Aging

Sepsis can lead to acute respiratory distress syndrome (ARDS) and is associated with a high mortality rate. This study investigated cellular senescence-related genes in sepsis and sepsis-induced ARDS to identify novel biomarkers. Using bioinformatics analyses including WGCNA and machine learning on public datasets, six hub genes (NFIL3, GARS, PIGM, DHRS4L2, CLIP4, LY86) were identified. These genes showed strong diagnostic value and were associated with immune cell infiltration and key pathways. Validation in lipopolysaccharide (LPS)-stimulated neutrophils showed significant upregulation of NFIL3. The findings highlight the role of cellular senescence in pathogenesis and identify promising therapeutic targets for sepsis-induced ARDS.

Background: Ageing is a systems level biological process underlying the onset and progression of multiple chronic disorders. Rather than arising from a single pathway, age related decline reflects interacting disturbances in metabolic regulation, inflammation, nutrient sensing, cellular stress responses, and tissue repair. Although GLP1 receptor agonists, sodium glucose cotransporter2 inhibitors, metformin, and rapamycin are usually evaluated against disease-specific endpoints. Objective: To develop an SBML compliant quantitative systems pharmacology model in which ageing is the primary pharmacological endpoint and to evaluate which combination therapy provides the greatest benefit for both metabolic and ageing related outcomes. Methods: We developed model comprising four layers: a metabolic/pharmacodynamic layer describing weight loss, HbA1c reduction, and nausea with tolerance; a drug layer capturing class-specific effects of GLP1 agonists, sodium glucose cotransporter2 inhibitors, metformin, and rapamycin; an ageing layer representing damage accumulation, repair capacity, frailty, and biological age gap; and a biomarker layer generating trajectories and estimated glucose disposal rate. Calibration was staged across semaglutide clinical endpoints. Bayesian hierarchical meta analysis, global sensitivity analysis, and practical identifiability analysis were used to assess robustness and interpretability. Results: The model reproduced semaglutide efficacy and tolerability dynamics and supported distinct drug-class profiles across metabolic and ageing axes. Rapamycin showed minimal glycaemic effect but emerged as a dominant driver of repair related ageing outcomes. Combination simulations predicted two distinct optima: one favouring metabolic improvement and one favouring ageing related benefit. Conclusion: The model supports the view that metabolic and ageing optimization are mechanistically distinct objectives and that weight loss and glycaemic improvement alone may be insufficient surrogates for health span benefit.

Protein misfolding plays a critical role in aging and disease, yet the involvement of specific proteins in metabolic dysfunction is still poorly understood. Here, we report studies on the development of a Real-time Quaking-Induced Conversion (RT-QuIC) assay to detect misfolded insulin, a peptide hormone required for blood glucose regulation. Although RT-QuIC assays were originally designed to amplify misfolded prion proteins implicated in neurodegeneration, we adapted the method to monitor conformational changes in insulin. We first validated the RT-QuIC insulin assay using recombinant insulin and insulin aggregates recovered from clinical infusion devices. Protein characterization by gel electrophoresis, circular dichroism, and particle size analysis suggests differences in insulin recovered from the infusion device. We then applied the RT-QuIC assay to tissue samples from a mouse model of metabolic disease. This work provides proof-of-concept of a novel assay for studying the role of insulin aggregation in disease progression and aging. The RT-QuIC assay for insulin may also provide new avenues to explore early detection, mechanistic insights, and therapeutic targets of metabolic disorders linked to aging and disease.

