Longevity Papers

Recent studies report that epithelial differentiated cells can undergo a reverse process called dedifferentiation in response to stem cell loss. However, the extent of this reversion and the plasticity of young versus aged-differentiated cells remain unclear. Here we show that dedifferentiated corneal epithelial cells acquire a transcriptomic state closely resembling native stem cells, sustain tissue homeostasis across lifespan and efficiently repair repeated tissue injury. Transplantation of stage-specific genetically traceable aged differentiated epithelial cells onto a denuded niche reveals reversion into a stemness-like state, restoring both quiescent and active stem cell compartments. This plasticity operates within the epithelial lineage, allowing transitions along the differentiation axis, but remains restricted across lineages, as transplanted conjunctival cells fail to regenerate the corneal stem cell pool. Mechanistically, we identify niche-derived cytokines that trigger reprogramming in vivo and enhance stemness in primary human corneal epithelial cells, revealing a conserved and therapeutically exploitable pathway for epithelial regeneration.

Gain-of-function screening in Drosophila melanogaster provides a powerful approach for identifying genes that modulate lifespan; however, induction strength and environmental stress can substantially influence phenotypic outcomes. Here, we performed a pilot Gene Search (GS)-based overexpression screen using a heat-inducible hs-GAL4 driver and compared lifespan analyses at 25 °C and 30 °C to evaluate the impact of induction conditions on the detectability of lifespan-modulating genes. Induction at 30 °C caused uniformly shortened lifespans across genotypes and did not reveal robust lifespan-extending candidates. In contrast, screening at 25 °C, where moderate hs-GAL4 induction produces robust and detectable transgene expression, revealed multiple longevity-promoting lines. Lifespan measurements at the two temperatures were poorly correlated, indicating that elevated temperature imposes a dominant physiological burden that masks gene-specific effects. Using this strategy, we characterized a candidate line overexpressing Drosophila Ankyrin repeat and MYND domain-containing protein 2 (dAnkmy2). Overexpression of dAnkmy2 significantly extended adult lifespan and enhanced resistance to oxidative stress without detectable changes in canonical antioxidant gene expression. In contrast, loss of dAnkmy2 caused larval lethality, indicating an essential developmental function. Given the conserved role of Ankmy2 in ciliary biology, our results raise the possibility that cilia-associated processes may be involved in lifespan regulation. Collectively, this study establishes a proof-of-principle framework for detecting subtle genetic modulators of aging in genetically robust systems.

Endothelial cell senescence represents a critical mechanistic driver in the initiation and progression of cardiovascular diseases. Senescent endothelial cells exhibit characteristic features, including cell cycle arrest-mediated primarily through the p53/p21 and p16 pathways-morphological transformations such as increased cell volume, elevated caveolin-1 expression, and loss of LaminB1, as well as activation of the senescence-associated secretory phenotype (SASP). The SASP facilitates the secretion of numerous inflammatory cytokines and chemokines, thereby fostering a state of chronic inflammation and contributing to tissue dysfunction. Key molecular regulators of endothelial senescence include transcription factors such as NF-κB and p53, along with the p38 MAPK signaling pathway, which collectively modulate inflammatory responses, cell cycle progression, and stress adaptation. This review offers a comprehensive and integrative perspective on endothelial senescence as a central element in cardiovascular pathophysiology. Its novelty stems from a systematic synthesis of classical pathways, including p53/p21 and p16, with more recently implicated players such as mammalian target of rapamycin (mTOR) signaling and associated microRNAs (miRNAs), accompanied by a focused examination of the SASP as a core pathological mechanism in chronic inflammation and vascular impairment. Moving beyond singular pathways, this work constructs a multidimensional framework that integrates cell cycle arrest, morphological changes, SASP activation, and transcriptional regulation to delineate a cohesive pathological sequence through which endothelial senescence promotes cardiovascular disease.

Plant-derived exosome-like nanovesicles (PDEVs) are emerging as breakthrough platforms for the treatment of age-related diseases (ARDs). These endogenous nanocarriers contain a variety of bioactive molecules, including microRNAs, proteins, lipids, and phytochemicals, which play crucial roles in therapy. PDEVs have strong potential to treat chronic inflammation, oxidative stress, cellular senescence, and mitochondrial dysfunction, all of which are related to aging. Their pleiotropic effects support wide therapeutic applications in neurodegenerative, cardiovascular, and metabolic diseases; sarcopenia; cachexia; and skin ageing. PDEVs have several advantages over synthetic nanoparticles and mammalian exosome-like nanovesicles, including good biocompatibility, low immunogenicity, and excellent in vivo stability. Being of natural origin, they can be produced on a large scale at low cost, and drugs can be effectively delivered via various routes, including oral, intravenous, and intramuscular routes. However, translating PDEVs into the clinic presents several challenges, including mass production, batch-to-batch consistency, standardized isolation and characterization methods, and regulatory issues. By combining natural plant compounds with modern nanomedicines, safe, effective, and targeted therapies for complex ARDs can be developed. However, oral delivery faces key limitations due to gastrointestinal barriers, including acidic pH, enzymatic degradation, bile salts, and mucus layers, which can compromise vesicle stability and bioavailability. Variability in intestinal uptake and microbiota interactions further affects therapeutic consistency. Protective strategies, including encapsulation, enteric coating, and surface engineering, may enhance stability and absorption. Emerging approaches such as ligand-functionalized PDEVs, hybrid nanovesicles, and stimuli-responsive delivery systems offer safer and more precise therapeutic options, improving targeting, controlled release, and translational potential.

Skin aging is driven by intrinsic and extrinsic factors. Epigenetic alterations are one primary hallmark of aging and powerful biomarkers of biological skin age. To investigate epigenetic skin aging mechanisms and their regulation as a skin longevity approach across diverse ethnicities and phototypes, we assessed epidermal methylomes from white, African, and Asian donors.

Cluster of differentiation 38 (CD38) is a multifunctional ectoenzyme regulating immune functions, calcium signaling, and nicotinamide adenine dinucleotide (NAD

Immunosenescence-the age-related decline of immune function-drives a state of chronic, sterile inflammation termed inflammaging. Far from passive deterioration, this process is actively orchestrated by distinct but interconnected hallmarks: erosion of lymphoid organs, myeloid-biased hematopoiesis, accumulation of immune-evasive senescent cells, and metabolic-epigenetic reprogramming that locks cells into dysfunctional states. These core nodes form a self-perpetuating cycle that propagates pathology across multiple organ systems, fueling neurodegeneration, cancer, musculoskeletal decline, and gut dysbiosis. Critically, the field has transitioned from descriptive phenomenology to mechanism-based intervention. This review synthesizes emerging therapeutic strategies targeting specific nodes of the immunosenescence network. We examine senotherapeutics that sensitize senescent cells for immune clearance, HSC and thymic rejuvenation to restore lymphocyte production, and metabolic-epigenetic interventions to correct intracellular deficits. By integrating these insights, we propose a precision medicine framework that moves beyond broad immunosuppression toward rational combinatorial regimens. This roadmap aims to decouple protective immunity from pathological drivers, extending healthspan and redefining the paradigm of geriatric care.

Aging is commonly viewed as a passive consequence of accumulated damage; however, emerging evidence suggests that it may also represent an adaptive response to environmental stress. Here, we combined transcriptomic and metabolomic profiling of Saccharomyces cerevisiae to investigate how short-term, long-term, and recovery phases of stress exposure shape cellular physiology and lifespan. Short-term stress-induced protective pathways and longevity-associated metabolites, including trehalose and 5'-methylthioadenosine, consistent with enhanced stress resilience and proteostasis. In contrast, prolonged stress activated heat shock proteins and epigenetic regulators, coupled with metabolic signatures associated with loss of proteostasis, reduced energy homeostasis, and shortened chronological lifespan. Upon recovery, beneficial metabolites such as S-adenosylhomocysteine were restored, highlighting the reversibility of stress-induced aging trajectories. Phylogenetic analysis demonstrated conservation of these stress- and aging-related genes across eukaryotes and prokaryotes, suggesting an evolutionary basis for aging as a long-term stress adaptation. Together, these findings suggest that aging-associated molecular changes are closely linked to conserved stress response pathways, with implications for understanding the hallmarks of aging.

Age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and related dementias, are increasingly understood as multifactorial proteinopathies involving co-aggregation of amyloidogenic proteins such as microtubule-associated protein-Tubulin-associated unit protein (Tau), α-synuclein (α-syn), amyloid-β (Aβ), and TAR DNA-binding protein 43 (TDP-43). Rather than acting independently, these proteins often cross-seed, co-localize, and modulate each other's aggregation dynamics and toxicity. This review critically examines the mechanistic and pathological underpinnings of heterotypic protein co-aggregation, integrating biophysical, cellular, animal, and human data. This review further proposes a conceptual framework that views neurodegeneration as a network of interacting misfolded proteins shaped by age-related changes in lipid membranes, redox balance, proteostasis, and genetic factors. Emphasis is placed on translational opportunities: co-aggregation-specific biomarkers in cerebrospinal fluid and extracellular vesicles, and emerging multi-targeted therapies including immunotherapy, proteostasis modulators, and autophagy-inducing chimeras. This review also discusses the clinical implications of co-pathology in mixed dementias and overlapping disorders. It is therefore time to move beyond the classical one protein-one disease paradigm and embrace models that explicitly incorporate heterotypic co-aggregation, mixed pathologies, and shared vulnerability pathways across age-related disorders. By reframing co-aggregation as a central pathogenic mechanism, this review highlights the need for diagnostics and therapeutics that address the interconnectivity of protein misfolding in the ageing brains.

