Longevity Papers

The rapid aging of the global population is expected to lead to an increase in the incidence and prevalence of neurodegenerative diseases. Endurance exercise training is considered one of the most effective forms of prevention against neurodegenerative diseases. This study investigated the effects of a 5-year exercise training intervention at varying intensities on cognitive function in healthy older adults.

As populations age, the number of people with age-related chronic diseases increases, causing significant social, economic and health problems. Natural variation in lifespan depends on multiple interacting genes and environmental exposures. Its short generation time and many resources make Drosophila melanogaster an advantageous model to uncover the genetic architecture that underlies variation in lifespan.

Social and structural determinants of health significantly impact well-being across the lifecourse and contribute to ethnoracial disparities in cognitive aging. Early-life exposure to parental disruption (i.e., death, divorce, or separation), which disproportionately affects ethnoracially diverse children, increases the risk of adverse brain health outcomes. Systemic inflammation, a key biological mechanism linking early stress to cognitive aging, affects neurocognitive pathways. However, little is known about how the relationship between parental disruption, inflammation, and cognition varies by ethnoracial group. This study examines the mediating role of systemic inflammation in the relationship between early-life parental disruption and late-life global cognition among non-Hispanic White (69.11 %), Black (16.45 %), and Hispanic (11.64 %) adults aged 55+ in the Health and Retirement Study (HRS). Data on systemic inflammation were obtained from the 2016 HRS Venous Blood Study, and early-life experiences from the 2015-2017 Life History Mail Survey. Using structural equation modeling (SEM), we constructed a latent variable of systemic inflammation based on Meier et al. (2023), incorporating CRP, IL-6, IL-10, IL-1RA, TNFR1, IGF-1, and the neutrophil-to-lymphocyte ratio. SEM with full information maximum likelihood (FIML) was used to address missing data and assess indirect effects. Inflammation was associated with lower cognition among non-Hispanic White and Hispanic participants, but not Black participants. Among non-Hispanic Whites, parental disruption was linked to higher inflammation, which in turn predicted lower cognitive performance. The pathway differed for Black participants, suggesting distinct psychosocial risk and resilience processes. Findings highlight the importance of lifecourse and culturally responsive approaches to addressing disparities in cognitive aging.

The aim of this study was to explore the developmental trajectories of social participation and cognitive function, as well as their interaction.

Understanding metabolic changes across the human lifespan is essential for addressing age-related health challenges. However, comprehensive metabolomic and lipidomic analyses, particularly in human plasma, remain underexplored. Herein, we performed untargeted metabolomics and lipidomics profiling of plasma collected from 136 individuals aged 0-84 years. This analysis reveals distinct metabolic signatures across life stages, with newborns displaying unique sphingosine (SPH) profiles, while aging was found to be characterized by elevated amino acid levels and lipid imbalances. Notably, we identified linear and nonlinear metabolic trajectories across the lifespan, highlighting critical transition points reflecting the key stages of metabolic reprogramming. By integrating these metabolic patterns, we developed an "aging clock" based on plasma metabolite profiling, thus providing a powerful tool to predict biological age. These findings offer new insights into the dynamic metabolic landscape of aging, paving the way for targeted interventions to improve healthspan and prevent age-related diseases.

Population aging is accelerating worldwide, with 16% projected to be aged ≥ 65 years by 2050. A practical index reflecting overall aging status is needed for population-based research, as existing indices often require specialised or cognitive assessments. We developed a Physiological Healthy Aging Index (PHAI) using accessible biomarkers and evaluated its association with mortality in Korean adults. A total of 6398 participants aged ≥ 40 years from the Korean Genome and Epidemiology Study (KoGES) Ansan-Ansung cohort followed up for an average duration of 16.5 years (2001-2022). The PHAI, based on systolic blood pressure, fasting blood glucose, serum creatinine, forced vital capacity, and C-reactive protein levels, was scored 0-10, with higher scores indicating healthier aging. Mortality risks across quartiles were estimated using Cox proportional hazard models. Long-term changes were classified as accelerated (decreased scores), stable (unchanged scores), or resilient (increased scores). During 105,597 person-years, 934 deaths occurred (778 age-related, 353 cancer-related, and 184 cardiovascular-related). Higher PHAI quartiles were linked with significantly lower mortality risk versus Q1. Fully adjusted hazard ratios (95% CIs) for all-cause mortality were 0.82 (0.69-0.98) for Q2, 0.50 (0.42-0.60) for Q3, and 0.51 (0.41-0.63) for Q4 (P for trend < 0.001). Similar associations were observed for age-related mortality (HR 0.51, 95% CI 0.40-0.64 for Q4 vs. Q1), cancer (HR 0.66, 95% CI 0.48-0.92), and cardiovascular mortality (HR 0.24, 95% CI 0.13-0.44). Resilient agers had much lower all-cause mortality than accelerated agers (HR 0.21, 95% CI 0.16-0.28), with stable agers also at reduced risk (HR 0.65, 95% CI 0.54-0.77). Higher scores also correlated with a lower cognitive impairment risk. The PHAI is a simple, robust predictor of mortality outcomes, supporting its use as a practical tool for assessing physiological aging in public health and clinical settings.

Aging-related retinal diseases lead to irreversible structural damages and vision loss. These conditions are characterized by cellular senescence, oxidative stress, neural degeneration, and neovascularization. Among these, chronic inflammation is a hallmark of aging, establishing a self-perpetuating vicious cycle that accelerates pathological process and physiological decline. cGAS-STING signaling pathway has been identified as a critical mediator of inflammation across multiple retinal disease contexts, functioning to regulate immune response by detecting the dsDNA resulted from tissue injury. Under pathological circumstances, it exhibits a state of persistent activation, which results in chronic inflammatory reactions in the microenvironment. The disrupted homeostasis is closely linked with the onset and progression of numerous aging-related retinal diseases. Given the strong association between cGAS-STING signaling and these conditions, this pathway may represent a promising therapeutic target for refractory retinopathies. Encouragingly, several inhibitors targeting this pathway have already been developed and yielded remarkable therapeutic outcomes. This review delineates the primary functioning factors and modulatory mechanisms of the cGAS-STING cascade. Furthermore, it discusses the specific role of cGAS-STING pathway in pathological process of age-related retinopathy and summarize the key inhibitors of the cGAS-STING pathway, highlighting their therapeutic potentials for age-related retinopathy. These findings will deepen the understanding of the crosstalk between cGAS-STING signaling and retinal aging, thus offering valuable insights for the future translation of laboratory findings into clinical interventions.

Aging is a complex biological process marked by a gradual decline in physiological function that contributes to increased vulnerability to disease and mortality. Numerous studies have investigated the cellular and molecular aspects of aging at single-cell resolution, yet the heterogeneity of cellular aging in an individual remains poorly understood. To enhance our ability to study aging at the single cell level, we developed a statistical framework to predict the age of individual cells based on their transcriptomic profiles. Our Bayesian approach estimates the most likely age of a cell given its read counts. We applied the model to data from Tabula Muris Senis and examined organ- and cell-type-specific transcriptomic signatures of aging. Compared with standard regression-based methods, our framework achieved higher predictive accuracy. We show that scBayesAge is a powerful tool for dissecting the cellular heterogeneity of aging and age-related functional decline.

Intervertebral disc degeneration (IDD), a major cause of low back pain, is closely linked to oxidative stress-mediated inflammation and nucleus pulposus cell (NPC) senescence; however, current clinical treatments fail to effectively target these underlying mechanisms. This study presents a multifunctional therapeutic platform that integrates engineered microalgae with a nucleus pulposus (NP)-like hydrogel to fill disc defects and mitigate senescence-associated IDD. Engineered microalgae, which exhibit nanozyme-like activity, demonstrate potent antioxidant effects through reactive oxygen species (ROS) scavenging. Meanwhile, the NP-like hydrogel activates platelets to release growth factors that counteract cellular senescence. In vitro, the engineered microalgae effectively scavenge intracellular ROS, stabilize mitochondrial membrane potential, reduce inflammatory cytokine secretion, and consequently alleviate NPC senescence while restoring extracellular matrix (ECM) homeostasis. Transcriptomic analysis reveals that the engineered microalgae diminish oxidative stress-mediated acute inflammatory responses, reduce production of inflammatory cytokines (TNF-α), and downregulate senescence-associated secretory phenotype factors (IL-6). In vivo, local injection of the engineered microalgae delays needle puncture-induced IDD in rats. Furthermore, given the limited clinical translatability of rodent models, a goat NP defect model is established. Implantation of the engineered microalgae-hydrogel platform effectively fills disc defects and promotes disc repair in goats. This platform represents a promising therapeutic strategy with strong translational potential for preventing and treating IDD.

Gamma-band synchronization is a key mechanism for healthy cognitive function, yet it tends to decrease with age. EEG-based Neurofeedback (EEG-NF) is a promising tool enabling subjects to modulate their brain activity. However, its efficacy at the individual level remains unclear, which may partly explain the heterogeneity of neurofeedback outcomes. The primary objective of this study was to investigate individual neural dynamics of Gamma-band synchronization through EEG-NF training. We analyzed data from a double-blind, placebo-controlled trial using an EEG-based brain-computer interface, involving healthy older adults with subjective memory complaints, randomly assigned to a neurofeedback or a sham feedback group. Specifically, we employed a two-step unsupervised machine learning framework: first, epoch-based Agglomerative Hierarchical Clustering to identify individual-level response patterns, then Spectral Bi-Clustering to uncover higher-order structure at the population level. Results revealed a subgroup of individuals within the real neurofeedback condition who successfully enhanced their Gamma-band synchronization, with effects extending across the broader frequency spectrum. In contrast, the remaining participants in the neurofeedback group exhibited neural responses comparable to those observed in the sham group. This randomized controlled trial offers novel insights into the individual neural dynamics underlying successful Gamma EEG-NF training,  highlighting its potential to promote healthy brain aging.