{Delta}133p53 is a naturally occurring isoform of the human p53 protein that inhibits p53-mediated cellular senescence. We recently reported that transgenic expression of this senescence-inhibitory p53 isoform counteracts aging-associated pathological changes and extends lifespan in progeria model mice (heterozygous LmnaG609G/+). The anti-aging effect of {Delta}133p53 was attributed in part to reduced levels of the proinflammatory cytokine IL-6. To comprehensively profile {Delta}133p53-induced changes in cytokines and chemokines, we in this study performed a Luminex-based multiplex quantitative assay of mouse sera collected from transgenic {Delta}133p53-expressing LmnaG609G/+ mice and non-expressing controls. This assay not only confirmed the {Delta}133p53-mediated repression of IL-6 but also showed that {Delta}133p53 reduced the levels of CXCL1 (also known as KC), IL-1, and CXCL10 (also known as IP-10). Among these factors, we further characterized CXCL10, which has not previously been associated with progeria in mice or humans. Consistent with reduced serum CXCL10 levels, both young (15-week-old) and old (10-month-old) {Delta}133p53-expressing LmnaG609G/+ mice showed reduced Cxcl10 expression, compared with age-matched non-expressing controls, in the liver, spleen, and brain, major organs known to produce CXCL10. In naturally aged wild-type mice (2-year-old), Cxcl10 expression was also significantly repressed by transgenic {Delta}133p53 in the spleen and brain. Analysis of gene expression datasets from human tissues demonstrated an inverse association between CXCL10 and {Delta}133p53 levels, suggesting physiological relevance to human aging. This study defines CXCL10 as a proinflammatory chemokine elevated in both accelerated and natural aging and as a potential target of the anti-inflammatory activity of {Delta}133p53.

Frailty is a multi-system syndrome causing increased susceptibility to health insults in older adults. Immune system dysregulation and inflammaging have emerged as mechanisms that may affect multiple organ systems in the frailty syndrome. This present study seeks to define the immune state in community-dwelling adults suffering from frailty. We evaluated a subgroup of 169 individuals enrolled in the Gut-brain Alzheimers disease Inflammation and Neurocognitive Study (GAINS). Participants in the GAINS study were scored for frailty using the Clinical Frail Scale. A panel of 27 inflammatory cytokines was analyzed from the serum of each participant. Frailty was present in 33 (19.5%) of the cohort, and was correlated with age, malnutrition, and cognitive assessments. Statistical analysis adjusting for clinical covariates revealed higher serum levels of IL-2, IL-10, and IL-17 in frail patients. Using machine learning classification, we developed a predictive model of frailty with strong discriminative performance (AUC 0.78). Individual element analysis via Shapley Additive Explanations (SHAP) revealed that inflammatory markers had the greatest influence on the model, and IL-7 was the single most important element in the prediction of frailty. Together, our data demonstrate a novel pattern in which T-cell regulatory inflammatory molecules as mediators of frailty, implicating cellular immunity as a potential mechanism of dysfunctional aging.

Background and Aims: Alterations in immunoglobulin G (IgG) N-glycosylation are implicated in inflammatory bowel disease (IBD); however, the robustness of IgG glycan signatures across IBD cohorts with diverse demographics and geographic origins remains underexplored. We aimed to determine whether compositional data analysis (CoDA) and machine learning (ML) can identify IBD-related IgG N-glycan signatures and whether these signatures capture disease-associated acceleration of biological aging. Methods: We analyzed the IgG glycome profiles of 1,367 plasma samples collected from healthy controls (HC), symptomatic controls (SC), and people with newly diagnosed Crohn's (CD), and ulcerative colitis (UC) across four cohorts (UK, Italy, United States, and Netherlands). IgG glycosylation was analyzed by ultra-high-performance liquid chromatography, yielding 24 total-area-normalized glycan peaks (GPs). Analyses were performed using cross-sectional data obtained at baseline. CoDA-powered association analyses were used to identify disease-related effects on GPs while controlling for demographic covariates. ML models were trained and evaluated to assess generalizability to unseen cohorts and demographic subgroups, with a focus on discrimination and reliability. Results: Across all cohorts, people with IBD demonstrated accelerated biological aging as quantified by the GlycanAge index. This was accompanied by consistent reductions in IgG galactosylation, with effects partially modulated by age. Classification models trained on glycomics and demographics achieved robust discrimination (AUROC~0.80) between non-IBD (HC+SC) and IBD across cohorts. Conclusion: These findings reveal accelerated biological aging in people with IBD and support the translational potential of IgG glycans as biomarkers and a novel route toward clinically interpretable personalized risk estimates.

