Longevity Papers

Vascular aging, a central feature of organismal aging, involves endothelial cell (EC) structural and functional alterations. Methylglyoxal (MGO), a key advanced glycation end product precursor, pathologically accumulates during aging. While MGO induces EC apoptosis via mitochondrial pathways and endothelial dysfunction, its role in cellular senescence remains unclear. The integrated stress response (ISR) sensor Eukaryotic Translation Initiation Factor 2 Alpha Kinase 2 (EIF2AK2), also known as PKR, has emerged beyond its well-established antiviral role as a critical regulator of cellular senescence. This study explores the novel mechanism of berberine (BBR) on targeting EIF2AK2 dimerization to attenuate MGO-induced EC senescence and apoptosis. In vitro, MGO-treated HUVECs assessed EIF2AK2 dimerization/phosphorylation and senescence (p16, p21) and apoptosis (cleaved caspase-3) markers. In vivo, three aging models (MGO-induced aortic injury, D-gal-induced accelerated aging, natural aging) evaluated MGO accumulation and EIF2AK2 pathway activation (phospho-EIF2AK2, ATF4), demonstrating BBR's efficacy via EIF2AK2 axis modulation. Here, we present the first evidence demonstrating that EIF2AK2 dimerization and subsequent activation significantly exacerbate EC senescence and apoptosis in both in vivo and in vitro models, characterized by upregulation of pro-apoptotic markers (Cleaved caspase-3, Bax) and senescence-associated proteins (P53, P21, P16), along with downregulation of the anti-apoptotic protein Bcl-2. EIF2AK2 has been identified as a key cellular target of the natural isoquinoline alkaloid BBR. Our findings further establish that BBR ameliorates MGO-induced vascular EC senescence and apoptosis through selective inhibition of EIF2AK2 dimerization and subsequent eIF2α phosphorylation. Notably, pharmacological suppression of EIF2AK2 with C16 synergistically enhances BBR's protective effects against MGO-induced EC senescence and apoptosis. Collectively, this study reveals a novel mechanistic pathway by which MGO drives EC senescence/apoptosis via EIF2AK2 dimerization/activation and validates BBR's therapeutic potential for vascular pathologies. EIF2AK2 emerges as a promising target for developing novel vascular protection strategies.

Preclinical and clinical studies have reported neuroprotective and geroprotective effects of tetracyclines that are independent of their antibiotic activity, but the underlying mechanisms remain unclear. Here, we systematically profile widely used tetracyclines, including impurities and degradation products, and identify translation attenuation as the shared driver of their neuroprotective and longevity-promoting effects, independent of classical tetracycline mechanisms. Instead, we uncover two mechanistically distinct classes of tetracyclines. Mitochondrial-targeting tetracyclines (MitoTets), exemplified by doxycycline, inhibit the mitochondrial ribosome and attenuate cytosolic translation through activation of the Integrated Stress Response (ISR). In contrast, atypical tetracyclines such as 4-epiminocycline and 12-aminominocycline act as cytosolic-targeting tetracyclines (CytoTets), directly inhibiting the cytosolic ribosome, bypassing the ISR, and protecting neurons from ferroptotic cell death. CytoTets are non-antibiotic, brain-penetrant, and neuroprotective in mouse and human neurons, establishing the tetracyclines as a tunable chemical scaffold for selectively targeting translation in aging and neurodegeneration. HighlightsO_LIThe tetracyclines broadly attenuate translation in multiple eukaryotic models C_LIO_LITranslation attenuation results from both ISR-dependent and ISR-independent mechanisms C_LIO_LIDiscovery of atypical, cytosolic targeting tetracyclines (CytoTETs) that protect from ferroptosis ISR-independently C_LIO_LICytoTETs inhibit translation and are neuroprotective in human-derived neurons and mouse hippocampus C_LI

Aging is a multifactorial biological process in which chronic inflammation and oxidative stress are central to the development of age-related disorders, including neurodegenerative decline. Fucoidan, a sulfated polysaccharide extracted from brown algae, has well-documented anti-inflammatory and antioxidant effects, and therefore has the potential to be a neuroprotective agent against cognitive impairment associated with aging. In the present study, the major fucoidan fraction (LJF-2) isolated from Laminaria japonica was examined for its neuroprotective properties in a D-galactose induced aging mouse model. Oral administration of LJF-2 for 8 weeks significantly improved spatial learning and memory and suppressed neuroinflammatory responses and oxidative stress while significantly reducing the activation of astrocytes and microglia. These neuroprotective effects were linked to the regulation of key proteins involved in neuronal protection and synaptic function, such as neprilysin and synapsin, by cAMP response element-binding protein signaling. Furthermore, LJF-2 significantly remodeled the gut microbiota through a reduction in the abundance of the Bacteroidota, Proteobacteria, and several putative pathogenic genera, which enhanced the intestinal barrier integrity and modified the microbial metabolite profiles, especially those associated with tryptophan metabolism. Fecal microbiota transplantation experiments further confirmed the role of the gut microbiota modulated by LJF-2 in mediating its neuroprotective effects through reduction of oxidative stress and inflammation. Collectively, these findings suggest that LJF-2 may be a promising therapeutic approach to address the aging-related cognitive decline by modulating the gut-brain axis.

The mass of inguinal white adipose tissue (iWAT) decreases with age, and its dysfunction contributes to systemic effects, including chronic inflammation, ectopic lipid deposition, and insulin resistance. However, the molecular and functional characteristics of aged adipose progenitor cells (APCs), as well as effective strategies to rejuvenate their adipogenic potential, remain poorly understood. In this study, we found that aged mice exhibited a reduced frequency of APCs, increased inflammatory activity, and impaired adipogenic differentiation capacity. Strikingly, while quercetin exerted concentration-dependent effects on the vitality and function of APCs, only moderate doses specifically restored the adipogenic differentiation of aged APCs. Mechanistically, this rejuvenating effect was primarily mediated through the suppression of pro-inflammatory pathways. Together, our findings provide novel mechanistic insights into APCs aging in iWAT and identify quercetin as a promising rejuvenative agent for the treatment of adipose tissue dysfunction and related metabolic disorders in aging.

Aging is characterized by a progressive decline in physiological function, driven by interconnected molecular hallmarks that increase the risk of chronic diseases. To extend health span, interventions targeting these hallmarks, including lifestyle modifications, pharmacological agents, and genetic strategies, have been developed. Among these, partial reprogramming, the transient expression of Yamanaka factors, has emerged as a powerful approach to reverse age-related cellular damage and restore youthful epigenetic and transcriptional signatures without erasing cell identity. This perspective highlights the therapeutic possibilities arising from the convergence of partial reprogramming with the innovative technology of ex vivo machine perfusion. These platforms offer a unique opportunity to apply rejuvenation therapies directly to suboptimal donor organs outside the body before transplantation. Combining these strategies could significantly improve organ quality, expand the donor pool, enhance transplantation outcomes, and advance regenerative medicine.

Aging is a multifactorial process marked by a progressive decline in physiological function and increased vulnerability to diseases such as neurodegeneration, cancer, cardiovascular disorders, and infections. A central feature of aging is inflammaging, a state of chronic low-grade inflammation driven by cellular senescence, mitochondrial dysfunction, and oxidative stress. Recently, two regulated forms of non-apoptotic cell death-ferroptosis and cuproptosis-have emerged as critical mechanisms linking redox imbalance, mitochondrial stress, and disrupted metal homeostasis to age-related pathology. Ferroptosis, an iron-dependent process characterized by lipid peroxidation and impaired glutathione peroxidase 4 (GPX4) activity, and cuproptosis, a copper-dependent mechanism associated with protein lipoylation stress, both intersect with aging-related changes in mitochondrial and metabolic function. Importantly, these two forms of cell death should not be viewed as entirely separate pathways but rather as interconnected axes within a broader metal-redox-metabolic network. Disturbances in copper or iron homeostasis, glutathione (GSH)/GPX4 dysfunction, mitochondrial and iron-sulfur (Fe-S) cluster compromise, and enhanced lipid peroxidation may converge to lower cellular survival thresholds, thereby exacerbating oxidative damage, immune dysfunction, and tissue degeneration and ultimately fueling aging and inflammaging. This review offers a unique integrated perspective that situates ferroptosis and cuproptosis within a unified framework of aging biology, emphasizing their roles in age-related diseases and the therapeutic potential of targeting these pathways through nutritional, pharmacological, and lifestyle interventions.

Advanced maternal age is correlated with increased infertility, often due to impaired decidualization and placentation. This study elucidated the senotherapeutic potential of chlorogenic acid (CGA), a phenylacrylate polyphenol as major compound of coffee, in endometrial stromal cells (ESCs). Using a passage number-induced senescence model, CGA reduced senescence markers (P16, P21), promoted proliferation, and upregulated decidualization markers (PRL, IGFBP1, FOXO1). In aged hTERT-immortalized ESCs, CGA enhanced mitochondrial biogenesis by upregulating mitochondrial complex genes and restoring mitochondrial function. Docking and molecular dynamics analyses demonstrated a high binding affinity of CGA toward mTOR (-8.29 kcal/mol), with stabilizing interactions at key residues. CGA treatment decreased mTOR expression in uterine tissue of aged mice in vivo. By modulating the mTOR/AMPK/SIRT1 pathway, CGA attenuates senescence and supports decidualization. These findings suggest CGA as a promising senotherapeutic candidate for improving endometrial function and addressing infertility related to advanced maternal age.

Oxidative stress and apoptosis mediated senescence of nucleus pulposus cells (NPCs) and the degradation of extracellular matrix (ECM), which represent a key mechanism underlying intervertebral disc degeneration (IVDD). Mesenchymal stem cell-derived exosomes hold therapeutic potential for tissue repair; however, their clinical application is limited by rapid clearance, short half-life, and poor target specificity. To overcome these challenges, this study developed poly(lactic-co-glycolic acid) (PLGA) microspheres as a sustained-release carrier for exosomes derived under either normoxic (Exos, 21% O₂) or hypoxic (H-Exos, 1% O₂) conditions. The PLGA microspheres demonstrated high exosome-loading efficiency and provided controlled release for over four weeks. Released hypoxic exosomes activate PPAR-γ pathway, exerting better effects by reducing NPCs SA-β-gal positive rate by 59.8% and elevates Col II and ACAN levels by 30.7% and 25.5%. Animal experiments confirmed that this system effectively attenuated IVDD progression indicating its potential for clinical translation.

