Longevity Papers

Skin aging involves progressive structural and functional decline, yet the underlying molecular mechanisms remain unclear. Here, we report that the antimicrobial peptide S100A7 is markedly reduced in aged keratinocytes and that its depletion leads to transcriptional alterations in differentiation-, autophagy-, and senescence-associated pathways. S100A7 knockdown partially recapitulated senescence-associated signatures, whereas supplementation increased autophagy and attenuated senescence-like phenotypes. These findings support a role for S100A7 as a context-dependent modulator of epidermal homeostasis and establish an AMP-autophagy axis that may contribute to cellular changes during skin aging.

Hematopoietic stem cell (HSC) aging leads to hematological dysfunction and diseases, but the regulatory factors involved remain incompletely characterized. In this study, the HSC Aging-Associated TFs Catalog System model was developed to identify transcription factors (TFs) that resist HSC aging. This approach revealed RORA as a key aging-negative-associated TF. Rora deletion in HSCs caused aged phenomes and functionally impaired their reconstitutive capacity. Additionally, Rora deficiency impaired leukemia stem cell proliferation and prevented chronic myelogenous leukemia. These findings establish RORA as a critical regulator in maintaining HSC function and provide insights into its therapeutic potential in hematological disorders.

DNA methylation algorithm values show promise as biomarkers for aging and adverse health outcomes, However, their comparative predictive utility for type 2 diabetes mellitus and its related mortality remains inadequately characterized. This study systematically evaluated twelve established epigenetic algorithms to address this knowledge gap.

Epigenetic clocks are emerging as promising biomarkers of biological aging, yet their sensitivity to short-term interventions remains unclear. This pilot study investigates whether the GrimAge clock can capture the effects of a 6-month cycling-based endurance exercise training intervention, with cardiorespiratory fitness (VO

Cerebral iron accumulation is a hallmark of aging and age-related neurodegenerative conditions. This study explored whether higher iron levels in deep gray matter (DGM) structures contribute to motor and cognitive decline and whether this association is mediated by demyelination in white matter (WM) tracts connecting the DGM to the cortex.

Reactive oxygen species (ROS) play a dual role in cellular homeostasis, but excessive levels of ROS lead to oxidative stress, accelerating skin aging. Environmental stressors like UV radiation induce ROS overproduction, overwhelming endogenous antioxidant defenses and causing cellular damage. While the skin possesses an intrinsic antioxidant network that provides moderate protection, excessive oxidative stress can trigger inflammatory responses, thereby necessitating exogenous antioxidant intervention. Microbe-derived antioxidants (MA), produced via probiotic fermentation of sea buckthorn and chestnut rose, have shown promise in mitigating ROS-induced damage. In this study, we evaluated two MA formulations, MA1 and MA2, for their ability to scavenge free radicals and alleviate hydrogen peroxide (H2O2)-induced oxidative stress in human dermal fibroblasts (HDF) and dermal papilla cells (HDP). Both formulations displayed dose-dependent DPPH radical scavenging activity and enhanced cell viability at low concentrations. Under H2O2-induced oxidative stress, MA1 and MA2 effectively restored intracellular ROS to baseline levels, demonstrating significant cytoprotective effects. UHPLC-MS/MS profiling identified 12 compounds shared by both formulations, and Gene Ontology Biological Process enrichment analysis revealed that their associated target genes were significantly enriched in antioxidant-related pathways. Five compounds--adenosine, citric acid, 5-hydroxymethylfurfural, myricetin, and phenylalanine--emerged as key contributors to the observed antioxidative effects. Together, these findings highlight the potential of fermented microbial antioxidants to re-establish redox homeostasis in human skin cells and support their further development as therapeutic or cosmetic interventions targeting oxidative stress and skin aging. Given the heightened oxidative sensitivity of aged fibroblasts, MAs ability to alleviate ROS may offer novel therapeutic strategies against skin aging and related pathologies.

Vascular smooth muscle cell senescence contributes critically to vascular remodeling and atherosclerosis, with mitochondrial dysfunction and impaired mitophagy recognized as major contributors. SRC, a stress-responsive tyrosine kinase, has been linked to aging, yet its role in vascular aging remains unclear. Here, we examined the role of SRC in regulating autophagy/mitophagy using in vitro and in vivo models. An accelerated vascular aging model was established using a high-fat diet and streptozotocin injection in ApoE

Healthy aging is a major public health priority, particularly for women, who have a longer life expectancy and a high prevalence of conditions associated with frailty, sarcopenia, and loss of functional independence. Therefore, the objective of this systematic review and meta-analysis was to evaluate the effects of functional exercise on physical and psychosocial outcomes in women over 60 years of age.

Aging is a time-dependent biological process characterized by degenerative changes in the body, influenced by genetics, environment, and dietary habits. Lycium barbarum polysaccharides (LBPs) have emerged as promising candidates for promoting health, with evidence supporting their role in enhancing immunity, maintaining gut microbiota homeostasis, and mitigating systemic inflammation induced by oxidative stress. However, influenced by multiple factors such as regional differences, diverse extraction methods, and structural complexity, LBPs have limitations in basic research and industrial applications, which impeded the in-depth development of LBPs in anti-aging and aging-related diseases mechanisms research, and industrial utilization. This review comprehensively summarizes the source, extraction, purification, structural characterizations of LBPs, and bioactivities on aging and aging-related diseases, including neurodegenerative diseases, cardiovascular diseases, diabetes, cancer, and musculoskeletal disorders. We reviewed the mechanisms through which LBPs exert their benefits, including immune regulation, modulation of gut microbiota, anti-oxidation properties, and overall host health. Additionally, we also discussed the applications of LBPs in functional foods, medicines, animal feed, and skincare products. The findings from ongoing and future clinical trials highlight the potential of LBPs to delay aging and alleviate aging-related diseases, offering valuable insights for their use in clinical settings and as functional food ingredients.

Aging is the most important yet unmodifiable risk factor for cardiovascular disease (CVD). As a result, targeting cardiovascular aging has emerged as a promising strategy to promote long-term cardiovascular health. This review summarizes current knowledge on the effects of aging within the cardiovascular system as well as systemic processes that modulate them. We highlight the roles of cellular senescence and the senescence-associated secretory phenotype (SASP), emphasizing their heterogeneous contributions to chronic low-grade inflammation and tissue remodeling-collectively termed inflammaging. Advances in biomarkers, animal models, and systems biology approaches have deepened our understanding of the interplay between senescence, inflammaging, and cardiovascular dysfunction, including the pivotal role of macrophages in senescent cell clearance. Therapeutic strategies are diverse, ranging from senolytic approaches designed to selectively eliminate senescent cells, to SASP modulation, and interventions targeting chronic inflammation and metabolic dysregulation. Of particular interest, drugs already in clinical use-such as metformin and other anti-diabetic agents-show beneficial effects on aging-related pathways, suggesting that their cardiovascular protection may in part reflect anti-aging properties. Despite these advances, therapies directly targeting senescence and inflammaging to reduce the global burden of CVD remain an urgent unmet need.

Human Immunodeficiency Virus (HIV) remains a major health challenge despite dramatic advances in treatment and prevention. People living with HIV (PLWH) continue to experience high rates of non-AIDS comorbidities, including cardiovascular, renal, pulmonary, oncologic, and neurocognitive disorders. These conditions persist under viral suppression, underscoring the lasting biological impact of infection. Epigenetic dysregulation has emerged as a key driver of these outcomes. HIV integration, viral proteins, chronic inflammation, and ART exposure have all been reported to alter DNA methylation, histone modifications, transcription factor networks, and non-coding RNA regulation. These changes extend beyond infected cells, reprogramming uninfected immune and tissue compartments. Long-lived cell populations display features of epigenetic aging contributing to chronic inflammation and multimorbidity. Epigenetic clocks consistently reveal accelerated biological aging in PLWH, linking infection to age-related disease risk. Overall, HIV should be viewed not only as a virologic condition but also as one of persistent epigenomic remodeling. Recognizing how durable reprogramming sustains inflammation, accelerates aging, and promotes comorbidity will be critical for advancing beyond viral suppression toward interventions that mitigate long-term health risks in PLWH.

Sarcopenia is a progressive, age-related condition characterized by a decline in skeletal muscle mass, strength and performance. Diagnosis remains challenging because current consensus criteria are difficult to scale and existing biomarkers lack accuracy. This study aimed to develop high-performance plasma-based diagnostic models for sarcopenia by integrating proteomic and metabolomic profiles.

Inflammation is increasingly recognized as a central driver of heart failure (HF), particularly in older adults, yet the underlying immune mechanisms remain diverse and incompletely understood. Clonal hematopoiesis (CH), defined by the expansion of somatically mutated hematopoietic clones, has emerged as a risk factor for the development of numerous age-related diseases including HF. Experimental and clinical evidence suggests that mutant clones carrying driver gene mutations promote a pro-inflammatory immune cell phenotype that contributes to cardiac injury, remodeling and adverse outcomes. Notably, CH has been implicated in HF across diverse etiologies, including both HFrEF and HFpEF, highlighting its broad impact on a vast array of HF syndromes. More recently, it has been discovered that hematopoietic loss of the Y chromosome (LOY) also contributes to HF. LOY appears to shift macrophages toward a fibrotic and away from a pro-inflammatory phenotype, contrasting with that observed for driver gene mutations and suggesting that different somatic alterations contribute to HF via divergent mechanisms. In this review, we examine the clinical and experimental associations between CH and HF. We also explore how CH may drive age-related immune heterogeneity in HF and highlight its potential to be leveraged for personalized interventions in patients with HF.

To elucidate the differential associations between total and added sugar consumption and frailty risk in older Korean adults.

The aging process leads to organ degeneration, including testicular aging, which not only impairs fertility but also increases the risk of reproductive system diseases, significantly reducing the quality of life in elderly individuals. Cynanchum auriculatum (C. auriculatum) Royle ex Wight exhibits anti-aging, antioxidant and anti-inflammatory properties; however, its effects on testicular reproductive function decline in naturally aging male rats remain underexplored.

Skin aging is a highly complex process embracing chronological aging and photoaging. Continuous advancement in the study of skin aging facilitates the innovations of skin rejuvenation therapies. However, the mechanism underlying skin aging remains largely unexplored. Herein, differential expression gene (DEG) analysis identified a gradual down-regulation of PIK3R1 in aged untreated skin, aged treated skin (treated with intense pulsed light), and young skin. Among 11 964 background genes, thousands of DEGs were identified in all aged/young and PIK3R1-low/high groups. Coexpression modules were created using weight gene correlation network analysis, showing an enrichment in PI3K/AKT, Rap1, regulating pluripotency of stem cells (rPSC), etc. Furthermore, DEGs with strong relation to skin vitality and PIK3R1 were extracted for network analysis, wherein cross-talking pathways of PIK3R1 including PI3K/AKT, Rap1, and rPSC were identified. The same cross-talking pathways were also replicated in aged untreated and treated skin, as implemented by enrichment analyses of DEGs in aged untreated versus young or aged treated skin. According to the area under the curve of 100% and 88%, PIK3R1 possibly predicted skin aging and skin rejuvenation, respectively. RT-PCR and western blot confirmed the decline of PIK3R1 expression in aged treated and young skin, compared with aged untreated skin. PIK3R1 knockdown led to increased p-AKT (Ser473) and Bcl-2, and decreased p-FOXO1 (Ser256) and MMP-1, which may be the cause of more resistance to ultraviolet A induced cell senescence, proliferation inhibition, apoptosis, and collagen synthesis decline in PIK3R1 knockdown HDFs. Our study preliminarily elucidates the comprehensive role of PIK3R1 in skin aging, providing a potential new target for skin rejuvenation.

The aging of the hematopoietic system is central to physiological aging, with profound consequences for immune competence, tissue regeneration, and systemic health. Age-related changes manifest as altered blood cell composition, functional decline in hematopoietic stem cells (HSCs), and deterioration of the bone marrow niche. Beyond hematologic dysfunction, hematopoietic aging acts as a systemic amplifier of age-related diseases through clonal hematopoiesis and inflammatory remodeling. This review integrates recent insights into the mechanisms and systemic impacts of hematopoietic aging, reframing it as a modifiable axis of systemic aging. We highlight emerging rejuvenation strategies-senolytics, metabolic reprogramming, and microbiota-targeted therapies-that aim to restore hematopoietic and immune function, offering promising avenues to improve healthspan and reduce age-related multimorbidity.

