Aging changes the lipidome and mitochondrial function in a sex-dependent manner, yet their associations remain poorly understood. Twenty-four younger (7M/17F) and forty-three older (21M/22F) adults underwent blood draws and skeletal muscle biopsies for this cross-sectional investigation. Plasma lipidomic profiling was performed via liquid chromatography-tandem mass spectrometry, while peak mitochondrial O2 utilization (OXPHOS) and hydrogen peroxide (H2O2) emission were assessed using high-resolution respirometry. Plasma lipidomic analysis annotated 535 lipid species across 28 different lipid classes. Lipid-age associations were identified in four lipid classes for both sexes with twelve lipid classes demonstrating sex-specific associations, including triglycerides (TG), carnitines (CAR), and fatty acids (FA). For lipid-OXPHOS interactions, the primary lipid class and species associated with higher OXPHOS exclusively in males were ceramides (CER) and dimethyl cholesterol esters (dimethyl-CE), while TG were the primary lipid species associated with impaired OXPHOS in females. For lipid-H2O2 interactions, the primary lipid class and species associated with higher H2O2 were methyl desmosteryl esters (methyl-DE), methyl cholesterol esters (methyl-CE), FA and TG in males whereas females exhibited 10 (CE, SM, LPC, dihexosylceramides (Hex2Cer), LPE, PI, HexCer, LPI, CAR, and hexosyl-N-acetylneuraminyl-ceramides (Hex2NeuAcCer)) lipid classes associated exclusively with H2O2 emission. These findings establish novel age- and sex-specific relationships between age-related changes in plasma lipids and skeletal muscle mitochondrial function, revealing distinct lipid signatures for respiration and H2O2 emission in males and females.

The American Heart Association (AHA) recently introduced a new clinical entity; the cardiovascular-kidney-metabolic syndrome (CKMS), to promote a multi-disciplinary approach for chronic disease management. This study aims to investigate the relationship between CKMS and major adverse outcomes in older populations in primary care. This study utilized data from 18,367 community-dwelling individuals aged ≥ 65, free from prior cardiovascular disease (CVD). Participants were classified into four CKMS stages (stage 0-no CKMS risk factor to stage 3-high CKMS risk) at baseline based on the AHA definition. The association with 14 health outcomes was analysed using multivariable cause-specific hazard models. Additional stratifications were performed by social disadvantage, inflammation levels, and number of CKMS components within each stage to refine risk staging. Over a median follow-up of 8.6years, the prevalence of CKMS stages 0 to 3 was 2.8%, 8.2%, 52.6%, and 36.0%, respectively. Compared to stage 0, stage 3 associated with all-cause mortality (HR 1.31, 95%CI 1.01-1.69), CVD mortality (3.11, 1.46-6.60), incident total CVD events (2.78, 1.86-4.15), myocardial infarction (2.37, 1.21-4.62), stroke (2.75, 1.50-5.04), heart failure hospitalization (4.56, 1.45-14.37), atrial fibrillation (2.63, 1.61-4.29), cancer (1.31, 1.04-1.64), depression (1.20, 1.04-1.39), and physical disability (1.92, 1.20-3.08). Social disadvantage, high inflammation, and CKMS component count further amplified these associations. No linear trend was observed for cognitive outcomes and non-CVD cause-specific mortality. This study is the first to establish relationships between CKMS and multiple age-related outcomes in older adults, providing critical insights for developing holistic approaches to primary care in the aged.

Non-cognitive, neuropsychiatric symptoms (NPS) are nearly universal in Alzheimer's disease (AD), but investigation of their underlying biology is complicated by comparative medicine approaches that incompletely capture spontaneous disease, primarily using transgenic rodent models. The aged companion dog, which spontaneously develops an AD-like disease called canine cognitive dysfunction (CCD), may help fill this translational gap. Using data from the Dog Aging Project with > 10,000 aged dogs (> 8years old), we identify numerous behaviors in dogs "at-risk" for and with CCD that mirror NPS in humans. Compared to dogs without CCD, our analysis shows that dogs with CCD are less physically active, exhibit fewer previously trained behaviors, demonstrate fewer motivated behaviors, have more daytime sleep, demonstrate more separation anxiety, have altered anxious responses to novelty, have changes in aggressive behaviors, and exhibit lower appetite. Using k-means clustering, we did not find evidence for behavioral sub-phenotypes. Overall, our analysis of a large number of aged dogs suggests clinically significant NPS are associated with CCD and that the companion dog may serve as an important comparative medicine approach to understand these debilitating symptoms across species.