Management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) has evolved dramatically over the past five decades, driven by discoveries that have fundamentally reshaped our understanding of the vitamin D endocrine system and its role in disease progression. This review synthesizes the key pathophysiological insights and clinical evidence underlying three critical paradigm shifts. The first shift moved beyond simple calcitriol replacement with the development of selective vitamin D receptor activators (VDRAs) designed to minimize hypercalcemia while maximizing PTH suppression. Crucially, these analogs revealed unexpected survival benefits, suggesting protective VDR actions extending beyond mineral metabolism. The second shift recognized the profound prevalence and independent mortality risk associated with nutritional vitamin D (25(OH)D) deficiency in CKD. This highlighted the kidney's complex role in maintaining systemic 25(OH)D supply and the importance of extrarenal vitamin D activation, although optimal assessment, targets, and supplementation strategies remain highly controversial due to CKD-specific pathophysiology (e.g., megalin loss, impaired uptake, obesity effects) and complex dosing paradoxes. The third, and most impactful, shift centers on the FGF23-Klotho axis. Pathologically high FGF23 is now established as a direct cardiovascular and skeletal toxin, acting via Klotho-independent pathways in CKD, while the profound deficiency of the protective, anti-aging hormone Klotho exacerbates systemic damage (inflammation, oxidative stress, impaired autophagy). This creates a major therapeutic dilemma, as VDRAs induce protective Klotho but worsen toxic FGF23, while calcimimetics do not increase FGF23 but offer no Klotho benefit. Furthermore, this complex interplay is obscured by significant limitations in accurately measuring FGF23 isoforms, soluble Klotho, and true vitamin D status. These paradigm shifts reveal a complex pathophysiology far beyond simple PTH control, demanding a move towards nuanced, potentially combined therapeutic strategies that balance FGF23 burden with Klotho preservation. Overcoming the profound diagnostic limitations to accurately monitor this axis and guide personalized therapy represents the critical next frontier in improving outcomes for patients with CKD.

Cellular senescence is a stress-induced process that contributes to adipose tissue dysfunction by promoting inflammation, impaired adipogenesis, and insulin resistance, alterations that are closely associated with age-related cellular dysfunction and metabolic disorders. In this study, we evaluated the protective role of chlorogenic acid (CGA), a polyphenol with known antioxidant and anti-inflammatory properties, against oxidative stress-induced senescence in murine 3T3-L1 adipocytes. The results obtained showed that CGA treatment significantly alleviated the senescent phenotype by restoring Lamin B1 levels and the Bcl-2/Bax ratio. Additionally, CGA downregulated key senescence-related cell cycle progression markers, modulating p53, p21, and MAPK signaling. CGA also restored insulin signaling through the PI3K-AKT-GLUT4 axis and improved glucose uptake, while attenuating oxidative stress, inflammatory cytokine expression, and extracellular matrix remodeling factors associated with SASP. Collectively, these findings support the role of CGA as a promising senotherapeutic nutraceutical able to reduce adipocyte senescence and its metabolic consequences, offering novel insights for the development of dietary supplements targeting age-related cellular dysfunction.

The muscle-brain axis integrates peripheral metabolic activity with central nervous system function. Among the endocrine signaling molecules regulating such crosstalk, the peptide hormone irisin released during muscle contraction seems to play relevant roles. Irisin is generated by the proteolytic cleavage of the fibronectin type III domain-containing protein FNDC5 and has emerged as a key regulator of neurotrophic and metabolic adaptation. Although initially described as a myokine, irisin is also expressed in adipose and neural tissues, acting through autocrine, paracrine, and endocrine mechanisms. Irisin binds to the αV/β5 integrin receptor complex and activates a network of signaling pathways which promote mitochondrial biogenesis, autophagy, oxidative stress resistance, and modulation of inflammatory responses. Within the central nervous system, irisin induces brain-derived neurotrophic factor expression and contributes to synaptic plasticity, neurogenesis, and cognitive preservation. Experimental models show that irisin reduces amyloid burden, limits α-synuclein pathology, suppresses neuroinflammation, and stabilizes blood-brain barrier integrity, supporting a disease-modifying role in neurodegenerative conditions. In skeletal muscle, irisin stimulates myogenesis, enhances anabolic signaling, and improves metabolic efficiency, suggesting broader relevance for sarcopenia and age-related metabolic decline. Herein, we discuss irisin as a promising biomarker and a candidate therapeutic target for disorders characterized by concurrent muscle deterioration and cognitive impairment.

Vaccination is the preferred strategy for preventing infections such as influenza in elderly individuals; however, its efficacy is often suboptimal due in part to age-related declines in immune function. In this study, we discovered that the infusion of mesenchymal stromal cells (MSCs) restored defects in the splenic stromal cell network and lymphocyte architecture in aged mice while also increasing specific antibody levels following vaccine immunization. This significantly protected aging mice from influenza infection. Mechanistically, the delivered MSCs localized in the splenic marginal zones, where they positioned themselves near marginal reticular cells (MRCs) and stimulated MRC proliferation, partially through the action of vascular endothelial growth factor A (VEGFA). This MSC‒MRC interaction orchestrated the reconstruction of the stromal network, thereby restoring lymphocyte homeostasis and germinal center reactions. Importantly, the MSC-mediated enhancement of the vaccine response was further validated in aged cynomolgus monkeys. Collectively, our findings provide new insights into the application of MSCs in addressing age-related immune decline and highlight splenic MRCs as critical therapeutic targets.

Plasminogen activator inhibitor-1 (PAI-1) is a central regulator of the fibrinolytic system and is increasingly recognized for its pivotal roles in a broad spectrum of physiological and pathological processes. In addition to its classical function in fibrinolysis, accumulating evidence highlights the involvement of PAI-1 in cellular senescence, differentiation, fibrosis, thrombosis, and tumorigenesis. This review systematically summarizes recent advances in understanding the multifaceted biological functions of PAI-1, with a particular emphasis on its dual regulatory roles in cellular differentiation and senescence. Through manual curation and analysis of the literature, we constructed a PAI-1-centered signaling network associated with differentiation and further integrated this framework with known senescence-related pathways. This integrative approach aims to elucidate the crosstalk between differentiation and senescence mediated by PAI-1. By providing an in-depth overview of PAI-1 functions across various experimental models, this review offers a theoretical foundation for exploring its potential as a therapeutic target and presents novel perspectives for the development of intervention strategies for complex chronic diseases.

In the central Lewy body diseases (LBDs) Parkinson's disease and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests, substantial central neurodegeneration has already occurred. Biomarkers of preclinical disease are needed to test strategies that might delay the onset of symptomatic central LBDs and extend healthspan. The prospective, longitudinal PDRisk study asked whether cardiac sympathetic neuroimaging, cerebrospinal fluid catecholamine metabolites, cardiovascular physiological biomarkers, and alpha-synuclein seeding activity predict central LBDs in at-risk individuals. This review highlights and builds on several findings from this unique study. Some concepts induced from the present and previous data are: 1) Central LBDs can begin outside the brain ("body-first"), with early involvement of cardiac sympathetic nerves as evidenced by ¹⁸F-dopamine positron emission tomography (PET) and normal initial putamen dopaminergic innervation by ¹⁸F-DOPA PET. 2) DLB can follow a similar body-first progression pattern. 3) Body-first LBDs entail tri-phasic temporal sequences, corresponding conceptually to homeostasis, dyshomeostasis, and symptomatic disease, noted in the heart years before the striatum. 4) LBDs feature a vesicular storage defect in extant catecholaminergic terminals, exemplifying the "sick-but-not-dead" phenomenon. 5) There are multiple other functional abnormalities in residual catecholaminergic terminals in LBDs. 6) Based on computational modeling, disease-modifying treatments begun in the dyshomeostatic phase might delay the onset of symptomatic LBDs, compressing morbidity.

Biomarkers are essential in drug development and diagnostics, aiding patient selection and disease monitoring. The lack of age-specific protein references complicates tracking patterns related to chronic disease or treatment. This exploratory, proof-of-concept study explores age-related changes in the serum proteome across the full human lifespan. Using proximity extension assays (Olink), we measured the Immuno-oncology panel in serum from 264 healthy individuals, another panel in a subgroup of 109, all without significant disease at blood draw, aged 0 days to 88 years. Cluster analysis of the Immuno-oncology panel revealed two clusters: cluster 1 included samples from children ≤11 days, cluster 2 encompassing samples with an age range from 2 months till 88 years old. Weighted correlation network analysis identified five protein modules, with four showing enrichment in specific pathways. The Organ-Damage panel showed similar age-related protein variations. Finally, we identified four protein patterns over age: constant, increasing, decreasing, or U-shaped and defined age-specific normal expression ranges. Altogether, our findings suggest that healthy aging across the entire lifespan involves alterations in protein expressions and distinct protein profiles exist in newborns, children, adults and older adults. We provide valuable reference data for the different protein patterns observed across the entire lifespan.

The gut microbiota changes throughout life, potentially influencing health and triggering physiological disorders. Frailty syndrome (FS) is an age-related condition that reduces quality of life and increases hospitalization and mortality risks, making early detection and prevention essential in older populations. This study analyzed 16S rRNA gene and metagenomics sequencing of fecal samples from 203 older adults (FS: n = 64, non-FS (NFS): n = 139) to assess the role of gut microbiota in FS and related comorbidities, such as sarcopenia and impaired lower extremity function (ILEF) or anthropometric variables. Consistent taxonomic patterns were observed: Eggerthella, Parabacteroides, and Erysipelatoclostridium were significantly abundant in FS, while Christensenellaceae R-7 group, Erysipelotrichaceae UCG-003, and Hungatella were enriched in NFS. Christensenellaceae R-7 group was also associated with better mobility. Metagenomics analysis identified 680 KEGG functions differing between groups, categorized into 28 metabolic pathways. FS individuals had overrepresented biotin metabolism, antimicrobial resistance, and energy production, but underrepresented ribosomal and protein synthesis and sporulation pathways. Resistome analysis found the tetM/tetO (K18220) gene most abundant, alongside tetracycline, β-lactam, and macrolide resistance, primarily mediated by antibiotic efflux and transporters. These findings highlight distinct microbial and functional signatures associated with FS, underscoring the complex interplay between the gut microbiota and host physiology in aging. Adjusting for covariates, age and diabetes acted as confounding factors in FS for both 16S gene and metagenomics sequencing. This study offers new insights into fundamental questions in the biology of aging and opens avenues for microbiota-targeted strategies to improve the quality of life in older adults.

The human lifespan has increased dramatically over the last few decades; however, reaching older age increases the risk of age-related diseases and ailments. To extend the healthspan, many have turned to supplements, including plant-based remedies used in traditional medicine, to promote healthy aging. One of these is

Social housing is desirable for the health and well-being of laboratory mice, as social interactions with conspecifics influence both behavioral and physiological outcomes. Although group housing benefits social species, it can introduce variability in mortality outcomes, and raise welfare concerns, particularly with the emergence of aggression or fluctuating cage densities. Despite this, few studies have evaluated how changes in the number of living cagemates over time are associated with survival, particularly in a sex-specific manner. We analyzed data from the National Institute on Aging's Interventions Testing Program (ITP; n = 2635 UM-HET3 mice), across three research sites to assess whether housing density influenced longevity differently in male and female mice. Mice were housed in same-sex cages (median = 3 per cage) without reassignment after cagemate death. We applied Cox frailty models incorporating nested random effects for cage and site, with fixed effects for sex, treatment, and time-varying number of living cagemates to estimate hazard ratios, which allowed us to assess the instantaneous risk of death associated with changes in cagemate number. Results showed a significant main effect of the number of living cagemates on mortality and a significant interaction between sex and cagemate count, indicating sex-specific responses. Female mice exhibited a pronounced increase in mortality rate as cage density declined, suggesting a potential role of social buffering in longevity. These findings emphasize the importance of considering social housing dynamics, particularly for female mice, in both experimental design and animal welfare protocols.