Chronic kidney disease (CKD) is projected to become the fifth leading cause of mortality by 2040. Tubular senescence drives kidney fibrosis, but current treatments do not target senescent cells. Here, we identify nicotinamide-N-methyltransferase (NNMT) as a critical mediator of tubular senescence and kidney fibrosis. Human CKD microarrays link NNMT to senescence and fibrosis transcriptomic signatures, and diabetic kidney disease (DKD) biopsies show NNMT protein associating with p21, fibrosis, and kidney function decline. Spatial transcriptomics in human biopsies demonstrates that NNMT-positive tubules are senescent, fibrotic, and surrounded by a pro-inflammatory microenvironment. Importantly, this pattern is conserved in aged and DKD mice, mimicking early-stage CKD features. Mechanistically, NNMT overexpression in tubular epithelial cells exacerbates senescence and partial epithelial-to-mesenchymal transition, while selective NNMT inhibition in senescent kidney cells, organoids, and in vivo is protective. Altogether, these findings position NNMT as a promising therapeutic target to reduce tubular senescence and fibrosis in early CKD.

Complex ecological systems obey universal scaling laws such as Taylors law, which links population variance to the sample mean. A natural question is whether other complex systems with integrated and segregated functional networks, such as the human brain, follow analogous scaling laws, and how these laws behave under synchronized activity. Addressing this is challenging because neural signals at all measurement scales contain both positive and negative values, whereas Taylors law was developed for non-negative ecological data. To overcome this limitation, we replace the sample mean with the root-mean-square (RMS) of detrended neural activity and formulate a generalized spatial scaling law applicable to signed data. This framework extends Taylor-like scaling to neural systems and other complex systems across disciplines and allows examination of how coordinated, synchronized activity shapes these laws. Synchrony is quantified using a dedicated metric of functional coordination. Analytical derivations and numerical simulations using multivariate Poisson, binomial, uniform, and gamma distributions demonstrate that the scaling exponent is inversely related to synchrony. Applying this framework to human fMRI data from three large lifespan cohorts (N =840, ages 18-88) reveals distinct age-related trajectories of the scaling exponent. Healthy aging is characterized by a substantial synchrony-induced reduction in the exponent. The synchrony-scaling relationship is stable during resting-state activity but progressively shifts during naturalistic tasks across the lifespan. Limbic, subcortical, and cerebellar regions show particularly strong synchrony-scaling coupling, indicating preservation at subnetwork levels. Finally, individuals with ADHD exhibit disrupted synchrony-scaling relationships, underscoring the potential clinical utility of this novel metric. Significance statementWe introduce a generalized scaling law that extends Taylors law from strictly non-negative ecological counts to signals with positive and negative fluctuations, such as detrended neural activity and other real-time measurements. This revision enables systematic characterization of scale-invariant variability in a broad range of complex systems. By applying this framework to large fMRI datasets spanning the adult lifespan, during both rest and naturalistic tasks, we show that synchrony-driven changes in the scaling exponent capture robust, age-dependent reconfigurations of brain-wide coordination. The synchrony-scaling relationship thus offers a compact, interpretable, and modality-agnostic marker of healthy brain aging and establishes a principled link between coordination dynamics and variability scaling in neural systems.

Age-related cognitive decline represents a major and unresolved challenge of human aging. Here, we identify the NAD

Replicative senescence frequently occurs in in vitro cell cultures and certain in vivo pathological conditions, characterized by multiple phenotypes, including cell cycle arrest. Previous studies suggested that the main mechanism underlying replicative senescence is that under continuous subculture, cells sense DNA damage during G1, which triggers G1/S arrest and the subsequent geroconversion. However, this explanation does not account for phenomena such as how DNA damage caused by replication stress in the mother cell directly affects the G1/S transition in the daughter cell. Recent advances in single-cell analysis techniques have enabled more detailed investigation of the G1/S transition process, leading to the development of new models. The updated model extends the window for cells to sense DNA damage from daughter G1 backward to mother G2, significantly prolonging the period during which DNA damage can regulate the G1/S transition. Despite these developments, the mechanistic understanding of replicative senescence has not been comprehensively revised based on the updated model. Therefore, this review systematically elaborates on the key process of G1/S arrest in inducing replicative senescence, based on the existing evidence: DNA damage accumulated during continuous passaging activates the p53-p21 and p16-Rb pathways at different cell cycle stages. The p53-p21 pathway promotes the initiation and progression of replicative senescence by primarily inactivating cyclin-dependent kinase complexes during mother G2 and daughter G1, thereby temporarily arresting the cell cycle. In the final stages of replicative senescence, the p16-Rb pathway predominantly substitutes for p21 to enforce an irreversible cell cycle arrest. The geroconversion process associated with these pathways ultimately facilitates the emergence of diverse senescence phenotypes.

With the aging population, treating age-related osteoporosis remains challenging due to the dysfunctional bone marrow microenvironment characterized by chronic inflammation, metabolic dysregulation, and impaired mitochondrial function in senescent cells. While mitochondrial transfer from macrophages to bone marrow mesenchymal stem cells (BMSCs) offers a promising therapeutic avenue, its efficacy is limited in aged niches where donor mitochondria exhibit functional deficits and poor recipient compatibility. We engineered KGM-PEG-SPIONs, functionalized Fe

Cigarette smoking induces epigenetic changes that can cause degenerative heterogeneity with aging and disease. In disease such as age-related macular degeneration (AMD), the leading worldwide cause of blindness among the elderly, retinal pigment epithelial (RPE) cell heterogeneity is a key change. Since smoking is a powerful risk factor for AMD, we hypothesized that smoke induces epigenetic-mediated degenerative RPE heterogeneity. We administered cigarette smoke condensate (CSC) to young and aged mice. Using snRNA-seq and single nuclear ATAC sequencing, we identified distinct healthy and dedifferentiated RPE clusters in both aged vehicle- and young CSC-treated mice. Dedifferentiated RPE had globally decreased chromatin accessibility and expression of genes linked to "hallmarks of aging." Notably, young, dedifferentiated RPE also exhibited a compensatory upregulation of hallmarks of aging-related genes including mitochondrial function and proteostasis while aged dedifferentiated RPE did not, which decreased their survival following CSC treatment, as experimentally verified with TUNEL labeling. Similar populations of dedifferentiated and healthy RPE were identified both in mice exposed to cigarette smoke for 4 mo and in macular RPE from a donor who smoked and another with early AMD, but not from a nonsmoker donor. Degenerative cellular heterogeneity that includes an abnormal cluster can jeopardize cell survival and represents a hallmark of ocular aging.

With the aging of the population, the incidence of postmenopausal osteoporosis (PMOP) is increasing. Extracts from Artemisiae Scopariae Herba, also known as Yinchen (YC), promote osteogenic differentiation and bone formation; however, the specific mechanism is unclear. The present study aimed to investigate the effects and mechanism of YC on PMOP. Ultra‑performance liquid chromatography‑tandem mass spectrometry was used to determine the potential predominant components of YC, and an ovariectomized (OVX) mouse model was established to evaluate the effects of YC on PMOP and its potential mechanisms. Initially, the therapeutic effect of YC on PMOP was assessed by micro‑CT bone analysis, pathological observation and ELISA detection. Combined with serum ELISA, reverse transcription‑quantitative PCR and immunohistochemical staining, the potential key anti‑PMOP pathway of YC was explored. A total of 2,072 compounds were identified in YC. The main active components of YC included chlorogenic acid, ferulic acid and caffeic acid. Experimental studies provided evidence that YC may improve bone loss and bone microstructure deterioration caused by ovariectomy. YC treatment also upregulated serum estrogen levels, and the expression of osteoprotegerin, runt‑related transcription factor 2 and glutathione peroxidase 4 (Gpx4) in bone tissue. Ovariectomy led to abnormal iron metabolism and increase the accumulation of lipid peroxides. YC reduced liver iron deposition, restored glutathione levels, and downregulated serum tartrate‑resistant acid phosphatase, osteocalcin, ferritin and hepcidin levels in mice. In addition, YC reversed the decreased expression of nuclear factor erythroid 2‑related factor 2 (Nrf2), solute carrier family 7 member 11 (Slc7a11) and Gpx4 in the bone tissues of OVX mice. In conclusion, the present study suggested the effectiveness of YC in potentially reducing ovariectomy‑induced osteoporosis in mice. YC promoted bone formation and improved bone microstructure, potentially by inhibiting ferroptosis via activation of the Nrf2/Slc7a11/Gpx4 pathway in OVX mice.

The Planetary Health Diet Index (PHDI) was designed to align environmental objectives with human health. This is the first study to assess the relationship between the PHDI and healthy aging, measured by intrinsic capacity (IC) and physical frailty.

Fish is rich in nutrients; however, concerns persist regarding its potential role in delaying aging due to the possible accumulation of cadmium. This study aimed to assess the association between fish consumption, dietary ω-3 polyunsaturated fatty acids (PUFAs), and Phenotypic Age Acceleration (PhenoAgeAccel) in the presence of cadmium exposure. The study used data from National Health and Nutrition Examination Survey (NHANES) 2011-2018. Multiple linear regression, restricted cubic splines (RCS), and subgroup analysis were used to assess potential associations. Mediation analysis further examined whether blood cadmium levels mediated the association between fish consumption and PhenoAgeAccel. Results showed that higher fish consumption and ω-3 PUFAs intake were significantly associated with lower PhenoAgeAccel. This association persisted even in the presence of cadmium exposure. Furthermore, the association between fish consumption or ω-3 PUFAs and PhenoAgeAccel was more pronounced in people with low cadmium exposure levels. RCS analysis revealed a non-linear relationship between fish consumption and dietary ω-3 PUFAs and PhenoAgeAccel. Blood cadmium levels partially mediated the association between fish consumption and PhenoAgeAccel. Our results support dietary recommendations to consume fish to slow biological aging. Even in the presence of cadmium exposure, fish consumption was negatively associated with PhenoAgeAccel.

Physiological aging involves a progressive deterioration of homeostatic mechanisms that cause obesity and defective glucose homeostasis, which develop age-related diseases increasing mortality risk and reducing lifespan. The brainstem is involved in glucose and metabolic homeostasis by integrating peripheral signals such as insulin and leptin. Here, we evaluated the brainstem response to intracerebroventricular administration of insulin or leptin and the relationship with physiological levels of key molecules implicated in their signal transduction pathway and inflammation in 3-, 6-, and 12-month-old mice which progressively increase adiposity and develop signs of insulin resistance. The initial steps of insulin and leptin signaling pathways decline with age, as well as the protein kinase B (Akt) phosphorylation response. Both hormones decrease the phosphorylation of AMP-activated protein kinase (AMPK) but, while the response to insulin increases with age, the response to leptin decreases in older animals. This insulin and leptin resistance is accompanied by changes in basal protein expression or phosphorylation of insulin and leptin receptors and insulin receptor substrates-1 (IRS-1), as well as the imbalance between basal levels of Akt-phosphorylated and non-phosphorylated protein, without changes in other serine kinases and/or inflammatory pathways such as glycogen-synthase-kinase-3 (GSK3), mammalian targets of rapamycin (mTOR), kinase-p70S6 (p70), protein kinase-C-ε (PKCε), p38 mitogen-activated protein kinase (p38), or c-Janus N-terminal kinase (JNK). High levels of proinflammatory cytokines and glial cell activation suggest the development of neuroinflammation in the brainstem with age, which could mediate the age-associated insulin and leptin resistance and the impairment in glucose and metabolic homeostasis commonly observed in the aging process.

Aging populations require scalable strategies to delay or prevent dementia. Beyond the prevention of neurological injury associated with seasonal influenza, vaccination may help mitigate vascular and neuroinflammatory injury underlying cognitive impairment. Influenza infection can cause a marked short‑term increase in myocardial infarction risk, and acute infections have also been associated with transient increases in stroke risk. Experimental models show prolonged microglial activation and synaptic loss even from non-neurotropic strains - processes likely modulated by vaccination. Epidemiologic data consistently support this evidence; a 2023 meta-analysis, including observational studies, of ~ 2.09 million adults identified a 31% lower risk of incident dementia; US matched cohorts demonstrated 40% lower risk of Alzheimer's disease (absolute decrease 3.4%); Veterans Health data showed a 0.86 hazard ratio for dementia; and UK Biobank data showed lower risk for all-cause (0.83 h), and vascular dementia (0.58 h) with a dose-response association by vaccination term. Randomized trials suggest fewer adverse cardiovascular events in vaccine recipients giving even more biological plausibility to this concept. Despite that, prevention through influenza vaccination is not fully realized in older adults due to low levels of perceived risk, vaccine confidence, and variations in clinical practice guidance. This public health perspective reviews the physiopathological and epidemiological evidence in support of influenza vaccination as a pragmatic, dementia risk-modifying intervention within healthy aging strategies and encourages the inclusion of vaccination status in hospital discharge and chronic-care pathways, integration of cognitive outcomes in monitoring, and equity-centered research to eliminate barriers to behavioral and implementation.