Insulin secretion from pancreatic β-cells is essential for maintaining glucose homeostasis and preventing type 2 diabetes, a condition closely associated with aging. Although previous studies in mice have shown that both basal and glucose-stimulated insulin secretion increase with age, the underlying mechanisms remained poorly understood. In this study, we identify protein kinase D (PKD) as a critical regulator of β-cell function during aging through its control of cellular senescence. Using β-cell-specific expression of dominant-negative PKDkd-EGFP and the selective PKD inhibitor CRT0066101, we demonstrate that inhibition of PKD activity in mature adult mice induced a senescent-like β-cell phenotype characterized by enlarged cell size and elevated β-galactosidase activity. These changes were associated with decreased expression of the antioxidant enzyme superoxide dismutase 2 and increased levels of reactive oxygen species. Surprisingly, despite promoting a senescent-like phenotype, PKD inhibition significantly improved glucose tolerance, enhanced glucose-stimulated insulin secretion, and protected against high-fat diet-induced glucose and insulin intolerance. These findings highlight the importance of PKD in preserving β-cell function under aging and metabolic stress conditions.

Reduction in growth hormone (GH) signaling throughout life is known to extend lifespan and enhance healthspan in mice, and congenital GH receptor (GHR) mutations in both mice and humans confer protection against age-related diseases such as cancer, diabetes, and cognitive decline. To explore the health effects of disrupting GH action during adulthood, we previously generated adult-onset GHR knockout (6mGHRKO) mice by ablating GHR at 6 months of age. Both male and female 6mGHRKO mice exhibited reduced oxidative stress, with males showing improved insulin sensitivity and resistance to cancer, while females demonstrated extended lifespan. In the current study, we performed RNA sequencing on subcutaneous adipose tissue (Subq AT) from 6mGHRKO and control mice to investigate molecular mechanisms underlying these health benefits. Differential gene expression, gene ontology, pathway enrichment, and upstream regulator analyses revealed that GHR ablation predominantly downregulated gene expression, particularly in males. Sex-specific gene expression differences were more pronounced in control mice than in 6mGHRKO counterparts. Among the enriched processes, pathways related to extracellular matrix (ECM) organization emerged as differentially regulated between sexes and genotypes. These transcriptomic findings are exploratory and hypothesis-generating, highlighting ECM remodeling as a potential area for future mechanistic validation.

Metabolic syndrome (MetS) can lead to accelerated brain aging and cognitive decline. Evidence has suggested the involvement of the microbiota-gut-brain axis in the relationship between MetS and cognitive dysfunction, but the underlying mechanisms are unclear. Using magnetic resonance imaging and 16S rRNA gene amplicon sequencing, we collected data of brain structure (gray matter volume and white matter integrity) and gut microbiome from 97 patients with MetS and 103 sex-, age- and education-matched healthy controls. The Trail-making Test A and auditory verbal learning test were used to assess executive function and memory. Group differences in gut microbiome, brain structure, and cognitive function as well as their plausible interactive links in patients with MetS were examined. We found that patients with MetS exhibited impaired executive function and memory ability, both depleted short-chain fatty acids (SCFA)-producing bacteria and enriched inflammation-triggering bacteria, gray matter atrophy of several brain regions and microstructural integrity damage of multiple white matter tracts. Of more importance, correlation and mediation analyses demonstrated that the abnormal brain structure mediated the associations between the depleted anti-inflammatory bacteria (i.e., Clostridium XlVa, Kineothrix and Acetivibrio) and the impaired cognitive function in patients with MetS. Our findings not only point to new hypotheses about potential neurobiological pathways by which gut microbial dysbiosis may lead to cognitive dysfunction in the context of MetS, but also highlight the potential therapeutic value of targeting gut microbiota for cognitive impairments in patients with MetS.

Saussurea involucrata, commonly known as snow lotus, is a rare medicinal plant that is traditionally used in several countries owing to its therapeutic properties. Snow lotus extracts have been shown to exert anti-inflammatory effects and reduce reactive oxygen species levels. Although various bioactive compounds have been identified in snow lotus, the biological activity and underlying mechanisms of DNA isolated from this plant remain unexplored. This study aimed to investigate the skin-regenerative properties of polydeoxyribonucleotide (PDRN) isolated from snow lotus. PDRN was extracted and purified from dried flowers of S. involucrata. Water-soluble tetrazolium salt 1, wound healing, and enzyme-linked immunosorbent assays were used to evaluate the effects of snow lotus PDRN on cell proliferation, cell migration, and collagen synthesis, respectively. We also measured matrix metalloproteinase 1 (MMP1) mRNA expression after snow lotus PDRN treatment. Snow lotus-derived PDRN was non-cytotoxic to human skin cells and significantly promoted cell proliferation and migration. Additionally, it enhanced collagen synthesis by suppressing the expression of MMP1. These findings demonstrate that snow lotus PDRN may be a promising anti-aging agent and may serve as a valuable ingredient in cosmeceutical formulations.

The availability and global scale-up of suppressive antiretroviral therapy (ART) has transformed HIV from a fatal infection to a chronic disease. While long-term survival is a positive development for people living with HIV (PLWH), the increased life expectancy comes with age-related comorbidities. These comorbidities affect PLWH at relatively earlier ages than the general population, and examples include cardiometabolic conditions, renal toxicity, lung and respiratory dysfunction, neurocognitive deficits, malignancy, and oral/dental pathology. Anticipatory management of early markers of non-communicable diseases (NCDs) can be especially advantageous for children and adolescents with perinatally-acquired HIV (CAPHIV), the vast majority of whom live in low-and middle-income countries. However, evidence for the mechanisms underlying age-related comorbidities in PLWH and implications for CAPHIV represent a still-emerging area of investigation. In this article, we review the current literature on comorbidities and age-related conditions experienced by CAPHIV, discuss the role of inflammation and chronic immune activation, and highlight accelerated biological aging and/or disruptions to the microbiome as underlying mechanisms. We recommend that HIV clinical care and health policy should reflect evidence on aging and comorbidities to optimize growth, development, and long-term health for CAPHIV globally.

The insulin/IGF-1 signaling (IIS) pathway is an evolutionary conserved regulator of longevity, and its modulation is a hallmark of aging research. The 1993 ground-breaking report of a daf-2 mutation (e1370) that reduced IIS and doubled C. elegans lifespan in hermaphrodite worms paved the way for molecular approaches to modulating aging. However, the impact of that mutation on the male sex has remained largely unstudied. Here we report that the same mutation extends male lifespan by fourfold, to over 110 days. This extreme longevity is coupled with a dramatic extension of healthspan as well. These findings establish sex not as a secondary variable but as a primary determinant of longevity potential, capable of amplifying the output of a core aging pathway to an astonishing degree. This work provides a new approach or dissecting the interplay between sex and aging and suggests that sex-specific interventions may be critical for developing future anti-aging therapeutics.

Lysosomes are critical hubs for both cellular degradation and signal transduction, yet their function declines with age. Aging is also associated with significant changes in lysosomal morphology, but the physiological significance of these alterations remains poorly understood. Here, we find that a subset of aged lysosomes undergo enlargement resulting from lysosomal dysfunction in C. elegans. Importantly, this enlargement is not merely a passive consequence of functional decline but represents an active adaptive response to preserve lysosomal degradation capacity. Blocking lysosomal enlargement exacerbates the impaired degradation of dysfunctional lysosomes. Mechanistically, lysosomal enlargement is a transcriptionally regulated process governed by the longevity transcription factor SKN-1, which responds to lysosomal dysfunction by restricting fission and thereby induces lysosomal enlargement. Furthermore, in long-lived germline-deficient animals, SKN-1 activation induces lysosomal enlargement, thereby promoting lysosomal degradation and contributing to longevity. These findings unveil a morphological adaptation that safeguards lysosomal homeostasis, with potential relevance for lysosomal aging and life span.

Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with dementia. Cellular senescence, widely acknowledged as a key hallmark of aging, has increasingly been recognized as a significant factor in the pathogenesis of AD, although the precise mechanisms underlying this relationship have yet to be fully understood. In the brains of individuals with AD, neurons, glial cells, and cerebrovascular endothelial cells exhibit premature senescence, characterized by irreversible cell cycle arrest, resistance to apoptosis, and the secretion of a diverse range of bioactive molecules collectively referred to as the senescence-associated secretory phenotype (SASP). These senescent cells profoundly influence the neural microenvironment through the release of SASP factors, thus exacerbating Aβ- and tau-induced neurotoxicity, promoting neuroinflammatory responses, and impairing the integrity of the blood-brain barrier (BBB), ultimately giving rise to a self-sustaining "senescence-neurodegeneration" cycle. Despite progress in therapies targeting Aβ and tau pathology, their clinical effectiveness remains limited, highlighting the urgent need for alternative therapeutic strategies. This review presents a comprehensive analysis of the molecular mechanisms connecting AD with cellular senescence, examines how the senescent microenvironment contributes to neurodegeneration, and evaluates the therapeutic potential of senotherapeutic interventions-including senolytics and senomorphics-as novel approaches for the clinical management of AD.

Epigenetic clocks are machine learning models that predict an organism's chronological age (the time elapsed since birth) or biological age (a proxy for physiological integrity) based on methylation levels from multiple genomic sites. To date, all epigenetic clocks rely exclusively on C5-methylcytosine (5 mC), the predominant DNA methylation mark in vertebrates. However, not all species possess detectable 5 mC levels. Here, we used N6-methyladenine (6 mA), a less-characterized DNA modification type, to develop a series of epigenetic clocks in the buff-tailed bumblebee (Bombus terrestris). Using long-read Nanopore sequencing, we generated genome-wide, base-resolution profiles of 6 mA and 5 mC in males of different ages (n = 15), and developed multiple epigenetic clocks based on distinct features of the aging DNA methylome. All clocks showed strong correlations between predicted epigenetic and chronological age. Moreover, they also detected pharmacologically induced lifespan extension, reflected by a reduction in predicted epigenetic age relative to chronological age, indicating that these clocks capture biological aging. These findings demonstrate that 6 mA can be used to build accurate epigenetic clocks and establish 6 mA as a promising biomarker of aging in animals.