While bone mineral density (BMD) remains the clinical standard for assessing age-related fracture risk, accumulating evidence indicates that bone quality, including matrix properties and microarchitecture, contributes to fracture susceptibility in ways not captured by BMD alone. As matrix-targeted therapeutics emerge, preclinical models that exhibit translationally relevant bone quality changes are needed. Here, we evaluated the Fischer 344 x Brown Norway (F344xBN) F1 rat, a strain characterized by hybrid vigor and non-pathological aging, as a model for studying matrix-related mechanisms of skeletal aging. Femurs from male and female rats aged 7, 15, and 22 months were analyzed to quantify age- and sex-dependent changes in bone microarchitecture, fracture resistance, and matrix properties. Microcomputed tomography analyses revealed sexually dimorphic aging trajectories. From 7 to 22 months, females exhibited moderate declines in trabecular microarchitecture and no change in cortical porosity, whereas males showed pronounced trabecular deterioration and increased cortical porosity. Whole-bone flexural testing demonstrated age-related declines in material properties that were not attributable to changes in geometry, while females maintained geometry-scaled bone strength. Both sexes exhibited reduced bone toughness with age. Raman spectroscopy identified matrix-level alterations in males by 15 months, whereas systemic markers of bone turnover remained unchanged across age or sex. Together, these findings indicate that males exhibit combined tissue-scale and whole-bone deterioration by midlife, while females exhibit declining fracture resistance preceding substantial cortical bone loss or overt matrix deterioration. These results support the F344xBN F1 rat as a translational model for investigating matrix-driven skeletal aging. Lay summaryF344 x BN F1 hybrid rats provide a healthy, matrix-driven skeletal aging model. This strain exhibits distinct aging trajectories dependent on sex. Strength and toughness decrease in both sexes by midlife. Fracture resistance declines in females prior to substantial bone loss.

Objectives. The association between skeletal muscle gene expression and knee osteoarthritis (OA) was examined among older adult participants of the Study of Muscle, Mobility and Aging (SOMMA). Methods. Inclusion criteria included knee radiographs and bulk RNA sequencing (RNAseq) in vastus lateralis muscle, resulting in 523 participants (56% female). Radiographic knee OA was determined by Kellgren-Lawrence (KL) grades. Differential gene expression was analyzed using a control group (KL [≤] 1, n = 326) and two nested case groups: (a) KL [≥] 2 (n = 197), (b) KL [≥] 3 (n = 112). Results. Compared with controls, there were 27 and 41 genes associated (FDR [≤] 0.05) with KL [≥] 2 and KL [≥] 3, respectively, and 16 genes significantly associated in both contrasts. For 15 of the 16 genes, the association magnitude was larger with more severe OA (KL [≥] 3). Genes associated in both contrasts included brain-derived neurotrophic factor (BDNF) and interferon regulatory factor-2 (IRF2). Gene sets enriched in KL [≥] 2 and KL [≥] 3 contrasts included DNA repair and branched chain amino acid (BCAA) catabolism. Conclusions. Our results in older adult SOMMA participants indicate that knee OA is associated with genes and pathways expressed in skeletal muscle that are involved in pain sensitization, BCAA catabolism, muscle function preservation, calcium transport and storage, inflammation, and extracellular matrix remodeling. Additional longitudinal studies will be needed to determine how these genes could affect the progression of knee OA.

Objectives: Cardiovascular disease (CVD) is a leading cause of mortality and disability in older populations. This study aimed to identify CVD risk factors in community-dwelling older adults and to examine whether frailty-related factors (sarcopenia and nutritional status) interact with chronic kidney disease (CKD). Methods: This cross-sectional study included 307 community-dwelling Japanese adults aged [&ge;]65 years between September 2024 and March 2025. CVD history was assessed based on self-reported physician diagnoses obtained through a structured questionnaire. Lifestyle-related factors included hypertension, diabetes, dyslipidemia, and body mass index (BMI). Frailty-related factors included sarcopenia (Asian Working Group for Sarcopenia 2019 criteria), nutritional status (Mini Nutritional Assessment-Short Form), and physical activity (International Physical Activity Questionnaire-Short Form). CKD was defined using the estimated glomerular filtration rate (eGFR): non-CKD ([&ge;]60 mL/min/1.73 m2) and CKD (<60 mL/min/1.73 m2). Multivariable logistic regression identified independent correlates of CVD, and interactions between CKD and frailty-related factors were tested. Results: The prevalence of CVD was 17.9%. Independent correlates included CKD (aOR 5.0), hypertension (aOR 4.0), male sex (aOR 3.1), undernutrition (aOR 2.7), sarcopenia (aOR 2.7), and low physical activity (aOR 2.5). No significant interactions were observed between CKD and sarcopenia (p = 0.70) or nutritional status (p = 0.40). Conclusions: CKD, sarcopenia, undernutrition, and low physical activity were independently associated with CVD, with no interaction between CKD and frailty factors. These findings suggest that integrated management addressing both renal function and frailty-related factors may be important for CVD prevention in older adults.