Early metabolic stress is a key factor influencing long term intergenerational adaptation in organisms. While excessive dietary methionine is known to disrupt one-carbon metabolism, it remains unclear whether early gestational methionine excess induces sustained epigenetic remodeling, thereby affecting redox stability in offspring. Using C. elegans as a model, we demonstrate that early gestational methionine excess in parental induces sustained metabolic stress in offspring, impairing their functional stability. This manifests as impaired motility, shortened lifespan, and elevated oxidative stress levels. Mechanistically, this intergenerational vulnerability is associated with metabolic reprogramming towards a serine-glycine-one-carbon axis. This leads to methyl donor imbalance and chromatin remodeling, characterized by SET-2/WDR-5.1 dependent H3K4 hypermethylation. Meanwhile, the stress response programs of DAF-16/FOXO and SKN-1/Nrf2 are restricted, thus affecting the redox adaptability of the offspring. Importantly, intervention with the dietary polyphenol epigallocatechin gallate (EGCG) can restore metabolic homeostasis and alleviate these chromatin and transcriptional restrictions. In summary, our findings reveal a metabolic and epigenetic framework by which early-life nutritional imbalances influence intergenerational redox resilience. We also emphasize that EGCG represents a potential nutritional strategy to alleviate metabolic stress caused by methionine excess.

Senescent cells drive ageing and age-related pathologies, including cancer. Consequently, senolytics, drugs that selectively kill senescent cells, have broad therapeutic appeal. Here we report a senolytic screen of a library of 10,480 electrophilic compounds. Among 38 identified hits, we found a subset of chloroacetamides with broad senolytic activity. Activity-based protein profiling, coupled with functional assays, identified the glutathione peroxidase GPX4 as a target. We show that senescent cells are primed for ferroptosis, displaying high levels of oxidative stress and intracellular Fe

Cellular senescence and mitochondrial dysfunction are prevalent in adipose tissues and disrupt metabolic homeostasis during aging, but the mechanisms are poorly understood. Here, we investigated the role of histone deacetylase 9 (HDAC9), an epigenetic regulator of adipogenic differentiation, in aging-related adipose tissue senescence and mitochondrial dysfunction. HDAC9 expression correlated positively with age in mouse adipose tissues. Compared to age-matched wild-type (WT) mice, Hdac9 knockout (KO) mice gained less weight and had reduced fat mass during aging, in conjunction with reduced senescence-associated beta-galactosidase (SABG) staining and expression of senescence markers in adipose tissues. Additionally, preadipocytes isolated from Hdac9 KO mice exhibited reduced baseline and stress-induced senescence compared to WT mice. Mechanistically, HDAC9 gene deletion resulted in coordinated upregulation of mitochondria-associated genes, in association with increased mitochondrial DNA content and adipose tissue mitochondrial oxygen consumption parameters (e.g., increased basal respiration, proton leak). Furthermore, thiosulfate sulfurtransferase (TST), whose downregulation is associated with mitochondrial dysfunction, was reduced in adipose tissues of aging mice and upregulated by HDAC9 gene deletion. Finally, silencing TST in preadipocytes upregulated expression of senescence markers and increased SABG staining. We conclude that deletion of HDAC9 ameliorates the development of adipose tissue senescence and mitochondrial dysfunction with aging, at least in part via upregulation of TST, suggesting that targeting HDAC9 may be a promising strategy to maintain healthy adipose tissue during aging.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a life-saving treatment for hematologic malignancies, but long-term survivors present with lower muscle mass and functional capacity. In adult HSCT survivors 10-20 years after treatment, single nucleus RNA sequencing uncovered elevated XRRA1 expression levels in all muscle nuclei populations, which was retained in primary muscle stem cell cultures. HSCT survivors were characterized in vivo by impaired neuromuscular innervation that associated with muscle weakness, and lower muscle stem cell neurotrophic action. Despite these impairments, the molecular and physiological responses to heavy resistance training (HReT) were preserved in HSCT survivors, as demonstrated in a pre-registered clinical trial (ClinicalTrials.gov: NCT04922970). After 12 weeks of HReT, gains in muscle mass and strength were similar in HSCT survivors and healthy controls. In addition, we observed that [~]9% of muscle-resident immune cells persist into adulthood and that bone marrow derived cells do not adopt alternative cell fates in muscle tissue, resolving long-standing questions in human muscle biology. Together, these findings uncover molecular mechanisms of HSCT sequelae in muscle nuclei and muscle stem cells, which, importantly, can at least partly be overcome by mechanical loading. Given the growing population of HSCT survivors and the multitude of benefits of HReT for all organ systems, our findings support the importance of HReT in this population to promote healthspan.

The specific neuroanatomy of mild cognitive impairment (MCI) is obscured by its clinical heterogeneity and confounding effects from normative variation. This problem is compounded by the inability of conventional neuroimaging methods to disentangle these overlapping influences. Leveraging data from the Beijing Aging Brain Rejuvenation Initiative (BABRI, n = 918) and the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 1293), this study employed a conditional variational autoencoder (CVAE) to: (1) systematically distinguish between aging-related cognitive decline and MCI-specific cognitive impairments; (2) implicitly disentangle latent, unknown confounding effects to identify MCI-specific structural brain alterations; and (3) construct individualized scores for predicting the risk of conversion to Alzheimer's disease (AD). The CVAE effectively extracted MCI-specific latent features from T1 structural MRI, significantly correlated with episodic memory, attention, and executive function impairments. Reconstructions revealed characteristic deformation in regions including the middle and medial temporal lobes, frontal lobe, limbic system, and cerebellum. The robustness of this structural-cognitive impairment association model established in BABRI dataset was validated in the ADNI dataset. Moreover, predictive modeling using these features achieved superior AD-conversion prediction (AUC = 0.83) versus whole-brain atrophy (AUC = 0.74; p < 0.001) or CSF biomarkers (AUC = 0.77; p < 0.001).This work establishes a novel paradigm for isolating MCI-specific brain alterations from physiological aging.

Sleep disruption increases with age and is associated with adverse age related outcomes, yet the molecular mechanisms linking these phenomena remain unclear. Here, through integrative analysis of human and mouse transcriptomic and proteomic datasets, we identify proteostasis related pathways whose aging trajectories align with transcriptional responses to chronic sleep disruption across tissues and cell types. In the human prefrontal cortex, gene expression exhibits coherent age associated directional shifts. Across human peripheral blood following sleep restriction and multiple aging mouse tissues and cell types, proteostasis pathways exhibit concordant downregulation. Among these, heat shock response pathways emerge as the most persistent and cross modal signatures, with components of the heat shock factor 1 (HSF1) mediated proteostasis network displaying diminished inducibility with age and chronic sleep insufficiency, in contrast to transient activation following short term sleep deprivation. This attenuation is particularly pronounced in neurons, where age-associated suppression of HSF1 target programs indicates selective vulnerability of neuronal proteostasis. Spatial and single cell analyses map this vulnerability to hippocampal circuits during aging and to superficial cortical layers and glutamatergic neurons in Alzheimers disease. These findings support a model in which repeated sleep disruption progressively reduces the inducible capacity of proteostatic stress responses, shifting from adaptive activation to progressive attenuation and accelerating age related decline in proteome maintenance. Consistent with emerging functional evidence, this identifies HSF1 mediated proteostasis as an integrative axis linking sleep stability and molecular aging, suggesting a self reinforcing relationship in which sleep disruption and proteostasis decline reciprocally exacerbate one another. These results connect transient molecular responses to sleep perturbations with long term aging trajectories, revealing a systems level mechanism through which cumulative sleep disruption may increase vulnerability during aging.

Cardiorespiratory fitness (CRF) is a heritable trait associated with improved metabolic health and longevity. To identify regulatory mechanisms underlying CRF, we integrated 546 transcriptomic and epigenomic profiles from skeletal muscle of 128 genetically heterogeneous rats selectively bred for high and low running capacity, a model that mirrors CRF-associated traits in humans. Selection drove genetic convergence in coordinated skeletal muscle enhancer networks linked to lipid metabolism and angiogenesis genes. We validated thousands of these genetic effects through integration of 426 genotype, gene expression, and chromatin accessibility profiles in an independent HCRxLCR F2 population (n=147). These 972 multi-omics profiles show that CRF-associated genetic variation reshapes the chromatin landscape to support energy metabolism and oxygen delivery, offering a molecular framework for identifying targets to reduce cardiometabolic disease risk.

Centenarians - individuals aged 100 years or older - constitute a biologically distinct human population that achieves exceptional longevity while frequently retaining functional independence and avoiding major age-related diseases or postponing their onset. Despite their advanced age, many centenarians show relatively preserved immune function and resistance to conditions linked to immunosenescence and chronic low-grade inflammation (inflammageing). These features are especially pronounced in semi-supercentenarians (105-109 years) and supercentenarians (≥110 years), whose immune profiles often resemble those of much younger individuals. In this Review, we explore how centenarians modulate key hallmarks of immune ageing across innate and adaptive immune compartments. We discuss evidence that they limit the pathological effects of inflammageing, potentially through reduced NLRP3 inflammasome activation, enhanced autophagy and a tempered senescence-associated secretory phenotype. Omics studies further reveal transcriptomic, epigenetic and microbial signatures consistent with preserved immune function, including youth-like gene expression patterns in circulating immune cells and beneficial shifts in gut microbiome composition. Together, these findings suggest that centenarians achieve longevity through coordinated adaptations that maintain immune homeostasis and disease resistance and may inform strategies to enhance healthspan in ageing societies.

