiming to identify novel clinical biomarkers. Follicular fluid contains diverse biomolecules-including hormones, growth factors, cytokines, oxidative stress markers, and exosomes-that shape oocyte maturation, fertilization capacity, and embryonic competence. Recent multi-omics studies suggest that metabolic and redox-related molecules, amino acid and lipid profiles, and exosomal microRNAs are associated with ART outcomes. Mitochondrial DNA (mtDNA) and cell-free mtDNA (cf-mtDNA) also emerge as promising indicators of mitochondrial function and oocyte developmental potential. However, variations in patient background, sample handling, and analytical methods limit reproducibility. Overall, FF provides a valuable, minimally invasive source for assessing the oocyte environment and understanding ovarian aging. Future studies should integrate metabolomic, proteomic, transcriptomic, and exosomal data through multi-omics and functional analyses to establish reliable clinical biomarkers. Such advances may enable precise assessment of oocyte quality, prediction of ART success, and early diagnosis of ovarian aging.

Prolonged three-dimensional culture exposes stem cells to sustained microenvironmental and mechanical stresses that can promote aging and senescence-associated phenotypic alterations. This study examined how long-term expansion of human bone marrow-derived mesenchymal stem cells (BMSCs) in a hollow fiber bioreactor (HFB) influences cellular senescence and the molecular composition of secreted small extracellular vesicles (sEVs). During extended HFB culture, BMSCs exhibited progressive morphological flattening and cytoskeletal disorganization, accompanied by increased senescence-associated {beta}-galactosidase activity and immunophenotypic remodeling characterized by reduced fluorescence intensity and spatial redistribution of canonical MSC markers, consistent with a stress-adapted, early senescence-associated cellular state. In parallel, sEVs were collected longitudinally over 40 days and characterized by nanoparticle tracking analysis, immunoblotting, and quantitative proteomics. While vesicle size, marker expression, and yield remained stable throughout culture, proteomic profiling revealed pronounced, phase-dependent remodeling of sEV cargo, including coordinated alterations in oxidative stress-related processes, lysosomal and extracellular matrix-associated pathways, and relative depletion of cytoskeletal and translational components. Notably, these vesicular signatures closely mirrored senescence-associated changes observed at the cellular level. The strong correspondence between cellular phenotypes and sEV proteomic profiles establishes vesicle analysis as a convergent and noninvasive readout of BMSC aging, enabling sensitive monitoring of senescence progression while reducing reliance on parallel, labor-intensive cellular assays. Collectively, these findings indicate that prolonged HFB culture promotes a controlled, stress-associated senescence program in BMSCs and position sEV proteomic profiling as a robust approach for assessing stem cell aging dynamics during long-term three-dimensional bioreactor culture

Addressing sarcopenia and frailty in aging populations is crucial for improving quality of life and reducing healthcare dependence among these patients. Although no specific drugs have been approved for treating sarcopenia, protein supplements rich in branched-chain amino acid (BCAA) have been reported to increase muscle mass and function in elderly individuals. Fermentation of salmon placenta protein is an effective approach to improve BCAA content compared to previous sarcopenia-related protein supplements. Therefore, this study aimed to evaluate BCAA content through salmon placenta protein (Sal) fermented with

The brain age gap (BAG) - the difference between chronological and neuroimaging-based predicted brain age - has emerged as a sensitive biomarker of brain health. A higher BAG, reflecting an older-appearing brain, has been linked to cognitive decline, neurodegenerative disease, and mental disorders. Whether such apparent aging can be mitigated by targeted interventions remains unclear. Oestradiol (E2), a sex hormone fluctuating across the menstrual cycle and known for its neuromodulatory and cognitive effects, may represent one such target intervention. To test this, we conducted a double-blind, randomized, placebo-controlled crossover study in 28 premenopausal females. Each participant was assessed twice during the follicular phase, with at least two cycles between sessions, and received either 12 mg E2-valerate or a placebo before undergoing a T1-weighted MRI scan. BAG was estimated using a pre-trained Simple Fully Convolutional Network model. Predicted brain age was significantly younger following E2 administration compared to placebo. Exploratory analyses indicated that this effect may be moderated by resilience factors for mental health: Higher self-esteem and use of greater social support seeking was nominally associated with lower BAG, whereas females applying more expressive suppression showed more apparent brain aging. These findings suggest that even short-term increases in E2, together with resilience factors, can influence brain age estimates. Thus, E2 interventions may provide a targeted approach to support both brain and mental health. These findings underscore the urgent need for further research into the impact of E2 on mental health across the female lifespan.

The progressive degeneration in neuroprotection and cellular homeostasis related to aging significantly contributes to the beginning and development of neurodegenerative diseases (NDs) such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. Autophagy as well as programmed cell death (PCD)—such as pyroptosis, apoptosis, and ferroptosis—play central roles in maintaining neuronal integrity and regulating brain aging. Recent discoveries underscore the essential function of the gut microbiota in modulating these pathways, with probiotic interventions emerging as promising modulators of autophagic flux and cell death signaling. This review explores the intricate crosstalk between probiotics, autophagy, and PCD mechanisms in the context of neurodegenerative diseases and aging. We highlight the capability of specific probiotics to influence molecular regulators such as Bcl-2 family proteins, caspases, and oxidative stress mediators, thereby restoring cellular balance and promoting neuronal survival. Additionally, we examine how probiotics metabolites act as signaling molecules that influence neuroinflammation, mitochondrial function, and epigenetic modifications. Emerging evidence supports the concept that probiotics may serve as non-invasive, adjunctive therapeutic agents capable of mitigating neurodegeneration by modulating autophagic and apoptotic responses. Understanding these mechanistic underpinnings paves the way for innovative microbiota-based involvements aimed at stimulating healthy brain aging and delaying the development of NDs.