The budding yeast

Frailty is often experienced by older adults, which can lead to long-term health problems. We aimed to examine associations with improvements in nutritional status, sarcopenia (age-related loss of skeletal muscle mass and strength), and frailty in four groups with different oral exercise frequencies.

Fibroblast growth factor 21 (FGF21) is a key hormone for metabolic homeostasis under conditions such as obesity, aging and diabetes. While extensively studied in males, its role in female physiology remains poorly defined. This study evaluated the effects of hepatic FGF21 deletion in 12-month-old female mice using a liver-specific FGF21 knockout (FKO) model. FKO females exhibited reduced body weight and improved glucose tolerance, with no changes in circulating FGF21 levels. In the liver, RT-qPCR analysis showed that the expression of genes involved in de novo lipogenesis, including

The gastrointestinal (GI) barrier maintains gut homeostasis by regulating nutrient absorption and preventing the entry of harmful agents. While its disruption has been linked to chronic disease, stress and dietary lifestyle, the role of aging in intestinal permeability remains subject of debate. Understanding how aging and age-associated inflammation affect barrier integrity is crucial for promoting GI health in the elderly. In this study, we used the Senescence-Accelerated Mouse-Prone 8 (SAMP8) mice and their normally aging Senescence-Accelerated Mouse-Resistant 1 (SAMR1) counterparts to investigate GI homeostasis at 2, 5, 9 and 11 months of age under basal conditions and during chronic colitis induced by repetitive dextran sodium sulphate (DSS) treatment. Until 9 months of age, no histological deviations were observed in either strain. At 11 months, SAMP8 mice exhibited low-grade colon inflammation marked by immune cell infiltration, including neutrophils and macrophages, and elevated expression levels of pro-inflammatory genes (Il1b, ccl5, cxcl1, cxcl10, Tnf and Saa3), while GI barrier function remained intact. However, after DSS-induced chronic colitis, aged SAMP8 mice showed a heightened disease activity index and intestinal hyperpermeability, unlike age-matched SAMR1 mice. Mechanistically, this impaired GI barrier recovery correlates with aberrant STAT3 signaling. Notably, SAMP8 mice exhibited increased epithelial proliferation and macrophage abundance at baseline, which did not further increase after DSS treatment. In conclusion, our findings support the notion that aging alone does not compromise GI barrier function but rather predisposes the gut to barrier dysfunction upon inflammatory challenge due to impaired resolution mechanisms.

The Reducing Inflammation for Greater Health Trial's (RIGHT) study is a single-center, randomized, double-blind, placebo-controlled trial designed to test whether clazkizumab, an interleukin-6 (IL-6) inhibitor, can improve or slow decline in physical, cognitive, and vascular function in older adults, when compared to a placebo. The trial will enroll participants meeting the following inclusion criteria: (1) ≥ 70 years of age, (2) with low to moderate physical function, defined as self-reported difficulty walking 1/4 mile or climbing a flight of stairs, but able to walk 400 m at baseline exam, (3) usual walking speed between ≥ 0.44 and < 1.0 m/s on a 4-m walk or a body mass index of ≥ 28 kg/m

Evidence on the link between adverse childhood experiences (ACEs) and psychological-physical multimorbidity (PPM) in older Chinese adults is limited.

Exercise-induced fatigue involves oxidative stress and metabolic dysregulation. While the anti-aging protein α-Klotho regulates metabolism and oxidative stress, its role in exercise fatigue is unexplored. This study investigated whether α-Klotho supplementation mitigates cumulative exercise-induced fatigue and elucidated the underlying tissue-specific mechanisms. Male C57BL/6J mice were divided into three groups (

Aneuploidy in human eggs, which rises sharply with age, is a leading cause of infertility, IVF failure, and miscarriage. This age-related aneuploidy is primarily driven by premature sister chromatid separation (PSSC), resulting from loss of the cohesin complex that holds chromatids together. How cohesin is destabilized in the long-lived mammalian oocyte is poorly understood. Here, we show that in mouse oocytes, pericentromeric transcription is essential for maintaining the cohesion protector Shugoshin 1 (SGO1) and PP2A at centromeres, which together safeguard the cohesin subunit REC8. With age, mouse oocytes lose pericentromeric transcription, SGO1, and PP2A, leading to destabilized cohesion and increased PSSC. Supplementing aged mouse oocytes with Sgo1 restores centromeric protection, and reduces PSSC to youthful levels. Aged human oocytes also show reduced SGO1, and SGO1 supplementation reduces the fraction of human eggs with PSSC by approximately half. These findings establish SGO1 supplementation as a potential strategy to preserve chromatid cohesion in aging oocytes.

Cellular rejuvenation through transcriptional reprogramming is an exciting approach to counter aging. Using a fibroblast-based model of human cell aging and Perturb-seq screening, we developed a systematic approach to identify single transcription factor (TF) perturbations that promote rejuvenation without dedifferentiation. Overexpressing E2F3 or EZH2, and repressing STAT3 or ZFX, reversed cellular hallmarks of aging-increasing proliferation, proteostasis, and mitochondrial activity, while decreasing senescence. EZH2 overexpression in vivo rejuvenated livers in aged mice, reversing aging-associated gene expression profiles, decreasing steatosis and fibrosis, and improving glucose tolerance. Mechanistically, single TF perturbations led to convergent downstream transcriptional programs conserved in different aging and rejuvenation models. These results suggest a shared set of molecular requirements for cellular and tissue rejuvenation across species.

Epigenetic mechanisms, including histone acetylation, regulate learning and memory and underlie Alzheimer's disease and related dementia (ADRD). Acetyl-CoA synthetase 2 (ACSS2), an enzyme generating acetyl-CoA, locally regulates histone acetylation and gene expression in neuronal nuclei. This regulatory mechanism may be a promising target for therapeutic intervention in neurodegenerative diseases. Previously, we showed that systemic ACSS2 knockout mice, although largely normal in physiology, exhibit memory deficits. Here, we investigated whether increasing ACSS2 levels could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology and the P301S transgenic mouse model for tau-induced memory decline. Our results show that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Additionally, boosting histone acetylation through ACSS2 countered age-related memory decline. These findings indicate that increasing ACSS2 is highly effective in countering age- and tau-induced transcriptome changes, preserving elevated levels of synaptic genes, and safeguarding synaptic integrity. These findings position ACSS2 as a key epigenetic regulator of cognitive aging and ADRD, highlighting its potential for targeted therapeutics to enhance brain resilience and function.

Aging profoundly reshapes how the brain integrates sensory evidence with prior expectations during perceptual decision-making. Combin ing behavioural modelling with high-density EEG, we show that older adults assign greater weight on prior information, resulting in stronger decisional bias and reduced sensory precision under probabilistic cues. Neural dynamics revealed a breakdown of anticipatory tuning in visual alpha rhythms, supporting sensory preparation in youth, alongside enhanced central beta activity, indicating a shift toward pre-emptive motor engagement aligned with expected responses. A data-driven decomposition further showed that, whereas prior-driven behaviour in younger adults emerges from a flexible interplay between sensory and executive oscillatory systems, it becomes dominated in aging by a rigid, response-centred mode. Together, these findings uncover a large-scale reconfiguration of predictive computations with age, marking a transition from adaptive sensory-executive coordination to a more automatized, action-oriented predictive strategy.

Short-wavelength blue light is commonly encountered in daily life and has been shown to be harmful to the health of organisms. This study aimed to examine the impact of blue light on aging and to explore the potential anti-aging effects of three flavonoids-luteolin, quercetin, and kaempferol-under conditions of blue light exposure. The experiment employed Drosophila melanogaster as a model organism, by feedingvarious concentrations of the three flavonoids and subsequent exposure to short-wavelength blue light. Administration of the highest concentration of the three flavonoids to D. melanogaster was associated with a reduced risk of mortality during adulthood. Male D. melanogaster receiving the highest concentration of flavonoids, as well as those receiving luteolin and quercetin individually, exhibited a reduced initial aging rate (b₀), resulting in an extended mean lifespan and a narrower lifespan distribution compared with the control group. In conclusion, this study demonstrated the effects of flavonoids on the aging process in organisms subjected to blue light. These findings provide important insights into the development of strategies to mitigate aging in the presence of blue-light-induced damage and contribute to a broader understanding of environmental influences on health and aging.

Aging, a major risk factor for numerous diseases, is associated with significant transcriptional changes across organs. However, the age of onset, extent of transcriptomic changes and how they unfold are not fully understood. We performed bulk RNA sequencing on eight organs (brain, heart, kidney, liver, lung, skeletal muscle, spleen, and testis) from male C57BL/6J mice across much of the murine lifespan covering 3-, 5-, 8-, 14-, 20- and 26-month-old animals. Our analysis revealed that age-related transcriptomic shifts vary in both timing and extent, with early shifts in lung, spleen, and testis; mid-life changes in heart, kidney, and skeletal muscle; and later alterations in brain and liver. The extent of age-related transcriptomic changes ranged from very low (testis) to high (kidney, liver, spleen). A linear mixed-effects model identified genes with tissue-specific aging trajectories. By integrating hub gene analysis and functional enrichment, we uncovered aging signatures that are either tissue-specific or shared across multiple organs, including those related to immune response, mitochondrial dysfunction, extracellular matrix remodeling, and cellular senescence. This study provides a systems-level resource for advancing aging research.

Reproductive history is closely linked to health, yet its relationship with biological aging and survival remains uncertain. We investigated this in the Finnish Twin Cohort, a population-based study that enables modeling of full childbearing history while controlling for common risk factors, through questionnaires and civil registries. We model the association between reproductive trajectories and survival in 14,836 women, and assess biological aging in a subset of 1054 participants using the PCGrimAge, an algorithm trained to predict biological aging and mortality risk from DNA methylation. We identify six distinct reproductive trajectories describing different timing and number of childbearing events. Women with the most live births throughout their lives (mean 6.8, SD 2.4) and nulliparous women showed accelerated aging and elevated mortality risk. These findings support the disposable soma theory of aging in modern humans, and provide valuable insights into the genetic and lifestyle-related determinants of lifespan.

The potential role of small interfering RNAs (siRNAs) produced from double-stranded RNA in aging has not been fully addressed. The networks of genes regulated by siRNAs and their partner Argonaute proteins are best understood in C. elegans, a pioneering model of aging and small RNA studies. Here, we describe synergistic lifespan extension of insulin/IGF-1 signaling (IIS) mutant age-1(hx546) by rde-4 or alg-3; alg-4 deficiencies. By analyzing gene expression and siRNA populations in these IIS and RNAi mutants, we show here that redundant spermatogenesis-specific Argonautes ALG-3 and ALG-4 are capable of regulating IIS, potentially through direct control of the Major Sperm Protein (MSP) genes in the germline. MSPs and MSP domains of some mammalian proteins are secreted and directly inhibit the Eph receptor (EphR). In turn, EphR interacts with and destabilizes PTEN, a major negative regulator of IIS. We show that enhanced MSP expression correlates with EphR mislocalization and elevated PTEN levels in oocytes of alg-3/4(-) worms. At the same time, ALG-3/4 expression is regulated by IIS. Thus, we propose mutual regulation of IIS and ALG-3/4 through secreted ligands.