With population ageing, multimorbidity has become a major public health concern. Although healthy lifestyles are associated with reduced risks of single chronic diseases and mortality, their relationship with multimorbidity patterns among older Chinese remains insufficiently explored.

Metacontrol, the ability to adapt cognitive control to task demands, declines with age and is thought to be reflected in aperiodic and periodic neural dynamics. Given that anodal transcranial direct current stimulation (atDCS) can modulate cortical excitability via membrane potential shifts, we tested whether atDCS alters the neurophysiological signatures of metacontrol in younger and older adults. In a mixed design, younger and older participants performed a Go/Nogo task under both atDCS and sham stimulation conditions; resting-state EEG data were also acquired. Aperiodic activity was analyzed using the FOOOF algorithm, and periodic activity was examined through time-frequency analysis. Behaviorally, younger adults showed higher accuracy and faster responses than older adults, but no significant stimulation effects emerged in either group. Results showed that, compared to sham, aperiodic activity (FOOOF exponent) increased after atDCS, particularly in older adults, indicating a steepening of the EEG spectrum and thus increased inhibitory tone in the aging process. However, resting-state aperiodic activity did not predict stimulation-induced effects within either group. In the periodic domain, we found no evidence that atDCS modulated task-related theta or alpha power. Moreover, exploratory analyses revealed no significant associations between atDCS-induced changes in the aperiodic exponent and oscillatory power. This dissociation indicates that, under the present conditions, the periodic and aperiodic components of the EEG signal reflect distinct and likely independent neurophysiological responses to neuromodulation. Targeting metacontrol mechanisms through neuromodulation may, with further validation, open new avenues for supporting cognitive health in older adults.

BackgroundPreserving cognitive and brain health is central for healthy aging. Cognitive reserve (CR) and brain maintenance (BM) support resilience against age- and disease-related cognitive decline. Physical fitness represents a plausible pathway to both CR and BM, yet the underlying neurobiological mechanisms remain insufficiently understood. This study examined how fitness relates to Alzheimers pathology and whether it moderates or mediates the pathology-cognition relationship. MethodsData were obtained from 345 cognitively unimpaired older adults (mean age = 73.11 {+/-} 8.03 years; 177 females) participating in the ongoing SFB1436 study. We assessed global cognition and delayed verbal memory performance, aerobic fitness (VO2max), and muscular capacity. Blood biomarkers included plasma A{beta}2/A{beta}, p-tau217, and GFAP (glial fibrillary acidic protein), and serum BDNF (brain-derived neurotrophic factor), VEGF (vascular endothelial growth factor), and Cathepsin-B. Neuroimaging measures comprised medial temporal lobe (MTL) tau burden ([{superscript 1}F]PI-2620 PET), MRI-derived hippocampal volumes, white matter hyperintensities, perivascular spaces (PVS) in basal ganglia (BG) and centrum semiovale, gray matter volume (GMV), and MTL thickness. To examine BM, we tested associations between fitness and brain pathology. To examine CR, we conducted moderation analyses assessing whether fitness attenuated the negative impact of pathology on cognition. Mediation analyses further evaluated whether hippocampal volume, total GMV, or MTL thickness mediated a potential association between fitness and cognition. All models controlled for age and sex (and education in mediation analyses), and multiple comparisons were FDR-corrected. ResultsPhysical fitness was not related to cognitive performance. Higher muscular capacity was associated with lower BG PVS volumes, while higher aerobic fitness was related to higher MTL thickness and total GMV. Elevated MTL tau burden was associated with poorer verbal memory performance. Although physical fitness did not significantly moderate the tau-memory relationship, model comparison provided weak evidence for CR effects (p = .015). ConclusionMuscular capacity was linked to lower BG PVS volumes, supporting resistance against pathology, while aerobic fitness related to preserved cortical integrity and tended to act as a CR proxy against MTL tau pathology. Physical fitness may support cerebrovascular and glymphatic function, thereby promoting cognitive resilience and extending healthspan by sustaining functional brain health and mitigating tau-related cognitive decline. Trial RegistrationThe study was retrospectively registered in the German Clinical Trials Register (DRKS00032449; date of registration: 2025-05-07; recruiting ongoing).

The Maillard reaction, a nonenzymatic browning reaction that occurs between amines and carbonyl groups during food processing and cooking, generates products with antioxidant activity. Dipeptides composed of leucine and lysine (Leu-Lys and Lys-Leu) are frequent sequences in a variety of food proteins. Previously, we demonstrated that these dipeptides exhibit antioxidant activity and extend the lifespan of the nematode

The clinical heterogeneity of depression has defied biological classification, limiting personalized treatment. Previous neuroimaging- or symptom-based subtyping of depression failed to clarify the underlying pathoetiology, while plasma proteins which integrates signals from multiple organ systems, offers a promising way to define biologically grounded subtypes. Using plasma proteomics from 2,127 incident depression cases in a cohort of 53000 individuals, we identified three biologically distinct subtypes differing in inflammation, aging, and metabolic profiles. The most prevalent subtype ( inflammation/ageing) was characterized by aging-related inflammation, poorest prognosis with hippocampal atrophy and highest suicide risk, mediated by age-related amygdalar atrophy; this subtype had highest anhedonia burden. A distinct inflammation/energy dysregulation group had metabolic pathway enrichment with high inflammation and lifestyle risk factors (smoking) but no ageing trend, predominantly physical/psychomotor symptoms and decreased thalamic volume. In contrast, the inflammation-resilient group had the lowest inflammatory proteomic loading, lowest depression severity, more resilient lifestyle and increased hippocampal volume. These proteomic signatures, detectable years before symptom onset, enable risk stratification and suggest subtype-specific targeted physical and lifestyle interventions.

Defining and quantifying exceptional familial human survival is a persistent challenge in longevity research. Traditional approaches rely on binary thresholds, arbitrary cutoffs, or simple descriptive measures, which discard information on variation among the oldest individuals, ignore differences in background mortality, and yield unstable family-level summaries. We propose a principled, model-based framework that transforms survival times into percentiles relative to population life tables, standardizing across birth cohorts, sexes, and populations. We extend beta mixed-effects regression to accommodate intentional left-censoring, which downweights early deaths while retaining their contribution to the likelihood, thereby focusing inference on extreme survival. Family-specific random effects provide interpretable, statistically grounded longevity scores, overcoming the limitations of ad hoc measures and enabling robust identification of long-lived families. Simulation studies and application to a large multigenerational Dutch cohort demonstrate that the method reliably identifies families enriched for longevity. This framework provides a flexible, interpretable, and robust tool for analyzing familial survival, offering a paradigm shift in the statistical study of exceptional human lifespan.

Hematopoietic stem cells (HSCs) are multipotent self-renewing cells that give rise to all types of blood cells. Past research has identified that long-term hematopoietic stem cells in young mice and humans produce a balanced output of lymphoid and myeloid cells, while in old age, they are largely replaced by myeloid-biased HSCs (My-HSC). It has not yet been determined whether this transition results from epigenetic changes in a single population of HSC or if two or more subsets of HSCs exist that gain or lose dominance with age via processes of selection. Whether epigenetic change or competition, several characteristics of each may exist to ensure that the appropriate subset is placed in niches that support them. HSC can be mobilized into the blood and home selectively to target tissues via expression of "homing receptors," but these molecules do not determine their intraorgan migration to appropriate niches. Chemokines are the class of molecules that determine intraorgan migration of cells. Here, we show that the chemokine receptor CCR5 is mainly expressed on My-HSCs, and therefore, the frequency of CCR5

Intercellular mitochondrial transfer is recognized as a central mechanism that shapes redox homeostasis, metabolic plasticity, and cellular resilience across multiple tissues. Through tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junction channels (GJCs), and cell fusion, mitochondria move between donor and recipient cells to restore bioenergetic capacity, buffer oxidative stress, and tune redox-sensitive signaling networks. Recent work has begun to clarify the regulatory framework governing donor-recipient specificity, cargo selection, and the stress-activated cues that trigger organelle exchange. Mitochondrial transfer also exerts distinct, context-dependent influences on disease trajectories. It mitigates injury in neurological damage, ischemia-reperfusion conditions, immune dysfunction, aging, and inflammatory pain, largely by reprogramming mitochondrial function and reactive oxygen species (ROS) dynamics. Conversely, in cancer, mitochondrial acquisition enhances metabolic flexibility, invasiveness, and resistance to therapy. Current therapeutic approaches, including mitochondrial transplantation, EV-based delivery systems, and mitochondria-enhanced immune cells, highlight the translational potential of manipulating mitochondrial exchange, yet face challenges such as mitochondrial fragility, inefficient targeting, and immunogenicity. Deeper mechanistic insight into how mitochondrial transfer remodels redox signaling and metabolic adaptation will be essential for converting this biological process into next-generation organelle-level interventions for redox-driven disorders.

Klotho was initially identified as an anti-ageing protein expressed mainly in renal distal tubular cells and the choroid plexus. The Klotho family comprises several members, including α-Klotho (αKl), β-Klotho (βKl), Klotho-LPH related protein (KLPH; lactase-phlorizin hydrolase), and Klotho-related protein (KlrP), which perform a multitude of functions related to various physiological processes. The effects of Klotho on various ageing-related and renal diseases, such as its antiapoptotic effects, ability to reduce oxidative stress, anti-inflammatory effects, and other functions, have extensively been reviewed, suggesting the significant cardiorenal benefits of Klotho. Klotho expression deficiency promotes age-related pathology and is correlated with renal impairment. Studies have shown that serum Klotho is significantly decreased in type 2 diabetes (T2DM) and is linked to the duration of diabetes, indicating that Klotho may be involved in multiple pathological mechanisms of T2DM. Insulin resistance (IR) plays an essential role in the onset and progression of T2DM. Research has demonstrated that the expression of Kl is closely correlated with insulin secretion, insulin signaling pathways, and insulin sensitivity and may serve as a potential predictive marker for the IR and diabetes risk. We comprehensively reviewed the relevant literature in PubMed using the keywords "Klotho", "Type 2 diabetes", and "Insulin resistance". This review summarizes the relationship between Klotho and IR.

Cytochrome P450 enzymes (CYPs) are central to metabolism and stress adaptation. In Caenorhabditis elegans, the CYP-13 family performs diverse and conserved functions beyond xenobiotic detoxification. cyp-13 links lifespan regulation to the APP ortholog apl-1 and the heterochronic factor lin-14, integrating with DAF-16/FOXO, HSF-1, and DAF-12 pathways. In apoptosis, cyp-13 contributes to the degradosome complex with CPS-6/EndoG and WAH-1, facilitating DNA degradation. Several isoforms are inducible by aflatoxin B1 and PCB1254, underscoring roles in toxicant metabolism. Notably, cyp-13A12 regulates behavioral responses to reoxygenation via the EGL-9-HIF-1-PUFA-eicosanoid pathway, paralleling mammalian ischemia-reperfusion responses. Epigenetic regulation adds another layer, as BRCA1/BARD1 homologs brc-1 and brd-1 repress distinct subsets of cyp-13A genes through H2A ubiquitylation. Collectively, CYP-13 emerges as a multifunctional hub linking developmental, apoptotic, metabolic, stress, and chromatin-level processes, with clear parallels to human CYPs, highlighting its translational relevance to aging, cancer, and toxicology.