Growing evidence implicates accelerated biological aging in environmentally induced psychiatric disorders, yet its role in metal-associated depression remains unclear. Using NHANES data, we evaluated associations between heavy metal mixtures and depression. Bidirectional mediation analysis was used to assess reciprocal pathways linking heavy metals, biological aging, and depression. Simultaneously, candidate genes linking heavy metal exposure to depression and biological aging were identified by mining the Comparative Toxicogenomics Database, analyzing differentially expressed genes (DEGs) from the Gene Expression Omnibus, and integrating the resulting evidence within a toxicogenomic framework to explore potential molecular mechanisms. The prevalence of depression among participants was 8.66 %. Metal mixtures significantly increased depression risk. Notably, cadmium and antimony increased the risk of depression (OR: 1.52, 95 % CI: 1.19, 1.94 and OR: 1.54, 95 % CI: 1.22, 1.93). Both metals have low thresholds (0.227 μg/L and 0.053 μg/L, respectively). Additionally, lead, cobalt, and molybdenum showed positive associations in specific models. Although population-level exposure to heavy metals declined from 1999 to 2020, concentrations remained sufficient to elevate depression risk. Our correlation analysis also identified a strong correlation between PhenoAge and chronological age (r = 0.84, P < 0.001). Mechanistically, we found that accelerated PhenoAge partially mediated the associations of several metals with depression risk, including monomethylarsonic acid (β = 0.004; 95 %CI: 0.003,0.006), cadmium (β = 0.006; 95 %CI: 0.003, 0.010), lead (β = 0.009; 95 %CI: 0.006, 0.011), cobalt (β = 0.010; 95 %CI: 0.006, 0.013), molybdenum (β = 0.009; 95 %CI: 0.006, 0.011), and antimony (β = 0.008; 95 %CI: 0.005, 0.011). Pathway analysis and DEGs implicated the contribution of neurodegeneration-multiple diseases pathway, with core molecular targets centering on BDNF, IL6, GSK3B, PTGS2, and SOD1. These findings, which imply biological aging as a potential link between metal exposure and depression, call for revised safety thresholds and pinpoint molecular targets for intervention.

DNA methylation is a hallmark of aging; yet, our understanding of epigenetic age acceleration (EAA) in relationship to frailty in people with HIV (PWH) is poor. We conducted an observational study among PWH from the Veterans Aging Cohort Study (VACS) to test the hypothesis that EAA markers were associated with frailty. Epigenome-wide DNA methylation data from blood samples were used to derive EAA markers based on four established epigenetic clocks: Horvath, Hannum, PhenoAge, and GrimAge. Frailty was defined using a previously studied VACS frailty-related phenotype based on ≥1 survey item characterizing frailty factors: exhaustion, slowness, low physical activity, or weight loss. Logistic regression tested the association of participant characteristics and EAA markers with frailty. Adjusted models included each EAA marker as the independent variable, with significant participant characteristics as covariates. Among 1,076 PWH, frailty was evident in 397 (36.9%) individuals. The characteristics associated with frailty included chronological age, CD4

Error-prone translation, resulting in inaccuracies in protein synthesis, is increasingly recognized as a critical contributor to proteostasis disruption and the pathogenesis of age-related neurological disorders. In recent years, numerous studies have elucidated that stochastic errors during mRNA translation may act as a molecular "tipping point" initiating pathogenic protein misfolding. A detailed analysis of how translation errors lead to protein misfolding, aggregation, and subsequent neurotoxicity will facilitate the identification of promising therapeutic targets for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This article explores the contribution of mistranslation to proteostasis decline, focusing on the unique vulnerabilities of neuronal cells. We review the sources of translation errors, effects of ribosomal ambiguity and error-restrictive mutations, role of proteostatic mechanisms (such as molecular chaperones, ubiquitin-proteasome system, and unfolded protein response), and provide a unified perspective that links age-related translational infidelity to neurodegeneration. By synthesizing the most recent data obtained with genetically modified cellular and animal model studies, we highlight how age-associated decline in translational fidelity exacerbates proteostasis failure and propose potential therapeutic interventions targeting translation accuracy to mitigate neurodegeneration.

A key characteristic of senescent and ageing cells is a reduction in number and increase in size of nucleoli. Although a number of pathways have been suggested, the mechanisms underlying this altered nucleolar phenotype, and the downstream consequences, remain poorly understood. The PolI complex component, TIF-IA, has previously been implicated in regulating this characteristic nucleolar phenotype in response to stress. Here we explored the role of TIF-IA in senescence and ageing. We show that TIF-IA accumulation, particularly in the nucleus and nucleolus, is an early response to oncogene- and therapy-induced senescence (OIS and TIS) in vitro. Using multiple mouse models, we also demonstrate accumulation of TIF-IA in response to senescence induction and ageing in vivo. We demonstrate that TIF-IA accumulation is not required for cell cycle arrest but that in OIS and TIS, it is essential for phenotypic changes to nucleoli, the senescence-associated secretory phenotype (SASP) and establishment of stable senescence. We demonstrate that in proliferating cells, TIF-IA binds the cargo receptor, p62 (SQSTM1), and that accumulation in senescence occurs as a consequence of ATM activation, which disrupts this interaction. Finally, we show that TIF-IA accumulation causes an increase in reactive oxygen species (ROS) levels. Together, these results establish TIF-IA accumulation as a key regulator of the nucleolar phenotype and the SASP in senescence and uncover a novel, p62-dependent mechanism driving this process. These findings offer significant new insights into nucleolar size regulation in senescence and ageing, and suggest a potential relationship with the inflammatory phenotype.