Age-associated hair loss is primarily driven by decreased function and proliferation of hair follicle stem cells (HFSCs), often exacerbated by increased inhibitory signaling and changes in the stem cell niche. Macrophage polarization to the anti-inflammatory M2 phenotype is known to increase stem cell proliferation. We investigated the effects of poly-D,L-lactic acid (PDLLA) on hair growth in middle-aged skin, focusing on its role in modulating macrophage polarization and HFSC activity. Senescent macrophages were analyzed for Piezo1 activity, macrophage polarization, and secretion of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) after PDLLA treatment. Downstream effects on HFSC proliferation, stemness, and Wnt signaling were assessed, including inhibition experiments using the Piezo1 blocker GsMTx4. In vivo analyses assessed hair follicle number, diameter, length, anagen duration, and hair coverage following PDLLA administration in middle-aged mice. PDLLA increased Piezo1 expression and activity in senescent macrophages, enhancing M2 polarization and secretion of HGF and IGF-1. This activated the RAS/ERK signaling pathway, promoting HFSC proliferation and stemness. Furthermore, PDLLA upregulated Wnt signaling molecules (Wnt3a, Wnt10b, and β-catenin) and anagen phase-related factor (Axin2, LEF1, and Lgr5), which were decreased by GsMTX4. In middle-aged animal skin, PDLLA administration led to increased hair follicle number, diameter, and length, as well as prolonged anagen and greater hair coverage. Collectively, these findings suggest that PDLLA rejuvenates the middle-aged skin microenvironment, at least in part through Piezo1-associated M2 macrophage polarization and enhanced HFSC function, offering a promising therapeutic strategy for age-related hair loss targeting both the immune and the stem cell compartments.

Aging leads to cognitive decline with considerable individual variability, yet the biological mechanisms remain unclear. Here we performed ultrastructural and proteomic analyses of the medial prefrontal cortex (mPFC) alongside behavioral assessments of attentional set shifting in mice across age groups. Although reduced synaptic density did not consistently lead to cognitive decline, proteomic analyses of synaptosomes and whole tissue revealed that the molecular signatures associated with individual variability in cognitive decline were distinct from those associated with chronological aging, and that synaptic mitochondria and their proteins were more abundant in aged mice with greater cognitive decline. Moreover, treatment with the mitochondria-targeted antioxidant MitoQ reduced the abundance of synaptic mitochondrial proteins, including pro-apoptotic proteins, and mitigated age-related cognitive decline. These findings demonstrate that synaptic mitochondrial oxidative stress in the mPFC, distinct from chronological age-related processes, contributes to individual variability in age-related cognitive decline and offers a potential target for prevention and intervention.

The development of geroprotectors, compounds that slow the biological aging process, is an important goal in modern medicine. These interventions hold the promise not only of extending lifespan, but more importantly, of extending healthspan-the period of life free from chronic disease. By targeting the fundamental mechanisms of aging, geroprotectors have the potential to simultaneously delay the onset and progression of multiple age-related conditions, thereby reducing the immense societal and economic burden of these illnesses. In this manuscript, we identified a new compound, MPOL_B_1, through a virtual screen targeting the proton-coupled folate transporter (PCFT). We describe the synthesis of MPOL_B_1 and two other lead compounds identified from the virtual screen. MPOL_B_1 had drug-like properties

Aging reduces the tissue regenerative capacity, promotes chronic inflammation, and contributes to neurodegenerative diseases, including age-related macular degeneration (AMD). AMD is a leading cause of vision loss in older adults and manifests as dry (atrophic) or wet (neovascular) disease. Although dry AMD is more prevalent, neovascular AMD (nAMD) causes the most severe vision impairment and remains a major public health burden. Oxidative stress-mediated inflammation and dysfunction of retinal pigment epithelium (RPE) cells and choriocapillaris drive early AMD. Neovascular AMD is marked by pathologic choroidal neovascularization (CNV), driven largely by dysregulated VEGF signaling. Anti-VEGF therapies are the current standard of care for nAMD but require frequent intravitreal injections, carry procedure-related risks, and are ineffective in a substantial subset of patients, underscoring the need for new therapeutic approaches. Caffeine, a widely consumed and well-tolerated adenosine receptor antagonist, has emerging relevance in vascular regulation and inflammatory signaling. Extracellular ATP and its metabolites, including adenosine, accumulate under stress and act through purinergic receptors to influence angioinflammatory processes. We recently showed that systemic caffeine administration suppressed CNV in vivo, an effect partly reproduced by the adenosine receptor A

Combined creatine monohydrate (CRE) and β-hydroxy-β-methylbutyrate (HMB) supplementation may counteract age-related declines in functional capacity, yet evidence in physically active older adults is scarce.

Gut microbiome plays an important role in several metabolic, immune, and inflammatory pathways; however, there is limited evidence for its role in body composition and musculoskeletal health. Sarcopenia, defined as a loss of skeletal muscle mass and function, and obesity, can co-exist in a condition known as sarcopenic obesity. This condition is highly prevalent among older adults, hence increasing the risk of negative health implications such as metabolic dysfunction, chronic inflammation, reduced physical performance, and poor quality of life. These age-related conditions are closely associated with alterations to the gut microbiome, including microbial profiles and a reduction in beneficial metabolites such as short-chain fatty acids (SCFAs). Probiotic, prebiotic, and synbiotic interventions are therefore emerging as promising strategies to improve the gut microbiome by enhancing microbial diversity and restoring microbial communities. This review utilizes current evidence on the impact of these interventions on gut microbiota composition, inflammatory and metabolic biomarkers, body composition, and functional outcomes in older adults with sarcopenia, obesity, and sarcopenic obesity. Probiotics, containing live beneficial microorganisms, have shown potential in enhancing SCFA production, reducing inflammation, and improving insulin sensitivity. Prebiotics are non-digestible fibers that selectively activate the growth of beneficial gut bacteria, further supporting gut health by proliferating the growth of SCFA-producing bacteria. Synbiotics, a combination of probiotics and prebiotics, provide a synergistic approach to gut health, accounting for the microbial composition and functional capability. Recent studies have demonstrated that probiotics, prebiotics, and synbiotics may reduce inflammation and improve muscle mass and strength among older adults with sarcopenia, obesity, and sarcopenic obesity. These interventions have the potential in mitigating obesity-related metabolic dysfunction and inflammation, particularly in individuals with sarcopenic obesity. Although, preclinical studies in mice exhibit beneficial effects, clinical studies in older adults remain limited, with heterogeneity of study design, intervention types, and outcome measures. This review highlights the need for robust, well-designed clinical trials to understand the mechanistic and molecular pathways through which probiotic, prebiotic, and synbiotic supplementation may modulate the gut microbiome and improve musculoskeletal health among older adults. These interventions may provide innovative, non-invasive therapeutic strategies for managing sarcopenia, obesity, and sarcopenic obesity, ultimately contributing to healthier aging and improved quality of life of older adults. This review also underscores the potential of microbiome-targeted interventions for aging populations, highlighting the need for further research.

The receptor for advanced glycation end products (RAGE) and its ligands are critical drivers of adipose tissue inflammation. While RAGE expression increases in ageing cells and pathological conditions, its specific role in high-fat diet (HFD)-induced adipose tissue senescence remains to be fully elucidated. In this study, we investigated the function of RAGE in the development of adipose tissue senescence associated with obesity. We observed that HFD-fed RAGE-deficient (RAGE

Aging is characterized by cellular senescence, inflammation, and physiological decline. Currently available antiaging therapies often have limitations due to their toxicity and off-target effects. However, natural compounds derived from Chinese herbal medicine, such as Rhapontigenin (Rhap), have shown potential as safer antiaging agents.

BackgroundAging impairs thermogenic and metabolic flexibility, increasing metabolic disease risk. We examined six aging male mouse strains for responses to chronic topical menthol, a pharmacological cold mimetic. Material and methodsMale (C57BL/6J, A/J, BALB/c, C3H/hej, DBA/2J, and FVB/NJ) mice were treated with 4g/kg of 10% menthol weight per volume cream once per day or vehicle as control using finger application for 15 days. After last application, core body temperature measurement, BAT thermography, Nesting behaviour, and metabolic tolerance test were performed, and gene expression was analysed in BAT. ResultsMenthol improved core temperature recovery via thermogenesis and enhanced insulin sensitivity across all strains. However, effects on BAT mass, nesting behaviour, and gluconeogenesis were strain-dependent. ConclusionCollectively, these findings highlight that genetic background modulates metabolic responses to cold mimetics, informing future precision strategies for age-related metabolic disorders.

A fundamental question in biology is whether cellular aging is inevitable. Embryonic stem cells (ESCs) challenge this paradigm as rare normal cells capable of indefinite in vitro passage. However, the mechanisms underlying ESC lineage immortality remain unresolved. Using long-term live-cell imaging to follow fates of single ESCs, we show here that ESC lineage renewal is achieved through sporadic entry into a state characterized by the expression of two-cell embryo-specific markers. During this state, cells undergo asymmetric divisions, segregating accumulated DNA damage into one daughter lineage destined for elimination, while producing a second lineage that reverts to the pluripotent state. Importantly, the latter lineage exhibits signs of rejuvenation, including reduced DNA damage and enhanced chimeric efficiency. These findings underscore the crucial role of asymmetric cell division in maintaining the long-term health of the ESC lineage against mounting damage within individual cells, a potential model for studying cellular aging and rejuvenation in mammalian cells.

Cellular senescence of retinal pigment epithelium (RPE) cells drives age-related visual decline, particularly in the pathology of age-related macular degeneration (AMD). While genome-wide association studies (GWAS) have identified genetic risk factors underlying AMD, the molecular mechanisms governing RPE senescence remain unclear. Here, single-cell RNA sequencing of young and old mouse RPE revealed dysregulated cell-matrix adhesion as a key feature of senescence, consistent with transcriptional changes in AMD patients. Hydrogel-based experiments confirmed that impaired integrin-mediated adhesion induces RPE senescence. Yes-associated protein 1 (YAP), a crucial mechanotransducer, mediated the protective effects of cell-matrix adhesion, and its activation alone reversed aging phenotypes in senescent RPE cells. Notably, treatment with TRULI, a small-molecule YAP activator, significantly improved visual function in AMD and naturally aged mice. These findings highlight the integrin-YAP mechanotransduction pathway as a fundamental regulator of RPE senescence and a potential therapeutic target for AMD.

Quantifying biological aging is essential for understanding functional decline and evaluating anti-aging interventions. We present SkinAGE, a fast and resource-efficient transcriptome-based aging clock built using a deep neural network (DNN) trained on gene expression profiles of human dermal fibroblasts. SkinAGE accurately predicts cellular aging status across independent cohorts and a UVB-induced photoaging model. In 23rd-passage HFF-1 cells, the model assigned an average age score of 44, which increased by 24 units after UVB exposure, indicating enhanced transcriptomic senescence. Treatment with human embryonic stem cell-derived extracellular vesicles (hESC-EVs) reduced this score by an average of 21.2 units, suggesting a potent ameliorative effect on cellular aging. Transcriptomic analysis supported this, showing restoration of aging-related gene expression, including enrichment of cell cycle progression and p53 signaling pathways. Overall, SkinAGE provides a scalable, accurate, and cost-effective framework for quantifying cellular aging and assessing rejuvenation strategies.