BackgroundBody composition strongly influences clinical outcomes in older adults, yet body mass index (BMI) lacks discriminatory power, and standard tools such as bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry are not routinely accessible. Deep learning enables scalable, opportunistic assessment of body composition from chest radiographs (CXRs), one of the most widely available imaging modalities. Methods and FindingsUsing the Inception-V3 architecture, we developed a deep-learning model using 107,568 paired CXR and BIA records (2016-2018). The model was temporally validated on a separate dataset of 77,655 records (2014-2015). Our model predicted skeletal muscle mass (SMM) and fat mass (FM) with high accuracy (SMM: Pearson r = 0.967, MAE 1.40 kg; FM: r = 0.924, MAE 1.61 kg). In a cohort of 5,932 older adults (aged [≥]65years), a 1-SD increase in CXR-predicted skeletal muscle index (SMI) was associated with a significant reduction in 10-year all-cause mortality (Hazard Ratio [HR] 0.65 [95% CI 0.58-0.73] for men; 0.80 [0.67-0.97] for women). In an external validation of 925 geriatric clinic patients, predicted SMI also showed comparable associations with geriatric parameters, including lower odds of sarcopenia (per 1 SD increase: 0.29 [0.22-0.38] for men; 0.25 [0.18-0.34] for women) and frailty (0.62 [0.48-0.78] for men; 1.00 [0.81-1.23] for women). These associations were more robust than those of BMI. Key limitations include the retrospective, single-center design and the use of a relatively healthy screening population. ConclusionA deep learning model applied to routine CXRs enables accurate estimation of skeletal muscle and fat mass, demonstrating prognostic and functional relevance comparable to BIA measurements. This approach may serve as a practical, low-cost tool for risk stratification and long-term care planning, particularly in older adults.

To analyze the association between physical activity, nutritional status, and the risk of sarcopenia in older adults.

Phenotypic age acceleration (PhenoAgeAccel) is a promising biological aging metric, but its associations with chronic digestive disease risk are unclear. This study evaluated these associations and assessed modification by genetic risk and lifestyle.

Low concentrations of chemicals are widespread in the environment, but exploration of the effects of their chronic exposures on animal life span in the wild is limited. Field investigations showed that fish populations of lake skygazer (

Osteoporosis and sarcopenia are age-related degenerative diseases that frequently co-occur in the older adults, yet their shared molecular mechanisms remain poorly understood. This study aimed to identify common biomarkers.

Oral health is a critical determinant of overall well-being and healthy aging, especially in countries with growing older populations and health disparities. Maintaining healthy teeth, gums, and orofacial structures improves the quality of life (QoL) while simultaneously reducing the risk associated with several non-communicable diseases through modifying shared risk factors and controlling inflammation. Oral diseases, such as dental caries and periodontal issues, affect nearly 903 million people in Southeast Asia (SEA), with a 61.4% increase in their prevalence from 1990 to 2019. Poor oral health, especially in older individuals, is associated with functional impairments, nutritional deficiencies, psychosocial challenges, and systemic health issues such as diabetes and cardiovascular diseases. Shared risk factors, including dietary habits, stress, and socioeconomic inequalities, compound these challenges. Functional limitations due to oral health inadequacies, such as edentulism, difficulty chewing, pain during eating, and speech impairments, negatively impact nutritional intake and social participation. The impact of oral diseases on QoL and their association with systemic health emphasize the need for preventive strategies and early interventions. Enhancing oral health can bridge the gap between lifespan and healthspan, thereby improving an individual's QoL, reducing healthcare costs, easing the burden on the healthcare system, and alleviating societal burdens for future generations. Most oral health issues can be managed and mitigated through integrated healthcare strategies, preventive interventions, and public education campaigns. This review emphasizes the need for awareness and a collaborative, interprofessional approach within the healthcare system to ensure equitable access to oral care and support healthy aging across SEA.

Environmental exposures are modifiable risk factors for accelerated aging, but research is frequently limited to individual countries due to inconsistent exposure assessment. Cross-national data provides broader perspectives but adds methodological complexities. This study evaluated spatial and temporal patterns of five environmental measures assigned to older adult pseudopopulations in eight countries to highlight opportunities and challenges for aging epidemiologic studies.

We previously identified distinct muscle and liver insulin resistance (IR) metabotypes in middle-aged and older adults. The PERSON study showed that a low-fat, high-protein, high-fiber diet benefits the muscle IR group, while a high-monounsaturated fatty acid diet benefits the liver IR group. We also developed the MetaboHealth score, reflecting risks of mortality, frailty, and cognitive decline. This study aimed to examine whether MetaboHealth interacts with IR metabotypes to influence (i) cardiometabolic health and (ii) body composition outcomes in the PERSON study, informing precision nutrition strategies.

Mitochondrial diseases progressively lead to multisystemic failure with treatment options remaining extremely limited. To investigate novel strategies that alleviate mitochondrial dysfunction, we have generated an ubiquitous and tamoxifen-inducible knockout mouse model of mitochondrial transcription factor A (TFAM), a nuclear-encoded protein involved in mitochondrial DNA (mtDNA) maintenance -- Tfamfl/flUbCre-ERT2 (iTfamKO) mice. Systemic TFAM deficiency triggers mitochondrial decline in a myriad of tissues in adult mice. Consequently, iTfamKO mice manifest multiorgan dysfunction including lipodystrophy, sarcopenia, metabolic alterations, kidney failure, neurodegeneration, and locomotor dysregulation, which result in the premature death of these mice. Interestingly, iTfamKO mice display intestinal barrier disruption and gut dysbiosis, with diminished levels of microbiota-derived short-fatty acids (SCFAs), such as butyrate. Mice with a deficient proof-reading version of the mtDNA polymerase gamma (mtDNA-mutator mice) phenocopy the dysfunction of the intestinal barrier and bacterial dysbiosis with reduced levels of butyrate, suggesting that different mouse models of mitochondrial dysfunction share deficient generation of butyrate. Transfer of microbiota from healthy control mice or administration of tributyrin, a butyrate precursor, delay multiple signs of multimorbidity extending lifespan in iTfamKO mice. Mechanistically, butyrate supplementation recovers epigenetic histone acylation marks that are lost in the intestine of Tfam deficient mice. Overall, our findings highlight the relevance of preserving host-microbiota symbiosis in disorders related to mitochondrial dysfunction.

Conventional epigenetic clocks encounter challenges in generalizability, especially when there are pronounced batch effects between the training and test datasets, restricting their clinical applicability for aging assessment. Here we present MAPLE, a robust computational framework for methylation age and disease-risk prediction through pairwise learning. MAPLE utilizes pairwise learning to discern the relative relationships between two DNA methylation profiles regarding age or disease risk. It effectively identifies aging- or disease-related biological signals while mitigating technical biases in the data. MAPLE outperforms five competing methods, achieving a median absolute error of 1.6 years across 31 benchmark tests from diverse studies, sequencing platforms, data preprocessing methods and tissue types. Furthermore, MAPLE performs well when assessing aging-related disease risk, with mean areas under the curve of 0.97 for disease identification and 0.85 for pre-disease status detection. Overall, we show that MAPLE has great potential for assessing epigenetic age and aging-related disease risk clinically.

Age-related inflammation plays a pivotal role in osteoarthritis (OA) pathogenesis, but the mechanism is not fully understood. Here, we identify decreased IL-36 receptor antagonists (IL-36Ra) in epidermal keratinocytes from a premature-aged skin mice model, aged mice and patients. Decreased IL-36Ra leads to increased secretion of IL-36 agonists to serum and joints, which activates proinflammatory signaling and promotes senescence in chondrocytes and synovial fibroblasts, thereby aggravates OA progression. Deletion of IL-36Ra in keratinocytes exacerbates, whereas intra-articular inhibition of IL-36R signaling effectively attenuates OA progression in male mice. Moreover, we also generate microneedles loaded with mouse recombinant IL-36Ra protein or spesolimab, insert them directly into skin to sustainably inhibit IL-36R signaling, which both clearly attenuate OA progression in male mice. Overall, our results reveal that IL-36 agonists are age-related systemic inflammatory factors released from skin to joints and contribute to OA development, and targeting IL-36R signaling in aged skin with microneedles represents a promising disease-modifying approach.

In silico druggability assessment helps shorten early drug discovery by identifying small molecules worth experimental testing as potential protein modulators. CCN1 is a multifunctional protein involved in various physiological processes and its dysregulation has been implicated in pathological conditions such as aging, fibrosis, inflammation, and cancer. The diverse, and sometimes contradictory, functions of CCN1 make it an important candidate for druggability assessment. In this study, we evaluated its druggability by predicting its 3D structure using AlphaFold 3, identifying binding pockets with Fpocket, and assessing ligand affinity with SwissDock. Our integrative in silico workflow identified multiple high-confidence druggable pockets within the CCN1 protein, with the top-scoring site located between the thrombospondin type 1 (TSP-1) and C-terminal cystine knot (CTCK) domains. Molecular docking predicted strong interactions with several clinically relevant compounds, including antioxidants and senolytics, with Metformin showing the highest affinity (SwissDock AC score: -200.26). Importantly, these ligand-binding interactions remained stable even after deletion of amino acids forming the predicted pocket and across naturally occurring CCN1 variants arising from SNPs, indicating that CCN1 is a genetically robust drug target. This study is the first to computationally demonstrate the druggability of CCN1 and to identify candidate small molecules with the potential to modulate its activity in aging- and disease-related contexts. Our findings provide both mechanistic insight and a scalable workflow for rapid screening of CCN1-targeted therapeutics.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β42 (Aβ42) neurotoxic peptides that cause oxidative stress and neurodegeneration. The current study examined the neuroprotective properties of salvianolic acid A (SalA), an antioxidant polyphenol, in a Drosophila melanogaster model of AD. Transgenic flies expressing human Aβ42 were assayed for eye morphology, life span, and locomotor function after SalA diet supplementation. RNA-seq and RT-qPCR were used to quantify transcriptional regulation with SalA treatment. Aβ42 expression resulted in classic AD phenotypes, including retinal degeneration, shortened lifespan, and compromised climbing ability. Partial rescue of the rough-eye phenotype, significant prolongation of lifespan, and improved locomotor function in aging flies were induced by SalA treatment. Transcriptome profiling showed the upregulation of glutathione metabolism-associated, cytochrome P450 activity-associated, and antioxidant defence-associated genes, while muscle development-associated, cell adhesion-associated, and apoptosis-associated genes were downregulated. Network analysis identified a SalA-responsive gene module enriched in detoxification and immune pathways that was conducive to enhanced cellular resistance to Aβ42 toxicity. These findings identify a redox-regulated aging mechanism whereby SalA maintains neuronal and systemic homeostasis during aging. SalA inhibits Aβ42-induced neurotoxicity in Drosophila via promoting redox equilibrium and detoxification. These findings present SalA as a potential multi-target lead drug for AD and other age-related neurodegenerative diseases.

Partner violence is associated with a wide range of negative outcomes, including poorer physical health in the form of increased risk for acute injuries, chronic disease onset, and premature mortality. Importantly, exposure to partner violence is not limited to adulthood and can be embedded within a larger context of interpersonal adversity extending from childhood into older age. In this review, we summarize recent research linking interpersonal adversity to poor health across the life course, focusing on psychosocial, behavioral, and physiological mechanisms relevant to health. We first highlight the importance of embedding the experience of partner violence and health into a broader context of interpersonal adversity spanning the life course. We then outline links from childhood interpersonal adversity to psychosocial and physiological dysfunction in adulthood, including a specific focus on recent studies examining emotion regulation, coping, attachment styles, and health behaviors. We next examine the current evidence linking interpersonal adversity to health-relevant psychosocial and physiological outcomes, including among older adults. In this section, we highlight recent findings linking interpersonal adversity to neural mechanisms, cognition, immune function, and accelerated biological aging. We end our review by identifying limitations of the current literature studying how interpersonal adversity could affect later health and present causal inference methodologies that could help address these challenges.