Cellular senescence is a stable cell-cycle arrest state associated with characteristic phenotypes, including enlarged cell morphology, altered secretory signaling, and pronounced lysosomal remodeling. Senescent cells commonly accumulate increased numbers of enlarged lysosomes with changes in acidity and degradative capacity, creating an opportunity for simple live-cell readouts of senescence-linked organelle remodeling. Here, I describe a live-cell lysosomal profiling protocol that uses LysoTracker Deep Red, an acidotropic fluorescent dye, to label and quantify acidic organelles in individual living cells as an indicator of senescence-associated lysosomal expansion. The method is demonstrated in IMR-90 human lung fibroblasts undergoing replicative senescence across serial passaging. The protocol details cell culture and passage tracking, LysoTracker staining, fluorescence imaging, and straightforward image-based quantification of lysosomal signal intensity and lysosome-enriched area per cell. As an optional validation step, senescence-associated {beta}-galactosidase staining is performed on parallel cultures to confirm senescent cell identity. Representative outcomes show increased LysoTracker signal and expanded lysosome-enriched regions in late-passage cultures compared to early-passage controls, consistent with lysosomal remodeling during senescence. This protocol is designed to be simple to adopt and can be adapted to other cell types or senescence-inducing stresses, providing a practical, quantitative complement to conventional endpoint assays. SUMMARYThis article presents a live-cell imaging protocol using LysoTracker Deep Red to quantify lysosomal remodeling as a marker of cellular senescence in IMR-90 human fibroblasts. We demonstrate quantitative lysosomal readouts derived from fluorescence imaging, including lysosome-enriched area and intensity measurements that can be summarized per cell and, when desired, as stitched-field, per-nucleus normalized metrics. Senescence status can be validated against senescence-associated {beta}-galactosidase (SA-{beta}-Gal) staining performed on parallel cultures. The method can be adapted to other cell types or senescence-inducing stresses and enables quantitative analysis of lysosomal remodeling during senescence.

CD31+ T-cells reportedly possess angiogenic properties. These cells have recently been termed angiogenic T-cells (TANG). Advancing age is associated with altered circulating T-cell phenotypes, including TANG, and reduced angiogenesis. We examined various TANG subsets (CD3+, CD4+, CD8+), and their VEGF-A intracellular content in young (n=16, 18-30 years) and older (n=16, 50-65 years) male adults using flow cytometry. Cardiorespiratory fitness ([V]O2max) was quantified in all participants using a graded cycling ergometry test to volitional exhaustion. Resting blood samples were collected to measure circulating IL-6 and cytomegalovirus serostatus. CD31+ T-cells (TANG) contained more VEGF-A than CD31- T-cells (CD31+: 9374 {+/-} 8587 AU vs CD31-: 8722 {+/-} 8149 AU, p = 0.021) which was also exhibited in CD4+ and CD8+ subsets. Older adults possessed fewer CD4+ TANG cells as a proportion of total CD4+ T-cells than younger adults (young: 35 {+/-} 11%; older: 24 {+/-} 9%, p = 0.004), and CD3+ and CD4+ TANG subsets from older adults exhibited higher VEGF-A levels than younger adults (CD3+CD31+: young: 6081 {+/-} 4001 AU; older: 13426 {+/-} 10945 AU, p = 0.019; CD4+CD31+: young: 6373 {+/-} 3972 AU; older: 15660 {+/-} 12829 AU, p = 0.011). TANG cells were not associated with circulating IL-6, and TANG VEGF-A content was not associated with[V] O2max. Advancing age is associated with a pathological TANG phenotype, which may contribute to age-related inflammation and warrants further investigation as a potential therapeutic target.