Background: The maintenance of skeletal muscle health plays a pivotal role in prolonging both the lifespan and healthspan. However, muscle mass and strength exhibit significant declines with age. Ageing is associated with a reduced muscle protein synthesis response to key anabolic stimuli, including the androgen hormone testosterone, termed anabolic resistance. Testosterone enacts its anabolic effects in muscle through androgen receptor (AR) mediated pathways. Emerging evidence suggests that AR availability may represent a rate-limiting factor in androgen signalling, with AR saturation occurring below physiological testosterone levels in some tissues. Prior research in rodents has reported age-related reductions in AR expression, suggesting changes in AR protein content may constitute a key component of anabolic resistance. However, reports of the effects of age on the human skeletal muscle AR are inconclusive and limited by small sample sizes. Therefore, this study aimed to characterise age-related changes in expression of the AR, its regulators and downstream target genes in human skeletal muscle. Methods: We developed and used a novel R-based pipeline, MetAR, to perform reproducible meta-analyses of publicly available bulk RNA-Seq datasets from NCBI GEO and investigate associations between target gene expression and variables of interest without the need for high-performance computing. Eligible datasets included skeletal muscle samples from healthy adult males aged [≥]18 years, with an age range of [≥] 10 years and sample size [≥] 6. Raw counts data were downloaded, appraised and TMM normalised. Dataset-level associations between age and target gene expression were assessed using linear and generalised additive models (GAMs). Random-effects meta-analyses were performed, and heterogeneity, publication bias and leave-one-out sensitivity assessed. Results: Sixteen skeletal muscle bulk RNA-seq datasets (n = 364; age 18-92 years) were eligible for inclusion in the meta-analyses. AR expression was negatively associated with age ({beta} = -0.006 log2 TMM-CPM per year, p < 0.001) corresponding to a 4.4% decrease in expression per decade. Age was also associated with a significant reduction in expression of various regulators of AR stability, transcriptional activity and nuclear transport. Additionally, steroidogenic enzymes and key downstream targets of the AR, including genes encoding for key structural proteins and mitochondrial function were negatively associated with age. Conclusions: Collectively, these findings suggest a multi-faceted age-associated remodelling of AR expression, signalling and nuclear transport that may contribute to the development of anabolic resistance and consequent age-associated muscle loss.

Declines in nicotinamide adenine dinucleotide (NAD+) are linked to metabolic stress accompanying aging and disease. While precursor-based approaches elevate systemic NAD, their clinical translation can be constrained by biosynthetic bottlenecks and first-pass metabolism. RENEWAL-NAD+ (ClinicalTrials.gov NCT07336836; retrospectively registered 01/04/2026) was a double-blind, randomized, placebo-controlled Phase 0/1b trial in healthy adults aged 45-75 years (60 randomized; primary analysis n=50) evaluating 5 days of oral LathMized(R) NAD+ (LNAD+), a physicochemically modulated formulation that alters the supramolecular organization and solution behavior of NAD+ while preserving its native molecular structure. The primary endpoints were change in intracellular NAD (icNAD), measured in whole blood, and circulating NAD (cirNAD), measured in separated plasma, relative to baseline. LNAD+ produced a rapid and pronounced increase in icNAD, with a 53% elevation versus placebo at Day 6 (p=5.48e-14; Hedges' g=3.66), while cirNAD was unchanged (p=0.60), demonstrating compartment-selective augmentation. Plasma NAD catabolites increased substantially (1-methyl-nicotinamide, MeNAM p=5.39e-13; N1-methyl-2-pyridone-5-carboxamide, 2PY p=2.95e-16), consistent with downstream engagement of NAD metabolic flux. Exploratory analyses identified non-overlapping correlates for the two compartments (cirNAD tracking inflammatory and metabolic markers, icNAD tracking red blood cell indices and NAM). Treatment was very well tolerated: symptom incidence was comparable between groups (p=0.68), only one mild adverse event (nausea, Grade 1) occurred in the LNAD+ arm, and no secondary clinical, vital-sign, wellbeing, or wearable-derived endpoint survived multiplicity correction. These data demonstrate rapid intracellular NAD augmentation after oral LNAD+ dosing with pharmacodynamic evidence of downstream metabolism, compartment-specific physiological signatures, and a favorable short-term safety profile, with exploratory multi-omic analyses ongoing.

The World Health Organization has declared 2021-2030 the "Decade of Healthy Ageing", aiming for the best quality of life through health as the population ages. Beyond healthy ageing, scientists are adopting artificial intelligence technologies for longevity science which can foreseeably enable humans to routinely live to 120 years and beyond. With such breakthroughs within reach, the challenges associated with longevity need to be considered, from the impact on the social system to the possibility of an international law right to longevity, along with associated considerations such as on sustainability. This article questions whether there already is, or should be, an international human right to facilitate considerably extended lifespans, along with other relevant legal frameworks.

Cognitive impairment (CI), spanning mild memory issues to severe dementia, impacts over 55 million people worldwide and have a significant effect that strains health, economy, and caregiving. Surprisingly, it occurs at any age. The glial cell ecosystem, particularly astrocyte-microglia crosstalk, is pivotal for brain homeostasis and cognitive function across the lifespan. Intriguingly, in recent discoveries, dysregulation of ecosystem contributes to neurodevelopmental disorders (NDDs), adult cognitive decline, and neurodegenerative diseases like Alzheimer's disease (AD), and astrocyte-derived interleukin-3 (IL-3), acting via the IL-3/CD123-related signals, may act as a key regulatory mediator of microglial function. Over the past few decades, extensive researches have been devoted to investigating aging-related regulatory factors with the aim of deciphering the "code" underlying cognitive developmental abnormalities, premature cognitive decline, and neurodegeneration. Astrocyte-microglia crosstalk governs age-dependent glial turnover via senescence-sensitive IL-3. Under pathological conditions, perturbed turnover's association with age-stratified CI and its regulators is poorly understood. This review integrates current evidence on glial crosstalk, cellular senescence, and repopulation to elucidate age-specific CI driven by dysregulated glial turnover, while identifying key biomarkers that can predict aging processes. Looking ahead, therapeutic strategies targeting the IL-3/CD123-related signals regulating glial crosstalk hold promise for advancing interventions in immune-mediated CI across the lifespan.

By 2050, one-fifth of the world is expected to be over 60, and the prevalence of age-related neurological conditions is predicted to increase dramatically. Aged animals are currently underutilised in neurological research, leading to a gap in knowledge about the contribution of biological age to the pathophysiology of age-related neurological conditions. Additionally, it is unclear whether age-related changes differ across species used in preclinical models, and how these differences may compare to the aged human brain. Understanding these points is critical for successful translation of findings from preclinical studies to the human context. The current study presents a cross-species characterisation of microglia, the key regulator of the brain's immune response, during ageing. Microglial number, proliferation and morphology were assessed in archival tissue from Sprague Dawley rats (males; 3 to 18 months old) and Merino sheep (males and females; 1 to 6 years old), with these two species selected for their relevance to preclinical modelling of neurological disease. Increased numbers of proliferating microglia were observed in the cortex, hippocampus and portions of the striatum in both species. This proliferation declined at the oldest timepoint assessed (i.e. 18 months old) in rats, a pattern not seen in the sheep. Total microglial number was largely unchanged with age in the rat brain; however, in sheep, the number of microglia decreased significantly in the dentate gyrus in older animals. Notably, microglia in 18-month-old rats were larger in all regions, but changes in branching were observed exclusively the striatum. Similarly, in sheep, morphological changes were localised to the striatum, with increased cell and soma size in the caudate nucleus, and increased cell size and process length in the putamen. These changes suggest a shift away from homeostasis in the cortex and hippocampus and towards a semi-ramified morphology in the striatum in late middle adulthood that is largely conserved across these two species. Nevertheless, the age of the oldest animals here equates to only ~ 60 years old in humans, rather than reflecting an aged human population. Thus, future work is needed to understand how species-specific differences continue to evolve in older age.

Extracellular vesicles have shown great potential in treating ultraviolet (UV)-induced skin photoaging. However, effective delivery of these bioactive agents to achieve long-term therapeutic effects remains a significant challenge. In this study, we have developed recombinant human collagen (RHC)-based microcarriers loaded with native exosomes as well as Collagen type I alpha 1 chain (COL1A1) mRNA-encapsulating nanovesicles (Emvs) to treat skin photoaging. The microcarriers mitigated UV-induced cellular senescence in HaCaT cells, as evidenced by reduced oxidative stress, decreased apoptosis, and attenuation of senescence-associated markers. In the animal model, the microcarriers not only attenuated wrinkle formation, but also promoted type I collagen deposition in UV-damaged skin. These results together with the demonstrated biocompatibility highlight the potential of the microcarrier delivery system in photoaging treatment.

