Biological age estimation is increasingly used in aging research, but evaluation often relies too heavily on mean absolute error (MAE) against chronological age. We conducted a narrative review of major molecular aging clocks and propose an operational framework that links clock selection to the intended task. Applications are organized into four tasks: chronological-age estimation, age-independent deviation, future disease or mortality risk, and longitudinal monitoring of aging pace or intervention response. For each task, the framework specifies the target construct, output, preprocessing and confounding checks, validation metrics, and interpretation limits. A complementary four-layer model distinguishes relatively stable molecular measures, pace-of-aging measures, dynamic functional markers, and organ-specific vulnerability. Published examples illustrate why no single metric is sufficient: low age-prediction error does not establish clinical relevance, and strong risk association does not establish responsiveness to intervention. Aging clocks should therefore be evaluated as task-bound measurement tools, with explicit attention to calibration, discrimination, reliability, transportability, uncertainty, and incremental value. This framework is intended to support transparent model selection, reporting, and interpretation rather than designate a universally superior clock.

Although the mechanisms underlying cognitive performance (CP) are increasingly understood, the genetic basis of the cerebral cortex and subcortical brain tissues and association with cognitive behaviors remain unclear. This study utilized the summarized expression quantitative trait loci (eQTL) data from the genotype-tissue expression (GTEx) v8 database along with CP data from genome-wide association studies (GWAS) on OpenGWAS. A total of 117 genes related to CP were identified, distributed across 9 brain regions: amygdala, anterior cingulate cortex, cortex, frontal cortex BA9, hippocampus, hypothalamus, accumbens, and caudate. Among them, 9 genes were present in at least 6 brain regions. Gene functional annotation revealed that these identified genes are primarily enriched in neuro-related pathways, associated with distinct brain cell types, and exhibit expression in peripheral tissues. The phenome-wide association study (PheWAS) highlighted the significance of genes related to CP for human health in multiple aspects, while the cognitive-behavioral association analysis revealed the association between 26 genes and specific cognitive behaviors. Furthermore, mendelian randomization (MR) analyses validated 9 genes (AFF3, TRIOBP, TYW5, CEP192, CHST10, WBP2NL, ANAPC4, GRK4, and LRPPRC) as biomarkers for CP. Notably, this study identified genes associated with CP in cortical and subcortical brain tissues and demonstrated that these genes are significantly associated with changes in cognitive behaviors. This crucial discovery offers new insights into the prevention and control of early cognitive deterioration in European-ancestry populations.

Adipose tissue aging is increasingly recognized as a systemic process involving altered fat distribution, ectopic lipid deposition, and metabolic dysfunction, yet its shared genetic architecture remains incompletely characterized. In this study, we constructed a latent multivariate genetic phenotype of adipose tissue aging by integrating genome-wide association summary statistics for seven adipose- and metabolism-related traits, including visceral adipose tissue volume, abdominal subcutaneous adipose tissue volume, thigh subcutaneous adipose tissue volume, liver proton density fat fraction, fasting insulin, adiponectin, and leptin. Using Genomic Structural Equation Modelling, we derived a latent phenotype termed mvAdiposeAge and further characterized its genetic and biological relevance through genome-wide association analysis, FUMA-based functional annotation, MAGMA gene-level analysis, transcriptome-wide association analysis, expression fine-mapping, pathway and tissue enrichment analyses, and Mendelian randomization. The Genomic SEM model supported a shared genetic dimension linking adipose distribution, ectopic lipid accumulation, and adipose-related metabolic traits. Genome-wide analysis identified a prominent signal at chromosome 16q12.2, with rs1421085 in the FTO region emerging as the lead variant. MAGMA identified 49 FDR-significant genes, while transcriptome-wide analysis prioritized 11 genes, with FOCUS fine-mapping highlighting expression-mediated signals involving FTO, RPGRIP1L, and AKTIP. Functional enrichment implicated neurotrophin signalling, synaptic organization, cAMP signalling, immune and phagocytic processes, endocrine regulation, and metabolic pathways, with tissue enrichment suggesting prominent brain-region-specific signals. Mendelian randomization further supported positive associations of adiposity-related traits with mvAdiposeAge and an inverse association with cognitive performance. These findings highlight mvAdiposeAge as a latent genetic factor capturing shared genetic variation across adipose-related phenotypes relevant to aging and provide a framework for further investigating their systemic biological associations.