AbstractAs organisms age, mitochondrial metabolic activity declines, and disrupted gene expression regulation mediated by histone acetylation induces the emergence of senescent physiological phenotypes in tissues. In this study, we found that periodic exposure to red light significantly increased histone H3 Lys9 acetylation (H3K9ac) levels in the tissues and organs of aged mice. Following red light exposure, silent information regulation factor 4 (SIRT4) protein levels in keratinocytes were notably reduced, whereas glycolysis, fatty acid metabolism, and the tricarboxylic acid (TCA) cycle were significantly activated in keratinocytes. The reduction in mitochondrial SIRT4 levels enhances the acetylation of mitochondrial metabolic proteins, particularly malonyl-CoA decarboxylase (MCD), a potent inhibitor of the key rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A) in fatty acid oxidation. This process promotes mitochondrial fatty acid oxidation and TCA cycle. Additionally, the decrease in SIRT4 activates SIRT1 through feedback mechanisms, thereby alleviating its inhibition on PPAR- in senescent keratinocytes and comprehensively activating the expression of genes related to lipid metabolism. This lipid metabolism activation ultimately facilitates the accumulation of acetyl-CoA within keratinocytes, increases H3K9ac levels, and reshapes the expression patterns of senescence-related genes. Eventually, cellular aging is effectively mitigated by the synergistic regulation of metabolism, inflammation, and gene expression. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/717004v1_ufig1.gif" ALT="Figure 1"> View larger version (76K): org.highwire.dtl.DTLVardef@a3387dorg.highwire.dtl.DTLVardef@1d1b083org.highwire.dtl.DTLVardef@19ba6f0org.highwire.dtl.DTLVardef@1ecf20e_HPS_FORMAT_FIGEXP M_FIG Mechanism of anti-aging action of red light: Red light can reduce SIRT4 signalling in keratinocytes, thereby reactivating lipid metabolism and increasing levels of acetyl-CoA. This promotes histone acetylation, which in turn reverses the expression of age-related inflammatory factors and genes. C_FIG

In our society, ageing, longevity, and neurodegenerative diseases are major concerns of public health. Recently, in Drosophila, we have identified a new cluster of three snoRNAs, including jouvence, and showed that each of them affect longevity and neurodegeneration. As these snoRNAs are required in the epithelium of the gut, these results point-out a causal relationship between the epithelium of the gut and the neurodegenerative lesions through the metabolic parameters, indicating a gut-brain axis. Here, we demonstrate that each snoRNA pseudouridylates a specific site on ribosomal-RNA, which consequently affects the amount of ribosomes as well as the translational efficacy. Moreover, using TRAP experiment assay, we also show that these lacks of pseudouridylations modify the translation of specific genes involved in lipid metabolism. Consequently, these lead to a chronic deregulation of trigycerides and sterols levels, whose correlate to an increase of neurogenerative lesions in old flies, as well as to a modification of longevity.

Frailty arising from loss of muscle function and mass is a significant health concern impacting quality of life and dramatically increasing health care costs as our population ages. Ameliorating frailty derived from reduced muscle function is thus a critical research priority to improve health span. Cell intrinsic defects in muscle stem cells (MuSC), or satellite cells, occur as skeletal muscle ages, reducing the capacity of MuSCs to maintain and repair skeletal muscle and are accompanied by cell nonautonomous changes. Although rejuvenating stem cells in aged tissues or organs has potential to improve muscle aging phenotypes, we found that the extracellular environment in aged mice abrogates rejuvenated muscle stem cell potential. MuSCs from young mice were unable to grow on extracellular matrix derived from aged mice that contains elevated collagen protein levels, establishing a critical role for the environment in contributing to muscle phenotypes in aging. Combining an inducible FGF receptor 1 (FGFR1) to rescue MuSC intrinsic aging defects with a drug to reduce fibrosis partially rescued muscle mass loss in aged mice. We conclude that aging affects tissues, and particularly skeletal muscle tissue, via complex multifactorial processes requiring multifaceted interventions to improve aging phenotypes.