Aging is accompanied by cumulative oxidative stress that promotes tissue degeneration and reproductive decline. Here, we show that deficiency of superoxide dismutase 1 (SOD1) accelerates oxidative injury and reproductive aging through a ferroptosis-linked redox imbalance, and that ginseng root extract (GR) confers protection across species. Aged hairless Sod1⁻/⁻ mice exhibited markedly elevated skin and plasma oxidative stress markers-including 8-isoprostane, malondialdehyde (MDA), and pentosidine-together with dermal cyst formation and atrophic pathology. Complementary studies in C. elegans revealed that SOD1-deficient strains displayed increased reactive oxygen species, depleted glutathione, and elevated iron and lipid peroxidation-canonical features of ferroptosis-associated oxidative stress. These redox alterations coincided with shortened reproductive span and reduced progeny output, both rescued by ferroptosis inhibition or GR supplementation. In female Sod1⁻/⁻ mice, GR restored folliculogenesis, normalized estrous cyclicity, and improved ovarian morphology. Collectively, these findings identify SOD1 loss as a driver of ferroptosis-associated oxidative and reproductive aging and highlight GR as a promising redox-targeted intervention.

Aging is a complex biological process characterized by molecular changes across multiple biological scales. While these alterations have been extensively studied in humans and rodents, the molecular changes associated with aging in dogs remain underexplored despite their relevance as a model for human aging. In this study, we profiled gene expression (n = 16,273 genes) and protein abundance (n = 2041 proteins) in whole blood and blood plasma from 40 laboratory beagles across young (3-5years old, n = 10), old (8-9years old, n = 17), and geriatric (10-14years old, n = 13) life stages. We identified 816 genes and 40 proteins that significantly changed in abundance during aging, converging on pathways involved in DNA repair, collagen processing, and inflammation. Notably, these canine aging signatures overlapped with human age-associated genes, including those tied to the hallmarks of aging, reinforcing the existence of conserved aging mechanisms across species.

Early identification of markers of cognitive decline in cognitively normal older adults is essential for dementia prevention strategies. Sensorimotor measures, such as gait speed, grip strength, and reaction time, may provide sensitive indicators of current and future impairment. This study examined associations between baseline sensorimotor function and cognitive decline in cognitively normal older adults. In this prospective cohort, 246 cognitively normal older adults from the DRIVES Project completed baseline assessments of grip strength, gait speed, simple reaction time, and the Preclinical Alzheimer Cognitive Composite (PACC). Participants were followed for a mean of 4years. Linear mixed-effects models adjusted for demographics, APOE ε4 status, and neighborhood deprivation. Cross-sectional analyses evaluated the associations between sensorimotor measures and cerebrospinal fluid (CSF) biomarkers of amyloid, tau, and plasma neurofilament light chain (NfL). Participants (mean age: 74.9 ± 5.17years; 48.8% female) had a mean baseline PACC score of 1.06 ± 0.50. Cross-sectionally, slower gait speed was associated with higher CSF tau/Aβ42 ratio (p = 0.027), CSF tTau/Aβ42 ratio (p = 0.009), and plasma NfL (p = 0.024). A slower reaction time was associated with lower baseline PACC scores (p = 0.028). Longitudinally, low grip strength (p = 0.002) and slow gait speed (p < 0.001) were predictive of lower cognitive performance, with slow gait speed also predicting a faster decline (p = 0.015). Sensorimotor function measures are associated with current and future cognitive performance, supporting their role in early identification of older adults at risk for cognitive decline.

Plasma biomarkers of Alzheimer's disease and related dementias (ADRD) are associated with the risk of dementia. However, the extent to which they could reflect cognitive ageing, and whether this is consistent across factors known to influence biomarkers (e.g. sex and chronic kidney disease) and in different populations, is unknown. Data were from a diverse community-dwelling cohort of older individuals without dementia in Australia (n = 11,930) and the US (n = 1,181). Global cognition, verbal fluency, episodic memory and psychomotor speed were assessed repeatedly over more than a decade. Plasma phosphorylated tau181 (p-tau181), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and amyloid beta (Aβ) 42 and 40 were measured using Simoa technology. Higher levels of p-tau181 (β: -0.001 to -0.212), GFAP (β: -0.022 to -0.300) and NfL (β: -0.022 to -0.219), and lower levels of Aβ42/40 ratio (β: 0.015 to 0.126) were associated with greater cognitive decline over time. Associations were strongest for global cognition, episodic memory, and psychomotor speed, and weaker/non-significant for verbal fluency. All associations were consistent across countries. Furthermore, in stratified analyses, the results did not differ by sex or depending on the presence of chronic kidney disease. We found robust associations between plasma ADRD biomarkers and cognitive change in initially healthy older individuals in both Australia and the US, and across both sexes. Despite chronic kidney disease influencing biomarker levels, associations were consistent among individuals with and without chronic kidney disease. This indicates the potential broad utility of these biomarkers.