Ginsenoside Rg1, the main active component of Panax ginseng, has been shown to improve mitochondrial function and delay cell aging by regulating chaperone-mediated mitophagy. However, how Rg1 works in Caenorhabditis elegans is still unclear. In this study, C. elegans was used as a model to study how Rg1 regulates autophagy and mitochondrial function, and to understand its anti-aging mechanism. The results showed that Rg1 treatment significantly kept cells alive and maintained muscle shape in aged C. elegans, and effectively extended their lifespan. Further studies found that Rg1 improved mitochondrial function by activating mitophagy, which helped the C. elegans better resist oxidative stress. In addition, by combining RNA sequencing and bioinformatics analysis, the transcription factor daf-16 was identified as a key target of Rg1. Experiments using daf-16 knockout strains confirmed that Rg1 produced its anti-aging effects through the daf-16 pathway, in which the activation of mitophagy and the improvement of antioxidant ability were both mediated by daf-16. In conclusion, this study shows that Rg1 slows aging in C. elegans through a daf-16-mediated mitophagy pathway, providing experimental support for the study and use of natural products in anti-aging research.

Minimal hepatic encephalopathy (MHE) is a neurological complication associated with chronic liver disease characterized by subtle cognitive impairment and neuroinflammation, particularly in the aging population. However, the molecular mechanisms underlying age-associated MHE remain poorly understood. The present study investigated the role of Fetuin-A-mediated neuroinflammation and its potential as a therapeutic target in the management of MHE in old rats using pioglitazone in a thioacetamide (TAA)-induced MHE model in aged rats. Old male rats were administered TAA (50 mg/kg) for 14 days to induce MHE, followed by pioglitazone treatment (3 mg/kg) for 7 days. Western blot and immunofluorescence analyses revealed elevated hippocampal Fetuin-A expression in MHE rats, accompanied by activation of the TLR4/MyD88/NF-κB signaling pathway and increased inflammatory cytokines (IL-6 and TNF-α). Pioglitazone treatment significantly reduced Fetuin-A expression and was accompanied by reduced TLR4, MyD88 and nuclear NF-κB expression, and by decreased astrocyte activation Furthermore, histological and Golgi-Cox analyses demonstrated restoration of neuronal density, dendritic arborization, and spine density in the hippocampus of pioglitazone-treated old MHE rats. Behavioral analyses further confirmed the molecular and histological findings. Thus, elevated hippocampal Fetuin-A is associated with TLR4/MyD88/NF-κB activation in aged MHE rats, and its pharmacological reduction by pioglitazone is accompanied by reduced neuroinflammation, restored hippocampal cytoarchitecture and recovered recognition memory. A causal role for Fetuin-A remains to be established by direct perturbation.