The thymus is the primary site of T cell development, central to the establishment of self-tolerance and adaptive immune function. In mammals, the thymus undergoes age-related involution, resulting in a global decline in immune function. The thymus has some regenerative ability that relies on pre-existing thymic remnants but is insufficient to prevent involution. Here, we show that the juvenile axolotl (

This review explores the anti-ageing potential of nine repurposed drugs: aspirin, atorvastatin, enalapril, metformin, canagliflozin, liraglutide, acarbose, N-acetylcysteine and dasatinib (commonly combined with quercetin). Specifically, it focuses on their mechanisms through the mechanistic target of rapamycin, adenosine monophosphate-activated protein kinase, nuclear factor kappa B and senescence-associated secretory phenotype pathways. The repurposed drugs show promise in extending healthspan and lifespan in model organisms by modulating ageing-related processes, e.g. reducing chronic inflammation, enhancing metabolic efficiency and improving cellular stress resistance. However, translating preclinical findings into clinical practice still faces major challenges, including species specificity and sex differences, the lack of reliable ageing biomarkers and the issue of dosage selection. This review synthesises progress and obstacles in transitioning drug development from targeting individual age-related diseases to addressing ageing as a unified biological process. Ultimately, the goal is to support a paradigm shift where ageing is recognised as a modifiable condition, enabling longer healthy human lifespans.

Senescent cells are characterized by a stable proliferation arrest and a senescence-associated secretory phenotype or SASP. Although these cells can have some beneficial effects, including protecting from tumor formation, their accumulation is deleterious during aging as it promotes age-related diseases, including cancer initiation and progression. Although the SASP has a critical role, its composition, regulation and dual role in cancer remain largely misunderstood. Here, we show that ANGPTL4 is one of the rare secreted factors induced in many different types of senescent cells. Importantly, ANGPTL4 knockdown during senescence or its constitutive expression, respectively inhibits or induces classical proinflammatory SASP factors, such as IL1A, IL6 and IL8. The latter effect is mediated upstream of IL1A, an early SASP factor, suggesting an upstream role of ANGPTL4 in SASP induction. This ANGPTL4-dependent proinflammatory SASP can promote human neutrophil activation in ex vivo assays, or tumor initiation in a KRAS-dependent lung tumorigenesis model in mice. This upstream activity of ANGPTL4 in regulating the proinflammatory SASP depends on its upregulation following a hypoxia-like response and HIF2A activation, and its proteolytic processing by the FURIN proprotein convertase. Altogether these findings shed light on a two-step activation of ANGPTL4 by HIF2A and FURIN in senescent cells and its upstream role in promoting the proinflammatory SASP, cancer and potentially other senescence-associated diseases.

Skeletal muscle atrophy represents a pathological condition characterized by impaired protein homeostasis that commonly occurs with aging, chronic inflammatory diseases, physical inactivity, and neuromuscular disorders. This condition significantly reduces patients' quality of life and increases mortality risk. Emerging research highlights the immune system, especially macrophages, as key regulators of this process. As core components of innate immunity, macrophages exhibit high plasticity and orchestrate muscle repair and the regulation of chronic inflammation through polarized pro-inflammatory (M1) and anti-inflammatory/reparative (M2) phenotypes. This review systematically examines the dual role of macrophages in muscle pathology. On one hand, they facilitate muscle regeneration by removing necrotic tissue and secreting growth factors like Insulin-like Growth Factor 1 (IGF-1) and Interleukin-10 (IL-10) to promote satellite cell activation. On the other hand, improper macrophage activation or polarization shifts toward sustained M1 dominance can release harmful cytokines such as Tumor Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6), activating Nuclear Factor-kappa B (NF-κB) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways that increase protein breakdown, inhibit muscle formation, and accelerate atrophy. Additionally, we evaluate macrophage-focused treatments including drug inhibitors, stem cell therapies, plant compounds that modify polarization, and genetic approaches to rebalance immune function and reduce muscle wasting. Collectively, these advances provide novel mechanistic insights into immune-mediated skeletal muscle pathology and lay the groundwork for a translational framework for targeted interventions.

Macrolide antibiotics, long recognized for antibacterial properties, have recently emerged as modulators of oxidative stress in eukaryotic cells, reflecting context-dependent effects and pharmacological activities distinct from their antimicrobial activities. The purpose of this review is to examine the capacity and outcomes of macrolides, using erythromycin as the most well-documented example, to modulate responses to stress from reactive oxygen species (ROS) and what this means for redox homeostasis. We compare evidence from studies of mammalian cells and the so-called PI3K/AKT/mTOR and PPARγ/NF-κB/Nrf2 signaling pathways to reveal erythromycin's suppressive effects towards oxidative stress-induced senescence, upregulation of antioxidant enzymes (e.g., superoxide dismutase and catalase), and related effects that mitigate mitochondrial dysfunction. These redox outcomes of exposure to erythromycin are particularly relevant to therapeutic strategies targeting inflammatory and age-related diseases, including chronic obstructive pulmonary disease and neurodegeneration. Conversely, studies of aquatic species, including fish, algae, and invertebrates, suggest that erythromycin induces oxidative damage and genotoxicity. In this review, we discuss factors that are likely to shape this dualistic nature of macrolides in redox modulation such as levels and duration of antibiotic exposure, type of antioxidant system, tissue specificity, and organism complexity. Emerging research in oxidative modulatory properties of erythromycin in eukaryotic and prokaryotic microorganisms, and properties that are shared among macrolides are also discussed. While erythromycin's protective redox effects are therapeutically promising, concerns over chronic use, antioxidant suppression, and other context-dependent outcomes merit the need for systems-level multi-omics approaches to define therapeutic thresholds and ecological risks. This review provides a consolidative overview of our up-to-date understanding of macrolides as redox modulators, and advocates for future investigation into the broad physiological and environmental impacts.

Findings on the association of both nicotinamide mononucleotide (NMN) and iron metabolism with antiaging or aging led us to speculate that some pharmacological functions of NMN may be achieved partially by affecting iron metabolism. Here, we investigated the effects of NMN on cell viability, iron contents, oxidative stress, and the expression of ferritins, transferrin receptor 1 (TfR1), ferroportin1 (Fpn1), hepcidin, interleukin 6 (IL-6), interleukin-1β (IL-1β), and signal transducer and activator of transcription 3 (STAT3) in BV2 microglia (BV-2) cells treated with 150 μM of ferric ammonium citrate. We found that NMN induced a significant reduction in iron concentration, ferritin expression, and reactive oxygen species level, and an increase in cell viability in iron-overloaded BV-2 cells. Also, NMN significantly up-regulated TfR1 and down-regulated Fpn1 and hepcidin expression as well as IL-6, IL-1β, and pSTAT3 contents in iron-overloaded BV-2 cells. We concluded that NMN is able to regulate the expression of iron transport proteins TfR1 and Fpn1, via IL6/STAT3/hepcidin and IL-1β/hepcidin pathways, and then down-regulate iron contents and the expression of ferritin and inhibit oxidative stress in iron-overloaded BV-2 microglia cells, supporting that some pharmacological functions of NMN may be partly associated with the effects of NMN on iron metabolism. Our results suggest that NMN may have beneficial therapeutic effects on iron-related diseases such as neurodegenerative diseases.

While previous studies have examined the link between Type 2 Diabetes Mellitus (T2DM) and cognitive function in middle-aged adults, no review has explored the long-term effects on cognition of T2DM when diagnosed at midlife. This review aims to investigate any association between T2DM and its metabolic correlates during midlife and measures of cognitive function, spanning from midlife into later life.

There is still relatively little known about the genetic underpinnings of proteomic aging clocks. Here, we describe a genome-wide association study of proteomic aging in the UK Biobank (n=38,865), identifying 27 loci associated with participants' proteomic age gap (ProtAgeGap). ProtAgeGap exhibits a strong genetic correlation with longevity (rg = -0.83), and in FinnGen a ProtAgeGap polygenic score (PGS) was associated with significantly increased odds of achieving longevity (n=500,348; OR = 1.43). Additional PGS analyses in All of Us (n=117,415), China Kadoorie Biobank (n=100,640), and ABCD Study (n=5,204) demonstrate reproducible associations across biobanks of ProtAgeGap PGS with obesity, cardiometabolic disease, and osteoarthritis in adults, and with developmental timing in children. Finally, colocalization analysis identified FTO as an obesity-related mechanism uniting diverse aging traits. Our results demonstrate a shared genetic architecture across the life course of ProtAgeGap with longevity, early developmental biology, and cardiometabolic and musculoskeletal diseases.

Cellular senescence is an irreversible state linked to aging that involves molecular and functional alterations. The mammalian hippocampus, a key brain region for learning and memory, is highly vulnerable to damage in age-related neurodegenerative diseases, yet the role of cellular senescence in hippocampal aging remains underexplored. Here, we report an early onset of senescence signatures in hippocampal astrocytes of the accelerated aging and frailty mouse model SAMP8. We examine how astrocyte senescence affects excitatory synapse formation, focusing on soluble signals released by astrocytes. Astrocytes isolated from SAMP8 brain and those differentiated from SAMP8 neural stem cells show senescence hallmarks (SA-{beta}-gal, p16INK4a, Lamin B1 loss), alongside a significant reduction in synaptogenic function. While astrocyte-conditioned medium (ACM) from control mice promotes excitatory synaptogenesis through thrombospondin-1 / 2{delta}-1 neuronal receptor signalling, ACM from senescent SAMP8 astrocytes lacks this capacity. Supplementing senescent ACM with thrombospondin-1 protein, or overexpressing thrombospondin-1 gene in senescent astrocytes, reinstates synaptogenesis. At the hippocampal level, thrombospondin-1 and synaptic puncta are reduced in SAMP8 mice. Our findings reveal that senescent astrocytes exhibit reduced synaptogenic capacity due to thrombospondin-1 loss, highlighting their contribution to synaptic dysfunction during aging. Preventing senescence in hippocampal astrocytes may thus restore astrocyte-mediated synaptogenesis in the aged brain.