Background: Prediabetes is highly prevalent in older adults and is characterized by heterogeneous clinical trajectories, including regression to normoglycemia and progression to diabetes. While prediabetes has been associated with impaired physical function and frailty, the longitudinal impact of both a single diagnosis and dynamic glycemic transitions on functional outcomes remains unclear. We aimed to evaluate associations between baseline prediabetes and glycemic transitions over time with trajectories of functional capacity and frailty in older adults. Methods: We conducted a pooled analysis of harmonized data from five nationally representative longitudinal aging cohorts (MHAS, HRS, CHARLS, ELSA, CRELES) within the Gateway to Global Aging Data, including adults aged [≥]50 years with [≥]1 HbA1c measurements. Prediabetes was defined per ADA criteria (HbA1c 5.7-6.4%). Functional outcomes included activities of daily living (ADL), instrumental ADL (IADL), and frailty assessed using Fried phenotype, FRAIL scale, and a deficit-accumulation Frailty Index (FI). Mixed-effects Poisson models estimated incidence rate ratios (IRRs) for baseline prediabetes, while generalized estimating equations assessed time-varying glycemic status and transition trajectories. Models were adjusted for age, sex, cohort, and time-varying covariates, with sensitivity analyses including BMI, smoking, and alcohol intake. Findings: Among 18,571 participants (median follow-up 13.6 years), baseline prediabetes was associated with increased progression of functional deficits and frailty compared with normoglycemia, including higher FI values and accelerated FI progression. Prediabetes was associated with higher incidence of ADL, IADL, and multimorbidity deficits from early follow-up, although time-dependent changes in incidence rates were not significant. In time-varying analyses (n=7,840), both prediabetes and diabetes were associated with higher incidence of functional deficits compared with normoglycemia, with diabetes showing the strongest effects across all outcomes. Diabetes was associated with greater FI burden and accelerated progression, whereas prediabetes showed a smaller increase, with attenuation over time. Among individuals with baseline prediabetes, regression to normoglycemia occurred in 20.8% and was associated with increased incidence of ADL and frailty deficits. In contrast, progression to diabetes occurred in 24.3%, and was associated with lower risk of incident ADL and Fried frailty deficits compared to stable prediabetes. Interpretation: Prediabetes is associated with increased risk of functional decline, frailty, and deficit accumulation in older adults, independent of progression to diabetes. Regression to normoglycemia was associated with higher risk of functional deterioration. These findings suggest that prediabetes reflects a state of metabolic vulnerability linked to biological aging rather than solely a precursor to diabetes and highlights a need to reframe its clinical significance in older populations. Funding: This research was supported by Instituto Nacional de Geriatria in Mexico. Keywords: Prediabetes; Glycemic transitions; Frailty; Functional decline; Aging; Multimorbidity

Aging is characterized by progressive functional decline, increased disease susceptibility, and dysregulation of cellular homeostasis. Among post-translational modifications, N-glycosylation has emerged as a key regulator of protein stability, signaling, and immune function with broad relevance to aging biology. Recent large-scale glycomic studies demonstrate that the human N-glycome undergoes consistent age-associated remodeling across plasma, immune cells, and tissues, including reduced galactosylation and sialylation, altered fucosylation, and changes in N-glycan branching. These shifts are particularly pronounced on immunoglobulin G (IgG), where Fc N-glycan profiles serve as robust biomarkers of biological age, inflammation, morbidity, and mortality risk. Beyond circulating markers, cell and tissue-specific analyses reveal that regulated changes in glycosylation directly influence receptor signaling, inflammatory tone, and organ level aging phenotypes in the cardiovascular, nervous, and immune systems. Mechanistically, age-dependent N-glycan remodeling reflects the integrated effects of transcriptional reprogramming of glycosyltransferase networks, metabolic regulation of nucleotide sugar availability, and altered spatial organization of glycosylation enzymes within the Golgi apparatus. Importantly, emerging evidence indicates that plasma N-glycosylation patterns are partially reversible through metabolic and lifestyle interventions. Together, these findings position N-glycosylation as a central and dynamic component of aging biology, linking metabolic and inflammatory states to functional outcomes across biological scales.

Understanding aging and complex diseases requires diverse data, ranging from molecular profiles to imaging and routine clinical tests. However, most multi-omic datasets measure only a subset of modalities and are confounded by batch effects. Here, we present AURORA (AI unification and reconstruction of omics reassembly atlas), a generative deep-learning platform that integrates seven modalities (including transcriptomics, metabolomics, microbiome, 3D and thermal facial imaging, and clinical laboratory tests) across 581,763 samples from 425,258 individuals. AURORA harmonizes batch effects and reconstructs missing data across modalities, enabling highly accurate multimodal aging clocks and disease risk predictors. It also supports personalized in silico perturbation analyses to predict intervention and drug responses, validated using longitudinal cohorts. As a proof of concept, we provide a prototype AI agent that converts single-input modalities into a multimodal report for users and researchers. Together, AURORA links non-invasive inputs to comprehensive aging biomarkers and therapeutic discovery.

DNA variants modulate mortality risks across an entire lifespan but their dynamic age-dependent effects have not been resolved in any species for either sex. Here we mapped variants that shape mortality using an actuarial approach, starting with a base population of 6,438 pubescent mice and ending with 559 survivors that lived beyond 1,100 days of age. Twenty-nine Vita loci influence lifespan with strong age- and sex-specific effects. Most act during distinct stages with polarities that often invert with age, but a minority have consistent age-dependent effects in one or both sexes. A separate set of 30 Soma loci influence correlations between body mass and life expectancy. Nineteen Soma loci mediate higher mortality in larger young mice, whereas 11 mediate lower mortality in larger old mice. All effects are stronger in male mice than in female mice. Vita and Soma loci form epistatic networks split strictly by sex. These findings provide a genetic bridge between evolutionary theories of ageing and molecular mechanisms that can guide interventions to extend healthy lifespan.

Cellular senescence, driven by the interaction between FOXO4 and p53, is increasingly recognized as a crucial mechanism in brain aging and the development of neurodegenerative disorders. The senolytic peptide FOXO4-DRI, which has been thoughtfully designed, selectively disrupts the FOXO4-p53 complex, inducing apoptosis in senescent cells while preserving healthy tissue. In aged mammalian models, administering FOXO4-DRI decreases the accumulation of senescent cells, restores cerebral blood flow and the integrity of the blood-brain barrier (BBB), reverses hippocampal atrophy, and enhances cognitive function. Furthermore, in models of Alzheimer's disease (AD) and tauopathy, this intervention eliminates amyloid-β and pathological tau, leading to improved memory performance. Preliminary human studies involving FOXO4-axis modulators, such as high-dose fisetin, show a reduction in the senescence-associated secretory phenotype (SASP) and enhancements in cognitive and physical measures among older adults. These findings collectively identify the FOXO4-p53 axis as a potential pharmacological target in brain aging and highlight senolytic therapy as a promising strategy for altering diseases to postpone or reverse age-related cognitive decline. This review consolidates recent findings indicating that FOXO4-dependent senescence significantly contributes to neuroinflammation, synaptic dysfunction, and impaired neurogenesis in the aging brain.

Cellular senescence is a heterogeneous cell state induced by diverse stressors, including telomere attrition, genotoxic agents, oxidative damage, and inflammation. Despite ongoing efforts to identify conserved senescence biomarkers, it remains unclear whether senescence-inducing stimuli converge at the level of individual genes or broader molecular processes. Here, we profiled transcriptomic changes in human primary lung fibroblasts (IMR-90) driven toward senescence by replicative exhaustion, bleomycin, H2O2, or ionizing radiation under matched, dose- or time-resolved conditions. Across all four senescent inducers, global transcriptomic variation aligned along a shared axis of senescence progression, consistent with established machine learning-based senescence classifiers. However, overlap at the level of individual genes was limited, with most responses being inducer-specific or only partially conserved. In contrast, pathway-level analysis revealed far more consistent enrichment across all conditions, including downregulation of proliferation-associated pathways and activation of stress-related and pro-inflammatory pathways, accompanied by distinct inducer-specific patterns. These results support a hierarchical organization of the senescent transcriptome, in which diverse senescence inducers converge on shared pathway-level features while maintaining gene-level heterogeneity. These results provide a foundational basis for interpreting senescence signatures and may facilitate the development of more robust transcriptome-based markers of cellular senescence in aging and disease.

Bone marrow adipose tissue (BMAT) is a unique fat depot. It has distinct metabolic-endocrine functions and negatively correlates with bone mineral density, increasing with aging and osteoporosis. Intriguingly, BMAT also expands during caloric restriction (CR), a lifespan-extending dietary intervention that also promotes bone loss; however, whether BMAT is a cause or consequence of this remains unclear. To address this, we studied 9-week-old male and female C57BL/6NCrl mice subjected to 30% CR for 1, 2, 4, or 6 weeks. Bone structure and BMAT volume were quantified by micro-computed tomography using a spatial method that precisely maps BMAT within bones. CR-induced BMAT expansion was site-specific, being greater in tibiae than femora and absent in humeri. Surprisingly, CR increased distal tibial BMAT despite prior suggestions that it resists such environmental modulation. Expansion was also duration-dependent, plateauing after 4 weeks; and region-specific, particularly in tibial metaphysis, femoral metaphysis, and the distal tibia. Similarly, CR altered trabecular and cortical bone in time-, region-, and sex-dependent ways, with BMAT levels more tightly associated with trabecular than cortical changes. CR also increased adiponectin, corticosterone, and ketones, while decreasing leptin, IGF-1, and insulin, in a sex- and/or duration-dependent manner. Metabolic phenotyping demonstrated that BMAT expansion was not associated with altered glucose tolerance, body mass, total fat mass, or fat percentage, but correlated with energy deficit and systemic lipid mobilisation. Together, our findings highlight the complex interplay between BMAT expansion, skeletal remodelling and metabolic homeostasis, providing new insights into BMAT formation and function and the health benefits of CR.

De novo lipogenesis (DNL) is a metabolic process by which carbohydrates are converted into fatty acids and used for immediate energy or stored as triglycerides for later use. Increased DNL in brown adipose tissue (BAT) is believed to be a marker of metabolic health, but indicates poor metabolism if upregulated in hepatic tissue. ChREBP is a primary regulator of whole-body DNL and promotes production of key enzymes including fatty acid synthase, acetyl-CoA carboxylase, and stearoyl-CoA desaturase. ChREBP is highly expressed in primary sites of lipogenesis such as the liver, intestines, and adipose tissue. In the liver, ChREBP is associated with aging-related symptoms such as increased insulin resistance and gluconeogenesis. In BAT, ChREBP plays an important role as a regulator of uncoupling protein 1 (UCP1) and DNL. Previous research has linked increased metabolic activity in BAT to increased longevity, but the effects of ChREBP-regulated DNL on aging have not been studied yet. To elucidate this relationship, we analyzed the expression of key enzymes and regulators associated with DNL in the liver and BAT of long-lived mutant mice (Ames, Snell, GHR-KO, Pappa-KO, and PTENOE). We observed a decrease in lipogenic enzymes (FASN and ACC1) and their regulator, ChREBP in the liver of the slow-aging mouse models and a contrasting increase in these same markers in BAT. Tissue-specific modulation of DNL is a shared trait among at least these five varieties of slow-aging mice, and may contribute to the extended longevity of these strains.