Aging is modulated by conserved nutrient-sensing pathways that integrate metabolic cues to regulate growth, stress resilience, and lifespan. Caloric restriction (CR) extends longevity across species, motivating the search for compounds that engage related physiology. Lysergic acid diethylamide (LSD), a classic serotonergic psychedelic with emerging therapeutic applications, remains unexplored in the context of aging. Here we show that chronic exposure to nanomolar LSD extends lifespan in Caenorhabditis elegans by up to 17.6% at the 25% survival timepoint, and reduces age-associated lipofuscin accumulation. This response involves serotonergic GPCR signaling: LSD failed to extend lifespan in ser-1 and ser-5 mutants and shortened lifespan in ser-4 and ser-7 mutants, yet remained effective, although with reduced magnitude, in tph-1 animals deficient in serotonin synthesis, indicating that endogenous serotonin production is not strictly required. LSD also elicited phenotypes that overlap with CR, including reduced reproductive output, smaller body size, delayed vulval development, and time-dependent remodeling of lipid stores and PHA-4 levels, while adult food-consumption assays detected no reduction in feeding under the conditions tested. Notably, the lifespan benefit was absent in eat-2 mutants and was lost under bacterial dilution, where LSD instead shortened lifespan, indicating that nutritional context shapes the response. Transient exposure during early adulthood was sufficient to extend lifespan. Together, these findings identify LSD as a tool to investigate how serotonergic signaling interfaces with conserved longevity-related pathways.

Cellular senescence is characterized by coordinated disruptions in mitochondrial function and epigenetic regulation, with perturbation of the mitochondria-chromatin axis emerging as a central hallmark of this process. Resveratrol (RSV) has been extensively investigated as a modulator of this axis; however, its clinical utility is constrained by dose-dependent cytotoxicity. Here, we evaluated the safety profile and anti-aging potential of resveratrol glucoside (R-glc), a glucosylated derivative of RSV. R-glc exhibited markedly reduced cytotoxicity compared to RSV and effectively attenuated multiple senescence-associated phenotypes at low concentrations. Mechanistically, R-glc enhanced mitochondrial function, as evidenced by increased oxidative phosphorylation and reduced glycolytic dependence. At the epigenetic level, R-glc upregulated the NAD[+]-dependent deacetylase SIRT6 and decreased histone H3 lysine 9 (H3K9) acetylation, indicating improved chromatin stability. Taken together, these findings identify R-glc as a safer and functionally effective modulator of the mitochondria-chromatin axis, supporting its potential as a clinically applicable intervention for age-related functional decline.

What explains the large variation in lifespan across species? I examine an information-turnover proposition-that ancestral environmental variability should shorten captive lifespan after controlling for body mass, temperature and extrinsic mortality (P1), with a possible lineage-fate interaction (P2)-against the classical extrinsic-mortality prediction that safer niches permit longer life. I state the decision rules in advance rather than register a third-party protocol. Integrating AnAge (4,219 records), PanTHERIA, WorldClim/CHELSA climate and a 4,100-species mammal phylogeny with Pagel's-λ phylogenetic generalized least squares (PGLS), together with Paleobiology Database fossils across two mass extinctions, the lifespan-mass scaling reproduces (slopes 0.158 mammals, 0.212 birds; P < 10[-][140]). P1 is not supported under the most conservative specifications: weak proxy signals attenuate or reverse at λ = 1 and under family fixed effects, and the set of analyses is best read as overlapping sensitivity and robustness checks rather than independent falsifications; equivalence intervals for the climate coefficients exclude large (arboreality-sized) effects but not small ones. A basal-metabolic-rate correlate likewise dissolves at λ = 1. Turning the same pipeline to niche safety, flight, arboreality, aquatic life and hibernation carry positive mass-corrected coefficients in raw and maximum-likelihood-λ contrasts; at λ = 1 in a joint model (n = 652) only multiply-origin arboreality is significant (b = + 0.106 dex, 95% CI 0.065-0.147, P = 5.8 × 10[-7]), whereas flight and aquatic life are inconclusive with wide confidence intervals. Ancestral reconstruction recovers dozens of independent arboreal gains (42 by parsimony; 45-50 by maximum-likelihood; stochastic-mapping median 70-81, 95% range ≈ 57-94) versus one to a few for flight or aquatic life. Bivalve geographic breadth is associated with survival across the K-Pg and end-Permian extinctions, although the effect weakens after controlling for sampling completeness and is a genus-level extinction phenomenon rather than an individual-lifespan mechanism. Turtles live ≈ 1.8 × longer than same-mass squamates (turtle-squamate comparison n = 179, P = 8 × 10[-8]). Human lifespan is an extreme outlier on the scaling plane. The comparative evidence is therefore most consistent with a strong association between extrinsic-mortality regime (niche safety) and lifespan, and with no detectable independent role for environmental fluctuation rate at the effect sizes this study could resolve; I report where inference is inconclusive rather than claim a null effect or a decisive causal setting. The focal analyses comprise 977 mammals and 1,063 birds for the scaling law, 798 species with climate data, 878 species with trait contrasts, 652 species in the joint phylogenetic model, and 349 species with basal metabolic rate (298 in the tree-matched model); each result reports its own sample size.