The long lifespan of humans is often not matched with health span. Thus, there is a need for rejuvenation strategies. Here, we first discuss the evolutionary benefits of the long human lifespan, particularly when coupled with an extended health span. We then highlight the importance of understanding the complexity of aging before interfering with it. This raises the question of the optimal target for rejuvenation. We propose the blood system and hematopoietic stem cells (HSCs). Their decline is associated with dysfunction and disease in other organs, crystallizing them as a central player in organismal aging. We present rejuvenation strategies targeting the hematopoietic system, especially HSCs, and explore their systemic benefits. Overall, we summarize the potential of the blood system to reverse aging. Impact statement There is a current need to reduce the economic burden caused by aging-related diseases. In this perspective article, we discuss the evidence that supports that rejuvenating or delaying aging of the blood system has a beneficial and systemic impact on human health.

Vascular endothelial cells (ECs) are pivotal in maintaining vascular homeostasis. Liraglutide (LIR) can prevent and reverse hyperglycemia-induced cell dysfunction. However, the mechanism by which it improves hyperglycemia-induced EC senescence remains unclear. This study investigates whether the La Ribonucleoprotein 7/Sirutin 1 (LARP7/SIRT1) signaling axis is essential for LIR efficacy in mitigating EC senescence and dysfunction. We treated senescent human umbilical vein ECs induced by high glucose levels with LIR and evaluated cell viability cell counting kit-8 (CCK-8 assay), senescence (SA-β-gal staining), and SASP alterations (qPCR). We also investigated the expression of senescence-related proteins and changes in the LARP7/SIRT1 signaling pathway using Western blot analysis. Additionally, reactive oxygen species levels were measured with 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA), and changes in oxidative stress-related factors were assessed using specific assay kits. The effect of LIR on endothelial dysfunction was examined by cellular tube-forming assay and transwell assay after LARP7 knockdown/overexpression. LIR markedly improved cell vitality and the senescence phenotype while reducing oxidative stress. The LARP7/SIRT1 pathway emerged as crucial for its effectiveness. Following LARP7 knockdown, the therapeutic efficacy of LIR was notably attenuated. The overexpression of LARP7 enhanced the therapeutic efficacy of LIR. The tube formation and transwell assays further supported the hypothesis that LIR's beneficial impact on endothelial dysfunction depends on the LARP7/SIRT1 signaling axis. Our study reveals a novel aspect of LIR as an antidiabetic agent in delaying vascular aging driven by high glucose through targeting the LARP7/SIRT1 pathway. This discovery enhances the therapeutic value of LIR and proposes a new strategy for addressing vascular aging in treatments for elderly patients with diabetes.

Aging profoundly alters the bone marrow (BM) microenvironment and impairs hematopoietic stem cell (HSC) function. Here, we identify decrease of miR-126 derived from arteriolar endothelial cells (ECs) as a key mechanism of impaired HSC self-renewal capacity during aging. In young BM, arteriolar ECs express high levels of miR-126, which is transferred to HSCs and supports these cells' homeostasis and functional integrity. Using young and aged wild-type, endothelial-specific miR-126 knockout (EC-miR-126 KO), EC-Spred1 knockout (a functional model of EC-miR-126 upregulation), and EC/Sca-1 dual fluorescent reporter mice, we show that age-related increase in inflammatory cytokines (such as TNFα) reduces EC miR-126 expression and in turn drives loss of miR-126high CD31+Sca-1high EC-lined arterioles in the aging BM niche. Loss of arterioles in turn decreases the EC miR-126 supply to HSCs, leading to expansion of HSCs with limited self-renewal capacity. Remarkably, administration of a synthetic miR-126 mimic oligonucleotide restores EC-HSC communication and rescues aging-related HSC dysfunction. Our findings uncover a novel, non-cell-autonomous mechanism of HSC aging and highlight EC-derived miR-126 as a promising therapeutic target to rejuvenate hematopoiesis.

With the rapidly growing global aging population, muscle atrophy affects ≈40% of older individuals, leading to severe impairments in daily activities. However, its treatment remains challenging due to adverse effects associated with drug accumulation, the difficulty of delivering drugs specifically to deep muscle tissues, and the inherent limitations of current therapeutic devices that rely on wired connections or battery-dependent external power systems. In this study, a body-coupled on-target stimulation (BOOST) system is introduced in combination with an active releasing muscle stimulation (ARMS) hydrogel, which possesses anti-drying properties and enables electroactive drug release. The BOOST system enables battery-free, wirelessly delivered electrostimulation and simultaneous drug delivery from the skin to deep muscle layers by leveraging charge accumulation in tissue capacitance. This in-body field amplification generates a muscle-targeted electric field that enables deep-tissue drug penetration. In addition, when combined with the electro-responsive ARMS hydrogel containing electrically bound dexamethasone phosphate (Dex) molecules, the BOOST system exhibits synergistic performance, achieving targeted internal electrostimulation and efficient Dex penetration into deep muscle tissue for effective transdermal-to-muscle delivery. The simultaneous application of ES and Dex effectively restores muscle cells severely damaged by oxidative stress, mimicking the pathological conditions of muscle atrophy.

The suprachiasmatic nucleus (SCN), the central circadian pacemaker, orchestrates daily metabolic rhythms, yet its role in substrate selection and thermogenic adaptation under stress remains insufficiently understood. Here, we show that SCN lesioning abolishes the adaptive suppression of brown adipose tissue (BAT) thermogenesis typically observed during time-restricted feeding in subthermoneutral environments (TRF-STE), a paradigm that imposes concurrent nutrient and thermal stress. Contrary to wild-type responses, SCN-lesioned mice maintain elevated BAT thermogenic activity, despite impaired lipolysis, instead shifting toward glucose-driven heat production. This phenotype is accompanied by sustained sympathetic tone and β3-adrenergic receptor (ADRB3) signaling in BAT. Mechanistically, we identify a SCN-regulated ADRB3-S100B signaling axis underlying this metabolic reprogramming. S100B, a nutrient-sensitive calcium-binding protein, is upregulated in BAT following SCN disruption, where it promotes thermogenesis by stimulating brown adipocyte proliferation and suppressing senescence. Functional studies reveal that S100B is both necessary and sufficient for sustaining BAT thermogenesis under TRF-STE. Furthermore, diverse SCN disruption models, including light-induced circadian arrhythmia, N-Methyl-D-aspartic acid (NMDA) excitotoxicity, and Caspase-3-mediated ablation, consistently elevate S100B expression in BAT, reinforcing its role as a convergent effector of SCN-regulated metabolic adaptation. Thus, in intact animal, the SCN restrains the ADRB3-S100B module, gating BAT thermogenic output in accordance with energetic availability. Disruption of SCN output lifts this restraint, unmasking a latent ADRB3-S100B program that preserves thermogenesis when lipid fuel is limited. These findings reveal a previously unrecognized role of the SCN in governing thermogenic flexibility and fuel partitioning, and position the ADRB3-S100B axis as a potential target for mitigating circadian misalignment and metabolic disease.

Data regarding the association between dietary behaviors and handgrip strength (HS) are limited. The current study aimed to evaluate the hypothesis that dietary patterns, eating behaviors, and physical activity are associated with HS measured in later life. The study used data of 2,615 Korean adults (1,101 men and 1,514 women aged 43-74 years) without sarcopenia, who participated in a population-based prospective cohort study and completed questionnaire-based interviews and health examinations during the period of 2005 - 2014. Baseline (year 2005 - 2006) information on eating behaviors and physical exercise was obtained with dietary data, which were obtained via a food frequency questionnaire and used for dietary pattern analysis. The study outcome was HS measured at 8-year follow-up (year 2013 - 2014). Factor analysis, linear regression analysis, and modified Poisson regression analysis were performed. Sex-specific factor analysis revealed two dietary patterns labeled as "a Balanced Diet" characterized by a high intake of a variety of foods, and "a Refined Carb Diet" characterized by a high intake of refined grain foods in both men and women. In the multiple regression analysis, a higher factor score (FS) for a Balanced Diet was associated with increasing HS among women (P < 0.05) whereas a higher FS for a Refined Carb Diet was associated with decreasing HS among men (P < 0.05). Among women, slow eating behavior and irregular eating of meals were associated with decreasing HS (P < 0.05) whereas the performance of regular exercise was associated with increasing HS (P < 0.01). Similar significant results were observed in the associations with low HS, possible sarcopenia, defined as < 18 kg for women; the multivariable adjusted risk ratios (95% confidence interval) of low HS were 0.86 (0.74, 0.99) for a Balanced Diet, 1.23 (1.09, 1.40) for slow eating behavior, and 0.84 (0.72, 0.97) for regular exercise compared with its corresponding reference. These results suggest that a healthy diet consisting of a variety of foods and regular physical exercise may attenuate aging-related declines in HS and further prevent sarcopenia.

The copper-to‑zinc (Cu/Zn) ratio is linked to inflammation and aging, but longitudinal evidence for sarcopenia remains limited. We examined associations of serum copper (Cu), zinc (Zn), and Cu/Zn ratio with adverse health outcomes and sarcopenia.

The current study examined the relationship between social engagement and cognitive function among older Mexican heritage Latinos in the U.S. Although social engagement has been identified as a factor that is protective against cognitive decline and dementia, its association with cognitive health in Mexican heritage Latinos is understudied.