Mitochondria-associated endoplasmic reticulum membranes serve as crucial signaling hubs mediating communication between the endoplasmic reticulum and mitochondria, and play a central role in calcium ion exchange. This dynamic interface regulates key cellular processes including bioenergetic metabolism, apoptosis, autophagy, and stress responses. Dysregulation of calcium transport associated with mitochondria-associated endoplasmic reticulum membranes can disrupt intracellular homeostasis, leading to mitochondrial dysfunction, oxidative stress, and neuronal death, which are hallmarks of aging and neurodegenerative diseases. This review systematically examines the functions of protein complexes within mitochondria-associated endoplasmic reticulum membranes and the pathogenic mechanisms of calcium signaling regulated by these membranes in neurodegenerative disorders. It places particular emphasis on structural alterations in calcium ion transport machinery as a common mechanism underlying various neurodegenerative diseases. In Alzheimer's disease, mitochondria-associated endoplasmic reticulum membranes exhibit a hyperactive state, promoting the generation of amyloid-β and enhancing calcium ion flux from the endoplasmic reticulum to the mitochondria. In contrast, in Parkinson's disease and amyotrophic lateral sclerosis, the activity of mitochondria-associated endoplasmic reticulum membranes is reduced, leading to a decline in mitochondrial calcium ion buffering capacity and exacerbating excitotoxicity. Proteins residing in mitochondria-associated endoplasmic reticulum membranes are disrupted across various neurodegenerative diseases, resulting in abnormal communication between the endoplasmic reticulum and mitochondria. Recent studies indicate that mitochondria-associated endoplasmic reticulum membranes play a bidirectional role in disease progression, and compensatory mechanisms often exacerbate the pathological process. Therapeutic strategies aimed at preserving the integrity of mitochondria-associated endoplasmic reticulum membranes hold promise for alleviating neurodegenerative damage. Therefore, calcium ion exchange mediated by mitochondria-associated endoplasmic reticulum membranes plays a key role in aging and neurodegenerative diseases, making it a highly promising therapeutic target.

While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is poorly understood. Our previous work has shown that targeting aging pathways can be neuroprotective in animal models of neurodegenerative disease. Based on these findings, we believe that by gaining insight into the aging process, that knowledge can be applied to identify novel therapeutic targets for neurodegenerative disease. To advance our understanding of aging, we used a genomics approach to identify genes regulated by multiple lifespan-extending pathways. We performed RNA sequencing on nine long-lived C. elegans mutants representing seven longevity pathways: insulin/IGF-1 signaling, dietary restriction, germline deficiency, impaired chemosensation, reduced translation, elevated mitochondrial ROS, and mild mitochondrial impairment. We found that most pairs of long-lived mutants exhibited a significant overlap in differentially expressed genes. Comparing gene expression across the entire panel of long-lived mutants revealed three distinct longevity groups that could be clearly distinguished by gene expression. Interestingly, two of these groups showed modulation of specific genetic pathways in opposite directions, suggesting that there are multiple alternative strategies to achieving long life. Filtering for genes similarly modulated in at least six mutants identified 196 upregulated and 62 downregulated aging genes. Upregulated genes were enriched in immunity, defense and metabolism, while many downregulated genes impacted translation and gene expression. To assess the ability of these genes to enhance longevity individually, we knocked down the commonly upregulated genes in long-lived mutants and evaluated the resulting effect on lifespan. Using this approach, we identified several genes that affect lifespan individually. Upregulation of at least some of these genes was sufficient to enhance stress resistance and extend lifespan in wild-type worms. Overall, the shared longevity genes identified in this work offer potential targets to promote healthy aging and decrease age-onset disease.

Aged individuals with somatic TP53 mutations manifest clonal hematopoiesis (CH) and are at high risk of developing myeloid neoplasms. However, the underlying mechanisms are not fully understood. Here we show that inflammatory stress confers a competitive advantage to p53 mutant hematopoietic stem and progenitor cells (HSPCs) by activating the NLRP1 inflammasome and increasing the secretion of pro-inflammatory cytokines such as IL-1β, inhibiting wild type (WT) HSPC fitness in a paracrine fashion. During aging, mutant p53 dysregulates pre-mRNA splicing in HSPCs, leading to enhanced NF-κB activation and increased secretion of IL-1β and IL-6, thereby generating a chronic inflammatory bone marrow microenvironment. Furthermore, blocking IL-1β with IL-1β neutralizing antibody or inhibiting IL-1β secretion using gasdermin D (GSDMD) inhibitor decreases the fitness of p53 mutant HSPCs. Thus, our findings uncover an important role for mutant p53 in regulating inflammatory signaling in CH and suggest that curbing inflammation may prevent the progression of TP53-mutant clonal hematopoiesis to myeloid neoplasms.

Aging and accumulation of α-synuclein (α-syn) oligomers in the brain are indisputably linked to Parkinson's disease (PD). Using an inducible α-syn oligomer mouse model, we demonstrate that the induction of PD-associated α-syn oligomers for the same time span caused PD-associated symptoms only in aged, but not in young mice. Biochemical studies revealed that α-syn oligomer formation precedes motor decline, with age and α-syn expression jointly determining the motor phenotype. Single-nucleus RNA sequencing (snRNA-seq) identified a PD-related transcriptional signature in basal ganglia neurons (BGNs), which overlapped in part with aging-associated changes. Short-term pharmacological inhibition of the small RhoGTPase CDC42 in aged, symptomatic animals improved motor function without reducing oligomer levels. These findings indicate that aging processes strongly influence the susceptibility to PD-like symptoms and that targeting age-related pathways, rather than α-syn oligomer burden alone, may provide effective strategies to improve outcomes in PD.