Vertebrates grow and mature with age after birth, deteriorate, and eventually die. However, the long lifespan of most vertebrates makes it challenging to identify markers of these distinct stages. Here, we leverage the short-lived vertebrate African Turquoise killifish (N. furzeri) to isolate molecular markers distinguishing gradual aging from late-onset aging. N. furzeri lifespan was divided into four stages-growth/maturation, young, midlife, and old-based on biological parameters. Cellular and molecular changes continually increasing or decreasing with age from young to midlife to old stages were defined as "gradual aging", and changes specifically between midlife and old stages as "late-onset aging". We discovered hepatic lipid droplets formed at birth and disappeared during the midlife stage. Metabolome and gene expression analyses of the liver where the majority of changes occurred identified several metabolites and genes as gradual aging markers (e.g., methylhistidine, glutarylcarnitine, and γ-butyrobetaine) and late-onset aging markers (e.g., creatine, homocitrulline, pipecolic acid, p21, htra1, and slc13a5 genes) providing insights into alternative mechanisms of gradual aging and late-onset aging that may be conserved. Thus, molecular markers reflecting gradual aging and late-onset aging at the organ levels can be isolated using N. furzeri.

Frailty is a complex trait that significantly increases the risk for negative health consequences, including hospitalization and disability. However, the evidence regarding the genetic basis of frailty phenotype (FP) is very limited. We conducted a genome-wide association study (GWAS) on FP using the data from the Canadian Longitudinal Study on Aging (CLSA). We classified the participants as non-frail, pre-frail, and frail, and performed a GWAS utilizing the ordinal logistic regression adjusted for sex, number of chronic conditions, and 10 principal components. Several post-GWAS analyses, including cis-eQTL analyses, were conducted to investigate the potential functional significance. In total, 23,105 participants and more than 8 million imputed SNPs were included in the analysis. The average age was 63 years, and 50.35% of the participants were female. Most participants were non-frail (11,297; 48.89%) or pre-frail (10,261; 44.41%), whereas only 1547 (6.70%) were frail. One novel genomic variant (rs147311617) at the 12p22 locus was found significant at the level of genome-wide significance (p = 4.98×10

Fatty acids (FAs), as the predominant organic acids, form a major component of the metabolome. We present a multi-tiered method that comprehensively captures FA diversity-including chain lengths (C2-C34), unsaturation, isomers, and endogenous forms-within a single biological specimen. This workflow quantifies the broadest range of free FAs reported to date. Integrated with two complementary tiers profiling the total FA pool from alkaline hydrolysis and esterified acyl compositions across lipid classes, our multi-tiered workflow enables the investigation of differential fatty acyl partitioning. Applying this platform to quantify >540 unique lipids (free and esterified forms) and polar carboxylic acids, we investigated FA remodeling in the brain, retina (eyeball), and skeletal muscles of young and aged mice. We found that aged glycolytic tissues preferentially partition odd-chain and diunsaturated FAs (with lower β-oxidizability) into triacylglycerols. Additionally, aging shifts the FA18:1 partitioning into diacylglycerols over anionic phospholipids, which may mitigate pro-aging lipid signatures in the skeletal muscle.

SIRT5 (sirtuin 5) is a member of the sirtuin family known to regulate cardiac metabolism, aging, and function. However, its role in cardiac fibroblast (CFB) metabolism, activation, and fibrosis remains elusive.

Aging is associated with significant alterations in systemic metabolism across species. We employed targeted metabolomics to investigate the effects of losartan, an angiotensin II receptor blocker, on the serum metabolome of aged mice and pre-frail older men. Losartan treatment resulted in a shift in serum metabolome aging signature to a more youthful state. This rejuvenation effect appears to be contingent on the presence of functional angiotensin II receptors, with receptor knockout mice showing no rejuvenation effect with treatment. Additionally, we observed a similar rejuvenation effect of losartan in the cardiac proteome of aged mice, with the most pronounced changes occurring in proteins involved in oxidative phosphorylation. While our study did not encompass a full lifespan analysis, in alignment with previous reports of lifespan extension in other models, we noted a statistically significant improvement in survival among geriatric mice treated with losartan. In parallel, we analyzed serum metabolomics data from pre-frail older men from a phase 2 randomized placebo-controlled trial of losartan, which indicated a dose-dependent metabolic rejuvenation effect. Correlation network analysis revealed divergent aging effects between species, with mice exhibiting broad decreases in metabolite concentrations and humans showing increases, particularly across lipid species. Principal component analysis further highlighted a global shift in metabolite levels, potentially linked to changes in lipoprotein metabolism, plasma volume, and amino acid metabolism with age. In summary, our results suggest that losartan can partially reverse age-related metabolomic changes in both male mice and humans, with distinct species-specific responses.

Alzheimer's disease (AD) emerges from multi-scale interactions between molecular pathology and disruptions in large-scale brain network dynamics. Understanding how these processes co-evolve and relate to disease stages is essential for advancing complex systems models of aging and AD, and for developing system-informed interventions. However, progress has been limited by a lack of large-scale longitudinal data. To address this, we examined the longitudinal relationship between subsystems of the default mode network (DMN) (posterior DMN, ventral DMN, anterior dorsal DMN) using task-free functional MRI (fMRI) and amyloid positron emission tomography (PET) imaging in a large longitudinal cohort spanning the clinico-biological spectrum of AD (n = 1,451; 2,763 time points) using mixed-effect models. We also assessed whether patterns of DMN connectivity predicted conversion to amyloid positivity, mild cognitive impairment (MCI), and dementia using Cox proportional hazards models. Our findings reveal a dynamic interplay between amyloid accumulation and connectivity within and between DMN subsystems, with both hyper- and hypoconnectivity emerging across DMN subsystems in association with increasing amyloid burden. Importantly, survival models showed that DMN connectivity patterns predicted conversion to critical stages of the disease, including not only conversion to MCI and dementia, but also conversion to amyloid positivity in otherwise clinically unimpaired individuals who were amyloid negative at baseline. These associations were independent of age, APOE4 status, sex, education, and in-scanner motion. These results support a model in which breakdowns in tightly regulated feedback loops governing DMN physiology represent a core systems-level pathophysiology of AD. Notably, this functional dyshomeostasis precedes detectable amyloidosis on imaging. Future studies should focus on the development of robust biomarkers of brain function that can be applied at the individual level, which could in turn help support the development of therapeutic approaches targeting system-level pathophysiology.

High altitude-associated pathophysiological processes may potentially accelerate aging trajectory, while evidence remains limited. We present immune landscape characterization in human populations residing at 3656-meter (Lhasa) and 5070-meter (Tuiwacun) elevations on the Qinghai-Tibet Plateau, complemented by multiorgan single-cell RNA sequencing and spatially enhanced resolution omics sequencing (Stereo-seq) of mice under simulated 5000-meter hypoxic conditions. Comparative analysis revealed significantly elevated neutrophil proportions in high-altitude population (HAP) cohorts relative to low-altitude population cohorts. Notably, aging-associated immune cells (AICs) including exhausted T cells, age-associated B cells, and high-aging-score immune cells showed marked enrichment in HAP cohorts, a pattern conserved in mouse models. Stereo-seq analyses further identified coordinated niche interactions between AICs and aging-related intestinal epithelial cells, suggesting accelerated gut aging trajectories. Our work establishes the multiomics framework for high-altitude immune remodeling while providing mechanistic insights into high altitude-associated pathophysiological processes.

Pirfenidone is a synthetic pyridone derivative that is primarily beneficial in treating idiopathic pulmonary fibrosis (IPF). Initially synthesized as an anti-inflammatory agent, it was later identified as the first oral antifibrotic therapy to improve progression-free survival in IPF, with an acceptable safety profile. Mechanistically, pirfenidone inhibits fibroblast proliferation, extracellular matrix deposition, and pro-inflammatory cytokine release by modulating the transforming growth factor-β (TGF-β) and its downstream pathways. Beyond IPF, emerging evidence suggests therapeutic potential across various fibrotic disorders related to aging, including systemic sclerosis-associated interstitial lung disease, cardiac fibrosis, uterine fibrosis, corneal fibrosis, liver fibrosis, intestinal fibrosis, wound healing, and lung cancer. However, high dose requirements and adverse events such as gastrointestinal intolerance and photosensitivity remain limiting factors of pirfenidone. To address these limitations, novel delivery systems, including lipid carriers, polymeric formulations, and other advanced systems, have been developed to enhance bioavailability, enable site-specific targeting, and sustain drug release over time. These developments underscore the evolving role of pirfenidone as a versatile antifibrotic therapy in the aging population with significant translational applications.