Vitamin D is essential for skeletal health, but its role in redox homeostasis and cellular senescence during aging

Caffeine is a globally consumed stimulant that has beneficial effects on biological processes including metabolism and aging, but its causal role in physiology remains incompletely understood. By using the roundworm Caenorhabditis elegans, here we show that caffeine extends lifespan by eliciting transcriptional remodeling that enhances lysosomal lipolysis. We found that transcriptomes of aged, caffeine-fed animals shifted toward youthful states. By comparing with three longevity-promoting regimens, including reduced insulin/insulin-like growth factor 1 (IGF-1) signaling, mild reductions in mitochondrial function, and dietary restriction (DR), we showed that caffeine induced a DR-like transcriptional program. Comparison with eat-2 mutants (a genetic DR model) identified lysosomal lipases lipl-1 and lipl-2 as commonly upregulated genes. The induction of lipl-1 and lipl-2 was required for increased lifespan and reduced neutral lipid accumulation by caffeine intake. Together, these findings indicate that caffeine promotes longevity in a DR-like metabolic reprogramming by enhancing lysosome-driven lipolysis.

Mitochondria play a central role in cellular energy metabolism, survival, and apoptosis, with their dysfunction implicated in numerous diseases, including neurodegenerative and age-related disorders. Modulating mitochondrial function therefore represents a promising therapeutic strategy. In this study, we demonstrate that high-frequency terahertz (THz) irradiation elicits frequency-specific effects on mitochondrial biogenesis. Through MitoTimer and MitoTracker assays, we observed that irradiation at 34.5 THz significantly enhanced mitochondrial biogenesis, an effect not observed at 36.1 THz. Electrophysiological and molecular analyses revealed that 34.5 THz irradiation elevates intracellular calcium flux and activates the calcium-mediated PGC-1α-NRF1/2-TFAM pathway, leading to increased cellular energy production and oxygen consumption. Computational modeling suggested a resonant coupling mechanism in which 34.5 THz irradiation interacts with the bending vibration of the glutamate C-C-C bond at the narrowest region of the calcium ion channel pore, thereby lowering the energy barrier for calcium influx. Our findings reveal a noninvasive, frequency-specific mitochondrial modulation by THz irradiation, which may offer a promising therapeutic avenue for addressing mitochondrial dysfunction.

The aging process is associated with gradual cognitive decline resulting from deficits in synaptic plasticity, the brain's natural ability to adapt and reshape its neural circuitry. This review highlights the importance of synaptic plasticity in cognitive function. It provides a full overview of the molecular, cellular, and systemic mechanisms involved in enhanced or diminished synaptic plasticity in the aging brain. We also go over issues in neurotransmitter systems, calcium signaling, neurotrophic support (ex., BDNF-TrkB), cellular signaling pathways (e.g. mTOR, CaMK, CREB, and MAPK/ERK), and neuroinflammation, oxidative stress, and vascular integrity, all of which redirect the trajectory of synaptic failure associated with cognitive decline in aging. Therapeutic approaches toward increasing or restoring synaptic plasticity are evaluated, including pharmacological (e.g., nootropics, cholinesterase inhibitors, NMDA receptor modulators), natural (e.g., curcumin, resveratrol, bacoside A), and new interventions (e.g., psychoplastogens, gene therapy, nanocarriers, and digital therapeutics). Lifestyle approaches, especially physical exercise, cognitive training, intermittent fasting, and mindfulness approaches to stimulation, have highly potent effects on plasticity enhancements and employ multiple neurobiological mechanisms. Despite much promise, there remain substantial translational challenges, including limited clinical efficacy, lack of personalized biomarkers, and ethical considerations concerning cognitive enhancement. As we look ahead, a multidisciplinary integrative approach that includes molecular therapeutics, lifestyle interventions, and next-generation neurotechnologies will be most useful for protecting cognitive health and enhancing brain resilience in aging individuals. This review highlights the immediate necessity for personalized, ethical, and evidence-based approaches to take advantage of synaptic plasticity for healthy cognitive aging.

Physical activity (PA) is well-established as a key factor in frailty prevention. However, existing evidence relies predominantly on cross-sectional studies, creating a gap in understanding the long-term impact of PA on frailty progression. This study therefore aimed to investigate the longitudinal associations of multiple PA dimensions with both the incidence and trajectory of frailty in middle-aged and older adults in China.

Skeletal muscle fibrosis, as occurs with age, in response to injury, or in the setting of degenerative diseases, results in impairments of muscle regeneration and function. Fibro-adipogenic progenitors (FAPs), a distinct population of muscle-resident mesenchymal progenitor cells that reside in the muscle interstitium, play a crucial role in normal muscle regeneration by supporting muscle stem cell proliferation. However, in pathological conditions such as severe or recurrent muscle injury, FAPs can aberrantly differentiate into fibrogenic cells, resulting in excessive deposition of extracellular matrix and fibrosis. In this study, we explore the molecular regulation of FAP differentiation along the fibrogenic lineage to gain insights into the mechanisms of fibrosis in aged muscle in response to injury. Our findings reveal that aging is associated with an increased expression of the complement component 1q (C1q) in muscle-resident macrophages and elevated expression of the complement proteins C1r and C1s in FAPs. Exposure of proliferating FAPs to C1q results in the activation of the Wnt signaling pathway, elevated expression of collagen genes, and FAP fibrogenic differentiation, leading to increased tissue fibrosis. We demonstrate that either pharmacological inhibition of the complement pathway or genetic ablation of C1s in FAPs in aged mice reduces fibrogenic differentiation of FAPs by suppressing Wnt signaling. This reduction in FAP differentiation attenuates the fibrotic response to injury in aged animals as well as in a mouse model of muscular dystrophy. Our study supports the inhibition of complement signaling as a potential therapeutic strategy for mitigating fibrosis in skeletal muscle injury or degeneration.

Postmenopausal osteoporosis results from excessive osteoclast activity, but the immune circuits that limit osteoclastogenesis in the bone marrow remain poorly understood. Here, we tested a clinically accessible immunotherapy low-dose interleukin-2 (IL-2) as a therapeutic intervention in mice with established ovariectomy-induced bone loss, integrating microcomputed tomography imaging, single-cell transcriptomics, genetic perturbation, and human monocyte-osteoclast assays. Therapeutic administration of IL-2 reversed trabecular bone loss, expanded CXCR3 regulatory T cells in bone marrow, and promoted IL-10- and CGRP-producing ILC2s that were required for protection. IL-2 also acted directly on the osteoclast lineage, suppressing mouse and human osteoclastogenesis through activation of a STAT1-IRF1-dependent IFN program in RANKL-stimulated monocytes. Together, these data define an IL-2-responsive skeletal-immune network that can be therapeutically engaged to suppress osteoclastogenesis, which opens new avenues for cytokine-based immunotherapies in postmenopausal osteoporosis and related bone disorders.

The brain is a highly metabolic organ primarily fueled by glucose, and it is well established that a decline in cerebral glucose metabolism accompanies neurodegenerative disease. Recent work using positron emission tomography (PET) has demonstrated that cerebral glucose metabolism is also reduced in healthy aging which commences as early as 20 years of age, driven almost exclusively by reductions in non-oxidative glucose metabolism, that is, aerobic glycolysis. Given the historical variability and assumptions in PET-based interpretations regarding cerebral glucose metabolism with aging, we aimed to establish whether a drop in global aerobic glycolysis is truly a component of healthy aging in adulthood using direct measures of carbohydrates and oxygen across the human brain via invasive cross-brain blood sampling. We accumulated resting data from 17 studies comprising 239 healthy adults aged 19-45 years and show that aerobic glycolysis remains stable during aging based on a regression analysis of the arteriovenous differences for oxygen, glucose, and lactate, and their resultant ratios (oxygen glucose/carbohydrate indices). The direct cross-brain data presented here indicate that declining brain aerobic glycolysis is not a feature of normal brain aging during early-mid adulthood.

Whether leisure-time physical activity modifies the association between frailty and mortality in older adults is unclear.

Postmenopausal women have an increased risk for age-related conditions like sarcopenia, osteoporosis and type 2 diabetes. Here we examined the effects of low-dose lithium (Li) supplementation, a well-known glycogen synthase kinase 3 (GSK3) inhibitor, on ovariectomized (OVX) mice, focusing on muscle strength and endurance, bone mineral density (BMD) and insulin sensitivity. 28-week-old female sham and OVX C57BL/6J mice were divided into three groups: sham, OVX and OVX-Li, with the latter receiving 50 mg/kg/day of Li in their drinking water for 8 weeks. Li supplementation enhanced isometric specific force and fatigue resistance of the soleus and extensor digitorum longus (EDL) muscles. Potential cellular mechanisms underlying these benefits include enhanced Ca

Lifelong oligodendrogenesis and myelination is critical for healthy brain aging. Using cumulative labelling with thymidine analogue, 5-ethynyl-2'-deoxyuridine (EdU) for 6-weeks commencing at 2-, 12- and 18-months of age in C57BL/6 mice, we found that oligodendrocyte progenitor cell (OPC) proliferation and oligodendroglial densities are relatively stable in the adult mouse optic nerve, corpus callosum and somatosensory cortex. We also found that more proliferative adult OPCs differentiate into oligodendrocytes in the somatosensory cortex than the corpus callosum during aging. To determine the role of neuronal TrkB in adult oligodendrogenesis in the older brain, we generated Thy1-CreER

Changes in cell state are often accompanied by altered metabolic demands, and homeostasis depends on cells adapting to their changing needs. One major cell state change is senescence, which is associated with dramatic changes in cell metabolism, including increases in lipid metabolism, but how cells accommodate such alterations is poorly understood. Here we show that the transcription factor p53 increases recycling of the lipid headgroups required to meet the increased demand for membrane phospholipids during senescence. p53 activation increases the supply of phosphoethanolamine, an intermediate in the Kennedy pathway for de novo synthesis of phosphatidylethanolamine, in part by increasing lipid turnover and transactivating genes involved in autophagy and lysosomal catabolism that enable membrane turnover. Disruption of phosphoethanolamine conversion to phosphatidylethanolamine is well tolerated in the absence of p53 but results in dramatic organelle remodelling and perturbs growth and gene expression following p53 activation. Consistently, CRISPR-Cas9-based genetic screens reveal that p53-activated cells preferentially depend on genes involved in lipid metabolism and lysosomal function. Together, these results reveal lipid headgroup recycling to be a homeostatic function of p53 that confers a cell-state-specific metabolic vulnerability.