On October 22nd, 2025, Brain Aging Symposium took place at Harvard Medical School bringing together leading researchers from academia and partner organizations to discuss recent advances in measuring and monitoring human brain aging trajectories, with a particular focus on Alzheimer's disease (AD). A central theme emerged: achieving "the right treatment for the right person and the right time" through precision medicine approaches. Key advances included the unprecedented validation of plasma-based biomarkers, particularly brain-derived p-Tau217 that can identify seeding AD pathology with remarkable specificity, making large-scale screening newly feasible. Integrating multi-level "omic" modalities, spanning genetic information, molecular biomarkers of nutrition, lipid and protein signatures, neuroimaging measures, cognitive assessments, and lifestyle factors, enhances disease risk modeling and trajectory prediction beyond the capacity of any single marker. Early findings highlight critical roles for nutritional and lipid metabolism, and myelin integrity in brain aging, with cell and sex-specific vulnerabilities identified in response to nutrition, social isolation, and metabolic stress. Computational approaches that combine single-cell genomics, epigenomics, and artificial intelligence have been shown to accelerate causal discovery and therapeutic development. However, significant challenges remain: current biomarkers explain only half the variance in cognitive decline, racial and ethnic differences in biomarker levels lack mechanistic understanding, and scalable tools for comprehensive brain aging assessment are needed. The symposium underscored that preventing AD will require intervening during the preclinical asymptomatic phase. These multimodal screening platforms, coupled with mechanistically driven therapeutics, reduction in modifiable risk factors, including nutrition, vascular health, and social determinants of health, could profoundly impact the field.

Accelerated immune aging has been implicated in patients with end-stage kidney disease, but a detailed examination of immune profiles correlated with long-term outcomes for these individuals has never been performed. Therefore, we conducted a prospective observational study ("Immunity in end-stage renal disease", iESRD) to investigate the effects of immune aging on mortality among these patients. An exploratory panel of immune cell subsets was analyzed by flow cytometry at baseline (neutrophils, CD3-negative lymphocytes, CD4 and CD8 T cell differentiation stages, and three subsets of monocytes). Immune cell distribution patterns were identified through data-driven principal component analysis (PCA).

This study aimed to investigate the effects of audiovisual N-back task training on working memory and audiovisual integration ability in older adults. Twenty healthy older adults underwent 40 sessions of audiovisual N-back training, while 18 healthy older adults served as controls. Event-related potentials (ERPs) and performance data were collected at baseline and end of the training period. The results indicated that working memory in older adults gradually improved with training. In the audiovisual 3-back task, the training enhanced the discriminability index (d') and reduced the latency of the N2 component evoked by target stimuli in older adults, compared with the control group. Furthermore, the training significantly enhanced the audiovisual integration abilities of older adults at the earlier stage of processing in 180-200 ms. This study demonstrates that audiovisual N-back training effectively improves working memory and early-stage audiovisual integration abilities in older adults. The findings highlight the potential of audiovisual N-back task training as an efficient method for enhancing cognitive and perceptual abilities in older adults and counteracting age-related brain decline.

Dolichol is a lipid uniquely important for retinal cells. Mutations affecting dolichol biosynthesis cause non-syndromic retinal degeneration. Aging is a major risk factor for leading causes of vision loss. We characterized age-related changes in dolichol levels in the retinas of C57BL/6 mice of both sexes at the age of PD (postnatal day) 5, 10, 15, 20, 30, 60, 180, 360, and 600 using liquid chromatography-mass spectrometry (LC-MS), a highly sensitive and specific method for dolichol analysis. All four major dolichol species-dolichol-17 (Dol-17), Dol-18, Dol-19, and Dol-20, increased dramatically with age. The largest increase was in Dol-18, which rose by a factor of 100 from PD 5 to PD 600. Age-related dolichol increases occurred in two distinct phases: Phase I (PD 5 to PD 30) and Phase II (PD 30 to PD 600). These phases coincide with the phases of postnatal development and adult aging, respectively. A shift in the dolichol chain-length profile with age was also observed. Dol-19 was the dominant species from PD 5 to PD 15 but Dol-18 became dominant after PD 20. Changes in cholesterol and coenzyme Q9 (CoQ9) followed the same biphasic pattern. The age-related increase in dolichol levels may influence the physical properties of cell membranes, act as an ultraviolet (UV) filter for retinal cells, and serve as a biomarker of retinal aging.

Age-related decline in adipose tissue function is closely associated with impaired insulin sensitivity and chronic low-grade inflammation, and these conditions contribute to type 2 diabetes (T2D) development in older adults. Therefore, reliable biomarkers may be helpful for early T2D diagnosis in older adults. We aimed to identify novel biomarkers linked to diabetes in older adults and to develop a predictive tool for diabetes diagnosis. We integrated transcriptomic analysis and machine learning to screen key genes associated with T2D in older adults. Gene expression datasets related to abdominal subcutaneous adipose tissue were obtained from the Gene Expression Omnibus (GEO) database. Through batch effect correction and differentially expressed gene (DEG) analysis of the combined dataset, 210 DEGs were identified. Functional enrichment analysis revealed that these DEGs were enriched mainly in inflammation- and immune-associated pathways. To extract T2D-predictive genes, we used three machine learning algorithms: LASSO, SVM-RFE and random forest. Two common genes, AIM2 and FHOD3, were consistently identified as the optimal biomarkers for distinguishing older adults with T2D from those without T2D. Receiver operating characteristic (ROC) curve analysis revealed high predictive performance. AIM2 and FHOD3 could serve as novel diagnostic and therapeutic targets for older adults with diabetes.

Codonopsis pilosula (CP), a traditional Chinese medicine, holds considerable potential in antioxidant and antiaging properties, however, the antiaging mechanism of its active components have been scarcely documented.

Kinship relationships between parents affect offspring fitness. Beyond its effects in heterozygosity or its impact in deleterious alleles that can be reduced to homozygosity and decrease the individuals' fitness, the consequences of parental relatedness in the offspring remain understudied. By leveraging the availability of detailed pedigrees of captive Peromyscus we explored how parental relatedness impacts the methylome and the epigenetic age estimation of the offspring. Global CpG methylation analysis showed that parental relatedness positively impacts lifespan expectancy and reduces epigenetic aging, contributing about 13% of variation in epigenetic age estimation. Global hypermethylation due to relatedness was considerably higher than hypomethylation, was more pronounced in the male offspring, and mainly affected chromosomal loci associated with development. A relatedness-associated methylation signature was described that predicts parental relatedness with high accuracy, providing the proof of concept that kinship relationships can be inferred by epigenetic analyses. These findings identify parental relatedness as a modifier of epigenetic aging and global methylation, suggesting that kinship relations should be considered when epigenetic, and potentially transcriptomic data are interpreted in the context of aging and of other pathophysiological processes.