Age-related cognitive decline and depressive symptoms are prevalent in later life, yet the genetic determinants of vulnerability remain unclear. Here, we investigated how genetic and epigenetic regulation of the serotonin transporter gene SLC6A4 contributes to susceptibility to these age-related conditions in later life. In community-dwelling older adults in Japan (N = 1,317), functional stratification of the serotonin transporter-linked polymorphic region (5-HTTLPR) revealed that participants with low-activity genotypes showed a robust co-occurrence of cognitive decline and depressive symptoms, whereas this comorbid pattern was not observed in those with the high-activity genotype. The genotype-dependent co-occurrence was consistently replicated across seven independent population-based cohorts (total N = 7,889). DNA methylation at a functional promoter CpG site increased with age and partially mediated age-related cognitive decline specifically among low-activity genotypes. In contrast, the high-activity genotype was associated with relative resistance to these functional declines, partly mediated by a protective effect on hippocampal volume during aging. Notably, genotype-dependent effects on hippocampal volume were absent in adolescence, indicating that the influence of SLC6A4 emerges in an aging-specific manner. Together, these findings identify SLC6A4 promoter activity as a key genetic factor modulating vulnerability and resilience in later life.

BackgroundThe composition and function of the gut microbiome have been shown to contribute to both health and disease. One of the most powerful modulators of microbial composition and function is diet. Materials & MethodsUsing the E{micro}-TCL1 murine model of B-cell chronic lymphocytic leukemia (CLL), we assigned male and female mice to a high-fat, high-carbohydrate Western diet (HF) or standard chow (CH) diet. ResultsMice consuming a HF diet had significantly shorter survival than those consuming a CH diet, irrespective of sex, with female mice exhibiting particularly poor outcomes. We also observed a significant increase in splenic involvement by CLL in the HF diet-fed mice at time of sacrifice. Mice receiving the HF diet demonstrated immediate and profound effects on the gut microbiome, marked by reduced alpha diversity and significantly different community composition as measured by beta diversity. Notably, there was a sustained increase in Akkermansia muciniphila and Bacteroidetes thetaiotaomicron in HF diet-fed mice, coupled with a corresponding increase in microbiome functional pathways related to arginine and histidine biosynthesis, chitin degradation, and nucleotide biosynthesis. DiscussionCollectively our data provides evidence of the profound and sustained impact of a high-fat Western diet upon the gut microbiome community and CLL pathogenesis in the E{micro}-TCL1 murine model of CLL.

Alzheimers disease (AD) is a devastating neurodegenerative disorder characterized by memory loss and a decline in cognitive function. Hallmarks of AD include an age-dependent accumulation of toxic amyloid beta (A{beta}) 42 in the brain, energy dyshomeostasis caused by mitochondrial dysfunction, and iron overload. However, the role of iron overload and mitochondrial dysfunction in AD pathology is unknown and their precise relationship with A{beta} 42 toxicity in AD pathology is unclear. C. elegans provide a powerful model system to untangle and clarify these relationships. In this study, we quantify the temperature-dependence of iron toxicity (16, 20 and 25C) in neurons and muscle of C. elegans that overexpress A{beta} 42. We found that A{beta} 42, regardless of the cell-type expression, caused accelerated paralysis compared to age-matched WT worms with the greatest degree of paralysis observed at an elevated temperature (25C). Moreover, the combination of iron toxicity and A{beta} 42 results in an enhanced paralytic phenotype at 16C. Thus, iron exposure potentiates A{beta} toxicity observed at low temperatures. Iron toxicity stimulated both maximum (State 3) and leak (State 4) respiration in WT and A{beta} 42 worms. A{beta} 42 worms also exhibited increased leak respiration at baseline that was further exacerbated by iron toxicity. Iron burden and sensitivity increased A{beta} 42 peptide toxicity. A{beta} 42 worms exhibited reduced levels of Ca, Zn, Mn, and K. Overall, our results suggest that iron potentiates A{beta} toxicity at low temperature and enhances A{beta} peptide mediated mitochondrial bioenergetic dysfunction in C. elegans. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/714217v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@9eaf46org.highwire.dtl.DTLVardef@542eforg.highwire.dtl.DTLVardef@16d9678org.highwire.dtl.DTLVardef@1b1b16d_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LITemperature stress modulates the synergetic interactions of iron toxicity and A{beta} 42 pathology C_LIO_LIIron sensitivity drives increased cell-type specific A{beta} 42 pathology C_LIO_LIEnergy dyshomeostasis via impaired mitochondrial function and increased proton leak contributes to iron- and A{beta}-induced pathology C_LI