Brain aging is a major factor in cognitive decline and Alzheimer's disease (AD) progression. Aging-induced microglial senescence critically drives inflammaging and brain aging processes. Nevertheless, the underlying reasons and mechanisms that promote microglial aging remain unclear. This study explores how 27-hydroxycholesterol (27-OHC), a key oxysterol, accelerates brain aging by promoting microglial senescence, iron overload, and neuroinflammation. Clinically, we observed a significant inverse correlation between plasma 27-OHC levels and Mini-Mental State Examination (MMSE) scores in AD patients, accompanied by reduced 24S-OHC concentrations. Experimental studies revealed that 27-OHC administration in mice induced hippocampal-dependent cognitive impairment and anxiety-like behaviors, concurrent with elevated expression of cellular senescence markers (P21, P16, SA-β-Gal) and M1 microglial polarization. In BV-2 cells, 27-OHC disrupted iron homeostasis (DMT1/ferritin/GPX4 dysregulation), elevating ROS and impairing mitochondrial function. Deferoxamine (DFX) mitigated microglial senescence and ferroptosis. These findings establish the 27-OHC-iron axis as a novel therapeutic target for combating cholesterol-driven neurodegeneration.

Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise and tissue repair, but declines in ageing and obesity. Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic-endoplasmic reticulum Ca

Accurate bone strength prediction is essential for assessing fracture risk, particularly in aging populations and individuals with osteoporosis. Bone imaging has evolved from X-rays and DXA to clinical computed tomography (CT), and now to advanced modalities such as high-resolution peripheral quantitative CT and synchrotron radiation CT, which offer unprecedented resolution of bone microarchitecture. However, analytical methods have not kept pace with these imaging advances. This study applied topological data analysis (TDA) to extract biomechanically relevant features from high-resolution bone images, offering a new framework for bone strength prediction. We extracted topological features, specifically those derived from persistent homology, and combined them with standard bone morphometric descriptors to train machine learning models for apparent strength prediction. Models based solely on topological features outperformed those using traditional morphometrics, highlighting TDA's ability to capture biomechanically relevant structure. In particular, internal voids, often dismissed as imaging noise, proved to be the most predictive. While limited by dataset size and class imbalance, these results suggest that TDA offers a promising approach for advancing osteoporosis risk assessment.

The determinants of chronic diseases are complex, and we demonstrated how lifestyle-related factors interact with physiological factors to influence the risk of healthspan termination (HST).

Epigenetic clocks have been extensively investigated in individuals of European ancestry and may be suboptimal in East Asians. We developed a novel epigenetic clock (KoMethylNet) using neural network analysis of DNA methylation (DNAm) data from the Korean population to predict chronological ages.

Foam cell formation is a critical pathological process that contributes significantly to the development of atherosclerosis, influenced by processes such as vascular senescence and autophagy-lysosomal pathways. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has recently received interest due to its role in foam cell formation, but its connection to senescence and autophagy are still not well defined. This research investigated the role of Nrf2 in modulating senescence and autophagy in foam cells using an

Biological brain ageing is a major risk factor for neurodegenerative diseases, which are characterized by selective degeneration of particular neuron types. We analyzed the impact of ageing on the transcriptome of neurons in the ventral tegmental area (VTA), substantia nigra pars compacta (SNc) and locus coeruleus (LC), that show differential vulnerabilities to Parkinson disease. Neurons were isolated from human post mortem brain tissues originating from 48 individuals ranging from 17 to 102 years of age and subjected to Smart-seq2 RNA sequencing. We identified 2,764 genes that were correlated with chronological ageing. This gene expression data was used to develop a feature selection-based Time Traversal algorithm, utilizing functionally grouped gene sets, GO terms, with high predictive accuracy of biological brain ageing. We identified 59 GO terms that can predict biological age using a linear regression model, where leave-one-out cross validation demonstrated a strong correlation between chronological age and predicted biological age (Pearson correlation coefficient = 0.946; adjusted R2 = 0.771). The algorithm was validated on five independent datasets with high predictive performance, demonstrating shared ageing features across the human brain. Nonetheless, our analysis also highlights brain region and neuron type specificity in particular ageing features. Resilient neurons showed a weaker association with age-related transcriptional changes, indicating that they age slower than their vulnerable counterparts, thus revealing targets that may be used to slow down ageing and prevent disease development.

Background: Cognitive training aims to prevent or slow cognitive decline in older adults, but outcomes vary widely. Engagement, describing how individuals allocate cognitive, affective, and physiological resources, is critical to training benefits, yet behavioral metrics lack real-time modeling of attention and do not reliably predict outcomes. We developed and validated a multimodal, AI-assisted biomarker that quantifies attentional states during computerized cognitive training and predicts cognitive improvements. Methods: We designed the Attentional Index using Digital measures (AID), leveraging a video-based facial expression encoder (pretrained on 38,935 videos), an ECG-based autonomic encoder (pretrained on 123,998 ECG samples), and a temporal fusion module. Using two processing speed/attention studies in older adults (> 65 years) with mild cognitive impairment, AID was trained and evaluated in BREATHE (n=50; ~300 hours from 368 sessions) and validated in FACE (n=20; ~150 hours from 219 sessions). Model training targeted session-level change in self-reported fatigue. Clinical validation tested relationships between AID scores and (1) behavioral attention, (2) cognitive outcomes, and (3) neural correlates. Findings: AID accurately detected engagement changes (BREATHE: accuracy 0.82, F1=0.81; FACE: accuracy 0.73, F1=0.74), outperforming unimodal models. AID scores were unrelated to session, task type, or demographics. In BREATHE, session-level AID scores significantly predicted executive function improvement (sessionxAID: Wald^2=7.85, p=0.005), whereas reaction time variability did not. Lower AID intercepts (B=-0.07{+/-}0.03, p=0.043) and steeper slopes (B=0.31{+/-}0.15, p=0.046) were associated with greater improvements. Post hoc analyses identified two engagement profiles linked to better attention: one characterized by low-RMSSD and focused periocular activation, and the other defined by coherent alignment between low-RMSSD and facial expression patterns. Interpretation: AID provides a reliable digital biomarker of effective engagement and predicts cognitive improvement beyond behavioral metrics. By capturing facial-autonomic dynamics of attention, AID offers a foundation for closed-loop cognitive intervention design. Funding NIH AG081723, NR015452, and AG084471; Stanford HAI seed funding.

The SARS-CoV-2 pandemic has affected millions worldwide, with aging being a key risk factor for severe disease outcomes. This study examines the rate of epigenetic aging, as measured by DNA methylation-based aging markers, in COVID-19 patients versus healthy individuals. We found that PCGrimAge, a next-generation epigenetic clock associated with immune dysregulation and inflammation, showed the strongest correlation with the chronological age of the European COVID-19 patients. Several other next-generation epigenetic clocks, including PCGrimAge, DunedinPACE, and ZhangY2017, also exhibited accelerated aging in both older and female COVID-19 patients. Interestingly, first-generation clocks, such as Hannum2013, indicated a significant reduction in epigenetic aging, likely reflecting limitations in their sensitivity to infection-related biological changes rather than an actual deceleration of the aging process. Our results also showed that immune dysregulation, rather than intrinsic cellular aging, may be the primary driver of accelerated epigenetic aging in COVID-19. This is supported by stronger associations observed in Age Acceleration (AA) and Extrinsic Epigenetic Age Acceleration (EEAA) compared to Intrinsic Epigenetic Age Acceleration (IEAA). Furthermore, immune dysregulation may be linked to CpG site demethylation, which in turn influences epigenetic clock dynamics. We also identified disparities between European and non-European populations, characterized by significantly higher IEAA for PCPhenoAge and DunedinPACE among non-European patients with COVID-19. In summary, our results underscore the differential sensitivity of epigenetic clocks to COVID-19-related biological changes.

We analyze 10,986 participants (mean age 77; 63% women; 54% non-White) across seven U.S. cohorts to study the relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA methylation. We identify 597 CpGs associated with heteroplasmy burden, generally showing lower methylation. These CpGs are enriched in dynamically regulated island shores and depleted in CpG islands, indicating involvement in context-specific rather than constitutive gene regulation. In HEK293T cells, we introduce a truncating mtDNA mutation (MT-COX3, mt.9979) and observe a positive correlation between variant allele fraction and methylation at cg04569152, supporting a direct mtDNA-nDNA epigenetic link. Many heteroplasmy-associated CpGs overlap with known methylation-trait associations for metabolic and behavioral traits. Composite CpG scores predict all-cause mortality and incident CVD, with one-unit increases associated with 1.27-fold and 1.12-fold higher hazards, respectively. These findings suggest an mtDNA-nDNA epigenetic connection in aging and disease, though its direction and mechanisms remain to be studied.

Irisin, a myokine released by skeletal muscle during physical activity, has emerged as a key regulator of energy metabolism, cellular stress responses, and longevity pathways. While previous studies have focused on aged animal-models or pathological states, the long-term impact of early-life interventions on molecular aging pathways remains poorly understood. This study investigated whether early-life irisin administration and physical exercise could modulate the renal-expression of Klotho and HSP70-two hallmark genes of cellular protection and anti-aging in young adult NMRI mice. Animals underwent 8 weeks of resistance training, endurance training, or irisin injection. Plasma irisin was quantified via ELISA, and renal Klotho and HSP70 expression levels were assessed using qPCR and Western-blotting. All interventions significantly increased circulating irisin and upregulated Klotho and HSP70 at both transcriptional and protein levels, with resistance training inducing the most pronounced effects. A 20-month survival analysis showed a trend toward improved longevity in all intervention groups. These findings suggest that early-life exercise and irisin exposure may activate renoprotective and longevity-associated pathways before the onset of molecular aging, supporting their potential as preventive strategies in translational geroscience.