Emerging evidence suggests gut microbiota modulation may influence neurocognitive function through the gut-brain axis. Although preliminary studies indicate probiotics' potential benefits for mild cognitive impairment (MCI), well-designed randomized controlled trials remain limited. This protocol paper describes a rigorously designed, registered clinical trial investigating the effects of targeted probiotic supplementation on cognitive and physiological outcomes in MCI participants.

Aging significantly impacts brain function and increases susceptibility to neurodegenerative diseases, with notable sex dimorphism observed in aging-related dementia, such as Alzheimer's disease. To better understand the molecular mechanisms of aging and dementia, it is essential to globally and accurately characterize biomolecules (e.g., proteins) in the brain as a function of age and sex. Here, we present one of the first studies of aging and sexual dimorphism in brains using the zebrafish (Danio rerio) model, employing mass spectrometry (MS)-based quantitative top-down proteomics (TDP). We analyzed proteoforms in male and female zebrafish brains across three ages (6, 16, and 24 months) using capillary zone electrophoresis-tandem MS (CZE-MS/MS). We revealed significant sex- and age-related differences in the abundance of key proteoforms, including those associated with neurofilament assembly, dopaminergic neuron differentiation, and synaptic vesicle priming. Notably, we identified a truncated proteoform of AP2B1, a subunit of the AP2 adaptor complex closely associated with clathrin-mediated endocytosis and cellular aging, in female zebrafish aged 24 months exclusively, suggesting potential age- and sex-specific roles in brain aging. Additionally, significant changes were observed in proteoforms involved in energy metabolism, structural maintenance, and neurotransmitter release, providing a new opportunity for a better understanding of the molecular mechanisms of brain aging and sexual dimorphism. These findings highlight the effectiveness of CZE-MS/MS in TDP for identifying and quantifying proteoforms, offering a deep view of sex-specific proteoform dynamics during brain aging.

Telomere length is a biomarker of ageing, with shorter lengths associated with higher risk of age-related diseases and mortality. Oxidative stress and inflammation predominantly contribute to telomere shortening. Diets rich in antioxidant and anti-inflammatory properties may help preserve telomere length. Nuts and seeds contain antioxidant and anti-inflammatory nutrients and bioactive compounds. Their consumption is recognised as protective against age-related conditions. The objective of this review is to evaluate the role of nut and seed intake on telomere length in humans. A systematic search was conducted in four databases from inception to 12 March 2024 to identify observational and interventional studies assessing nut and seed intake and measured telomere length as an outcome in adults (aged ≥18 years). Data from the included articles were extracted by one reviewer and verified by another reviewer. Out of the nine observational studies included, three reported positive associations between nut and seed intake and telomere length. None of the four interventional studies included reported a significant positive effect. Meta-analysis was not performed due to high variability in reporting telomere length measurements. The evidence is insufficient to confirm a beneficial role of nut and seed intake on telomere length. Adequately powered long-term intervention studies are needed.

Population aging heightens the burden of cognitive decline and brain disorders, yet trajectories of brain aging vary widely across individuals. Because the human brain is intrinsically lateralized, age related shifts in hemispheric asymmetry may reveal latent aging subtypes that are masked by bilateral averages. Here, we derived reproducible and interpretable asymmetry based brain aging modes and validated their behavioral, genetic, and molecular signatures. Using UK Biobank MRI, we computed cortical thickness asymmetry across 68 Desikan Killiany regions, transformed signed asymmetry into non-negative channels, and assembled a region-by-participant matrix. We then applied non-negative matrix factorization (NMF) to estimate spatial mode maps and participant specific loadings, selecting the factorization rank by reconstruction error elbow criterion (k = 13). Age associations were assessed with covariate adjusted partial correlations controlling sex and handedness and corrected for multiple testing using false discovery rate (FDR). Generalizability was evaluated by projecting an independent cohort (Cam CAN; n = 608) onto UK Biobank derived spatial maps. We additionally tested sex differences, lifestyle/behavioral correlates, transdiagnostic polygenic neuropsychiatric/neurodegenerative risk disorders, score (PRS) coupling across 12 and imaging transcriptomic pathway enrichment using Allen Human Brain Atlas expression and Metascape. We identified five age linked asymmetry modes that replicated directionally in Cam CAN. Modes differed systematically by sex and displayed distinct lifestyle signatures spanning sleep, physical activity, alcohol intake, diet, device use, and smoking. Genetic coupling was mode specific, with different modes aligning with distinct constellations of transdiagnostic PRS. Imaging transcriptomic analyses further indicated mechanistic dissociability, implicating mitochondrial bioenergetics, antigen presentation, innate immune/inflammatory pathways, and synaptic/ neurodevelopmental programs. Hemispheric asymmetry decomposes into reproducible, mechanistically diverse aging modes that connect to modifiable behaviors and transdiagnostic genetic liability. This asymmetry informed, mode based framework advances subtype oriented phenotyping of brain aging and provides a foundation for individualized risk stratification and mechanistic hypothesis generation.