Cellular senescence has a dual role in both tumor suppression and the promotion of age-related diseases. This paradox suggests the existence of functionally distinct "beneficial" and "detrimental" senescent states, yet the molecular basis that governs their fate has remained elusive. Here, we reveal that the dynamic exchange of histone H2AX on chromatin functions as an essential quality control mechanism that dictates the quality of senescence. We demonstrate that the histone acetyltransferase TIP60, in complex with the chaperone FACT, acetylates H2AX at lysine 5 (K5), which in turn drives its dynamic exchange. This histone exchange is indispensable for promoting the degradation of the DNA damage response mediator MDC1, a process we uncover is mediated by a novel DNA-PKcs-p97 signaling axis. Disruption of this TIP60-FACT-H2AX exchange pathway leads to the hyperaccumulation of MDC1 and a shift toward error-prone nonhomologous end joining (NHEJ), inducing a pathological senescent state with oncogenic potential. Our study redefines histone exchange from a passive chromatin event to an active regulatory hub that determines the fate of aging cells. These findings provide a molecular basis for the heterogeneity of senescence and establish a rationale for developing "senomorphic" therapies aimed at improving the quality of aging.

Aging is intricately linked to neurodegenerative diseases and cognitive decline, with the prefrontal cortex (PFC) playing a critical role in higher cognitive functions such as decision-making and memory. Despite advances in transcriptomic profiling, our understanding of cell type-specific and spatial regulatory mechanisms in brain aging remains incomplete. This study integrates single-cell RNA sequencing (scRNA-seq), single-cell ATAC sequencing (scATAC-seq), and spatial transcriptomics to uncover molecular and cellular alterations associated with PFC aging. We analyzed data from 51 healthy human PFC samples, categorized into young, middle-aged, and elderly groups. Differential gene expression (DEG) analysis identified 3932 aging-related DEGs, among which excitatory neurons exhibited the most significant molecular alterations. This study suggests that EGR1 may serve as a potential key regulator of synaptic plasticity during aging; our findings indicate that reduced chromatin accessibility in the excitatory neurons of elderly individuals may subsequently lead to the downregulation of EGR1. Spatial transcriptomics revealed enriched EGR1 expression in specific cortical layers and its progressive decline with age. Furthermore, EGR1 targets-including YWHAZ, CTNNB1, and CDC42-were implicated in synaptic plasticity pathways such as the Wnt and Hippo signaling pathways. These findings suggest that EGR1 dysfunction may contribute to synaptic deficits and cognitive impairment during aging. This study provides a comprehensive view of cell-type-specific and spatial molecular mechanisms underlying PFC aging, highlighting EGR1 as a potential biomarker and therapeutic target for age-related cognitive decline. Our integrative approach advances the understanding of brain aging and lays the groundwork for anti-aging interventions.

Understanding the direct connections between metabolism and chromatin dynamics may uncover potential mechanisms involved in the aging process of renal physiology. Despite known differences in incidence and aging renal disease, how biological aging intersects with renal metabolism and epigenetics in a sex-specific context remains poorly understood. Here, we determined the effect of age on renal metabolic pathways and metabolite cofactors of epigenetic modifiers in a sex-specific manner. We measured metabolites in kidney homogenates from young and aged mice by HPLC-TripleTOF (LC-MS). The major metabolic adaptations observed with aging include increased glycolysis, decreased fatty acid oxidation, mitochondrial dysfunction, oxidative stress, and impaired metabolic waste clearance in 24-month-old (aged) mice compared to 4-month-old (young) sex-matched mice. Additionally, we found elevated levels of methylation and acetylation of intermediate metabolites also known as 'epimetabolites' in aged mice. Furthermore, age-related alterations were detected in metabolites (acetyl-coenzyme A, flavin adenine dinucleotide, and α-ketoglutarate) that are essential cofactors for the activities of epigenetic enzymes. Sex-specific changes were observed with age such as, significantly enhanced amino acid catabolism and tryptophan metabolism and reduced lysophospholipase activity and ammonia clearance in aged female vs aged male mice. Our results reveal age- and sex-associated alterations in renal metabolic pathways, characterized by an increase in epigenetically modified intermediate metabolites with aging. These findings suggest a complex interplay between renal metabolomics and epigenetics and offer new insights into the mechanisms underlying sex-specific renal physiology of aging kidneys.

Aging has traditionally been studied through the lens of protein-coding genes, with a strong bias toward data derived from male organisms. As a result, the role of non-coding elements and potential sex-specific differences remains largely unexplored. Transposable elements (TEs), mobile sequences capable of altering genome structure and regulating gene expression, have recently gained attention for their roles in development and aging. However, despite this growing interest, key aspects of TE expression dynamics are still poorly characterized, particularly in female tissues. To address this gap, we analyzed TE expression in RNA-Seq liver tissue from male (8, 26, 60, 78, and 104 weeks) and female (3, 24, 48, and 72 weeks) mice. Our results reveal distinct TE expression trends between sexes. While previous studies report increased TE expression with aging, we identified a subset of TEs with decreasing expression over time, differing between males and females. We also observed inverse expression trends between a few TEs and their nearby genes, supporting a potential regulatory relationship. We identified TEs with changing expression (CE TEs) through age associated with nearby genes showing strong expression correlations (|ρ|≥ 0.6). In males, correlated genes such as Txnrd2, Mthfd1, and Dkk3 are involved in redox regulation, one-carbon metabolism, and Wnt signaling, respectively, while in females, Thrb and Cd55 are linked to metabolic regulation and immune protection. These associations suggest that TE activity may be functionally coupled to transcriptional programs relevant to liver physiology and aging. These findings highlight the importance of examining TE expression in both sexes and suggest their potential regulatory roles in age-related liver physiology.

AbstractUnderstanding how a stable structural connectome supports flexible cognition, especially in aging, is a fundamental question in neuroscience. While static structure-function coupling (SFC) is well-studied, the dynamic decoupling of functional activity from structural constraints--dynamic SFC (DSFC)--remains poorly understood. Leveraging MRI data from 34,067 UK Biobank participants (ages 45-82), we characterized the distinct roles of SFC and DSFC in aging, cognition, and health. We found that SFC and DSFC followed spatially divergent aging trajectories: SFC declined primarily in sensorimotor systems, whereas DSFC decreased most prominently in higher-order networks. Both SFC and DSFC in higher-order networks were positively correlated with cognitive performance (e.g., fluid intelligence). However, the associations with mental and physical health diverged between the two measures: reduced DSFC was predominantly linked to health burdens in high-order default/limbic networks, whereas weakened SFC was primarily associated with health burdens in low-order sensory-motor networks. Genetic analyses revealed that Alzheimers risk, specifically APOE {varepsilon}4 dosage, significantly reduced DSFC in higher-order cognitive networks and SFC in visual cortex. Mediation analyses further demonstrated that aging and APOE {varepsilon}4-linked cognitive decline were mediated via visual SFC and ventral attention DSFC. These findings position static and dynamic coupling as complementary mechanisms: static SFC preserves network robustness, while dynamic SFC enables transient reconfiguration for complex integration. Together, our results highlight these dual mechanisms as crucial for maintaining cognitive flexibility, providing potential biomarkers for age-related neurodegeneration.

Aging frequently correlates with the progressive decline in skeletal muscle mass and function, a condition termed sarcopenia. Epigenetic modifications, including DNA methylation, histone alterations, and microRNA regulation, critically influence gene expression changes throughout aging. This review elucidates molecular mechanisms underlying epigenetic alterations in aging skeletal muscle and their functional consequences. We elucidate how shifts in DNA methylation, histone modifications, and microRNA profiles contribute to muscle atrophy and dysfunction. Furthermore, we examine emerging therapeutic strategies targeting epigenetic pathways to mitigate age-related muscle deterioration. A deeper understanding of these epigenetic processes could facilitate the development of interventions to promote healthier aging and improve muscle function in older adults. A comprehensive understanding of these processes will guide therapeutic strategies aimed at improving elderly muscle health.

Frailty is an age-associated condition characterized by a state of vulnerability that compromises the quality of life and independence of older adults. To date, no studies have employed Mendelian randomization (MR) to investigate the causal relationship between obesity and frailty risk. Therefore, this study utilized a two-sample MR approach to elucidate the potential causal link between obesity and frailty. A two-sample MR analysis was conducted to assess the causal relationship between body mass index (BMI) or waist circumference and frailty. Independent genetic variants associated with obesity and frailty were selected as instrumental variables (IVs). MR analyses were primarily performed using inverse variance weighting, MR-Egger, weighted median, simple, and weighted models. In addition, the Mendelian Randomization Pleiotropy RESidual Sum and Outlier framework was applied to assess horizontal pleiotropy and to identify potential outlier variants. Through a rigorous and meticulous screening process, we identified 68 and 41 single nucleotide polymorphisms as IVs for BMI and waist circumference, respectively. Our analyses uncovered a significant positive causal association with frailty for both BMI (β = 0.1283, SE = 0.0255, P = 5.2589e-07) and waist circumference (β = 0.1340, SE = 0.0357, P = .0001). Cochran Q-test indicated the presence of heterogeneity among the IV estimates attributable to individual variant effects in both analyses (Q = 153.8575, P < 8.753493e-09; Q = 111.1552, P < 7.432416e-09). Besides, no significant pleiotropy was detected for the association of BMI, waist circumference and with frailty (intercept = 0.002609868, P = .2054007; intercept = 0.003445858; P = .7968586). The Mendelian Randomization Pleiotropy RESidual Sum and Outlier analysis identified no outliers for either exposure, and thus no single nucleotide polymorphisms were excluded. This study substantiates the significant association between obesity and an elevated risk of frailty, thereby offering a robust theoretical foundation for policymakers to institute more stringent weight management strategies.

Chromatin undergoes dramatic changes during the ageing process. In the brain, these chromatin changes are thought to underlie age-associated deficits in the activity-dependent gene transcription necessary for memory consolidation. Here, we show that the levels of a specific histone post-translational modification (PTM), trimethylation of lysine 4 on histone 3 (H3K4me3) is markedly increased in the hippocampus of aged mice and that the activity-induced increase in H3K4me3 that is observed in response to a learning stimulus in young mice, is severely blunted in the aged hippocampus. H3K4me3 typically marks open, accessible chromatin at the transcriptional start sites (TSSs) of actively transcribed genes. We identify altered H3K4me3 peaks at TSSs and show that ca. 90% of the activity-induced H3K4me3 changes at TSSs are either absent or reduced in the aged hippocampus. To understand the biological significance of these age-associated changes, we screened a library of pharmacological compounds for compounds that can alter H3K4me3 levels in hippocampal neurons. We show that treatment of aged mice with one of these, the LSD1 inhibitor ORY-1001, restored normal learning and memory in object location and recognition tasks. Furthermore, we show that ORY-1001 treatment increased long-term potentiation (LTP), a form of synaptic plasticity deficient in the aged hippocampus. These findings suggest that targeting the epigenetic machinery that regulates activity-dependent gene transcription may represent an avenue for treating age-associated cognitive impairment.

Ferroptosis, iron-dependent regulated cell death, drives age-related cardiac dysfunction. This review examines aerobic exercise modulation of ferroptosis in aging cardiomyocytes via Parkin-ACSL4 axis. Parkin promotes ACSL4 ubiquitination/degradation, reducing lipid peroxidation and ROS. Exercise activates PINK1/Parkin mitophagy and hepcidin, enhancing mitochondrial resilience and iron homeostasis. Despite promising preclinical evidence, molecular mechanisms remain unclear. Aerobic exercise offers non-pharmacological cardiac protection against ferroptosis in aging.