Vascular remodeling (VR) is a structural and functional adaptation of the vessel wall to hemodynamic, metabolic, and inflammatory stress. When persistent and dysregulated, it contributes to the progression of atherosclerosis, hypertension, pulmonary arterial hypertension, and brain microvascular disease. Endothelial senescence is increasingly recognized as a key component of this maladaptive transition, characterized by impaired endothelial homeostasis, reduced nitric oxide bioavailability, and a senescence-associated secretory phenotype (SASP) that can reshape vascular cell-cell communication and extracellular matrix remodeling. Recent evidence further suggests that mitochondrial dysfunction is closely linked to endothelial senescence through multiple mechanisms, including mtROS accumulation, mitochondrial DNA (mtDNA) damage and leakage, disturbed mitochondrial dynamics, and impaired mitophagy flux. In this review, we integrate these findings into a vascular-bed- and disease-stage-stratified conceptual framework, termed the mitochondrial dysfunction-endothelial senescence-vascular remodeling (MD-ES-VR) axis. Within this framework, mechanisms and interventions are interpreted according to evidence strength, causal level, vascular context, and remodeling stage. Current evidence most consistently supports roles for mitochondrial dysfunction in amplifying endothelial injury, inflammatory senescence-like signaling, and remodeling progression, whereas definitive proof for reversal of established structural lesions remains limited. We therefore propose that future studies should combine endothelial-specific and time-resolved designs with quantitative mitochondrial and senescence readouts and robust structural endpoints to better define causality, therapeutic windows, and translational potential.

Oxidative stress (OS) is a major contributor to aging and the pathogenesis of numerous conditions, including diabetes, neurodegenerative, cardiovascular, and autoimmune disorders. Consequently, therapeutic strategies aimed at enhancing endogenous cytoprotective pathways have gained significant interest. Plant-derived essential oils represent attractive sources for such interventions due to their natural origin and low toxicity; specifically, the monoterpenoid geraniol, a principal component of rose oil, has demonstrated promising antioxidant properties in vitro. In this study, we utilized Caenorhabditis elegans to investigate the in vivo efficacy and molecular mechanisms of geraniol effect. Our results show that geraniol significantly reduces intracellular reactive oxygen species and enhances resistance to acute OS induced by juglone. Mechanistic characterization using GFP-reporter strains revealed that geraniol activates the DAF-16/FOXO and SKN-1/Nrf2 transcription factors, while surprisingly causing a slight but consistent downregulation of the HSF-1-mediated heat-shock response. Crucially, genetic epistasis analysis using null/hypomorphic mutants demonstrated that only SKN-1 is strictly essential for geraniol-mediated protection against induced OS. In conclusion, this study underscores the utility of C. elegans as a robust and accessible platform for the pharmacological screening of natural products. Our findings establish geraniol, a key constituent of rose oil, as a multifunctional modulator of cellular defenses that orchestrates multiple cytoprotective pathways, identifying the SKN-1-dependent response as a critical driver of its antioxidant efficacy in C. elegans. By delineating this specific genetic requirement, these results provide a mechanistic foundation that supports the therapeutic potential of geraniol in mitigating aging and pathophysiology driven by OS.

Brain aging is characterized by memory loss and cognitive impairment. With the growth of the population and advances in medical care, the size of the aging population is increasing. Therefore, the discovery of anti-aging drugs has become a popular topic in recent years. Fibroblast growth factor 21 (FGF21) has been reported to inhibit oxidative stress, reduce inflammation, and delay senescence. The present study was designed to investigate the effects of recombinant human FGF21 (rhFGF21) on senescence in the brain in a mouse model of D-galactose (D-gal)-induced aging. The behavioral tests revealed that rhFGF21 improved D-gal-induced learning and memory impairment in mice. RhFGF21 improved the morphology of cortical and hippocampal neurons and increased the expression of PSD95 in the model mice. RhFGF21 reduced the number of microglia and astrocytes in the cortex and hippocampus, increased the activities of the antioxidant enzymes (GSH-PX, CAT, and SOD), and inhibited the expression of p-NFκB and p53 proteins, as well as the mRNA expression of the inflammatory cytokines (IL-1β, IL-6, TNFα, and iNOS). SIRT1 regulates senescence and inflammation, and FGF21 participates in physiological and pathological processes by binding to the FGFR1. Therefore, we measured SIRT1 and activated FGFR1 (p-FGFR1) levels. RhFGF21 administration increased the expression of cortical and hippocampal SIRT1 and p-FGFR1 in D-gal-induced aging mice. These data suggested that rhFGF21 alleviated learning and memory impairment in a mouse model of D-gal-induced aging by increasing antioxidant enzyme activity, inhibiting inflammation, and senescence-related gene expression via modulating FGFR1 and SIRT1.

Nicotinamide adenine dinucleotide (NAD) is a classical coenzyme regulating cellular energy metabolism. Emerging evidence demonstrates the causal relationship between defective NAD metabolism and various age-associated diseases. The major purpose of the present study was to investigate the role of adipocyte mitochondrial NAD biology in age-associated metabolic diseases. To this end, we focused on solute carrier family 25 member 51 (SLC25A51), a recently identified mitochondrial NAD transporter. We found that aging was associated with decreased adipose tissue SLC25A51 expression in both humans and mice. We next generated and analyzed novel knockout and overexpression models, which we have named adipocyte-specific Slc25a51 knockout (ASKO) and Slc25a51 overexpressing (ASLO) mice. ASKO mice had a marked decrease in adipose tissue mitochondrial NAD levels and exhibited age-associated systemic metabolic complications, such as obesity, glucose intolerance, insulin resistance, hyperinsulinemia, metabolic inflexibility, dyslipidemia, and hepatosteatosis. Mechanistically, loss of Slc25a51 reduced mitochondrial respiratory function, fatty acid oxidation capacity, and adiponectin production in adipose tissue, likely contributing to the development of systemic metabolic complications. Conversely, ASLO mice were protected from obesity and insulin resistance caused by aging. In conclusion, our results provide novel mechanistic and therapeutic insights into understanding the critical role of adipocyte mitochondrial NAD transporter SLC25A51 in the pathophysiology of age-associated metabolic diseases, particularly obesity and insulin resistance.

Aging is associated with declines in balance, gait, and cognitive functions, increasing fall risk and diminishing quality of life. Exergame training, which integrates cognitive and motor tasks, has emerged as a promising intervention to address these issues.

Semaglutide, a GLP-1 receptor agonist, improves metabolic health and reduces liver fat in people with HIV (PWH) and metabolic dysfunction-associated steatotic liver disease (MASLD). This post hoc analysis of the 24-week SLIM LIVER single-arm trial (ACTG A5371, No. NCT04216589, registered 02nd Jan 2020) in 41 PWH with MASLD receiving semaglutide (1.0 mg weekly) aimed to evaluate its effect on epigenetic aging and determine whether changes in epigenetic clocks associate with clinical responsiveness. Over 24 weeks, we observed DunedinPACE median change +0.018 (IQR -0.023 to +0.053), PCDNAmTL -0.006 kb (IQR -0.073 to +0.054), and PCGrimAge +0.54 years (IQR -0.33 to +1.26). Participants with decreased DunedinPACE (41.5%) showed greater liver fat reduction (p = 0.024) and trend towards improved gait speed (p = 0.081). Increased PCDNAmTL was associated with better gait speed (p = 0.012). These data suggest early signals of semaglutide responsiveness and relationships to epigenetic age biomarkers. Epigenetic biomarkers may enhance precision in GLP-1RA therapy and enable noninvasive monitoring of biological aging. Trial Registration: ClinicalTrials.gov ID: NCT04216589, registered 02nd Jan 2020.

Puerarin (PU), a natural bioactive isoflavone derived from the edible root of Pueraria lobata, exhibits multi-pharmacological activities, including antioxidant, lipid metabolism-regulating, and immunomodulatory properties. The decline in the reproductive performance of hens is primarily attributed to age-related dysbiosis of gut function and reduced function of the liver-ovary axis. However, the systemic mechanisms linking puerarin-induced microbiota changes to improvements in hepatic and ovarian function in aged hens remain poorly defined. In this study, we performed a multi-omics investigation to explore the effects on gut microbiota, liver metabolism, ovarian function, and the associations among them induced by dietary puerarin in aged hens.

Yeast protein (YP) is rich in high-quality protein and a variety of bioactive compounds and has been shown to confer beneficial effects on overall health. In this study, we systematically evaluated the comprehensive health benefits of YP in mice through a one-month dietary intervention. The results demonstrated that YP supplementation improved muscle strength, bone mineral density, bone mineral content, and the proportion of lean mass in mice. Moreover, it effectively ameliorated pathological morphology in multiple tissues and organs, alleviated fibrosis, and downregulated the expression of senescence-associated biomarkers, including SA-β-gal, p16, p53, p21, and γ-H2AX. Importantly, YP intervention modulated the gut microbiota composition, notably enriching beneficial bacteria such as

Obesity impairs subcutaneous adipose tissue function, which predisposes to chronic cardiometabolic comorbidities and accelerated biological aging. However, regulatory variants, their target genes and epigenomic landscape underlying this predisposition in each subcutaneous adipose tissue cell-type remain elusive. Our subcutaneous adipose tissue cell-type level cis-expression quantitative trait and colocalization analyses reveal cis-expression quantitative trait locus variants, regulating 279 genes for 33 cardiometabolic disease and aging traits. Most of these genes are cell-type-specific (90%), led by adipocytes (55%), and missed in previous bulk tissue colocalization studies. Conducting subcutaneous adipose tissue cell-type level epigenome analysis, we discover that the vast majority (81%) of these colocalized cardiometabolic disease and aging risk variants map to the active chromatin compartments that comprise only 45% of the human genome, revealing three-dimensional epigenome in the center of cardiometabolic disease and aging risk. These findings uncover genetic and epigenomic regulation of genes underlying 33 cardiometabolic disease and aging traits in subcutaneous adipose tissue cell-types and offer critical insights into the principal role of three-dimensional chromatin in disease risk.