Highly regenerative animals often have a seemingly limitless capacity for tissue growth and stem cell proliferation, which often requires molecular and organismal capacities associated with pre-malignancy. Yet, these same organisms do not develop stem cell driven cancers. Here, we explored if the regenerative flatworm Schmidtea mediterranea has evolved mechanisms to modulate regeneration depending on underlying DNA damage or neoplastic risk. We first challenged worms to regenerate after increasing doses of ionizing radiation and found that even sublethal doses (500-1250Rads) transiently inhibit regeneration. After amputation, stem cells could divide and accumulate near injuries but did not increase proliferation rates in response to amputation or restore missing tissues. By leveraging published single cell sequencing datasets, we found that ionizing radiation increased activin ligand expression, particularly in the intestine. RNAi knockdown of 18 different activin signaling homologs identified activin ligands, activin receptors, and downstream Smad transcription factors whose depletion partially or fully rescued regenerative capacity after radiation. Notably, depletion of activin-2 did not alter radiation-induced stem cell loss. Instead, it increased stem cell expansion and amputation-induced proliferation, fully restoring regeneration despite prior DNA damage and depleted stem cell numbers. Together, our results indicate that Activin signaling levels are a central regulator of planarian stem cell behaviors, coordinating shifts between repair of pre-existing tissues following systemic damage, homeostatic tissue turnover, and whole-body regeneration. Moreover, Activin signaling may function as a conserved tumor suppressor in Schmidtea mediterranea by inhibiting stem-cell driven regeneration when damage levels are too high.

Aging is associated with progressive synaptic deterioration and cognitive decline; however, therapeutic strategies capable of restoring both structural and functional deficits remain limited. This study evaluated the effects of aging on dendritic spine dynamics and recognition memory across multiple brain regions, and evaluated whether chronic treatment with cerebrolysin (CBL) could ameliorate age-related alterations (3, 6, 12 and 18 months of age). We additionally assessed the effects of CBL on key molecular markers of synaptic plasticity in aged (18-month) C57BL6 mice. Aging impaired locomotor activity (12- and 18-month groups) and produced deficits in short- and long-term recognition memory relative to young controls. Notably, CBL selectively enhanced locomotion in 18-month group and improved short-term memory in the 12-month group. At the structural level, aging reduced spine density and decreased the proportion of thin and mushroom spines in the prefrontal cortex and dorsal hippocampus, whereas CBL treatment increased spine density in the dorsal hippocampus and basolateral amygdala, and promoted the formation of mature mushroom spines in a region and age-dependent manner. Importantly, CBL elevated β-actin, synaptophysin and brain-derived nerve factor expression across multiple regions in the 18-month group. This study provides the first integrated demonstration that CBL enhances dendritic spine maturation and dendritic structural remodeling while concurrently improving cognitive outcomes within the same cohort of aged animals. Collectively, our findings position CBL as a promising therapeutic candidate to counteract age-related synaptic loss and cognitive decline, advancing current understanding of neuroprotective interventions in aging.

Previous research examining the contribution of white matter hyperintensities (WMHs) to cognitive decline has focused on overall lesion burden. A new approach, afforded by the Lesion Quantification Toolkit (LQT), measures localized connectivity disruption from WMHs to better estimate their impact on cognition. This methodology shifts the focus from lesion volume to the level of network disruption between brain regions. In this novel study, we applied the LQT approach to healthy aging and linked the degree of disconnection of gray matter by WMHs to both cognitive impairment and resilience via cognitive reserve. Using three pre-existing MRI datasets of older adults (total N = 259), we used the LQT to examine localized disruptions to brain connectivity due to WMHs. We then used partial least-squares path modeling to examine the relationships between this disruption, cognitive performance, age, and cognitive reserve. The results support a link between connectivity disruption and reduced cognitive performance. Results from all three individual datasets, one of which included a detailed measure of cognitive reserve, showed a link between cognitive reserve and higher cognitive performance, suggesting cognitive reserve allows for maintained cognitive function in spite of the negative impact of WMHs.

Proinflammatory cytokines are essential for initiating immune responses; however, excessive or aging-related chronic inflammation impairs immunity and reduces vaccine efficacy. In this study, we developed lipid nanoparticles (LNPs) encapsulating anti-inflammatory microRNA-192 (miR-192) to attenuate inflammation and improve vaccine performance in the elderly. Results revealed that specific proinflammatory cytokines, including interleukin (IL)-6 and tumor necrosis factor (TNF)-α at the vaccination site, diminished antigen-specific antibody production. Notably, miR-192 endowed LNPs with strong anti-inflammatory properties, markedly enhancing vaccine efficacy, especially in aged mice. Transcriptomic analyses demonstrated that miR-192 downregulated multiple pro-inflammatory cytokines, such as senescence-associated secreted phenotype factors, which hinder vaccine responses. Additionally, miR-192 inhibited key components of the JAK-STAT signaling pathway, crucial for cytokine receptor signaling in myeloid cells. Overall, these findings indicate that miR-192 effectively suppresses harmful inflammatory responses, substantially enhancing vaccine efficacy, and highlight the therapeutic potential of the anti-inflammatory microRNA-based adjuvants for improving vaccination outcomes in the elderly.

Clinical evidence supports the anti-photoaging efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT), yet its mechanism remains elusive. Paradoxically, ALA-PDT generates reactive oxygen species (ROS), a key mediator of ultraviolet radiation (UVR)-induced photoaging, raising questions about its rejuvenating effects. Here, we employed a multi-omics approach to clarify this paradox. A UVR-induced hairless mouse model of photoaging was treated with ALA-PDT, followed by transcriptomic, proteomic, and metabolomic profiling of skin biopsies. In vitro, fibroblast senescence was induced by UV irradiation to evaluate ALA-PDT's protective effects. Mitochondrial function and citrate (CA) levels were assessed pre- and post-treatment. ALA-PDT significantly ameliorated photoaging phenotypes in mice, with multi-omics data revealing sustained improvements in epidermal structure, extracellular matrix integrity, and immune responses. Key mechanistic findings included ALA-PDT-induced mitohormesis and tricarboxylic acid cycle reprogramming, notably reduced intracellular CA. In vitro, low-dose ALA-PDT downregulated senescence markers and CA content in UV-stressed fibroblasts, concomitant with upregulated mitohormesis markers. These effects were abrogated by inhibiting mitochondrial ROS, suggesting ROS-dependent mitohormetic signaling. Collectively, our data demonstrate that low-dose ALA-PDT alleviates photoaging by mitigating cellular senescence via mitohormesis-mediated CA reduction, offering a novel metabolic intervention strategy for age-related skin disorders.