Baker's yeast is a long-standing model for studying mechanisms of aging. Due to asymmetric division, yeast mother and daughter cells are distinguishable, and mother cells usually cease division after 15-25 budding events. However, yeast suspensions consist predominantly of young cells. Here we investigated whether, under harsh environmental conditions, replicative aging-defined by the number of buds produced-manifests at early replicative ages. To test this, we adapted a flow-cytometry-based pulse-chase labeling method to track the survival of cells of increasing replicative age, from daughter cells to mother cells that had produced up to eight buds on average. We found that stress-induced mortality increased with replicative age across all nine stress conditions tested. Mitochondrial dysfunction, caused by depletion of mitochondrial DNA, altered basal stress resistance for some stresses but largely preserved the age-dependent decline in stress resistance across conditions. Similarly, deletion of FOB1, which extends replicative lifespan under optimal conditions, did not markedly alter this decline under heat shock or acetic acid. In contrast, deletion of SIR2, which shortens replicative lifespan, steepened the age-mortality slope under acetic acid stress but not under heat shock. Together, our data indicate that aging manifests early in life under various extreme environments, and that the genetic determinants of maximum replicative lifespan tested here are largely dispensable for the early decline in stress resistance.

Finasteride is one of the core medications for treating androgen-associated diseases in men. It exhibits multiple therapeutic functions, including inhibiting 5α-reductase, reducing dihydrotestosterone levels, and improving conditions, including prostate enlargement and hair loss. Using Drosophila as the primary model and a mouse behavioral assay as a complementary approach, we combined developmental and behavioral assessments, morphological analyses of motor and sensory neurons, transcriptomics, and genetic methods to investigate developmental, neuronal, and behavioral changes associated with Finasteride exposure and explore their potential molecular basis. Our results indicate that Finasteride exposure is associated with increased intestinal reactive oxygen species (ROS) accumulation and shortened lifespan in both sexes, together with significantly reduced starvation resistance in males. In addition, Finasteride exposure was also associated with altered neuromuscular junction (NMJ) morphology, reduced locomotor performance, and decreased cask expression. Motor-neuron CASK overexpression improved NMJ morphology and locomotor performance in Finasteride-exposed flies. Overall, this study reveals changes in lifespan and locomotor phenotypes associated with Finasteride exposure and further highlights the importance of investigating its broader biological effects in other experimental systems.

Age-related changes in hepatocyte ploidy, binucleation, proliferative activity, and senescence-associated cell-cycle arrest may jointly influence liver regenerative capacity, but these features are usually evaluated separately. We developed two composite indices and examined their behavior in a long-term rat model of chronic circadian disruption. Male Wistar rats were assigned to control lighting, constant illumination (dark deprivation; DD), or constant illumination with melatonin (DD + melatonin, 10 mg/kg five times weekly) and assessed at 6, 12, 18, and 24 months. The Index of Regenerative Reserve (IRR) was defined as the proportion of binucleated hepatocytes divided by mean hepatocyte ploidy. The Integrated Index of Regenerative Status (IRS) further incorporated Ki-67 (a marker of active cell proliferation) and p21 (a cyclin-dependent kinase inhibitor associated with cell-cycle arrest) as fractional terms: IRS = IRR × (1 + Ki-67)/(1 + p21).In DD animals, IRR declined from 2.00 ± 0.42 at 6 months to 0.386 ± 0.19 at 24 months; the corresponding 24-month IRS was 0.32 ± 0.17. In DD + melatonin animals, 24-month IRR and IRS were 2.285 ± 0.41 and 2.08 ± 0.16, respectively. Exploratory receiver-operating-characteristic analysis yielded areas under the curve of 0.843 for IRR and 0.905 for IRS. These findings support IRR and IRS as experimental composite descriptors of the hepatic regenerative phenotype. External validation and direct functional regeneration assays are required before broader biological or clinical interpretation.