The role of aromatic gut-derived bacterial metabolites (GDBMs) in shaping immune cell metabolism and function remains poorly explored. Using ex vivo metabolomic profiling of paired plasma and CD4 T-cells from people living with HIV-1 (PLWH), we identified a network of aromatic GDBMs whose cell-associated abundance, rather than systemic levels, was linked to broad alterations in CD4 T-cell metabolic and functional states. Among these metabolites, p-cresol sulfate (PCS) emerged as a mechanistic prototype investigated in depth. Ex vivo flow cytometry and single-cell RNA sequencing of CD4 T-cells stratified by cell-associated PCS levels revealed dose-dependent enrichment of transcriptional programs associated with impaired differentiation capacity, regulatory-like identity, and cellular senescence. Consistently, in vitro transcriptomic and proteomic analyses of PCS-exposed CD4 T cells demonstrated induction of cell-cycle arrest, mitochondrial dysfunction, and senescence-associated programs, including upregulation of p16 and p21. Integration of these immunometabolic features with measurements of HIV-1 reservoir size in PLWH revealed that CD4 T-cell states defined by cell-associated GDBMs track with intact proviral DNA levels in vivo. Together, these findings define a microbiome-derived axis that reshapes CD4 T-cell metabolism and fate and promotes immune aging-associated states in PLWH. Our data suggest that cell-associated GDBMs may foster immunometabolic CD4 T-cell states previously linked to long-term HIV-1 reservoir persistence in vivo. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/699280v1_figa1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1b27a4forg.highwire.dtl.DTLVardef@7bece5org.highwire.dtl.DTLVardef@1fdca55org.highwire.dtl.DTLVardef@ee9378_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO PCS-driven metabolic reprogramming and senescence promoting CD4+ T-cell immune cell aging.Dietary proteins are metabolized by proteolytic gut microbiota into p-cresol, which is absorbed and converted in the liver to PCS. Circulating PCS accumulates in CD4 T-cells, where it activates the aryl hydrocarbon receptor (AhR). AhR signaling reduces glycolysis and mTOR activity, while enhancing TGF-, Wnt/-catenin, and TCF7 pathways, driving a regulatory-like and stem-like transcriptional program. These changes are associated with increased expression of p16 and p21, leading to cell cycle arrest and cellular senescence promoting CD4+ T-cell immune cell aging. C_FIG

With aging, the responsiveness of bone tissue to mechanical loading progressively declines, leading to altered bone homeostasis and continuous bone loss. Piezo1, a recently identified mechanosensitive calcium channel, plays a critical role in bone development, formation, and homeostatic regulation in a load-dependent manner. The Wnt signaling pathway is also essential for mechanotransduction in bone cells; however, the precise role of Piezo1 in maintaining osteogenic homeostasis remains unclear. Here, through transcriptomic analysis of bone tissues from young and aged mice, we found that both Piezo1 and Wnt signaling pathways were significantly downregulated in aged mice compared with young controls. Further investigations revealed that the expression of Piezo1 and Wnt5a/FZD4 decreased with age in osteoblasts. Loss of Piezo1 in osteoblasts exacerbated age-related bone loss and suppressed the Wnt5a/FZD4 signaling cascade. Conversely, activation of Piezo1 enhanced osteogenesis and stimulated Wnt5a/FZD4 signaling, while treatment with a Wnt5a agonist partially rescued the impaired osteogenic capacity caused by Piezo1 deficiency. Moreover, Wnt5a activation modestly alleviated osteoporosis in aged mice. Collectively, our study provides the first systematic evidence that the mechanoreceptor Piezo1, via downstream Wnt5a/FZD4 signaling, plays a central role in skeletal mechanoadaptation and age-associated bone loss. These findings highlight the activation of Wnt5a downstream of Piezo1 as a potential therapeutic strategy for preventing bone loss due to impaired mechanotransduction during aging.

Age-related decreases in follicle numbers and oocyte quality are major contributors to the decline in female fertility, which is associated with increased infertility rates. Emerging evidence suggests that targeting granulosa cell senescence could delay ovarian aging and depletion of the ovarian reserve, highlighting the potential for therapeutic interventions focused on granulosa cells. Advanced glycation end products (AGEs) accumulate with age and result in oxidative stress in the follicular microenvironment, but their direct impact on human granulosa cell (hGC) senescence and the fundamental processes are still mostly unknown. In this study, we found that AGEs treatment significantly exacerbated hGC senescence, impaired mitochondrial function, and suppressed mitophagy in a concentration-dependent manner. Importantly, these deficits were lessened by urolithin A-induced mitophagy activation, whereas Cyclosporine A-induced mitophagy inhibition had the reverse consequences. In addition, silencing Sirtuin 3 (SIRT3) or PINK1 further aggravated these adverse effects, while SIRT3 overexpression attenuated senescence and restored mitochondrial function by enhancing mitophagy. Furthermore, SIRT3 overexpression promoted the synthesis of estradiol-17β and progesterone, key hormones for ovarian function. Our findings demonstrated that AGEs induced hGC senescence by disrupting mitochondrial function and inhibiting mitophagy, with SIRT3 playing a protective role. Enhancing mitophagy by targeting SIRT3 may be a promising treatment approach to counteract age-related declines in female fertility.

Skeletal muscle differentiation is classically triggered by reducing serum-derived mitogenic cues; however, the extracellular matrix-associated factors that actively maintain a proliferative, differentiation-resistant state remain poorly defined. Here, we identify vitronectin (VN) as a key extracellular matrix gatekeeper that controls myogenic cell fate. VN is abundant in fetal bovine serum but largely absent from horse serum, rapidly declines upon differentiation induction, and selectively suppresses myogenic differentiation while sustaining proliferation through integrin v{beta}3-dependent signaling. VN maintains growth factor receptor activity and cell-cycle progression even under differentiation conditions, thereby preventing myoblast commitment. These effects extend to three-dimensional culture and primary embryonic chicken myogenic cells, indicating evolutionary conservation. Importantly, VN progressively accumulates during long-term passaging, coinciding with replicative senescence and impaired differentiation, and inhibition of v{beta}3 signaling partially restores myogenic competence in senescent cells. Together, our findings redefine a long-standing myoblast culture paradigm by identifying a serum-derived extracellular matrix protein as a decisive regulator linking extracellular environment, proliferative niche maintenance, and age-associated decline in myogenic competence.

Neuroimaging techniques offer valuable insights into the structural characteristics of the brain. For example, a salient feature of the cerebrum is the distinct transition of voxel intensity at the interface of gray matter (GM) and white matter (WM). Leveraging the inherent difference in tissue composition - lower GM and higher WM signal on T1-weighted (T1W) magnetic resonance imaging (MRI) - we introduce a novel metric, distance between peaks of WM and GM intensities, which unlike GM/WM contrast does not rely on segmentation and demonstrate its efficacy in capturing age-related effects. A single 3D T1W whole brain MRI (MP-RAGE, 1 mm isotropic voxels) image was acquired at 3 Tesla from each of 178 healthy participants (18-91 years (54.78 ± 21.37), 103 Female) between 2019 and 2023. Before peak differentiation calculation, non-brain tissue was removed, and voxel intensities were corrected for RF coil profile. We define peak differentiation as the difference between means of two Gaussians fitted to the T1W voxel intensities, scaled by their common standard deviation. Age dependence of peak differentiation is examined using a linear model with biological sex included as a covariate. Similar analysis was performed by limiting to voxels within 5 mm of the Freesurfer-defined cerebral gray matter-white matter interface (GWI) in six lobes: orbitofrontal, frontal, occipital, temporal, parietal, and cingulate. Reduced whole-brain peak differentiation was associated with older age ([Formula: see text] = - 0.012, 95% CI [-0.0132, -0.0105], p < 0.001), indicating a decline in WM-GM distribution sharpness with advancing age. Each GWI subregional peak differentiation exhibited the same pattern of decline with age, but differed in magnitude region (p < 0.001). The cingulate region exhibited the sharpest decline with age ([Formula: see text] = -0.014, 95% CI [ - 0.0160, - 0.0126], p < 0.001). We demonstrate feasibility of an automated whole brain peak differentiation measurement to characterize brain aging in a group of healthy individuals, with minimal reliance on segmentation or other processing, with implications for understanding normal trajectories and identifying pathological deviations from expected aging processes.

Anorexia of ageing - the age-related reduction in appetite and food intake - is a public health concern for an ageing global population. However, current understanding of the aetiology of the condition is limited. In this review, evidence of gut hormone responses to feeding in older adults is reviewed, and it is proposed that a dysregulation of this process is a mechanism driving low appetite in later life. The evidence is synthesised to critically present this case, spotlighting recent data demonstrating a highly anorexigenic gut hormone profile in older adults exhibiting low appetite, which is not observed in older adults exhibiting a "healthy" appetite. These findings and this theory are interrogated with an appreciation that appetite control is complex and multifactorial, not least in the context of anorexia of ageing; it is posited that changes in gut hormone secretions are

Skeletal muscle deterioration accelerates with age, leading to muscle atrophy and dysfunction. Musculoskeletal ultrasound as a nonradiative, inexpensive, and portable tool, has potential to evaluate age-related muscle changes. This study aims to detect age-related muscle features based on muscle texture analysis and machine learning approach, and to investigate muscle features that are related to function.

Despite age-related declines in the structure and function of auditory and language-related regions, many older adults retain a relatively preserved ability to understand speech in noisy environments. However, the neural mechanisms supporting this ability remain unclear. In this study, 30 older adults (59-71 years) with normal hearing listened to narratives spoken by a separate group of speakers at varying noise levels, with their neural activity recorded using functional near-infrared spectroscopy (fNIRS). Speaker-listener neural coupling analysis revealed that older listeners' neural activity across broad brain regions, including classical language regions and the prefrontal cortex, was coupled with the speaker's speech-production-related neural activity. Compared to younger listeners, older adults exhibited stronger prefrontal neural coupling, which was stably integrated with language-region coupling across noise levels. Crucially, as noise levels increased, prefrontal neural coupling became more strongly correlated with comprehension performance. These findings elucidate the neural mechanisms supporting natural speech-in-noise processing in the aging brain, highlighting the compensatory involvement of the prefrontal cortex in facilitating speech-in-noise comprehension in older adults and indicating it as a potential target for neuromodulatory and cognitive interventions to promote successful aging.

The Drosophila proventriculus is a bulb-shaped structure at the juncture of the foregut and the midgut, which plays important roles in ingestion, peritrophic membrane synthesis, and the immune response to oral pathogens. A previous study identified a population of cells in the proventriculus which incorporate bromodeoxyuridine (BrdU), a marker of DNA synthesis, and proposed that these cycling cells are multipotent stem cells that replace dying cells elsewhere in the tissue. Here, we re-investigate these cycling cells and find that they do not undergo mitosis, do not generate clonal lineages, and do not proliferate in response to tissue damage, and are therefore not stem cells. Instead, we find that these cells continually endocycle throughout the flys life, increasing their ploidy and size, while at the same time cells in this tissue are lost into the gut lumen as the fly ages. Functionally, these cells play a critical role in the synthesis of peritrophic membrane components, and we show that when endocycling in these cells is experimentally increased or decreased, there is a concomitant change in ploidy, tissue size, and peritrophic membrane synthesis. Further, we show that inhibition of endocycling makes flies more susceptible to orally infectious bacteria. Altogether, we show that continual endocycling of these cells is critical for maintaining tissue size and function in the face of cell loss due to aging or tissue damage.

Age-related skeletal muscle deterioration is a commonly reported disability among older adults, attributed to several factors including mitochondrial dysfunction, a major hallmark of aging. Therapies to attenuate or reverse mitochondrial decline are limited. Despite identified positive relationships between vitamin B12 (B12) and mitochondrial biology, the impact of B12 supplementation on skeletal muscle mitochondria, in advanced aged, has not been examined. Thus, the impact of B12 supplementation on skeletal muscle mitochondrial biology was examined in (i) aged female mice, given 12 weeks of B12 supplementation (SUPP) or vehicle control, and (ii) in human primary myotubes. In the mouse model, mitochondrial DNA and content were measured with PCR and citrate synthase activity, respectively; mitochondrial morphology was examined using transmission electron microscopy; mitochondrial function was examined using extracellular metabolic flux analysis; and proteins and pathway enrichment was identified with proteomics. In the cell model, ROS and glutathione was measured using luminescent assays. The results demonstrated that SUPP in aged mice increased muscle mitochondrial content and improved morphology. Further, differentially expressed proteins were enriched in TCA cycle, OXPHOS, and oxidative stress pathways. In the cell model, B12 supplementation reduced ROS levels. This is the first study, to our knowledge, examining the impact of B12 supplementation on skeletal muscle mitochondrial biology in aged female mice. Results suggest that B12 supplementation improves mitochondrial biology in aged female mice.