Cardiovascular disease (CVD) predominantly affects elderly individuals and is the leading cause of morbidity, disability, and mortality worldwide. Systemic ageing, especially cardiovascular ageing, contributes to the development of CVD phenotypes and outcomes. Therefore, in this review, we innovatively summarize the five major etiologies and risk factors for cardiovascular ageing, including lifestyle and behavioral factors, metabolic disorders and physiological dysregulation, environmental exposures and physicochemical determinants, genetics and epigenetics, and host biology and sociodemographic determinants. Furthermore, we enumerate the structural and functional changes that occur in the cardiovascular ageing process. The twelve hallmarks of cardiovascular ageing, including genomic instability and epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, oxidative stress, and inflammation; cellular dysfunction; cellular senescence; stem cell exhaustion; metabolic changes; and the renin‒angiotensin‒aldosterone system, β-adrenergic signaling, growth signaling, and mechanosignaling, stratify across three dimensions: molecular, cellular, and systemic levels. Given the elucidated role of cardiovascular ageing in diverse pathologies, we propose specific rejuvenation strategies to mitigate residual cardiovascular risk in older adults: targeting senescent cells, adjusting energy sensor pathways, addressing central inflammatory pathways, modulating neurocardiological dynamics, adopting healthy lifestyles, and assessing and preventing the degree of ageing. We also list FDA-approved drugs and clinical trials targeting cardiovascular ageing, thus serving as a cutting-edge reference for developing intervention strategies.

Aging is a major risk factor for cancer incidence and mortality, but its effect on tumor evolution and metastatic progression remains incompletely understood. A recent study by Patel and colleagues published in Nature reveals a paradoxical role for aging in cancer biology: while aging constrains primary tumor growth, it simultaneously enhances metastatic spread. Using genetically engineered mouse models and patient-derived data, the authors demonstrate that aging epigenetically reprograms mutant KRAS-driven lung adenocarcinoma through activation of the integrated stress response (ISR). Central to this process is the transcription factor ATF4, which promotes epithelial plasticity and metabolic adaptations, thereby enabling metastasis. This work provides a mechanistic framework linking host aging to tumor cell state transitions that favor distant spread of cancer cells. Importantly, it challenges a long-held assumption that tumor aggressiveness is primarily reflected by primary tumor growth kinetics and properties, and instead, it highlights metastasis as a distinct, age-influenced evolutionary trajectory. The identification of ATF4-driven ISR signaling as a mediator of metastasis highlights new therapeutic vulnerabilities, such as an acquired dependence on glutamine, particularly for older patients who comprise the majority of lung cancer cases. More broadly, this study underscores the need to incorporate aging biology into cancer models and therapeutic strategies, redefining how we conceptualize tumor progression across the lifespan.

Understanding the factors that contribute to the preservation of cognitive abilities into advanced age despite brain injury or disease is a key goal of ageing research. Up until the last two decades, the extent of brain pathology could only be fully appreciated at autopsy. Advances in laboratory and imaging biomarkers now mean that cognitive function can be understood in the context of markers of brain injury and specific pathologies (eg, Alzheimer's disease, Lewy body disease, and cerebrovascular disease). Knowledge on the characteristics of individuals displaying cognitive resilience and its social determinants across the lifespan can inform strategies to enhance resilience at individual and population levels. There is some evidence of the effectiveness of interventions to improve cognitive functioning from high-income countries, supported by biomarker data. Looking ahead, translation of cognitive resilience research to low-income and middle-income countries-the regions with the fastest growth in dementia burden-will require addressing key challenges and seizing opportunities.

Disrupted processing of prelamin A causes Hutchinson-Gilford progeria syndrome (HGPS) and related premature aging disorders. The farnesylated prelamin A variant produced in HGPS, termed progerin, alters actin-nuclear interactions mediated by nesprin-2 and SUN2 LINC complexes resulting in defective cell polarization. To explore further how prelamin A causes these cellular defects, we examined other disease-causing mutations that prevent cleavage of lamin A or reduce the activity of the processing enzyme ZMPSTE24. Accumulation of prelamin A or an uncleaved variant in cells reduced diffusional mobilities of nesprin-2 and SUN2 and inhibited their function in cell polarization in a farnesylation-dependent manner. Expression of short carboxyl-terminal tail fragments of prelamin A variants disrupted cell polarity in a farnesylation-dependent fashion. These results show that retention of the farnesyl moiety in the tails of prelamin A or its variants is the common element responsible for disrupting actin force transmission to the nucleus in premature aging syndromes and support the idea that altered function of actin-dependent LINC complexes is a critical component of premature aging.

Frailty and obesity frequently coexist in older adults, particularly among Veterans, contributing to loss of independence, physical disability, and increased healthcare utilization. Lifestyle interventions improve mobility and function but often lead to loss of lean mass and bone density. Metformin, a widely used antidiabetic agent with geroprotective properties, may mitigate these adverse effects by targeting cellular mechanisms of aging.

Skeletal muscle mass and force decline with age, and the loss of muscle force precedes muscle atrophy. However, the underlying mechanisms remain unclear. Here, we investigated the role of the myosin co-chaperone, uncoordinated mutant number-45 myosin chaperone B (UNC45B), in regulating muscle mass and force. UNC45B expression decreased in mouse gastrocnemius muscle with age, particularly at 24 months old, and adeno-associated virus vector-mediated knockdown of Unc45b in 3-month-old mouse triceps surae muscle first reduced plantar flexor torque and then decreased gastrocnemius muscle mass. In addition, Unc45b knockdown in the triceps surae muscle resulted in lower bone mineral density. While maximum Ca

The Davos Alzheimer's Collaborative (DAC) Egypt Cohort (DAC-Egypt) is a newly established longitudinal study of cognitive aging in a community-based convenience sample of older Egyptian adults. The cohort's purpose is to characterize trajectories of cognitive decline and dementia risk factors in an understudied population, filling a critical gap in aging research in the Middle East. Participants (n = 1,530) aged 55 and above were recruited via regionally diverse convenience sampling, with detailed baseline data collected on demographics, health status, lifestyle, and cognitive function. Cognitive assessments included both traditional neuropsychological testing and innovative digital tools (digital voice/speech & olfactory-sensory assessments) to enable comprehensive monitoring. Key preliminary findings indicated a high prevalence of chronic diseases and notable socioeconomic disparities in cognitive performance among older Egyptians. Blood samples were collected from 98% of participants, and dried blood spot (DBS) cards were obtained for 88% of participants to facilitate future biomarker and genetic research. This study seeks to enrich the scientific field of dementia and Alzheimer's disease and related disorders (ADRD) for early detection and intervention strategies for cognitive health in aging populations.

BackgroundThe cellular mechanisms that promote the maintenance of cognitive abilities in very old people designated as successful agers remain under-investigated. Here, we report an episodic memory performance-based criteria that differentiates superior cognitive function from normative cognitive function in adults aged 80 and older.ObjectiveUsing this new criteria, we demonstrate how neuropathological and neurobiological underpinnings of superior cognitive performance can be investigated.MethodsThe most recent verbal episodic memory WMS-R Logical Memory Delayed Recall (LM-DR) score was derived from 144 participants with no cognitive impairment (NCI) 80 years or older participants from the Rush Religious Orders Study classified with Superior Cognitive Performance (SCP, LM-DR ≥ 14) or Normal Cognitive Performance (NCP, LM-DR 13 ≥ 7). Both groups were compared on neuropathological measures for neuritic plaque (NP), diffuse plaque (DP), and neurofibrillary tangle (NFT) load.ResultsNP (p = 0.44), DP (p = 0.27), and NFT (p = 0.28) burden did not differ between SCP and NCP cases. LM-DR scores did not correlate with NP (r = -0.08, p = 0.32), DP (r = -0.14, p = 0.07), or NFT (r = -0.12, p = 0.13) load. Biochemical analysis revealed significantly higher levels of heat-shock protein HSPB6 in SCP compared to NCP (p < 0.001).ConclusionsHeat shock protein differences were observed between NCP and SCP groups. This suggests that our proposed criteria for SCP can help identify neurobiological mechanisms of successful cognitive aging. Our SCP criteria are also concordant with the SuperAger criteria which supports the generalizability of the SCP criteria to other datasets.

The liver is a major metabolic organ, responsible for synthesizing and breaking down diverse metabolites. Recently, the liver's immunological functions have gradually been unveiled: combating pathogens and maintaining tissue homeostasis. Age-related functional alterations in these immune cells emerge as potential drivers of hepatic dysfunction and age-associated pathologies. However, systematic investigations into spatiotemporal immune cell dynamics during liver aging remain limited. To address this gap, we analyzed young and old mouse livers using single-cell/nuclei and spatial transcriptomics, revealing T cells as the immune cell population with the most pronounced transcriptomic alterations, marked by enrichment of exhausted CD8

The naked mole-rat (NMR), Heterocephalus glaber, is an unusual mammal that lives underground in eusocial colonies. NMRs show remarkable longevity and are resistant to cancer, neurodegeneration, and cardiovascular disease. The gut microbiome is known to modulate human health and disease; here, we investigate the microbiome of NMRs, comparing fecal samples from individuals over different social ranks and over a span of more than three decades. In contrast to a cohort of C57BL6/J mice, which showed extensive age-related changes, we found little difference in the microbiota of NMRs from different age cohorts. Only the archaea Methanomassiliicoccus intestinalis, which was present in the NMR gut but not the murine gut, showed an increased proportion with older age. Pregnant queens were found to have higher microbial diversity, potentially a consequence of their aggressive coprophagia. Overall, these findings provide a rich and dynamic picture of the NMR microbiome and starting points for future investigation.