Cellular senescence and necroptosis are two cell fates, which trigger an inflammatory response and increase with age, that have been proposed to play a role in inflammaging. In this study, we performed the first study to directly test the possible interaction between necroptosis and cellular senescence. Using a novel Mlkl-KI mouse model, we were able to specifically induce (~ 4-fold) the overexpression of MLKL, the necroptotic executioner, in hepatocytes (hMlkl-KI mice). The overexpression of MLKL led to increased necroptosis and cell damage/death in liver, as shown by increased levels of MLKL-oligomers, TUNEL staining, and Ki-67 staining in the livers, as well as increased ALT activity and HMGB1 levels in the plasma. The increase in necroptosis was paralleled by an increase in cellular senescence. We observed increased levels of p16INK4A and p21Clip1/Waf1 as well as SASP-factors. As expected, inflammation, as measured by the levels of proinflammatory factors and mononuclear cell clusters, was increased in the hMlkl-KI mice. Transcriptomic analysis revealed that MLKL overexpression altered the expression of genes involved in cellular senescence, inflammation, and drug metabolism. The increase in inflammation, necroptosis, and cellular senescence in the livers of 6-month-old hMlkl-KI mice was associated with an increase in liver fibrosis. The data from our study suggest that necroptosis has the potential of inducing inflammation through two pathways: (1) the initial inflammatory storm triggered by DAMPs released from necroptotic, dying cells and (2) SASP-factors produced by senescent cells that were induced by necroptosis.

Gait performance depends on numerous aspects of brain functioning that are also relevant to key cognitive processes throughout the lifespan. The Timed Up and Go (TUG) test has been shown to be a reliable tool for assessing age-related mobility changes and risk of falls in older adults. This study aimed to predict TUG performance using motor-cognitive inter-network connectivity, cognitive performance and socio-demographics. 189 participants without cognitive impairment were included. Mobility was measured with the TUG through a wireless inertial sensor device. Functional connectivity between the somatomotor hand, cerebellar, and cognitive-related networks was assessed using pairwise correlations among 264 predefined regions assigned to large-scale functional networks. Connectivity between networks was summarized by averaging Fisher z-transformed values across all ROI pairs linking each network pair. Three linear regression models were constructed including the dependent variables TUG total time, turning time and turning peak-angular velocity (PAV) and the independent variables age, sex, years of education, memory and executive performance, and inter-network connectivity patterns. Somatomotor hand - ventral attentional and cerebellar - DMN inter-network connectivity were significant predictors of TUG total time. Memory performance, somatomotor hand -salience and -cingulo opercular inter-network connectivity were significant predictors of turning time. Age, years of education, somatomotor hand - dorsal attentional and cerebellar - cingulo opercular network activation were significant predictors of turning PAV. Findings indicate different contributions of attentional systems to gait performance in aging.

Previous findings on the link between metabolic syndrome (MetS) and the risk of all-cause dementia, Alzheimer's disease (AD), vascular dementia (VD), and cognitive decline are inconsistent. We systematically searched Embase, PubMed, Web of Science, the Cochrane Library, and Scopus up to June 2025 for prospective cohort studies conducted in community-based settings among adults aged 18years or older that reported risk estimates (e.g., relative risks, hazard ratios, or odds ratios) for the association between MetS and the risk of dementia or cognitive decline. Risk of bias for studies were assessed using ROBINS-I, and the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was applied to evaluate the certainty of evidence. Relative risks (RR) with 95%CI were computed using a random-effects inverse-variance method. Twenty-eight cohorts involving 6,753,197 participants were examined. MetS was significantly associated with a higher risk of all-cause dementia (RR = 1.11, 95%CI: 1.07-1.14; absolute risk difference: 2 more cases per 1000 persons), VD (RR = 1.33, 95%CI: 1.21-1.46; absolute risk difference: 7 more per 1000), and cognitive decline (RR = 1.24, 95%CI: 1.10-1.40; absolute risk difference: 5 more per 1000), all based on low-certainty evidence. No significant association was found between MetS and AD, with very low certainty. MetS components of hypertension, hyperglycemia, and low HDL-C were key risk factors, with a dose-response relationship observed between the number of MetS components and dementia risk. Subgroup analyses indicated MetS increased all-cause dementia risk in individuals under 70 (p-value for interaction: 0.048). MetS was positively associated with increased risk of all-cause-dementia, VD, and cognitive decline, but not AD. However, the effect sizes were modest and the certainty of evidence was low. Further prospective cohort studies are needed to confirm the associations.