FOXOs constitute a class of evolutionarily conserved transcription factors that play pivotal roles in diverse cellular processes, including glucose and lipid metabolism, energy homeostasis, oxidative stress response, and autophagy. They are recognized as central regulators of longevity. This review details the mechanisms linking FOXO to aging. FOXO activity is regulated via nucleocytoplasmic shuttling, a process controlled by phosphorylation and dephosphorylation through the insulin/insulin-like growth factor (IIS) signaling pathway. This shuttling influences the expression of aging-related genes, thereby modulating aging-related phenotypes in tissues such as muscle and liver. Furthermore, FOXO can also regulate the autophagy pathway through multiple mechanisms: On one hand, it transcriptionally activates core autophagy genes such as Ulk2 and Becn1; on the other hand, it enhances autophagic activity by modulating miRNAs or epigenetic modifications, thereby promoting the elimination of damaged cellular components, and ultimately delaying organismal aging. Moreover, as a key sensor of oxidative stress, FOXO is activated by reactive oxygen species (ROS), thereby inducing the expression of antioxidant enzymes that mitigate oxidative damage and delay cellular aging. This review provides an in-depth exploration of the dual roles of FOXO in various aging-related diseases. This includes neurodegenerative diseases (such as Huntington's disease, Parkinson's disease, and Alzheimer's disease), metabolic disorders (such as type 2 diabetes), and various cancers. Meanwhile, this review also discusses drugs targeting the FOXO pathway in recent years (such as canagliflozin, metformin, resveratrol, and berberine). These FOXO-targeting compounds demonstrate great potential in improving metabolic disorders and delaying the onset of aging phenotypes.

Bone aging compromises skeletal integrity and increases vulnerability to osteoporosis and other age-related disorders, underscoring the need for new therapeutic strategies. Although pharmacological and genetic approaches have been widely explored, how cellular mechanical remodeling contributes to bone aging remains unclear. Here, we find that senescent bone marrow stem cells show markedly reduced intracellular force and impaired mechanical behavior. Moderate mechanical stimulation in cell culture and in mice restores cellular force, increases chromatin accessibility at the FOXO1 locus, activates its expression, and reverses cellular senescence and bone aging. These mechanical interventions also improve physical performance in aged female mice and show a tendency to reduce systemic inflammation, whereas excessive force induces chromatin overextension and DNA damage, indicating the necessity of precise force control. In this work, we show that optimized mechanical stimulation provides a simple and effective strategy to counteract age-related bone deterioration and systemic inflammation, offering potential for clinical translation.

Frailty is a common geriatric syndrome associated with increased mortality, yet its underlying biological mechanisms and potential value for early risk stratification remain inadequately understood. In this large prospective cohort of more than 260,000 UK Biobank participants with plasma metabolomic profiling, we identified and validated metabolomic signatures of physical frailty and a 49-item frailty index using 50-times repeated 10-fold cross-validated elastic-net regression. The signatures demonstrated strong internal stability and geographic reproducibility and reflected coordinated alterations across lipid, amino acid, energy, and inflammatory pathways. Higher signature levels were significantly associated with increased risks of all-cause and cause-specific mortality, including cancer, cardiovascular, respiratory, and digestive deaths. Individuals in the highest-risk tertile had more than 2.5-fold higher risks of cardiovascular, respiratory, and digestive mortality. At age 60, individuals above the median signature level were estimated to have 4.1 fewer years of life expectancy. Mediation analyses indicated that the metabolomic signatures statistically explained up to 35% of the observed frailty-mortality association. Associations were stronger among younger individuals and differed by sex and BMI. These findings suggest that frailty-related plasma metabolomic signatures capture systemic metabolic correlates of biological aging and may support early mortality risk prediction and personalized prevention strategies in aging populations.

The ability to recall learned movements and rapidly adapt to environmental changes, known as locomotor savings, is crucial for mobility in community-dwelling older adults. However, the influence of aging on locomotor savings and the underlying mechanisms remains poorly understood. Attentional compensation is a particularly relevant mechanism because the control of automatic motor behaviors like walking tend to recruit more attentional/executive resources with aging. We hypothesize that locomotor savings is diminished with age and relies on attentional rather than automatic control of walking. To test this, we compared savings of a novel walking pattern learned on a split-belt treadmill, where each leg moves at a different speed, across multiple days in 21 older and 21 younger adults. Attentional control of walking was assessed by overground dual-task walking while prefrontal cortex (PFC) activity was recorded using functional near-infrared spectroscopy (fNIRS). We found that older adults exhibited less locomotor savings than younger adults after practice. Older adults also relied more on attentional resources during dual-task walking. Importantly, greater locomotor savings was associated with higher attentional control of walking in older adults, suggesting that the use of attentional resources during challenging walking facilitates the recall of previously learned movements. These results indicate that cognitive compensation strategies utilizing attentional resources are important neural mechanisms modulating locomotor savings. Understanding the role of cognitive compensation in locomotor savings may inform rehabilitation design to enhance mobility in older adults ensuring movement corrections practiced in clinical settings are saved for long-term benefit in daily life. Significance StatementSuccessfully navigating everyday environments requires adapting and recalling learned walking patterns, a process known as locomotor savings. We found that older adults showed locomotor savings across multiple days following structured practice, but to a lesser extent than younger adults. With aging, walking becomes less automatic and more reliant on attentional control, which is traditionally considered detrimental. Interestingly, we found that greater attentional control during walking was linked to better locomotor savings in older adults. These results suggest that attentional compensation during walking may support motor memory retrieval and adaptability in healthy aging, highlighting a potentially beneficial role of cognitive control in maintaining mobility during aging.

Cellular reprogramming, a method of "resetting" the epigenetic clock by reversing the differentiation state of cells, has emerged as a promising approach to anti-aging, offering new strategies to slow down the aging process. Researchers convert differentiated cells into a pluripotent stem cell state through transcription factors or chemicals, restoring cellular youthfulness and regenerative capacity. This technology holds potential for tissue repair, lifespan extension, organ function improvement, and treatment of age-related diseases. In addition, cell reprogramming provides a novel pathway for disease modeling and drug screening, potentially accelerating the development and clinical application of anti-aging drugs. However, it faces challenges including safety, efficiency, and ethical considerations. This article focuses on the prospects of small-molecule-induced cell reprogramming for anti-aging, covering its mechanisms, applications, current limitations, and future directions to facilitate clinical translation and breakthroughs in human healthspan extension.

In living systems, protein function relies on many intra- and intermolecular interactions within a network called the interactome. The majority of available interactome data has been acquired with isolated proteins and complexes, but visualization of interactome changes in living systems is crucial to advance understanding of functional changes with diseases and for the development of improved therapies. With model animal systems, quantitative cross-linking mass spectrometry has been successfully applied to uniquely reveal interactome changes with mitochondrial dysfunction both in heart failure and with age-related muscle function decline. In this study, we investigated the feasibility of qualitative cross-linking mass spectrometry for mitochondrial interactome studies with clinically relevant human muscle biopsy samples and amounts. Analysis of biopsy samples from two volunteers resulted in the identification of 1350 nonredundant peptides from 177 mitochondrial proteins from all mitochondrial subcompartments. Many of the identified human biopsy cross-linked peptides were derived from protein complex and supercomplex assemblies that exhibited altered levels in model systems of heart failure and aging. The findings demonstrate the initial feasibility that these and other cross-linked species can be detected in human muscle biopsy samples to enable future studies of age- and disease-related changes in mitochondrial structure-function relationships.

Age-associated decline in mitochondrial membrane potential (MMP) is a ubiquitous aspect of eukaryotic organisms and is associated with many aging-related diseases. However, it is not clear whether this decline is a cause or consequence of aging, and therefore whether interventions to reduce MMP decline are a viable strategy to promote healthier aging and longer lifespans. We developed a screening platform in Saccharomyces cerevisiae to identify mutations that slowed or abrogated the age-associated decline in MMP. Characterization of the longest-lived mutant revealed that reduced internal potassium increased MMP and extended lifespan. Distinct interventions improved cellular MMP and lifespan: deleting a potassium transporter; altering the balance between kinases and phosphatases that control potassium transporter activity; and reducing available potassium in the environment. Similarly, in isolated mitochondria, reducing the concentration of potassium was sufficient to increase MMP. These data indicate that the most abundant monovalent cation in eukaryotic cells plays a critical role in tuning mitochondrial function, consequently impacting lifespan.

Traumatic brain injury (TBI) of any severity is associated with long-term systemic inflammation and increased risk of peripheral comorbidities, yet the mechanisms driving immune dysregulation and accelerated aging after repeated mild head impacts remain poorly defined. Here, we investigated the acute and chronic effects of repeated mild TBI (rmTBI) on distal and proximal bone marrow compartments in the femur and calvaria, respectively. Using a modified weight-drop mouse model delivering rotational and acceleration-deceleration forces (3 hits/week for up to 16 weeks), rmTBI produced no mortality, skull fracture, hemorrhage, or brain leukocyte infiltration. One day after three consecutive impacts, rmTBI induced robust proliferation of LSK stem/progenitor cells in both femoral and calvarial marrow, evidenced by Ki67 expression, BrdU incorporation, and increased monocyte output. By 8 weeks (24 impacts), injury-induced proliferation subsided and LSK cells exhibited increased senescence-associated {beta}-galactosidase activity and upregulation of tumor suppressor genes. At 16 weeks (48 impacts), LSK populations were depleted at both sites, displaying reduced proliferative capacity, telomere shortening, and pancytopenia in otherwise young adult mice. Calvarial bone marrow cells exposed to rmTBI released a distinct cytokine and proteomic secretome marked by elevated IL-6, suppressed mitochondrial and metabolic signaling, and enhanced DNA repair pathways. Notably, skull-derived secretome factors impaired cortical and hippocampal mitochondrial metabolism, and reduced microglial mitochondrial membrane potential. Together, these findings identify replicative senescence of the brain-adjacent bone marrow niche as an early and progressive consequence of repeated mild head injury, linking rmTBI to long-lasting metabolic dysfunction, impaired immunity, and accelerated aging. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/699107v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@683c8eorg.highwire.dtl.DTLVardef@15fc42forg.highwire.dtl.DTLVardef@48f398org.highwire.dtl.DTLVardef@170bbcc_HPS_FORMAT_FIGEXP M_FIG C_FIG

Mitochondrial dysfunction is a key pathogenic component of neurodegenerative disorders. Mitochondrial stress, created by accumulation of misfolded proteins, reactive oxygen species, and other mechanisms, triggers signals that promote changes in protein translation and gene transcription aimed at protecting and restoring mitochondrial function and maintaining cellular homeostasis. These quality control responses are the integrated stress response and the mitochondrial unfolded protein response. When triggered by mild mitochondrial stress, these adaptive responses promote mitohormesis, which enhances cell survival and lifespan. The exchange of information between mitochondria allows mitochondrial stress in specific tissues to initiate beneficial adaptations affecting mitochondrial populations in remote tissues and organs. Experimental and human observational studies indicate that approaches to trigger mitohormesis, such as physical exercise, have beneficial effects in neurodegenerative disorders.

Cockayne Syndrome is an ultra-rare premature aging condition associated with UV sensitivity, neurocognitive decline, retinopathy, metronidazole-induced lethality, and sensorineural hearing loss. In 70% of affected patients, bi-allelic pathogenic variants in ERCC6 are identified. Although the role of ERCC6 in DNA damage repair has been studied, little is known about the mechanism for defective ERCC6 function in clinical findings, particularly hearing loss. To identify the mechanism of disease caused by pathogenic variants in ERCC6, we developed a zebrafish (Danio rerio) ercc6 loss of function model. We assessed survival after UV and metronidazole exposure, measured basal respiration rates, and evaluated mechanoelectrical transduction function and counts of lateral line hair cells. We found that UV exposure significantly reduces ercc6-/- larval viability. Metronidazole treatment results in complete lethality; wildtype controls show nearly complete survival. ercc6-/- embryos have significantly increased oxygen consumption, suggesting abnormal mitochondrial function. Phalloidin staining of lateral line hair cells with and without UV treatment shows no difference in hair cell counts per neuromast between treatment groups. Mechanoelectrical transduction function after UV exposure, measured by FM1-43 uptake, is reduced. Metronidazole lethality is reduced, oxygen consumption rates are restored, and mechanoelectrical transduction function is preserved by treatment with Mn(III)tetrakis(4-benzoic acid)porphyrin Chloride (MnTBAP), a superoxide dismutase mimetic. We propose that defective mitochondrial function and increased reactive oxygen species levels provide a mechanism for hair cell dysfunction in this model of Cockayne Syndrome. These results provide a foundation for further experiments to explore disease mechanisms and treatment modalities for this premature aging condition.