Oxidative stress resistance is an important trait that contributes to the long lifespan of Drosophila melanogaster, but its epigenetic inheritance via transgenerational transmission has been poorly studied. In this study, using reciprocal crosses between normal-lifespan (NLS) and long-lifespan (LLS) lines, we investigated the transgenerational inheritance of paraquat-induced oxidative stress resistance across the parental, F1, and F2 generations, assessing survival, locomotor performance, and antioxidant biochemical defenses. The results showed that LLS flies had significantly higher resistance to paraquat than NLS flies, with females being more resistant than males. We also observed a sex-specific maternal effect on female survival, with N♂ × L♀ offspring having significantly lower mortality than L♂ × N♀ offspring in the F1 and F2 generations. Locomotor resilience was found to be the most robust transgenerational maternal effect (in both sexes and generations). Our narrow-sense heritability for negative geotaxis in males provided a measure of differential transgenerational transmission of locomotor resilience through mothers. Among the measured antioxidant defenses, glutathione was the most consistent transgenerational maternal antioxidant trait. N♂ × L♀ offspring had significantly higher glutathione levels than L♂ × N♀ in F1 and F2 generations in both sexes, with positive F2 recombination values, indicating transgenerational amplification of glutathione-based antioxidant capacity. Catalase had near-zero heritability, consistent with its predominantly nuclear regulation. Variance partitioning analysis revealed prominent maternal contributions to ROS, LPO, SOD, and locomotion in the parental generation, which were reduced in subsequent generations. Taken together, these findings indicate that the adaptive stress resistance linked with longevity is heritable in Drosophila in a trait-dependent fashion, predominantly driven by the maternal lineage. Locomotion and glutathione regulation are the most maternally inherited traits, making them the primary subjects of subsequent studies on the cytoplasmic, epigenetic, and mitochondrial pathways that mediate transgenerational stress resistance.

To investigate whether CT-derived radiomic features capture imaging patterns associated with chronological age groups in mice and to assess the influence of imaging platform and photon-counting CT reconstruction strategy on classification performance. Female C57BL/6NRj mice from three chronological age groups (28, 88, and 99 weeks; n = 11) underwent clinical photon-counting CT (PCCT) and preclinical Albira II CT. Heart, liver, and spleen were segmented and radiomic features were extracted. The individual mouse was defined as the independent biological unit. Model development and evaluation used nested leave-one-mouse-out cross-validation with all preprocessing, feature selection, model selection, and, where applicable, reconstruction-energy selection restricted to the respective training folds. Organ-level class probabilities were averaged to generate one mouse-level prediction. Monoenergetic PCCT reconstructions from 40 to 180 keV were evaluated, including a fully nested energy-and-pipeline selection analysis. A grouped mouse-level permutation analysis with 200 permutations was performed for the primary monoenergetic workflow. Albira II correctly classified 5/11 mice (45.5%; 95% CI, 21.3-72.0%), whereas PCCT-SPP correctly classified 10/11 mice (90.9%; 95% CI, 62.3-98.4%). The fully nested monoenergetic PCCT workflow correctly classified 9/11 mice (81.8%; 95% CI, 52.3-94.9%; balanced accuracy, 83.3%; macro-F1, 83.3%). Energy-specific performance varied considerably: 110 keV showed the highest accuracy (81.8%) and was selected in 7/11 outer folds, whereas the highest macro one-vs-rest AUC occurred at 130 keV (0.867). None of the 200 permuted analyses reached the observed fully nested monoenergetic accuracy (plus-one corrected Monte-Carlo p = 0.005). CT-derived radiomic features showed chronological age-group-associated patterns in this exploratory murine cohort, with classification performance varying substantially across imaging platforms and reconstruction strategies. PCCT-SPP showed the numerically highest performance, while monoenergetic PCCT demonstrated pronounced energy dependence without evidence for a universally optimal reconstruction energy. These findings require validation in larger independent cohorts and correlation with independent biological-aging reference measures.