Aging humans and non-human primates both exhibit a similar pattern of cognitive decline beginning in middle age that is characterized by progressive impairments in rule learning, executive function, and working and recognition memory-functions often associated with dysfunction of prefrontal and medial temporal lobe regions. The heterogeneity and inter-subject variability in aging and age-related cognitive impairments present challenges for developing effective therapeutics and can be attributed to differing degrees of cortical white matter (WM) damage and alterations to local and long-range prefrontal and temporal networks. A promising therapeutic that has been shown to be efficacious in mitigating WM damage and improving cognitive function in rodent models is mesenchymal cell-derived extracellular vesicles (MSC-EVs). In the present study, late middle-aged rhesus monkeys were systemically administered monkey-derived MSC-EVs every 2 weeks for 18 months. We demonstrate that MSC-EV treatment improves spatial working memory and decreases the frequency of perseverative responses with largely no effects on recognition memory. These cognitive improvements were associated with increases in MRI diffusion measures of WM structural integrity over time as well as preservation of inter-network functional connectivity as measured by resting-state functional MRI. These findings suggest that MSC-EV treatment can slow or reverse age-related cognitive decline while strengthening WM integrity and improving functional connectivity in late middle-aged rhesus monkeys.

Mitochondrial dysfunction plays a critical role in cardiovascular aging and is a key player in the development of cardiovascular diseases (CVDs) such as hypertension, arteriosclerosis, aneurysms, and heart failure. Aging disrupts mitochondrial function through impaired oxidative phosphorylation, excessive reactive oxygen species generation, mitochondrial DNA mutations, endoplasmic reticulum stress, mitochondrial enzyme dysregulation, and impaired calcium homeostasis. These alterations drive endothelial dysfunction, arterial stiffening, cardiac remodeling, and ultimately exacerbate age-related cardiovascular decline. Despite extensive research, the precise mechanisms by which mitochondrial aging impairs the function of endothelial cells, vascular smooth muscle cells, and cardiomyocytes remain poorly understood. Therefore, this review synthesizes current evidence on how aging-associated mitochondrial dysfunction contributes to endothelial dysfunction, arterial stiffening and remodeling, and cardiac dysfunction. It also outlines emerging pathophysiological mechanisms linking mitochondrial dysfunction to age-related CVDs, offering insights into potential therapeutic targets to promote cardiovascular health in aging populations. This review highlights key biomarkers of declining mitochondrial function to facilitate early diagnosis of CVD-related mitochondrial dysfunction. We show that aging disrupts key regulators of mitochondrial dynamics and quality control in the vasculature and heart across human studies and preclinical models of aging. Recent evidence indicates that impaired mitochondrial function in aging cardiomyocytes results in valvular degeneration, left ventricular hypertrophy, diastolic dysfunction, atrial fibrillation, and diminished exercise capacity. Therefore, understanding the pathophysiological mechanisms linking mitochondrial dysfunction to cardiovascular aging may guide the development of new therapeutic strategies for mitigating age-related cardiovascular decline in older adults.

The global aging crisis has increased the prevalence of skeletal disorders, necessitating innovative therapeutic strategies. This review employs the brain-bone axis (BBA) framework to examine the role of the sympathetic nervous system (SNS) in bone metabolism. The research systematically elucidates the molecular mechanisms by which the SNS mediates signaling pathways through neurofibers and neurotransmitters, such as norepinephrine, dopamine, neuropeptide Y, and leptin, regulating interactions between bone-related cells to maintain skeletal homeostasis. It also identifies the pathological associations between the dysregulation of these pathways and the progression of bone-related conditions, such as osteoporosis, osteoarthritis, and intervertebral disc degeneration. By integrating current evidence, we identify novel therapeutic targets within the BBA and propose neuro-centric intervention strategies to mitigate skeletal diseases. This review deepens the understanding of neuro-skeletal interactions and lays a foundation for innovative treatments for bone-related pathologies.

As life expectancy increases, cognitive impairments such as Alzheimer's disease (AD) create serious problems for older adults. Women regardless of ethnicity and age group, are disproportionately affected, accounting for two-thirds of AD cases, with post-menopausal women representing over 60 % of those affected. Sarcopenia, defined by gradual reduction of skeletal muscle mass, strength, and activities, is increasingly correlated with an elevated risk of cognitive decline in post-menopausal women. Menopause-related hormonal decline (particularly estrogen loss) and aging contribute to sarcopenia, characterized by muscle mitochondrial dysfunction, oxidative stress, and insulin resistance. This sarcopenia-driven reduction in muscle mass and functional capacity further reduces the production of myokines (e.g., BDNF, irisin), impairing neuronal proliferation, adult neurogenesis, and spatial learning/memory. These pathophysiological changes show a contributing link between sarcopenia and AD progression in post-menopausal women. This review is unique in that it discusses the triangular interplay between menopause, sarcopenia, and AD, offering an integrated mechanistic framework that links hormonal decline, muscle loss, and neurodegeneration. We aim to clarify the pathophysiological causes behind the muscle-brain axis and suggest viable treatment approaches to slow down sarcopenia and cognitive deterioration in postmenopausal women based on current evidence. The formulation of targeted strategies for enhancing the quality of life and lessening healthcare expenditures in this expanding population depends on the advancement of understanding this complex interconnection between menopause, sarcopenia and cognition.

The hippocampus plays a central role in episodic memory and has been the focus of extensive research over past decades. A substantial body of work has demonstrated that age-related memory decline is linked to changes in how the hippocampus functionally interacts with distributed brain networks. While functional connectivity changes in ageing are well documented, relatively little is known about alterations in the structural connectivity (SC) of the hippocampus, despite its foundational role in supporting communication across neural systems. In this study, we combined high-quality data from the Human Connectome Project and advanced diffusion-weighted imaging (DWI) methods to investigate age-related changes in hippocampal SC. Using a recently developed tractography pipeline that allows greater anatomical specificity than conventional approaches, we systematically compared connectivity patterns between younger (26-30 years) and older (56-60 years) adults. Results revealed reduced hippocampal SC with the entorhinal cortex and medial parietal cortices in older participants, alongside increased SC with anterior temporal areas. This paradoxical pattern suggests that ageing is associated with both vulnerability and reorganisation of hippocampal networks, with increased hippocampal-temporal connectivity potentially reflecting compensatory plasticity in response to reduced posterior medial connection. These findings provide in vivo evidence of cortico-hippocampal structural reorganisation in late middle age, a critical period when pathological processes such as tau deposition are already detectable in cognitively healthy individuals. More broadly, they demonstrate the power of our anatomically refined tractography pipeline as a proof of concept for detecting subtle, regionally specific changes in hippocampal pathway density. This approach holds promise for charting normative ageing trajectories and identifying early biomarkers of vulnerability and compensation in memory-related networks.

Assessing aging pace through biological age offers a precise perspective and underscores the need for further investigation into organ-level disparities.

Sarcopenia is a progressive age-related condition characterized by the decline of skeletal muscle mass and function. Its development involves multiple cellular and molecular mechanisms, including chronic inflammation, apoptosis, mitochondrial dysfunction, and impaired muscle regeneration. Human umbilical cord mesenchymal stromal cells (HUC-MSCs) have emerged as a promising therapeutic strategy due to their potent immunomodulatory properties, paracrine effects, and ability to promote tissue repair. The regenerative potential of HUC-MSCs is largely mediated by the secretion of bioactive factors that suppress apoptosis, attenuate inflammation, enhance angiogenesis, and remodel the extracellular matrix, thereby establishing a microenvironment conducive to muscle regeneration. Nevertheless, challenges such as limited cell survival, differentiation efficiency, and long-term integration within host muscle, as well as variability in cell sources, delivery routes, and host immune responses, continue to constrain their clinical translation. In this review, we systematically summarize the biological characteristics of HUC-MSCs, their interactions with inflammatory and catabolic pathways in atrophic muscle, and their regulation of key signaling mechanisms involved in muscle repair. We also discuss current limitations and highlight future strategies-such as cellular preconditioning, biomaterial-assisted delivery systems, optimized transplantation protocols, and emerging organ-on-a-chip technologies-to enhance therapeutic efficacy and accelerate clinical application.

Nemertea is a speciose phylum of marine invertebrate predators ubiquitous in the world's oceans, which includes Lineus longissimus (Gunnerus, 1770)-the world's longest documented extant animal, yet much about the life histories of these remarkable animals remains poorly understood. For example, it is not known how long nemerteans live. We report a maximum known age of a nemertean individual, identified by morphology and DNA-barcoding as belonging to Baseodiscus punnetti (Coe, 1904), which has been kept in aquaria for at least 26 years. This finding confirms previous speculations that at least some species of nemerteans may live for many years and highlights a dearth of knowledge of the longevity of nemerteans and of marine invertebrates more broadly.

Smoking is a leading risk factor for numerous adverse health outcomes. However, in the context of a dramatically increasing aging population, evidence on how different dimensions of smoking characteristics is associated with biological aging remains limited and inconclusive.

The ketogenic diet (KD) is recognized for its broad therapeutic potential across metabolic, neurological, immunological, and aging-related domains; however, its efficacy and durability in females remain underexplored. This study investigated the effects of a short-term, intermittent KD on neurobehavioral function, lipid metabolism, immune response, and gut microbiota composition in sham-operated (intact) and ovariectomized (OVX, estrogen-deficient) female mice, aiming to delineate the interactions between diet and gonadal hormones. In sham females, KD reduced circulating estradiol levels and induced low-grade systemic inflammation, without producing measurable behavioral benefits. Conversely, KD exhibited reduced compulsivity, anxiety, and depression-like behaviors with improved well-being in OVX females, suggesting enhanced neurobehavioral resilience under estrogen-deficient conditions. Biochemical analyses revealed KD-induced hyperlipidemia in both groups, although the lipid load was attenuated in OVX mice. KD further decreased low-density lipoprotein cholesterol but led to uremia and histopathological evidence of hepatic steatosis and fibrosis in OVX females, despite unaltered liver function markers. 16S rRNA sequencing revealed hormone-dependent remodelling of the gut microbiota, characterised by distinct compositional shifts between the sham and OVX cohorts. Correlation analyses linked microbial alterations to improved lipid profiles and reduced anxiodepressive behaviors, implicating the gut-metabolic-brain axis in mediating the effects of KD. Collectively, these findings suggest that KD confers neurobehavioral and metabolic benefits in the absence of ovarian hormones but may also pose risks to the liver and kidneys. These results highlight ketogenic nutrition as a potential non-pharmacological strategy to mitigate menopause- and aging-associated neurobehavioral, metabolic, and immune dysfunctions through modulation of the gut microbiota.