Sarcopenia is a prevalent and debilitating skeletal muscle disorder in the aging population, characterized by progressive loss of muscle mass, strength, and function. Despite its significant impact on mobility, independence, and healthcare systems worldwide, effective pharmacological treatments remain limited. Recent advances in the understanding of sarcopenia pathophysiology have identified myostatin-a potent negative regulator of muscle growth-as a promising therapeutic target. Myostatin inhibitors-comprising direct agents such as monoclonal antibodies and small molecules, as well as indirect modulators including follistatin-based strategies and other pathway regulators-have demonstrated encouraging results in preclinical and early clinical studies by increasing muscle mass and improving muscle function. This comprehensive review summarizes current knowledge of myostatin's molecular mechanisms in muscle homeostasis, evaluates the efficacy and safety of various myostatin-targeted therapies in sarcopenia, and discusses the translational challenges and future directions for clinical application. The integration of myostatin inhibition into therapeutic regimens offers the potential to address a critical unmet need in sarcopenia management and improve the quality of life for elderly individuals.

Aging is an inevitable consequence for all organisms. According to the mitochondrial free radical theory of aging (MFRTA), reactive oxygen species (ROS), which are predominantly generated in mitochondria, are assumed to play a key role. Calorie restriction (CR) delays aging by improving mitochondrial function; however, the molecular mechanisms underlying the effects of ROS and CR on mitochondria remain poorly understood. Oxidative protein modifications in mitochondrial proteins from the heart and cerebrum of young (6.5 months) and old (27 months) rats were quantified and the effects of short-term and lifelong CR interventions were investigated. Mass spectrometry was leveraged to achieve an unbiased and comprehensive analysis of various types of oxidative postranslational modifications (oxPTMs). Contrary to the MFRTA, aging did not cause significant increases in mitochondrial protein oxidation in the heart and cerebrum. CR markedly diminished the overall level of oxPTMs in the heart, particularly in transmembrane proteins. Similarly, the level of oxidative modification of transmembrane proteins in cerebrum was reduced by CR, whereas it perplexingly increased in mitochondrial proteins. The absolute level of oxidized mitochondrial protein was always higher in the heart than in the cerebrum under all conditions. Carbonylation, a prevalent marker of protein oxidation and aging, increased in the heart with age and was notably reduced by CR. However, this trend was not consistent in cerebrum or for some other types of oxPTMs. Therefore, protein oxidation in the heart and cerebrum exhibits distinct responses to chronological aging and dietary interventions, with the latter exerting a stronger influence.

During myogenic differentiation the cellular architecture and proteome of muscle stem cells and myoblasts undergo extensive remodeling. These molecular processes are only partially understood and display alterations in disease conditions as well as during aging resulting in impaired regeneration. Here, we used mass spectrometry to quantify the temporal dynamics of more than 6000 proteins during myogenic differentiation. We identified the actin nucleator leiomodin 1 (LMOD1) among a restricted subset of cytoskeletal proteins increasing in abundance in early phases of myogenic differentiation. We show that LMOD1 is already expressed by muscle stem cells in vivo and displays increased abundance during skeletal muscle regeneration, especially during early regeneration suggesting that LMOD1 is important for induction of myotube formation. Of note, knockdown of LMOD1 in primary myoblasts and during skeletal muscle regeneration severely affects myogenic differentiation, while overexpression accelerates and improves the initiation of myotube formation suggesting that LMOD1 is a critical component regulating myogenic differentiation. Mechanistically, we show that LMOD1 physically and functionally interacts with the deacetylase sirtuin1 (SIRT1), a regulator of myogenic differentiation, especially at the onset of myogenic differentiation. We demonstrate that LMOD1 influences SIRT1 localization and the expression of a subset of its target genes. Consistently, depletion or pharmacological inhibition of SIRT1 partially rescues the impairment of myogenic differentiation observed after knockdown of LMOD1. Our work identifies a new regulator of myogenic differentiation that might be targeted to improve muscle regeneration in aging and disease.

With the intensification of global population aging, research on aging-related diseases has become increasingly critical. Bone marrow mesenchymal stromal cells (BMSCs), residing in bone marrow microvironment, serve as precursors for osteoblasts and adipocytes while playing unique roles in regulating hematopoietic and immune systems. However, BMSCs undergo progressive senescence during aging, characterized by diminished proliferative capacity, skewed differentiation potential, compromised immunomodulatory functions, and the development of a senescence-associated secretory phenotype (SASP). These age-related alterations exacerbate inflammatory responses within the bone marrow microenvironment, contributing to the pathogenesis of degenerative diseases such as osteoporosis and osteoarthritis, while potentially inducing hematopoietic dysfunction and oncogenic transformation. Notably, senescent BMSCs secrete pro-inflammatory cytokines that establish a chronic inflammatory milieu, which not only impairs hematopoietic stem cells (HSCs) functionality but also promotes bone marrow adipogenesis. Despite these insights, the intricate interplay between BMSC senescence and microenvironmental alterations remains incompletely understood. This narrative review Comprehensively synthesizes current knowledge on the molecular mechanisms underlying BMSCs senescence, with particular emphasis on telomere attrition, DNA damage accumulation, oxidative stress, epigenetic dysregulation, and bidirectional microenvironmental crosstalk. Furthermore, we critically evaluate emerging therapeutic strategies aimed at mitigating BMSCs senescence and optimizing their clinical applications in age-related disorders.