As life expectancy increases globally, ageing has emerged as the main risk factor driving the increasing burden of neurological disorders. Although advances have been made in understanding their pathogenesis, current therapies remain largely symptomatic and do not prevent disease progression. There is a growing body of evidence that these disorders share common molecular mechanisms, including oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy, ferroptosis, and blood-brain barrier disruption. Recently, the Hippo signalling pathway has been identified as a key regulator of these processes through its downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). In addition to its well-characterised functions in the regulation of organ size and tissue regeneration, Hippo signalling has crucial roles in neuronal survival, maintenance of neural stem cells, synaptic plasticity, neurovascular integrity and cellular responses to metabolic and mechanical stress. Dysregulation of this pathway in aging contributes to cellular senescence, impaired tissue repair and progressive neurodegeneration. This review summarizes the physiological functions of Hippo-YAP/TAZ signaling in the aging brain and discusses its mechanistic involvement in major neurological disorders. We further highlight the extensive crosstalk between Hippo signalling and key pathways regulating inflammation, oxidative stress, autophagy, and mitochondrial homeostasis. Finally, recent advances in therapeutic strategies targeting Hippo signalling, including small-molecule modulators, drug-repurposing approaches, and natural bioactive compounds, are discussed along with current challenges and future perspectives. Collectively, the available evidence positions the Hippo-YAP/TAZ pathway as a promising therapeutic target for developing disease-modifying interventions against ageing-associated neurological disorders.

Due to increase in life expectancy, aged population is growing exponentially, globally which has impact on human health as well as biomedical research. Research highlighted coordination between aging and arthritis where aging is the underlying hallmark of arthritis progression. Despite knowing the route of pathogenesis regarding most prevalent joint disorders like Osteoarthritis (OA) and rheumatoid arthritis (RA); efficient curable approach is still challenging. Worldwide 7-8% populations suffer from OA while 0.2-1% people are invaded by RA. Due to high cost, inadequate pharmacological action and adverse effects, NSAIDs are considered as secondary treatment option. Today, demographic changes towards polyherbal medicine usage targeting inhibition of pro-inflammatory cytokines are the challenge of the day. This study focused on Triphalaguggul (TG); a polyherbal formulation for treatment of arthritis targeting down regulation of pro-inflammatory cytokines and its signaling pathways. Toxicology study along with anti-OA and anti-RA evaluation in MIA and CFA induced rat model respectively. TG could reduce 96.15% inflamed knee, 95.18% paw edema and also helped in regrowth and rearrangement of chondrocytes properly in OA. In arthritic condition, increased hematological parameters like SGPT, SGOT, AlkP, CRP, RF were reinstated to normal range after treatment (p < 0.05). ELISA revealed that elevated IL-6, TNF-α, IL-1β were decreased after drug treatment (p < 0.05). Enhanced expression of p-JAK2, p-STAT3, NFκβ/p65 were downregulated (p < 0.05) after treatment which was validated by western blot and immunohistochemistry. Finding suggested that TG exhibited anti-arthritic activity down-regulating pro-inflammatory cytokines, JAK/STAT and NFƘβ signaling pathway as a therapeutic biomarker to protect from geriatric disease.