Cardiorespiratory fitness (CRF) is associated with better cognition in older adults. However, the long-term associations between CRF levels and cognitive outcomes remain unclear. This study aimed to investigate the association between baseline CRF, changes in CRF (from baseline to year 1 and year 3) and cognition in older adults.

Brain aging significantly affects human lives, particularly among the elderly, leading to various diseases and constituting memory and cognitive decline. Hippocampal neurogenesis, the process of generating new neurons throughout life, decline with aging, which contribute to cognitive decline and dementia. D-galactose (D-gal) induces brain aging by increasing oxidative stress and inflammation, resulting in neurodegeneration and memory dysfunction. Oroxylum indicum fruit extract (OIFE), a traditional Thai herb, possesses strong antioxidant and neuroprotective properties. We investigated whether OIFE extract mitigates D-gal-induced memory decline, assessing its phytochemical profile, antioxidant capacity and neuroprotective effects. The results revealed that OIFE possessed strong phytochemical properties using measures such as total phenolic content (TPC), total flavonoid content (TFC), 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), and high-performance liquid chromatography-ultraviolet (HPLC-UV). Liver and kidney function tests on blood samples showed no significant differences among the groups. For memory function testing, sixty male Sprague Dawley rats were divided into six groups and treated with OIFE (125 or 250 mg/kg, p.o.) and D-gal (50 mg/kg, i.p.) for eight weeks. D-gal administration resulted in significant memory deficits (accessed via the novel object location [NOL] and novel object recognition [NOR] test). These deficits were correlated with a decrease in the number of immature neurons and reduced neuronal cell survival in the subgranular zone (SGZ), as observed using doublecortin (DCX) and 5-Bromo-2'-deoxyuridine/Neuronal nuclear protein (BrdU/NeuN) immunofluorescence staining, respectively. However, co-treatment with OIFE ameliorates D-gal-induced these impairments. Therefore, OIFE could mitigate memory and neurogenesis impairments in D-gal-induced brain aging in rats.

Traditional epigenetic aging clocks are limited because they do not incorporate clinical information and functional tests, and rely on DNA samples and methylation profiling infrastructure which are not easily accessible. To address these limitations, we built a new framework, FusionAge, with which we trained 26 aging clocks using interpretable nonlinear models, including deep neural networks (DNNs). Our results show that multimodal clocks built with DNNs significantly outperform clocks derived from single modalities or traditional linear models. FusionAge-derived biological age is more strongly associated with incident disease and mortality compared to chronological age in UK Biobank individuals. We validated these findings in the National Health and Nutrition Examination Survey, confirming that cardiorespiratory fitness is a major, consistent driver of biological age. Finally, we applied FusionAge to demonstrate its utility in detecting biological age changes in astronauts following spaceflight. Together, we demonstrate a powerful, portable framework for assessing biological age that captures the complex, multifactorial nature of human aging.

Cellular reprogramming with transient OSKM expression can reverse aging phenotypes, but genetic factor delivery introduces heterogeneous expression, reprogramming-associated stress, and barriers for therapeutic use. Small-molecule chemical reprogramming is an alternative, yet its performance relative to genetic approaches in human cells is unresolved. We directly compared a human-optimized chemical reprogramming protocol with doxycycline-inducible OSKM in progerin-induced aged fibroblasts and primary fibroblasts from donors over 85. Both reprogramming methods reduced senescence, mitochondrial ROS, and age-associated gene expression, with chemical reprogramming matching or exceeding OSKM efficacy. The two approaches, however, followed distinct trajectories. OSKM generated heterogeneous populations, including subsets acquiring pluripotency markers while others retained fibroblast identity. Chemical reprogramming produced uniform CD13-low populations without pluripotency marker induction. OSKM induced acute senescence that required a chase period to resolve, whereas chemical reprogramming lowered senescence during active treatment. In old fibroblasts, chemical reprogramming reversed multiple aging hallmarks while preserving fibroblast identity and avoiding telomerase activation. These results show that human-optimized chemical reprogramming can rejuvenate aged human fibroblasts with comparable efficacy to OSKM while generating more homogeneous outcomes and lower cellular stress, supporting small-molecule approaches as promising avenues for therapeutic rejuvenation.

Cell-free DNA (cfDNA) methylation sequencing holds promise for developing epigenetic aging clocks. However, current clocks - primarily trained on array-based data - do not readily generalize to high-throughput sequencing (HTS) cfDNA profiles. Using datasets with technical replicates encompassing HTS data from both cfDNA and gDNA, alongside gDNA methylation array data, we systematically assessed factors influencing clock accuracy and reproducibility. We identified key strategies to overcome HTS-specific challenges: maintaining [≥]10x mean target depth, applying elastic net regression with strong L2 regularization, and imputing unreliable beta-values. Transfer learning further enhanced accuracy robustly across multiple independent cohorts. Our findings demonstrate that array-derived epigenetic clocks can be effectively adapted to cfDNA sequencing data. This work offers critical methodological insights and practical guidelines, advancing the feasibility of minimally invasive aging assessment using cfDNA.

Accumulation of senescent cells promotes ageing and age-related diseases. While senescent cells are heterogenous and increasingly persistent in vivo with age, the mechanisms underlying their heterogeneity, resistance to apoptosis, and tissue accumulation remain insufficiently understood. Here we report that in response to DNA damage, a subset of senescent cells upregulates the v-type ATPase subunit, ATP6V1B2 (V1B2) on the cell surface. This upregulation is associated with altered lysosomal activity and changes in intracellular pH. Heterogeneity of senescent cells marked by cell surface V1B2 (csV1B2) is present in naturally occurring senescent cells within both ageing and fibrotic lungs. Senescent cells expressing csV1B2 show an age-independent transcriptional signature associated with DNA repair and resistance to apoptosis. Consistent with this, we show that csV1B2 expression correlates with senescent cell resistance to ABT-737-induced apoptosis in culture. Our study identifies a subset of senescent cells, marked by csV1B2, with a distinct signature of apoptosis resistance. Understanding the functional heterogeneity of senescent cells and the mechanisms accountable for persistence of specific subpopulations in tissues may facilitate the development of improved senotherapeutic strategies for age-related diseases.

Aging is an important pathological basis of age-related diseases. However, the similarities and differences among different types of senescent cells of different species and their role in normal homeostasis are poorly understood. Herein, in order to comprehensively map age-related transcriptome changes in multiple tissues of vertebrates during the ageing process, we analyzed 581 samples from 54 aging transcriptome datasets spanning 4 species including Homo sapiens, Mus musculus, Rattus norvegicus and Danio rerio, and identified the novel age-related differentially expressed genes, and obtained specific enriched expression of age-related pathways. Protein-protein interactions of differentially expressed genes in different species with the PTPRC or CD45 as the core were predicted. Through this study, we screened the key biomarkers and signaling pathways that regulate the aging process of tissues and organs in multiple species, which is of great significance for improving age-related tissues and organs by identifying senescent cells.

Obstructive sleep apnea (OSA) and consequent intermittent hypoxia (IH) is increasingly recognized as a driver of adipose tissue dysfunction, insulin resistance, and aging. However, current in vitro experimental models inadequately capture the long-term effects of IH on human adipocytes. Here, we report the development and optimization of a robust long-term human adipocyte organoid culture system that faithfully recapitulates IH-induced adipocyte aging in vitro. Human stromal vascular fraction (SVF) cells, isolated from subcutaneous abdominal fat biopsies, were embedded in Matrigel and seeded into Biofloat U-bottom 96-well plates. Using a 1:1 Matrigel-cell mixture and optimized seeding volumes (5-20 uL), we established adipocyte organoids that formed within 10-12 days and remained viable with stable morphology for up to 90 days or more. Matrigel was essential for organoid integrity, while alternative matrices such as gelatin and low-melting agarose failed to support proper organoid formation. Subcutaneous preadipocyte medium with 10% FBS from ZenBio was superior to \"Advanced/F12K\" medium for adipogenic differentiation and long-term maintenance. To model OSA-related hypoxic stress, we exposed organoids to intermittent hypoxia using a programmable hypoxia chamber. IH treatment suppressed adipogenesis, as shown by reduced lipid accumulation, downregulation of adipogenic markers (e.g., PPARG, adiponectin, FABP4), and smaller intracellular lipid droplets. Transmission electron microscopy (TEM) revealed IH-induced structural abnormalities, including ER fragmentation, mitochondrial disruption, nuclear enlargement, and heterochromatin formation, all of which are hallmarks of cellular aging. Furthermore, IH upregulated HIF1A, H2AX, and aging-associated histone methylation markers (H3K9me3, H3K79me3, H4K20me3), as well as extracellular matrix remodeling proteins such as fibronectin and LOX. Insulin signaling was also impaired, evidenced by decreased phosphorylation of PI3K and AKT. Collectively, these results establish a reliable platform for long-term human adipocyte organoid culture and demonstrate its utility in modeling IH-induced adipocyte dysfunction and aging. This system offers a physiologically relevant tool for mechanistic studies and preclinical therapeutic screening targeting hypoxia-related metabolic disorders. Keywords: Human adipocyte organoids; intermittent hypoxia; OSA; cellular aging; fat organoid aging model.