Brain aging is accompanied by cognitive decline and an increased risk of neurodegenerative disease, with neuronal aging being a key causative factor. Studies have shown that the earliest damage to blood-brain barrier (BBB) integrity occurs in the hippocampus, leading to the abnormal accumulation of Fe²⁺;however, the mechanisms underlying subsequent neuronal aging remain unclear. Using single-cell and spatial transcriptomic analyses, this study focuses on the phospholipid flippase ATP11B. We found that ATP11B deficiency facilitates the transport of Fe²⁺ from ependymal cells to hippocampal neurons, activating the Hippo signaling pathway and inducing mitochondrial respiratory dysfunction and dynamic imbalance, which results in neuronal ferroptosis and exacerbation of aging phenotypes. Mechanistically, ATP11B blocks mitochondrial respiratory function by regulating the chromatin accessibility of KLF4 to mitochondrial respiratory chain complex genes. Simultaneously, it impairs the mitochondrial quality control system, resulting in elevated levels of reactive oxygen species(ROS) and enhanced neuronal aging. The mitochondria-associated metabolite, lactate, facilitates histone lactylation of ferroptosis and the key aging-related genes Acsl4, Trp53 and Cdkn1a via the TEAD-YAP complex, thereby promoting transcription. This research uncovers the molecular mechanism through which ATP11B mediates neuronal aging: regulating the iron transport-mitochondrial plasticity axis. This provides a novel avenue for targeting iron homeostasis to intervene in cognitive decline and neurodegenerative disease.

To investigate the effects of exercise on bone marrow stem cells (BMSCs) and determine underlying molecular network mechanisms through bioinformatics analysis combined experimental validation.

As the population ages, defining how biological processes change over the lifetime has become increasingly important. Acute and chronic lung diseases are more prevalent in older adults and emerging research is beginning to uncover the mechanistic and cellular pathways that link aging to conditions such as pneumonia and COPD. Additional mechanisms, particularly those involving extracellular vehicles (EVs), the microbiome, and sex differences, are now recognized as potential contributors to age-related changes in lung health yet remain underexplored. Advances in experimental models and analytical tools have accelerated progress in the field. Three-dimensional lung models such as organoids, precision cut lung slices, ECM scaffolds, and lung-on-a-chip systems offer more physiologically relevant systems than traditional two-dimensional cultures, improving translatability to in vivo biology. Meanwhile, the expansion of genomics, transcriptomics, proteomics, and metabolomics has enabled comprehensive, multi-omics approaches for mapping disease mechanisms, and such datasets are increasingly available. However, deeper integration with patient metadata and spatially resolved methods are still needed to advance precision medicine approaches to exploit aging mechanisms in chronic lung diseases. In this review, we highlight the importance of investigating EVs, the microbiome, and sex differences and their contribution of age-associated mechanism in the context of pneumonia and COPD and discuss how innovations in 3D lung models and omics technologies are reshaping our understanding of the pathological mechanisms that underlie these diseases.

The identification of genetic factors influencing cardiac senescence in natural populations is central to our understanding of cardiac aging and to identify the etiology of associated cardiac disorders in human populations. However, the genetic underpinning of complex traits in human is almost impossible, due to the infeasibility to control genetic background and gene-environment interactions. Drosophila has striking similarities in cardiac aging with humans, highlighting the conserved nature of cardiac aging for organisms with a heart. Leveraging on a large collection of inbred lines from the Drosophila Genetic Reference Panel (DGRP), we provide an accurate analysis of cardiac senescence in a natural population of flies. This permitted the discovery of an unprecedented number of variants and associated genes significantly associated to the natural variation of cardiac aging. We focused on the function of the PAR domain bZIP transcription factor Pdp1 for which several variants were found associated with natural variation of the aging of multiple cardiac functional traits. We demonstrated that Pdp1 cell autonomously plays a central role in cardiac senescence and might do so by regulating mitochondria homeostasis. Overall, our work provides a unique resource regarding the genetics of cardiac aging in a natural population.

Cellular senescence, a state of irreversible cell cycle arrest, is implicated in age-related diseases. While it is well known that senescent cells resist apoptosis, studies on their resistance to ferroptosis are limited and not fully understood. Senescent cells remain sensitive to ferroptosis induced by direct inhibition of glutathione peroxidase 4 (GPX4) but resist ferroptosis from cystine starvation, suggesting a role for mitochondrial metabolism. Here, we found that this resistance is mediated by peroxisome proliferator-activated receptor α (PPARα)-dependent upregulation of pyruvate dehydrogenase kinase 4 (PDK4), which inactivates pyruvate dehydrogenase (PDH) and suppresses mitochondria-derived reactive oxygen species, a key driver of ferroptosis. Our findings identify the PPARα-PDK4-PDH axis as a metabolic switch regulating ferroptosis sensitivity in senescent cells and provide insight into the senescence-ferroptosis interaction.

Adult-born hippocampal neurons are highly plastic but there remains uncertainty about the magnitude of neurogenesis and its long-term functional consequences. Theoretical predictions indicate that adult neurogenesis should lead to substantial growth of the dentate gyrus (DG) granule cell population. However, in practice, most studies find no changes in total cell number across adulthood. This discrepancy may partly be a sensitivity issue, where small sample sizes and the examination of older age windows (when neurogenesis is reduced) have prevented detection. However, neurogenic growth could also be masked by the turnover of developmentally-born DG neurons, which are known to die off in normal aging. To address the question of how neuronal birth and loss impacts DG population dynamics, here we quantified numbers of developmentally-born neurons, proliferating Ki67+ cells (as a proxy for adult-born neurons), and total DG neurons from 2-18 months of age in the rat. We estimate that over this timeframe 670,000 adult-born neurons are added (30% of the total population). Consistent with neurogenic growth, the total number of DG neurons increased across adulthood. However, net growth was only 385,000 cells, which is less than predicted by adult neurogenesis alone. Indeed, 20% of developmentally-born neurons were lost over the same interval, and so we propose that the difference is explained by neuronal turnover. Neuronal persistence and turnover may be relevant for theories of hippocampal long-term memory, as well as for understanding psychiatric conditions that are characterized by hippocampal plasticity and atrophy.

Osteoporosis, marked by decreased bone mineral density (BMD), poses a major public health concern by increasing fracture risk, lowering quality of life, and raising healthcare costs in aging populations. Accurate risk prediction is essential for early diagnosis and targeted intervention. While machine learning (ML) models have been used to predict osteoporosis risk based on clinical factors, their accuracy and generalizability are limited. Multi-omics studies, especially in genomics and proteomics, have shown promise in predicting osteoporosis-related traits, such as BMD and fracture risk. However, the integration of metabolomics, critical for bone metabolism, remodeling, and mineralization remains underexplored in this context. This study aimed to identify novel metabolites associated with osteoporosis risk and assess their predictive utility. Using hip BMD measurements, clinical data, and metabolomic profiles from 2041 participants aged 40 and older, we developed a predictive model integrating metabolomics with clinical risk factors. Model performance was evaluated using the area under the receiver operating curve (AUC). We identified 44 metabolites significantly associated with osteoporosis risk (

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide which was shown to be released in the hypothalamo-hypophyseal system but subsequently demonstrated in the entire nervous system and nearly all peripheral organs, including skeletal elements. PACAP has an important function in the regulation of chondrogenic differentiation, protecting in vitro chondrogenesis during various stresses and in osteogenesis. PACAP knockout (KO) mice show early signs of aging. Its most potent receptor is PAC1-R, the activation of which leads to enhanced Sox9 expression and subsequently, increase in the expression of collagen type II, glycosaminoglycans, and aggrecan. In the present experiments, we investigated the effect of the absence of PAC1 receptor in PAC1 KO homozygous and heterozygous mice focusing on joints of hind limb in young and aged animals. Thickness and extracellular matrix content of articular cartilage of joints increased in the absence of PAC1 receptor with aging. A thicker cartilage was detected in aged animals in mechanically affected joints. Interestingly, the disturbance of PACAP signaling pathways increased the nuclear translocation of P-Sox9 transcription factor in various joints. In summary, the alteration of PAC1 receptor regulated signalization elevated cartilage formation and protected cartilage architecture during aging suggesting a balancing effect of the receptor in chondrogenesis.

Sarcopenia is a progressive skeletal muscle disorder characterized by the loss of muscle mass and strength. The concept of pro-anabolic modulators (including vitamin D, leucine, omega-3 fatty acids, and probiotics) as nutritional agents to counteract sarcopenia has been introduced as a promising strategy to restore anabolic balance in aging muscle. This systematic review aimed to synthesize recent evidence on the effectiveness of these compounds on muscle mass and physical performance. A total of 53 randomized controlled trials were included: 30 evaluated vitamin D, 8 leucine, 9 omega-3, and 6 probiotics. Across studies, although results for vitamin D were heterogeneous, daily supplementation suggested a more consistent potential for beneficial effects compared to bolus regimens, particularly when co-administered with other agents or physical exercise. Leucine demonstrated greater efficacy when combined with resistance training or other pro-anabolic agents. Most studies on omega-3 fatty acids reported improvements in muscle strength and functional outcomes, especially in long-duration interventions. Probiotics also showed promising results, with almost all studies reporting positive effects on muscle mass and strength, despite variability in strains and protocols. Given the low to very low certainty of evidence for most outcomes (except for physical performance, which reached moderate certainty), these results should be interpreted with caution, despite a general trend toward favorable outcomes. These findings suggest that combining pro-anabolic modulators (or pairing them with exercise or additional nutrients) may enhance their efficacy on muscle-related outcomes. Further research is warranted to define optimal protocols and to clarify the mechanisms underlying their potential synergistic effects.