Time-restricted feeding (TRF) aligned with an organisms circadian rhythm has been shown to improve health, but its long-term effects on healthspan and lifespan in mammals, especially under normal dietary conditions, remain unclear. Here, we examined the impact of 12-hour (h) and 8h nightly TRF windows in male and female mice fed regular chow. TRF improved multiple health measures, including behavioral rhythmicity, body weight and composition, frailty, and disease onset. These effects were most pronounced in the 8h-TRF group, which exhibited voluntary caloric restriction in addition to time restriction. A composite Healthspan Index revealed that TRF extended healthspan in both sexes, though the benefits were more prolonged in females relative to their total lifespan. Median lifespan was significantly extended in males under 8h-TRF by 12%, whereas females showed no significant lifespan extension, highlighting sex-specific responses to TRF.

Dietary protein intake mediates healthy aging in diverse species, with consumption of a low protein (LP) diet improving metabolic health in both humans and mice. In mice, the benefits of LP diets are sex-specific, with males exhibiting a stronger response to a LP diet than females. The reason for this sexually dimorphic response is unknown, but we hypothesized that sex hormones might be responsible for this difference. Here, we tested the role of sex hormones in the response to a LP diet by feeding intact and gonadectomized mice of both sexes either a Control (21% of calorie from protein) or LP (7% of calories from protein) diet, and assessing the effects on weight, body composition, glycemic control, and energy balance over the course of three months, followed by molecular and histological analysis of tissues from each group. We confirm that males show a stronger metabolic response to an LP diet than females, but that ovariectomy sensitizes female mice to the metabolic effects of an LP diet, making them respond more similarly to males; conversely, castration does not substantially impact the response of males to an LP diet. Molecularly, we find that gonadectomy and sex are important interactors that mediate the response of mechanistic target of rapamycin (mTOR) signaling, lipid homeostasis, and thermogenesis to an LP diet. Together, this data shows that the resistance of female mice to an LP diet is mediated by ovarian hormones and suggests the possibility that older female humans might receive enhanced benefits from LP diet feeding.

Introduction: Frailty is a dynamic condition associated with increased vulnerability to adverse health outcomes in older adults. While previous research has primarily focused on deficit-based mental health factors, such as depression and loneliness, less is known about the role of positive mental health determinants, including well-being, resilience and social connectedness, in the development and progression of frailty. Understanding both risk and protective factors is essential for informing public health strategies aimed at promoting healthy ageing. This study aims to examine the longitudinal relationship between mental health and frailty in a nationally sampled population of adults aged 50 years and older in Slovenia. Methods and analysis: This longitudinal observational study will collect data at four time points over a two-year period (January 2026-March 2028). A stratified random sample of community-dwelling adults aged 50-84 years will be drawn from the national population registry, with 5,000 individuals invited to participate in the first wave. Frailty, mental health and a set of social, psychological, and health-related factors will be assessed. Data will be analyzed using a combination of descriptive, inferential and longitudinal statistical methods to examine associations between frailty and mental health over time. Potential explanatory factors will also be explored within the longitudinal framework, and additional analyses will assess the impact of attrition. Ethics and dissemination: The study has been approved by the Ethics and Deontology Committee of the National Institute of Public Health. Participation is voluntary, and informed consent will be obtained from all participants. Data will be anonymized and handled in accordance with applicable data protection regulations. Findings will be disseminated through peer-reviewed publications, conference presentations and public health reports to inform strategies for promoting healthy ageing.