Selective elimination of senescent cells (SnCs) through senolytic strategies can counteract the progression of age-related dysfunction, but achieving precise, broad-spectrum, and controllable senolysis remains challenging. Here, we report PG@FBC, a polymeric senotherapeutic that exploits senescence-associated β-galactosidase (SA-β-gal) to trigger supramolecular disassembly and controlled photosensitizer release, enabling photodynamic senolysis with real-time imaging. Briefly, PG@FBC is composed of an amphiphilic block copolymer, POEGMA-

Endothelial dysfunction is a hallmark of vascular inflammation and aging. However, the role of cellular bioenergetics in the age-dependent resilience of endothelial function to inflammation has not yet been characterized. Therefore, the aim of this study was to determine whether IL-1β-induced inflammation differentially influences vascular metabolism and endothelial function in the isolated aorta of aged mice compared to young mice. Aorta from young (3-8 months) and old (22-28 months) C57BL/6 mice was isolated and subjected to ex vivo analysis of endothelial function using wire myography and vascular NO production by electron paramagnetic resonance spectroscopy (EPR). Cellular bioenergetics was assessed with the Seahorse extracellular flux analyzer for the measurement of mitochondrial respiration and glycolysis.

Diminished ovarian reserve (DOR) is a major cause of female infertility and a significant indicator of reproductive aging, yet its underlying pathogenesis remains poorly understood. In this study, we initially assessed the expression of core circadian genes in ovarian granulosa cells from DOR patients and in ovaries from cyclophosphamide (Cy)-induced DOR model rats. We observed dysregulated expression of circadian genes in DOR ovaries. Proteomic analysis further revealed a significant decrease in riboflavin kinase (RFK) expression in DOR rat ovaries, concomitant with abnormal elevation of the clock proteins BMAL1. RFK deficiency impairs riboflavin metabolism, thereby inhibiting the synthesis of flavin adenine dinucleotide (FAD). FAD competes with CRY proteins for binding to the E3 ubiquitin ligase substrate receptor, thereby reducing CRY degradation, while the CRY inhibits the transcriptional activity of BMAL1. Subsequent molecular experiments demonstrated that RFK knockdown not only reduced FAD synthase (FADS) levels but also exacerbated CRY1/2 degradation, disrupted circadian regulation, impaired ovarian granulosa cell function, and accelerated ovarian aging. Our findings indicate that aberrant riboflavin metabolism may accelerate ovarian functional decline by compromising circadian regulation. Collectively, this study elucidates a pivotal role for RFK in DOR pathogenesis and provides a theoretical foundation for developing novel therapeutic strategies targeting circadian pathways.

Cataract, the leading cause of blindness worldwide, results from age-related misfolding and aggregation of long-lived crystallin proteins in the eye lens. The cytoplasm of fiber cells in the lens core becomes increasingly oxidizing with age, allowing non-native disulfides to drive light-scattering aggregation of {gamma}-crystallins. Despite this vulnerability to non-native disulfides, and despite lacking any native-state disulfides, {gamma}-crystallins are unexpectedly Cys-rich. To understand this paradox, we investigated how replacing all four Cys residues in the aggregation-prone N-terminal domain of {gamma}D-crystallin affects its stability and aggregation. Cys removal precludes the disulfide-driven aggregation pathway we reported previously. Here, we characterize two full-length human {gamma}D-crystallin variants: C18S/C32S/C41S/C78S (NCS) and C18T/C32A/C41A/C78A (NCA/T). Thermodynamic and kinetic stability measurements indicate the N-terminal domain was greatly destabilized in both variants relative to WT, with NCS more destabilized than NCA/T. Upon mild heating or partial denaturation, both variants formed light-scattering aggregates, which were amorphous by transmission electron microscopy. Surprisingly, the aggregation proceeded exclusively from a native-state dimer held together by a C-terminal disulfide bridge. Aggregation was strongly suppressed by the lens native chemical chaperone, myo-inositol. The aggregation rate depended linearly on protein concentration, indicating that the rate limiting step was a transformation of the native-state dimer to a misfolded dimer. The native-state dimer forms readily even in the WT protein, and evidence of it has been found in the lens. We propose that many age-related chemical modifications could destabilize the native fold of human {gamma}D-crystallin, favor misfolding within its native-state dimer, and thereby cause aggregation.

Ionizing radiation (IR) accelerates aging and increases the risk of death in organisms. The two scallops, Argopecten purpuratus (7-10 years) and A. irradians (less than 14 months), have markedly different lifespans and exhibited different tolerance to IR. However, little information was available for understanding why the A. purpuratus had a higher survival rate after IR. In the present study, we first investigated genetic responses to IR in the two scallops by comparative transcriptome analysis. After IR exposure, the A. purpuratus has more significantly up-regulated expressed genes (mainly involved in neuroactive ligand-receptor interaction, peroxisome, autophagy, and DNA repair), but the A. irradians has more significantly down-regulated expressed genes (mainly involved in lysosome, peroxisome, autophagy, DNA repair, and apoptosis). In addition, the main genes and pathways that respond to IR are completely different between the two scallops. The expression of ATG5, BAX, CTSL, CTSB, ULK2, and ATG9A, which are important genes for autophagy, was significantly downregulated in the A. irradians, which may contribute to its early mortality. However, the expression of SOD1, CAT, SCD, and ACOX1, which perform the function of antioxidation, significantly increased in the A. purpuratus, potentially mitigating ROS-induced cellular damage. In addition, the ROS level in the A. purpuratus was significantly lower than the A. irradians after IR. These findings suggested that ROS potentially contribute to bivalve tolerance to IR, and also suggest potential biomarkers for breeding scallops with a high survival rate.

Deterioration of cognitive function with aging is a significant public health issue, particularly in individuals with diabetes mellitus (DM). Exercise has been shown to enhance cognitive function. However, the threshold effect of physical activity on cognitive function in older adult people with DM remains unclear.