Pharmacological modulation of monoaminergic signaling, a process targeted by many therapeutic and recreational drugs via receptors, transporters, degradation enzymes, or reuptake mechanisms, is emerging as a promising aging intervention and as a strategy to treat various maladies. Monoamines (including dopamine, serotonin, and norepinephrine) are central to the regulation of mood, movement, sleep, memory, and systemic physiology. Here, we demonstrate that Reserpine, chronic inhibitor of the vesicular monoamine transporter (VMAT), robustly extends lifespan in Drosophila melanogaster in a dose-dependent manner. However, reserpine-treated flies also exhibit reduced locomotor activity and impaired survival under acute heat-stress, indicating a context-dependent trade-off between lifespan extension and stress resilience. Transcriptomic profiling revealed that reserpine induces a transcriptionally repressed, low-energy state characterized by downregulation of metabolic, immune, and stress-response genes in treated aged animals. Notably, under heat-stress, reserpine blunts the induction of canonical protective genes, including heat shock proteins and antioxidant genes, resulting in increased proteotoxic vulnerability. These findings highlight the potential trade-offs of monoaminergic modulation and support further investigation of VMAT inhibitors, monoamine modulators and other hypertension drugs as geroprotective agents.

AbstractO_ST_ABSBackgroundC_ST_ABSAlzheimers disease is associated with impairments in decision making that undermine autonomy, health behaviors, and quality of life. Effort-based decision making, the process of weighing reward value against effort costs, is particularly disrupted in aging and Alzheimers disease. However, aging is also characterized by a shift toward socioemotional and prosocial goals, which may preserve motivation and effortful behavior. Understanding prosocial effort-based decision making and its neural substrates in individuals at risk for AD may reveal early alterations in decision making and neural circuits that support healthy aging. MethodsFifty-two older adults from the PREVENT-AD cohort (mean age = 68.48, 38 females, 18 APOE4 carriers) completed an effort-based decision-making task comparing monetary rewards obtained for oneself or for charity. Decision response (accept/reject), response time, and vigor were analyzed using mixed-effects models controlling for demographic and clinical covariates. Reward-effort relationships were modeled using various functions and compared using Bayesian model comparison. Seed-to-voxel resting-state functional connectivity from the ventromedial prefrontal cortex and anterior cingulate gyrus examined neural substrates of prosocial effort-based decision making, and ROI-to-ROI connectivity within the frontostriatal reward network was compared between APOE4 carriers and non-carriers. ResultsParticipants were more likely to accept effort for prosocial compared to self-oriented rewards. The relationship between reward and effort in both conditions was best captured by a sigmoid function, with higher bias away from effort expenditure for self-oriented compared to prosocial rewards. Across all participants, lower bias away from effort expenditure for prosocial compared to self-oriented rewards was associated with vmPFC and ACCg resting-state functional connectivity to frontal, temporal, and parietal regions. APOE4 carriers showed greater overall bias away from effort expenditure but higher vigor for prosocial than self-oriented rewards, along with reduced nucleus accumbens-dorsal anterior cingulate connectivity that was associated with bias away from effort. ConclusionsProsocial incentives may be an effective strategy for motivating effortful behavior in older adults at risk for Alzheimers disease. Although APOE4 carriers show greater aversion to initiating effort, they exhibit heightened vigor when working for prosocial compared to self-oriented rewards. Leveraging prosocial motivation and its underlying neural circuitry may therefore represent a promising strategy to sustain goal-directed behavior and decision making, promote physical and cognitive activity, and support emotional and brain health in aging.

The human prefrontal cortex (PFC), whose laminar organization is essential for cognitive function, is among the first regions to show age-related functional decline1,2. Single-cell sequencing studies revealed cell type-dependent aging effects but lacked spatial specificity3-6. Spatial transcriptomics (ST) advanced our molecular understanding of the human PFC7, yet whether aging-driven changes differ across PFC layers remains unclear. Here, we performed whole-transcriptome ST on postmortem PFC from 37 individuals across the adult lifespan. We mapped cortical layers and revealed aging mechanisms across layers. This represents one of the largest and most comprehensive lifespan ST analysis of the human PFC brain, offering crucial insight into how the brain ages and identifying potential molecular targets to mitigate cognitive aging and extend healthspan.

Evolution has tuned epigenetic resilience to preserve chromatin organization, transcriptional networks, and cellular identity under relentless stress. Over time, however, all eukaryotic life faces an inevitable rise in entropy that erodes the chromatin landscape at the genomic scale. This entropic decay of epigenetic information, epigenetic aging, is a primary driver of biological aging and systemic dysfunction. The brain is particularly vulnerable to epigenetic aging, with post-mitotic neurons accumulating lifelong chromatin erosion, and the glial epigenome drifting toward pro-inflammatory states. Defining the drivers and consequences of epigenetic aging in the brain forms the basis for restoring youthful chromatin landscapes, cellular identity, and cognitive capacity.

Aging represents a fundamental evolutionary feature shared across all living organisms, intrinsically coupled with development and lifespan. It is orchestrated by a complex polygenic architecture involving numerous small-effect variants distributed across diverse biological pathways, giving rise to striking interindividual variation in aging trajectories and lifespan. Over the past decade and a half, genome-wide association studies (GWAS) have uncovered multiple loci associated with lifespan, healthspan, exceptional longevity, and aging, converging on key biological processes such as lipid metabolism, inflammation, insulin/IGF signaling, and DNA repair. These discoveries have illuminated conserved molecular networks underlying the regulation of aging and longevity. Nevertheless, the identified variants collectively account for only a modest fraction of heritability, underscoring that aging and longevity arise from the cumulative and coordinated actions of myriad common alleles within complex biological networks. In this minireview, we synthesize major genetic insights from GWAS of aging and longevity, delineate recurrent pathways and molecular themes, and discuss how these findings refine our understanding of the genomic foundations of lifespan variation. We further highlight outstanding challenges, including phenotypic heterogeneity, ancestry-specific effects, and the limited predictive power of current models, and propose conceptual directions for future research aimed at establishing a more comprehensive and mechanistic framework for the genetic architecture of human aging and healthy longevity.

Systemic physiological aging is largely driven by disrupted metabolic homeostasis, yet the central mechanisms of this metabolic dysfunction remain poorly defined. Here, we identify the hypothalamus as a critical hub driving systemic aging through neuroimmune-mediated mechanisms. Single-cell transcriptomic and immunohistochemical analyses revealed that aged hypothalami exhibit significant infiltration of CD8 T lymphocytes, beginning in middle age, with signatures of activation and tissue residency. These T cells intimately interact with tanycytes and microglia, promoting neuroinflammation and progressive tanycyte loss, a defining hallmark of hypothalamic aging. T cell receptor profiling revealed a substantial presence of invariant natural killer T (iNKT) and mucosal-associated invariant T (MAIT) cells, likely activated through cytokine-driven, antigen-independent mechanisms. In aged hypothalamus, microglia secrete chemokines CCL3 and CCL4, whose ectopic expression in young mice was sufficient to trigger persistent hypothalamic T cell infiltration and accelerated systemic aging. Circulating oxidized LDLs (OxLDLs) were identified as upstream inducers of this chemokine response. Notably, pharmacological blockade of the CCL3/4-CCR5 axis with Maraviroc and Cenicriviroc prevented T cell recruitment and ameliorated metabolic and physiological impairments. Given the clinical safety of CCR5 antagonists and individuals lacking functional CCR5 remain generally healthy throughout life, our findings highlight midlife CCL3/4-CCR5 inhibition as a translatable therapeutic target for delaying age-related decline and promoting healthspan.

Aging is a major risk factor for a wide range of chronic diseases. Elucidating the molecular mechanisms underlying aging-associated disorders is essential for developing effective preventive and therapeutic strategies. Recent research has unveiled the regulatory roles of non-coding genomic regions. Among these, alternative polyadenylation (APA), a conserved co-transcriptional mechanism, has emerged as a key modulator of gene expression, with an established involvement in various age-related pathologies. APA alters the length of the mRNA 3' untranslated region (3' UTR), thereby affecting mRNA stability, localization, translational efficiency, and ultimately protein expression. Notably, approximately 70% of human genes undergo APA-mediated regulation, underscoring its extensive influence on cellular function. This review summarizes the advances in exploring the role of APA in aging-related diseases, including musculoskeletal disorders, neurodegenerative diseases, cardiovascular and respiratory diseases. These findings can verify the potential of APA as a novel regulatory player in aging biology and a mechanistic contributor to the pathogenesis of age-associated diseases, highlighting its promise as a therapeutic target.

Chronological age is an inadequate proxy for the biological processes that drive disease risk, progression, and treatment response in older adults. This editorial advocates for a minimal standard in age-related disease research: the inclusion of one prespecified biological aging measure and one prespecified immune aging measure when biospecimens are available. Drawing on studies featured in this issue, we illustrate how biological and immune age account for heterogeneity across diverse domains, including cancer, neurodegeneration, vascular disease, immunosenescence, pain, and fibrosis. In the absence of aging readouts, biologically distinct states remain obscured, obscuring biological variation, weakening inference, and limiting translational relevance. We propose a practical framework for incorporating aging metrics into stratification, interpretation, and study design, with the goal of advancing both mechanistic insight and clinical application in aging biology.

With the increasing trend of delayed childbearing, the decline in oocyte quality associated with advanced maternal age has emerged as a pressing concern. However, the mechanism remains unclear, and effective strategies for improvement are currently lacking. Previously, we reported that the downregulation of the mevalonate pathway in aged granulosa cells (GCs) contributed to meiotic defects in oocytes, which may implicate farnesyl pyrophosphate-mediated protein farnesylation. Nevertheless, the role of farnesylation in ovarian aging and its impact on oocytes requires further investigation. In this study, using cumulus-oocyte complexes (COCs) from young and aged female mice, we observed impaired cumulus expansion and concurrent meiotic defects during aged oocyte maturation, accompanied by significantly reduced protein farnesylation in aged GCs. Furthermore, inhibiting farnesylation with FTI-277 in young COCs recapitulated the aging phenotype, disrupting cumulus expansion and inducing meiotic defects similar to those in aged COCs. Conversely, restoring farnesylation via farnesol supplementation effectively ameliorated these deficits in both aged COCs (in vitro) and aged mice (in vivo). Proteomic analysis and experimental validation identified prostaglandin E2 synthase 2 (PTGES2) as a farnesylated protein. Mechanistically, age-related decline in PTGES2 farnesylation in GCs reduces its endoplasmic reticulum localization and impairs prostaglandin E2 (PGE2) production, thereby compromising PGE2-dependent cumulus expansion and oocyte maturation. Collectively, our findings highlight the detrimental effects of decreased farnesylation in aged GCs on oocyte quality and propose a potential therapeutic strategy for improving the developmental competence of aged oocytes.

As individuals age, there is a gradual increase in the levels of inflammation in the body, with macrophages, essential immune cell types, assuming a critical role in modulating inflammatory responses and eliminating senescent cells. Prolonged inflammatory reactions can result in tissue damage, the advancement of diseases, and the acceleration of aging processes. Hevin (also known as SPARCL1, secreted protein acidic and rich in cysteine-like protein 1) is involved in regulating inflammatory responses and the polarization of macrophages. The current study seeks to elucidate the role of Hevin in the context of cardiac aging. Aging or young C57 BL/6 male mice were intravenously injected with Hevin or knocked down Hevin with adeno-associated virus serotype 9 (AAV9) vectors. To screen the underlying mechanisms, RNA-seq was used. Meanwhile, RAW264.7 cells were employed to investigate the role of Hevin in macrophage polarization. Aging mice displayed elevated Hevin serum levels compared to their younger counterparts, along with increased Hevin expression associated with poor cardiac function. Administration of Hevin enhanced aging-related cardiac remodeling, whereas Hevin knockout ameliorated such remodeling and dysfunction. RNA-seq analysis unveiled that Hevin triggered CCL5 activation in aging hearts, and blocking CCL5 reversed the adverse effects of Hevin-induced cardiac aging in vivo. Functionally, circulating Hevin released by iWAT stimulated cardiac macrophages via TLR4, prompting their polarization and CCL5 release, exacerbating cardiac dysfunction and attracting more inflammatory cells for the secretion of pro-inflammatory factors. During aging, Hevin expression inversely correlates with cardiac function, and its absence effectively mitigates aging-related cardiac dysfunction by diminishing inflammatory responses. Our study uniquely identifies Hevin as a promising predictive and therapeutic target for cardiac aging.