A hallmark of aging is loss of information in gene regulatory networks. These networks are tightly connected, raising the question of whether information could be restored by perturbing single genes. We develop a simple theoretical framework for information transmission in gene regulatory networks that describes the information gained or lost when a gene is "knocked in" (exogenously expressed). Applying the framework to gene expression data from muscle cells in young and old mice, we find that single knock-ins can restore network information by up to 10%. Our work advances the study of information flow in networks and identifies potential gene targets for rejuvenation.

Aging is a dysbiotic and pro-inflammatory process that increases susceptibility to multiple chronic comorbidities. Centenarians and supercentenarians offer a unique biological model for elucidating the molecular determinants of healthy aging and exceptional longevity, as they display distinctive epigenetic signatures and a gut microbiome configuration that diverges from both younger and typically aging individuals, although substantial interindividual variability exists. The gut microbiota constitutes a strategic hub of microorganisms and bioactive metabolites with probiotic and postbiotic potential that modulate host epigenetic circuits through precursors and substrates for epigenetic "writer" and "eraser" enzymes, thereby shaping the aging trajectory. In this review, we examine the interactions between the microbiota and its metabolites, including short-chain fatty acids, lipopolysaccharides, trimethylamine N-oxide (TMAO), p-cresol, and secondary bile acids, and their roles in epigenetic modulation associated with healthy aging. We highlight (i) the attenuation of classical pro-inflammatory pathways through downregulation of NF-κB/COX-2, modulation of the Th17/Treg balance, and also the lower systemic LPS levels of centenarians, which are associated with enhanced SIRT1 activity (↑LPS/↓SIRT1); (ii) the reprogramming of energy metabolism via activation of SIRT1/AMPK and SIRT1/p-53, modulation of mTOR, and attenuation of the IGF-1/insulin axis; (iii) the strengthening of the intestinal barrier through upregulation of tight junction proteins such as ZO-1, occludin, and claudins, resulting in reduced permeability and zonulin levels; and (iv) the optimization of antioxidant defenses. Collectively, these findings suggest translational potential for microbiota-derived metabolites in gerobiotic strategies, although clinical evidence remains limited.

Gastrodia elata (GE) is a precious Traditional Chinese Medicine (TCM) with an extensive history of medicinal and dietary use in China. GE is renowned for its abilities to calm internal wind to relieve convulsions, pacify liver yang, expel wind to unblock collaterals, and promote longevity. It remains widely used as a dietary supplement for anti-aging purposes. Modern pharmacological studies have demonstrated that GE possesses significant anti-inflammatory, antioxidant, anti-aging, anticonvulsant, sedative, and neuroprotective properties.

Cardio-kidney-metabolic (CKM) syndrome is a complex, multi-system health condition that affects aging populations, potentially contributing to frailty. This study aimed to examine the association between baseline CKM syndrome, its transitions over time, and the onset of frailty, using data from the China Health and Retirement Longitudinal Study (CHARLS).

Aging is associated with a progressive decline in both cognitive and physical function, and neuroinflammation and metabolic dysregulation often exacerbate this decline, particularly in older women. This study investigated the effects of a 12-week intermittent combined exercise program on cognitive function, physical performance, and neurophysiological biomarkers in community-dwelling women aged 75 years and older. Forty participants were recruited from a local welfare center and randomly assigned to an exercise group (n=20) or a control group (n=20). The exercise group participated in three supervised sessions per week that integrated aerobic exercise, resistance exercise, functional exercise, and cognitive exercise. Cognitive domains (attention, language, and memory) were assessed using the Seoul Neuropsychological Screening Test-II. Physical function was assessed using the Geriatric Physical Fitness Test (chair stand, arm flexion, grip strength, and 6-min walk). Blood samples were analyzed to measure serum brain-derived neurotrophic factor (BDNF), interleukin (IL-6), tumor necrosis factor (TNF)-α, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). Paired and independent

Metformin alleviates oxidized low-density lipoprotein (ox-LDL)-induced macrophage senescence, a key process in atherosclerosis. Our in vitro findings demonstrate that metformin suppresses ox-LDL-induced overexpression of the nuclear receptor NR4A1 in macrophages. This inhibition subsequently reduces excessive mitophagy, improves mitochondrial membrane potential and decreases reactive oxygen species (ROS) production. The amelioration of this mitochondrial dysfunction directly attenuated cellular senescence markers and reduced the secretion of inflammatory cytokines. Furthermore, we identified Caveolin-1 as a critical regulator of metformin's protective effects. Overexpression of Caveolin-1 was shown to reverse metformin-mediated improvements in mitochondrial function. These results establish that metformin mitigates macrophage senescence by targeting the NR4A1-mitophagy pathway, with Caveolin-1 serving as an essential modulator. This NR4A1-mitophagy axis represents a promising therapeutic target, positioning metformin as a potential candidate for slowing atherosclerosis progression by preserving mitochondrial health in macrophages.

Alveolar epithelial cell (AEC) senescence is a crucial driver of pulmonary fibrosis (PF). Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid through the cytochrome P450 cyclooxygenase (CYP) pathway. We have reported that EETs inhibit AEC senescence, alleviating bleomycin (BLM)-induced PF in mice. However, EETs have a short half-life in vivo and are rapidly degraded to low-active end-product diols by soluble epoxide hydrolase (sEH). We observed a significant increase in sEH expression in senescent AECs, but the underlying mechanism remains unclear. In this study, we found that inhibition of sEH significantly attenuated senescence in AECs and lung senescence in premature aging mice. Mechanistically, bioinformatics results showed that the spleen focus forming virus proviral integration oncogene (Spi1) might be a key transcription factor upstream of sEH in AECs. ChIP assay showed that Spi1 could bind to the sEH promoter. Knockout of Spi1 in AECs mediated by lentivirus significantly reduced BLM-induced sEH expression and AEC senescence, while overexpression of Spi1 had the opposite effect. Furthermore, specific silencing of Spi1 in AECs significantly inhibited BLM-induced PF in mice. Taken together, these findings provide new ideas for the treatment of PF by targeting Spi1 to improve AEC senescence. KEY MESSAGES: Spi1 is a key transcription factor upstream of sEH in AECs. Inhibition of Spi1 significantly attenuated AEC senescence. Inhibition of Spi1 alleviated pulmonary fibrosis in aging mice.

Frailty is a common geriatric syndrome that compromises quality of life and worsens health outcomes. The aim was to examine the effect of physical activity on frailty and to explore the potential mediating role of cognitive function. We used data from 11,751 adults aged ≥ 45 years from the 2018 China Health and Retirement Longitudinal Study (CHARLS). Frailty was measured using a Frailty Index, cognitive function with the MMSE, and physical activity categorized by total MET scores. Logistic regression assessed independent and joint associations. Restricted cubic spline analyses based on MMSE scores were conducted to explore nonlinear relationships and identify a cognition threshold (13 points). Mediation analysis with bootstrapping evaluated the mediating role of cognition, with subgroup analyses by sex, education, and residence. A total of 11,751 participants (mean age 60.46 ± 9.02 years) were included in the analysis, of whom 8.1% were classified as frail. Participants with frailty were older, had lower cognitive scores, shorter sleep duration, lower educational attainment, and were less physically active. Higher levels of physical activity were associated with a lower risk of frailty (OR = 0.30, 95% CI: 0.26-0.36), and each one-point increase in cognitive score was also linked to reduced frailty risk (OR = 0.89, 95% CI: 0.87-0.90). A nonlinear association was identified between cognitive function and frailty, with an inflection point at approximately 13 points on the MMSE-derived cognitive score, below which the risk of frailty increased more sharply. Mediation analysis showed that cognitive function partially mediated the association between physical activity and frailty, with a total effect of - 0.14 (95% CI: -0.16 to - 0.12), a direct effect of - 0.13 (95% CI: -0.15 to - 0.11), and an indirect effect of - 0.01 (95% CI: -0.02 to - 0.01), accounting for 8.37% of the overall association. Cognitive function partially explains how physical activity reduces frailty risk. This mediating pathway differs across population groups. Interventions promoting both physical and cognitive health may help delay frailty and support healthy aging.

Intervertebral disc degeneration (IDD) is the main cause of low back pain and is related to the aging of nucleus pulposus (NP) cells (NPCs). However, the underlying mechanism for senescence of NPCs has not been well understood. NPCs (control-NPCs and IDD-NPCs) were separated from the NP tissues of patients, diagnosed with graded I and IV IDD. The proliferation and senescence levels were detected by MTT assay and senescence-associated β-galactosidase staining, respectively. The expression of cyclin B1 and caveolin-1 was evaluated by Western blot analysis. RNA-sequencing technology was used to screen differentially expressed genes (DEGs) in IDD-NPCs. Finally, through the interference and overexpression of MYB proto-oncogene-like 2 (MYBL2), the effect of MYBL2 on cell senescence was explored. Compared with control-NPCs, the proliferation ability of IDD-NPCs was significantly reduced and the senescence level was obviously increased. 1,061 DEGs were screened in IDD-NPCs. By analyzing DEGs related to aging and aging-related pathways and terms, cell cycle arrest was identified. Knockdown of MYBL2 promoted the senescence of control-NPCs, and overexpression of MYBL2 inhibited the senescence of IDD-NPCs. The study found that upregulation of MYBL2 ameliorated the senescence of IDD-NPCs, providing a potential way to inhibit the senescence of NPCs.

Reprogramming of somatic cells into induced pluripotent stem cells through the introduction of transcription factors Oct3/4, Sox2, Klf4, and c-Myc (OSKM) represents a landmark advance in regenerative biology. Building on this foundation, partial reprogramming can help reset epigenetic age. It further opens opportunities to treat degenerative diseases without the tumorigenic risks associated with full pluripotency. The review advances the field in three ways: it links lineage-preserving partial reprogramming to quantifiable rejuvenation endpoints; defines mesenchymal drift as an age- and disease-associated trajectory amenable to reversal; and maps strategies beyond OSKM, including small-molecule programs and CRISPR-based control circuits. Convergent phenotypes are surveyed in nervous, metabolic, musculoskeletal, and craniofacial systems, with emphasis on improved tissue repair and regeneration. A translational checklist is proposed that emphasizes schedule, delivery, and safety pharmacology to guide rigorous preclinical studies and de-risk early clinical entry points for partial reprogramming therapies.

Brain health is closely linked to bone homeostasis. Skeletal aging is characterized by inadequate bone formation and marrow adiposity, but whether the brain contributes to this imbalance remains unknown. This study shows that aged brain neurons, mainly those in the hippocampus and cerebral cortex, produce excess WD repeat and FYVE domain containing 1 (WDFY1) protein and transfer it to the bone via extracellular vesicles (EVs), leading to bone-fat imbalance and osteoporosis. Increasing brain Wdfy1 expression causes premature skeletal aging. Conversely, suppressing Wdfy1 in the whole brain, hippocampus or neurons, genetically deleting neuronal Wdfy1, and selectively inhibiting neuronal EV release all improve bone health. Mechanistically, WDFY1 binds to the retromer complex to promote the endosome-to-Golgi recycling of cathepsin D and peroxiredoxin 2, thus inhibiting osteogenesis and augmenting adipogenesis. This study identifies the role of aged brain neuronal EVs as an important messenger in triggering bone-fat imbalance by transferring WDFY1 to bone.