Skin aging is driven by both extrinsic factors, such as daily ultraviolet (UV) exposure, and intrinsic processes, including oxidative stress, inflammation, and glycation. Plant-derived medicinal agents and supplements hold promise as interventions against skin aging due to their anti-inflammatory and antioxidant properties. Grape seed extract (GSE), a polyphenol-rich natural product, has demonstrated skin health benefits and is commonly incorporated into various skincare formulations. However, its efficacy and underlying mechanisms, particularly in addressing both intrinsic and extrinsic aging factors, remain incompletely understood. Procyanidin C1 (PCC1), a B-type trimeric procyanidin found in GSE, possesses senolytic properties and has been shown to extend both lifespan and health span in mice. In this study, a newly processed PCC1-rich GSE, named NSPCC1, was evaluated against UV- and d-galactose (d-gal)-induced skin aging in a mouse model. NSPCC1 supplementation mitigated skin cell death, collagen degradation, and structural atrophy while partially restoring skin elasticity and hydration. It also enhanced antioxidant defenses in serum and skin tissues. RNA sequencing revealed that NSPCC1 modulates the MAPK and AMPK pathways, counteracting their dysregulation observed in aged skin. These findings highlight the potential of NSPCC1 to combat skin aging, providing an alternative strategy for skincare interventions targeting both extrinsic and intrinsic aging processes.

How lipid droplets (LDs) buffer metabolic stress and redox imbalance in aging oocytes remains poorly understood. Here, we identify de novo LD remodeling as a metabolic capacitor that couples lipid storage to mitochondrial fitness and oxidative resilience in mammalian oocytes. Live imaging revealed pronounced LD dynamics, with LD number peaking at metaphase I and declining by metaphase II, while LD area shifted inversely. Despite stable triacylglyceride and free fatty acid pools, Beta oxidation increased sharply, indicating elevated lipid turnover during meiotic progression. Spatial mapping and fatty-acid tracing demonstrated that newly synthesized lipids are actively incorporated into LDs, which arise primarily from the endoplasmic reticulum and engage with lysosomes and mitochondria. Acute inhibition of DGAT1, the rate-limiting enzyme of LD biogenesis, disrupted meiotic maturation and triggered oxidative stress, mitochondrial aggregation, and ultrastructural damage. Proteomic profiling revealed robust PANK2 upregulation and suppression of NRF2-linked antioxidant pathways. Mechanistic analyses showed that Beta oxidation blockade, PANK2 inhibition, antioxidant supplementation, or NRF2 activation each partially rescued DGAT1-dependent defects, and genetic validation in NRF2-null oocytes confirmed pathway dependence. Notably, aged oocytes exhibited reduced de novo LD biogenesis and impaired DGAT1-ER organization despite increased LD accumulation, resulting in smaller, metabolically inert droplets and a mismatch between lipid formation and utilization. Inhibiting PANK2 alleviated oxidative stress in aged oocytes, further implicating the DGAT1-PANK2-NRF2 axis in redox control and oocyte quality. Together, these findings establish LD biogenesis as a core metabolic capacitor safeguarding mitochondrial and organelle integrity during meiosis and reveal dysfunction of the DGAT1-PANK2-NRF2 axis as a mechanistic driver of reproductive aging.

Heart failure with preserved ejection fraction (HFpEF) is one of the most common forms of heart failure with no effective treatment. While chronic systemic inflammation, triggered by comorbidities, is a critical factor of HFpEF pathophysiology and a relevant target for therapy, mechanisms underlying inflammation remain poorly understood. Here, we aim to understand the upstream mechanisms driving inflammation, including immune dysregulation and cellular senescence.

Sex-specific differences in neurodegenerative disease susceptibility suggest distinct molecular mechanisms underlying brain aging between males and females. In this study, we investigated transcriptomic profiles of complement system components, microglial markers, and astrocyte/neuronal proteins across the lifespan to elucidate sex-dependent synaptic pruning mechanisms. Comprehensive transcriptomic analysis was performed on brain tissue samples spanning multiple age groups and regions, examining expression patterns of complement genes (C1QA, C1QB, C1QC, C1R, C1S, C3, ITGAM, ITGB2), microglial markers (TMEM119, P2RY12, CSF1R, NLRP3, TREM2, AIF1), and astrocytic, neuronal, and tissue markers (MAP2, SYP, SNAP25, MAPT, GFAP, CHI3L1). Complement system components demonstrated pronounced sex bias. Males exhibited distinct U-shaped age-related patterns, with middle-late childhood (MLC) consistently showing the highest expression for most genes, decreasing in middle age, followed by partial reactivation in nonagenarians, and then a further reduction in centenarians. An oscillatory trajectory across the lifespan was observed in females, with a peak in centenarians. Regional analysis revealed diencephalic predominance and occipital suppression patterns. Microglial activation markers exhibited complex sex-dependent patterns, with males showing higher expression during childhood/adolescence and females demonstrating an elevation in advanced age. These genes displayed limbic and diencephalic enrichment with cerebellar reduction. Neuronal/astrocytic markers showed opposing trajectories: neuronal markers (MAP2, SNAP25, SYP, MAPT) generally declined with age, while astrocytic markers (GFAP, CHI3L1) increased. Males demonstrated compartmentalized gene clustering, while females showed integrated neuro-microglial networks. Functional enrichment analysis confirmed these networks coordinate complement-mediated synapse pruning, representing systematic age-related synaptic remodeling mechanisms that differ fundamentally between sexes and may influence neurodegenerative susceptibility patterns. These findings demonstrate that female brains maintain heightened complement-mediated synaptic pruning throughout aging, representing a double-edged mechanism that may confer adaptive plasticity while increasing vulnerability to neurodegeneration. Male brains exhibit more stable neuronal environments with reduced glial activation, potentially underlying sex-specific trajectories in brain aging and neurodegenerative disease susceptibility.

Aging, characterized by a gradual decline in physiological function, is a major risk factor for chronic diseases. White tea, one of China's traditional tea types, exhibits various health benefits due to its unique chemical composition, with its anti-aging potential drawing increasing attention. Gallic acid (GA), one of the important bioactive components in white tea, possesses antioxidant and anti-inflammatory properties, but its anti-aging mechanisms remain unclear. In this study, high-performance liquid chromatography was used to analyze the evolution of GA content and to determine the antioxidant capacity of aged white tea. Results revealed that the GA content increased with storage time, accompanied by a corresponding enhancement in the antioxidant potency composite index (APC). Network pharmacology predicted 40 potential anti-aging targets of GA, and protein-protein interaction network analysis identified six key targets (MAOA, PTGS2, BCL2, APP, IGF1R, SERPINE1). Functional enrichment analysis indicated that the anti-aging effects of GA are mediated through multiple pathways, particularly those related to oxidative stress. Molecular docking results demonstrated that GA could bind effectively to the six key targets via hydrogen bonding and hydrophobic interactions. Furthermore, molecular dynamics simulations confirmed the binding stability of GA with MAOA, PTGS2, and BCL2. This study systematically elucidates the evolution of GA in aged white tea and its potential anti-aging mechanisms, providing a theoretical basis for the development of GA and aged white tea as functional anti-aging additives.

Retinol plays a crucial role in promoting skin repair and regeneration, but is challenged by instability, skin irritation and low bioavailability. Herein, a multifunctional hydrogel (CS/BG/Cys/RLs) is developed by compositing retinol liposomes (RLs) with chitosan (CS)/β-glucan (BG)/cystine (Cys) hydrogel, where CS and BG are non-covalently crosslinked by Cys. Peak shifts in FTIR spectra confirm the formation of supramolecular interactions. The CS/BG/Cys/RLs hydrogel retains 95 % of its virgin antioxidant acitivty after 72 h of photo-aging, attributed to the UV absorption capacity of the disulfide bond in the 200-300 nm range, which protects retinol from UV damage. The irritation of retinol is alleviated by liposome and hydrogel, reducing the hemolysis rate from 57 % (retinol) to 3.7 % (hydrogel) at a retinol concentration of 4 mg/mL. In vitro, the hydrogel repairs UVB-induced HaCaT cell damage by suppressing oxidative stress (ROS, NO) and NF-κB expression, while upregulating PPAR-α and promoting cell proliferation. In vivo, it effectively treats UVB-damaged mouse skin by downregulating pro-inflammatory factors (NF-κB, TNF-α, CD130, Stat-3, and Bcl-2) and enhancing collagen systhesis. Thus, this study presents a multifunctional hydrogel that combines stability, safety and efficiency for retinol delivery, offering a promising approach for repairing UV-induced skin damage and anti-aging therapy.

Environmental stressors, such as ionizing radiation, accelerate aging by causing DNA damage and triggering pathways that lead to cell cycle arrest, apoptosis, and subsequent inflammation. The thrombopoietin receptor agonist romiplostim (RP), which is used as a clinical treatment for chronic idiopathic thrombocytopenic purpura and aplastic anemia, is known to be promising in reducing radiation-induced tissue damage. In this study, we established a mouse model of radiation-induced premature aging to evaluate the potential of RP in ameliorating this process. Female C57BL/6JJcl mice were subjected to total body irradiation with various irradiation schedules. Mice irradiated with 5 Gy every 4 weeks (total dose of 10 Gy over 2 months) showed a significant aging phenotype, including graying hair and elevated serum aging markers (CDKN2A/p16

Life-history trade-offs between reproduction and survival are well documented, yet the biological mechanisms underlying costs remain unclear. Telomere length (TL) is a potential biomarker for such costs, although its association with reproductive efforts is mixed. Bats, particularly the long-lived greater horseshoe bat (

Sarcopenia, the age-related loss of muscle mass and function, significantly impacts health outcomes in older adults. Despite its prevalence, molecular diagnostics and targeted therapies remain limited due to incomplete understanding of its pathophysiology.