There are various well-validated taxonomic classifiers for profiling shotgun metagenomics data, with two popular methods, MetaPhlAn (marker-gene-based) and Kraken (k-mer-based), at the forefront of many studies. Despite differences between classification approaches and calls for the development of consensus methods, most analyses of shotgun metagenomics data for microbiome studies use a single taxonomic classifier. In this study, we compare inferences from two broadly used classifiers, MetaPhlAn4 and Kraken2, applied to stool metagenomic samples from participants in the Integrative Longevity Omics study to measure associations of taxonomic diversity and relative abundance with age, replicating analyses in an independent cohort. We also introduce consensus and meta-analytic approaches to compare and integrate results from multiple classifiers. While many results are consistent across the two classifiers, we find classifier-specific inferences that would be lost when using one classifier alone. Both classifiers captured similar age-associated changes in diversity across cohorts, with variability in species alpha diversity driven by differences by classifier. When using a correlated meta-analysis approach (AdjMaxP) across classifiers, differential abundance analysis captures more age-associated taxa, including 17 taxa robustly age-associated across cohorts. This study emphasizes the value of employing multiple classifiers and recommends novel approaches that facilitate the integration of results from multiple methodologies.

The decrease in muscle performance during aging will not only lead to challenges in movement but also increase the risk of fractures, diabetes, and other diseases, which seriously impacts the overall quality of life in the elderly. In the present study, we used D-galactose (D-gal)-induced 8-week C57BL/6J mice to establish a sarcopenia model and to explore the effects of Nobiletin (Nob), a naturally occurring small molecule derived from orange peel, on skeletal muscle function. Our findings demonstrated that Nob significantly improved exercise endurance, grip strength, glucose tolerance, cold tolerance, and energy expenditure in D-gal-induced aging mice. Additionally, Nob ameliorated mitochondrial morphology and enhanced aerobic metabolism of myofibers in D-gal-induced aging mice, thereby providing increased energy for the body. Notably, Nob activated the SIRT1/PGC1α/Nrf2 pathway to enhance superoxide dismutase (SOD) activity and scavenge reactive oxygen species (ROS) in the skeletal muscle of D-gal-induced aging mice. In conclusion, Nob improved the metabolic capacity and function of skeletal muscle by augmenting its antioxidant capacity and optimizing mitochondrial function.

Alzheimer's disease (AD) is a progressive neurodegenerative condition in which aging serves as the predominant risk factor. Emerging research underscores the importance of bile acids (BAs), traditionally recognized for their role in digestion, as key signaling mediators involved in both systemic metabolism and neural communication. Disruption of bile acid (BA) metabolism during aging arises from altered hepatic synthesis, gut microbial imbalance, and defective receptor signaling. These changes have been implicated in several neurodegenerative processes, including Aβ accumulation, tau protein abnormalities, mitochondrial impairment, and disturbances in immune regulation. Aging induces a shift in BA composition toward more cytotoxic species, contributing to blood-brain barrier disruption and enhanced neuronal damage. Multi-omics analyses have identified distinct BA signatures in plasma and cerebrospinal fluid of individuals with mild cognitive impairment and AD. These alterations show strong correlations with brain atrophy and progressive cognitive decline. Experimental and early clinical findings suggest potential neuroprotective effects of hydrophilic BAs such as ursodeoxycholic acid and tauroursodeoxycholic acid, along with therapeutic opportunities through modulation of BA receptors and microbiome-driven BA regulation. In the current era of AD research, the gut-liver-brain BA axis emerges as a novel mechanistic framework linking systemic metabolic aging to neurodegeneration. This review examines the molecular pathways through which BA dysregulation influences aging and AD, emphasizing its therapeutic relevance and supporting the development of biomarker-based and precision medicine approaches for neurodegenerative disorders.

Stress granules (SGs) are dynamic cytoplasmic assemblies composed of RNAs and proteins that form in response to cellular stress, serving to halt translation and protect cellular integrity. In neurons, SGs mediate adaptive, pro-survival responses to acute stress; however, their dysregulation has been increasingly associated with both aging and neurodegenerative diseases. Aging neurons frequently exhibit changes in SG dynamics - with an increased propensity to form SGs while displaying reduced efficiency in their clearance - resulting in persistent granules that can facilitate the accumulation of pathological protein aggregates (e.g., TDP-43 or tau). Aberrant SG formation and defective clearance mechanisms are implicated in the pathogenesis of key neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD). Recent findings have shown that SGs interface with organelles such as lysosomes, mitochondria, and the endoplasmic reticulum, utilizing autophagic and other protein quality-control mechanisms for clearance. As these clearance pathways progressively decline with age, SGs can transition from promoting cellular adaptation to contributing to cellular dysfunction. In this mini-review, we examine how aging influences SG biology, detail the role of SGs in neurodegenerative diseases, and discuss emerging mechanistic insights and therapeutic strategies aimed at modulating SG dynamics in the context of brain aging.

Senescent cells display indefinite growth arrest and a pro-inflammatory, senescence-associated secretory phenotype (SASP). As the accumulation of senescent cells in tissues with age plays detrimental roles in age-related pathologies, there is much interest in finding therapeutic strategies to eliminate them or suppress the SASP. In this study, we investigated the impact of the secretome and extracellular vesicles (EVs) derived from human trophoblast stem cells (hTSCs) on senescent human fibroblasts. We found that the hTSC conditioned medium (hTSC-CM), and in particular the EVs (hTSC-EVs), significantly reduced the levels of mRNAs encoding SASP factors and the secretion of SASP factors including CXCL1, IL8, and GDF15. Proteomic analysis of hTSC-CM and EVs indicated an enrichment in proteins involved in cell adhesion, tissue repair, and remodeling of the extracellular matrix (ECM). Furthermore, incubation of senescent cells with hTSC-EVs attenuated DNA damage and inflammatory signaling, at least in part by suppressing the function of NF-κB, a major transcriptional regulator of the SASP program. Our findings underscore the value of hTSC-CM and EVs therein in therapeutic approaches directed at senescent cells.

Chronic pain is highly prevalent, costly, and has significant impact on individuals' quality of life, yet evidence on its relationship with mortality remains inconsistent. While most prior studies have focused on the presence and severity of pain, relatively little attention has been given to the distinct role of pain interference (i.e., limitations in daily activities due to pain) in predicting mortality risk. Furthermore, potential differences in the pain-mortality relationship across socio-demographic subgroups remain understudied. This study examines whether pain severity or pain interference is more strongly associated with all-cause mortality among U.S. adults aged 51 and older and explores whether these associations vary by race/ethnicity, socioeconomic status (i.e., education, wealth), and sex. Using 20 years of longitudinal data from the Health and Retirement Study (1998-2018, N=19,487), this study fits Cox proportional hazards models to estimate mortality risk and includes multiplicative interaction terms to assess sociodemographic heterogeneity. Findings show that in fully adjusted models, pain severity itself is not significantly associated with increased risk of mortality, but pain interference is (Hazard Ratio: 1.33; 95% Confidence Interval: 1.27-1.39). The associations between pain interference and mortality risk vary only slightly by race/ethnicity, sex, education, and wealth. These results indicate that pain interference may be a strong risk factor for mortality- potentially more so than pain severity. Clinicians should attend more closely to pain interference as a potentially sensitive indicator of mortality risk among middle-aged and older adults. Interventions aimed at reducing the functional impacts of pain may offer meaningful benefits in improving longevity. PERSPECTIVE: Pain interference is a stronger predictor of mortality risk than pain severity in older adults. Clinicians should prioritize assessing and addressing the functional impacts of pain to potentially improve longevity.

This study assesses the association between exposure to volatile organic compounds (VOCs) and phenotypic age acceleration, and evaluates the potential synergistic interaction by dietary micronutrient intake.

Ageing negatively affects quality of life and healthspan, and interventions are needed to slow this progressive decline. Previously, we have demonstrated the potential functional benefits of combining a genetically modified probiotic (GMP) targeting the non-canonical arm of the renin-angiotensin system (RAS) with exercise training. Initial RNAseq studies indicated the potential of the interventions to influence circadian physiology. Therefore, the objective of this study was to evaluate the expression of circadian-related genes in the tibialis anterior and soleus muscles in male and female aged rats in response to the administration of the GMP, exercise training and multiple controls. Following 12 weeks of the intervention, circadian-related genes were differentially expressed in male and female aged rats and between tissues, primarily influenced by the exercise intervention, with potential additive effects of the GMP. Several genes were also significantly associated with measures of physical performance. Thus, combining exercise with a RAS-related GMP may have potential functional benefits in late life, potentially related to circadian-related impacts within skeletal muscle.

Sex differences in musculoskeletal aging are often attributed to gonadal hormones, but the independent role of sex chromosomes remains unclear. Using the Four Core Genotype mouse model, which dissociates sex chromosomes (XX vs. XY) from gonadal sex (ovaries vs. testes), our goal was to examine sex chromosomes and gonads independent and interactive effects on bone, muscle and organ phenotypes from 8 to 20 months of age in XXO, XYO, XXT, and XYT mice. XYO mice showed high mortality (38.7%-survival by 20 months) when compared with other genotypes (67-86.7%). Between 8 and 20 months, XYO mice showed increases in lean mass and femoral BMD and improved bone structural parameters, yet lower cortical tissue mineral density. XXO mice displayed pronounced late-life gains in body weight, lean and fat mass not observed in other genotypes, although lean mass differed only versus XXT mice at 20 months. Total and spine BMD declined in XXO mice, accompanied with lower structural parameters and higher tissue mineral density than XYO mice. XXT mice displayed bone loss at all skeletal sites, whereas XYT mice showed a selective decline in spine BMD. Overall, chromosome sex adversely affected bone and muscle mass in XX versus XY mice, while gonadal sex influenced bone structure and absolute muscle mass, with mice bearing ovaries generally exhibiting lower muscle mass. Organ weight effects were modest and limited to spleen (XYO > XXO/XYT) and brain (XYT > XXT). Collectively, these findings reveal a previously unrecognized, tissue-specific contribution of sex chromosomes to musculoskeletal aging, independent of gonadal sex.

Alzheimer's disease (AD), the most common cause of dementia in the aging population, is marked by amyloid-beta (Aβ) plaques, tau tangles, and progressive neuronal degeneration, placing heavy clinical and socioeconomic burdens on healthcare worldwide. Aging remains the strongest risk factor, with chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, and impaired proteostasis creating a vulnerable brain environment that accelerates AD onset and progression. Recent evidence highlights the gut-glia-immune axis as a critical pathway linking age-related microbiome changes to glial dysfunction. Microbial metabolites, such as short-chain fatty acids and tryptophan derivatives, regulate microglial maturation, astrocytic activity, and neuroimmune signaling. However, age-associated dysbiosis disrupts glial homeostasis, amplifies neuroinflammation, and impairs amyloid clearance, thereby worsening neurodegeneration. Preclinical models including germ-free mice and fecal microbiota transplantation along with clinical studies of elderly AD patients, provide compelling evidence of microbiome-driven modulation of disease. From a therapeutic perspective, microbiome-targeted interventions including probiotics, prebiotics, synbiotics, and microbiota-directed small molecules offer promising strategies to restore glial balance, reduce inflammation, and protect cognitive function. This review highlights the therapeutic potential of probiotics, synbiotics, and fecal microbiota transplantation for mitigating neuroinflammation and cognitive decline in Alzheimer's disease. However, given the multifactorial nature of neurodegenerative disorders, these strategies are unlikely to be universally effective and must be tailored to individual patient profiles.

Lactate is a metabolite with immunoregulatory functions. We evaluated lactate secretion and its effects on B cells from individuals with different body composition: Y

Intervertebral disc degeneration (IVDD) is often accompanied by the senescence of nucleus pulposus (NP) cells and narrowed intervertebral disc space. Zinc metalloproteinase STE24 (Zmpste24), a common anti-aging gene, has been studied in several diseases but remains understudied in IVDD. This study aimed to investigate the relationship between IVDD and alterations in Zmpste24 expression. Immunohistochemical staining revealed that reduced Zmpste24 expression in patients with IVDD.