Aging significantly increases the risk of cardiovascular disease, characterized by progressive cardiac dysfunction. The vascular niche is crucial for maintaining cardiac homeostasis, yet endothelial cell (EC) impairment during aging remains poorly understood. This study investigates epigenetically regulated mechanisms underlying EC-dependent cardiac aging and identifies a critical role for zinc finger and BTB domain-containing protein 16 (ZBTB16).

Clonal haematopoiesis of indeterminate potential (CHIP) is an ageing-related condition associated with a substantial fraction of circulating leukocytes having descended from a single somatically mutated haematopoietic stem cell (HSC). CHIP increases the risk of haematological malignancies and several chronic diseases (for example, cardiovascular pathologies) and contributes to persistent, low-grade inflammation or inflammageing. Inflammageing, in turn, promotes functional impairment of normal HSCs, including reduced self-renewal potential. By contrast, CHIP-mutant HSCs not only are resistant to inflammageing-induced functional decline but also gain a selective expansion advantage in an inflammatory environment. A recent surge of discoveries has increased our understanding of the CHIP-inflammageing interplay, from a mechanistic and clinical perspective, highlighting its broader relevance to age-related diseases. In this Review, we discuss the molecular and cellular mechanisms that cause CHIP, its interplay with inflammageing, as well as the pathophysiological consequences and the translational implications for diseases that affect older individuals.

Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are marked by progressive neuronal loss and aberrant protein aggregation, presenting substantial global healthcare challenges. Recent research has illuminated the pivotal roles of RNA-binding proteins (RBPs) and non-coding RNAs (ncRNAs), notably microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in the molecular pathogenesis of age-related neurodegeneration. RBPs orchestrate RNA metabolism and engage extensively with miRNAs and lncRNAs to modulate gene expression at the post-transcriptional level. Dysregulation of these interactions precipitates pathological phenomena such as protein misfolding, stress granule formation, and disrupted RNA processing, thereby exacerbating neuronal dysfunction and death. Specific miRNAs have been implicated in regulating key neurodegenerative biomarkers, including tau and amyloid-β in AD, motor neuron maintenance in ALS, and survival pathways in HD. Elucidating the intricate interplay between RBPs and ncRNAs holds significant promise for the development of therapeutic strategies aimed at ameliorating RNA-mediated mechanisms in neurodegenerative disorders.

Mitochondria-targeted antioxidants can selectively accumulate within mitochondria at low doses, thereby significantly enhancing therapeutic efficiency while minimising potential side effects. SKQ1, a novel mitochondria-targeted antioxidant, operates through a well-defined mechanism: a lipophilic cation enables mitochondrial targeting, while plastoquinone exerts antioxidant activity. SKQ1 primarily exerts its potent antioxidative effects by directly neutralising reactive oxygen species (ROS), thereby protecting mitochondrial function. Numerous studies have explored the biological functions of SKQ1, identifying its significant potential in anti-ageing, immune regulation, and antimicrobial activity. In this review, we summarise all available therapeutic evidence of SKQ1. We propose that SKQ1 represents a promising candidate for treating mitochondrial dysfunction-related diseases; however, its safety profile warrants further investigation.

The expression and/or activity of sirtuins (SIRTs), nicotinamide adenine dinucleotide (NAD

Human adipose-derived stem cells (hADSCs) are pivotal for tissue regeneration and wound healing, and their directed migration is a prerequisite for exerting these therapeutic effects. Electric fields (EFs) are well-recognized as key cues guiding cell migration during wound repair, yet the electrotactic behavior of hADSCs -- especially how donor characteristics (e.g., age) regulate this behavior and its underlying molecular mechanisms -- remains poorly understood. This knowledge gap limits the optimized application of hADSCs in regenerative medicine. In this study, we first validated the existence of electrotaxis in hADSCs and confirmed its voltage dependence: under direct current electric fields (DCEFs) of 100-200 mV/mm, hADSCs migrated directionally toward the anode, with stronger EF intensities enhancing both migration directionality and speed (versus at 0 mV/mm control). We then compared hADSCs from young female donors (27.00 ± 4.58 years) and elderly female donors (62.33 ± 4.04 years) using RNA sequencing (RNA-seq) after 200 mV/mm DCEF stimulation. Transcriptomic analysis identified 747 upregulated and 624 downregulated genes in elderly hADSCs, with differentially expressed genes (DEGs) enriched in biological processes/pathways critical for electrotaxis -- including sodium ion transmembrane transport, voltage-gated sodium channel activity (GO terms), and the PI3K-Akt signaling pathway (KEGG pathway). Functionally, elderly hADSCs exhibited significantly reduced anodal migration (decreased accumulated distance, Euclidean distance, and directness) compared to young hADSCs under DCEF stimulation. This study provides the first evidence of age-dependent electrotaxis in hADSCs, demonstrating that donor age correlates with impaired electrotactic capacity. It further reveals that dysregulated sodium channel activity and PI3K-Akt signaling may underlie this age-related decline. These findings point to the potential regulatory mechanisms of hADSC electrotaxis and offer new insights for tailoring hADSC-based therapies (e.g., selecting optimal donors or targeting sodium/PI3K-Akt pathways) to improve tissue regeneration and wound healing outcomes.

Arterial stiffness is a cardinal marker of vascular aging, representing the cumulative impact of mechanical and biological stressors on the vessel wall resulting from aging and various cardiovascular risk factors, which lead to alterations in the material properties and wall mechanics of both central and peripheral arteries. Arterial stiffness has been identified as an independent predictor of cardiovascular morbidity and mortality. Based on whether the stiffness assessment is performed at a specific anatomical location or across a segment of the arterial tree, arterial stiffness measurements are broadly categorized as local and regional assessments. Local measurement involves quantifying arterial wall properties, including compliance, distensibility, or elastic modulus, while regional assessment is based on measuring the velocity of pulse wave propagation along an arterial segment. Here, we present a validated, image-free, ultrasound-based approach capable of simultaneously assessing both local and regional arterial stiffness in humans. The technique involves insonating the common carotid artery using a single-element piezoelectric ultrasound probe and real-time tracking of echoes originating from the arterial walls to capture the carotid artery distension waveform. Local measures of arterial stiffness are derived from distension data and carotid blood pressure. An oscillometric cuff applied to the thigh is used to simultaneously acquire the femoral pulse waveform and compute carotid-femoral pulse wave velocity by determining pulse travel times to the carotid and femoral sites, along with surface-measured arterial path lengths.

The gradual decline in estrogen levels during perimenopause is strongly associated with an increased risk of metabolic and cardiovascular diseases. However, the specific relationship and underlying mechanisms remain incompletely understood. This study combines population data, network pharmacology, and mouse models to explore the detailed mechanisms underlying estrogen's organ-protective effects.

Semantic cognition (use of acquired world knowledge to guide behavior) is critical in everyday life. Semantic cognition is often assumed to be preserved in later life, compensating for functional declines in other cognitive domains. However, aging research rarely considers age-related effects on nonverbal knowledge or on semantic control processes that regulate how knowledge is activated and used. We addressed this by conducting the most detailed assessment of semantic cognition across the adult lifespan to date, involving 537 adults aged between 20 and 91. Verbal semantic knowledge increased linearly across adulthood while nonverbal knowledge reached a plateau at age 50. In contrast, controlled semantic processing showed age-related decline, particularly in the ability to inhibit task-irrelevant semantic knowledge. These results indicate that semantic cognition is not uniformly preserved in old age: Though older people know more than young people, they are less able to use their knowledge flexibly in novel situations. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

HIV persists in long-lived CD4 T cell reservoirs despite antiretroviral therapy (ART)1. Elite controllers suppress viraemia without ART2, yet reservoir reactivation emerges with immune ageing3. Here we show that transient reprogramming of patient-derived CD4 T cells restores their ability to eliminate HIV-infected reservoirs, excising integrated proviral DNA. A defined compound, or physiological induction, drove rapid reprogramming ex vivo, enabling clearance of HIV DNA within hours to days of treatment, independently of ART. Single-cell RNA sequencing revealed activation of an antiviral telomere transfer programme4 that exceeds elite-like control. In humanised mice, adoptive transfer of reprogrammed patient CD4 T cells, or in vivo reprogramming of murine T cells, eliminated HIV DNA across reservoirs, with undetectable viral genomes persisting for months. Modelling predicted that residual proviral reactivation would be governed by rare stochastic events, rendering viral rebound unlikely within a human lifespan. These findings identify a previously unrecognised form of intracellular immunity and establish a defined route to a functional HIV cure arising from the CD4 T cell itself.

Aging impairs tissue function and tolerance to cellular stress by reprogramming the behavior of resident cells. With global increases in lifespan, the prevalence of chronic and degenerative musculoskeletal disorders, including tendon degeneration, continues to rise; however, effective interventions to counteract age-related decline remain limited. Here, we investigate how a central age-associated stressor, inflammation, differentially modulates tendon cell behavior derived from young and mature-aged donors. Using super-resolution microscopy to resolve nanoscale chromatin organization in conjunction with epigenomic and transcriptomic profiling, we identify age-dependent regulatory mechanisms that govern inflammatory responsiveness. Mature-aged tendon cells exhibit exaggerated pro-inflammatory and catabolic responses across chromatin, gene expression, and protein signaling levels, characterized by enhanced TNF receptor organization, elevated accessibility at pro-inflammatory regulatory elements, and robust induction of matrix-degrading enzymes. Notably, the AP-1 transcription factor family emerges as a central age-dependent regulator, displaying distinct motif accessibility patterns that bias mature tenocytes toward inflammatory and degenerative transcriptional programs. Taken together, our findings demonstrate that age-dependent epigenetic priming amplifies inflammatory sensitivity and constrains reparative gene regulation in mature tendon cells. This work provides a mechanistic framework linking chromatin remodeling to tendon degeneration and holds potential to identify epigenetic and transcriptional pathways as potential targets for rejuvenation strategies in aging musculoskeletal tissues.

Inference of gene regulatory networks (GRNs) can reveal cell state transitions from single-cell genomics data. However, obstacles to temporal inference from snapshot data are difficult to overcome. Single-nuclei multiomic data offer a means to bridge this gap and derive temporal information using joint measurements of gene expression and chromatin accessibility in the same single cells. We developed popInfer to infer networks that characterize lineage-specific dynamic cell state transitions from joint gene expression and chromatin accessibility data. Benchmarking against alternative methods for GRN inference, we showed that popInfer achieves higher accuracy in the GRNs inferred. popInfer was applied to study single-cell multiomics data characterizing hematopoietic stem cells (HSCs) and the transition from HSC to a multipotent progenitor cell state during murine hematopoiesis across age and dietary conditions. From the networks predicted by popInfer, we discovered gene interactions controlling entry to/exit from HSC quiescence that are perturbed in response to diet or aging.

Currently, aging issues are becoming more prominent, and the aging population is expanding. The reliance on medical or pharmaceutical means of combating aging and disease raises concerns about the long-term safety and economic impact. Therefore, sustainable and friendly strategies need to be explored urgently. Phenolic-rich antioxidant dietary regimens and exercise integrated into daily habits contain great anti-aging potential. Research on natural laws for anti-aging based on phenolics and exercise is in full swing.