GeroScience

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: 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.

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

INTRODUCTIONHealthful dietary patterns may attenuate dementia risk by preserving cerebrovascular health. Prior work has focused on systemic arterial stiffness, but cerebrovascular measures may be more sensitive to neuroprotective effects of diet. We examined associations between Mediterranean diet adherence, prefrontal cortex (PFC) arterial elasticity, and cognition in older adults. METHODSParticipants were 198 older adults (58% female; mean age 65.6 years) from the Newcastle ACTIVate cohort. Mediterranean Diet (MedDiet) scores were derived from the Australian Eating Survey food frequency questionnaire. Pulse Relaxation Function (PReFx), an index of PFC arterial elasticity, was measured using pulse Diffuse Optical Tomography. Cognition was assessed with CANTAB and a cued task-switching paradigm. RESULTSHigher MedDiet was associated with higher PFC arterial elasticity. MedDiet was not associated with cognition, and PReFx did not mediate diet-cognition associations. DISCUSSIONGreater Mediterranean diet alignment was cross-sectionally associated with PFC arterial elasticity, suggesting a pathway through which diet may influence brain health in ageing.

BackgroundAgeing is a sex-specific process characterised by a progressive decline in physiological integrity. DNA methylation represents a primary epigenetic hallmark of ageing, yet sex-specific patterns of epigenetic ageing within and across tissues remain poorly understood. This study aims to address these gaps through an integrated analysis of sex-moderated epigenetic ageing across eight human tissues. MethodsA total of 137 DNA methylation datasets comprising over 36,000 individuals aged 10-114 years were analysed using a meta-analytic workflow to identify age-associated differentially methylated positions (aDMPs) and regions (aDMRs), meta-regression to assess sex moderation, and pathway enrichment analyses to interpret functional relevance. FindingsIndividual tissues displayed distinct age-related methylation trajectories, but some DMP sites showed consistent hyper- or hypomethylation across tissues. Across tissues, we identified 68,630 aDMPs (10%) robustly associated with ageing. Age-associated changes at the regional level were less common, with only 80 robust age-associated aDMRs detected across tissues, representing 0.09% of analysed regions. Sex moderation was observed for only 16 aDMPs (0.002%), indicating that sex effects on age-associated DNA methylation are largely tissue-specific rather than shared across tissues. InterpretationOur findings indicate that age-associated DNA methylation changes predominantly occur at isolated CpG sites rather than extended genomic regions and are strongly dependent on tissue and genomic context. The minimal overlap of sex-moderated methylation signals across tissues suggests that age-related sex differences at the epigenetic level are more likely attributable to tissue- and cell-type-specific variation rather than to broadly conserved epigenetic mechanisms shared across tissues. FundingThis study was funded by an Australian Research Council (ARC) Discovery project (DP200101830). Severine Lamon was funded by an ARC Future Fellowship (FT210100278). Nir Eynon was funded by NHMRC Investigator Grant (APP1194159), and a Hevolution/AFAR New Investigator Award in Aging Biology and Geroscience Research. Mandhri D. Abeysooryia was supported by an Australian Government Research Training Program (RTP) Scholarship. Research in context Evidence before this studyDNA methylation is widely recognised as a central epigenetic hallmark of ageing. Previous research has demonstrated that some age-related methylation changes are conserved across tissues, forming the basis of pan-tissue epigenetic clocks. Most studies to date have primarily examined age effects in isolation. Although biological sex influences ageing trajectories and susceptibility to nearly all age-related diseases, sex-moderated epigenetic ageing has received limited investigation. Specifically, pan-tissue clocks, including GrimAge and PhenoAge, are "sex-aware" but were trained and validated in mixed-sex cohorts, limiting their capacity to disentangle tissue-specific sex effects. Consequently, it remains unclear whether sex-moderated epigenetic ageing signals are shared across tissues or are tissue-specific. Added value of this studyThis study provides a large-scale, comprehensive multi-tissue analysis of sex-moderated epigenetic ageing, integrating 137 DNA methylation datasets across eight human tissues and more than 36,000 male and female individuals spanning the lifespan. Our findings show that while age-associated methylation changes are widespread at the CpG level, sex-moderated effects are rare and largely tissue-specific, with minimal overlap across tissues. Implications of all the available evidenceTogether, the available evidence indicates that epigenetic ageing is predominantly driven by shared, conserved age-related methylation changes, whereas sex differences in epigenetic ageing are modest and context dependent. These sex-related effects are more likely to reflect tissue- and cell-type-specific variation rather than widespread, shared mechanisms. This underscores the need to develop sex-specific epigenetic clocks and to conduct longitudinal cohort and intervention studies to more precisely characterise sex-specific dynamics of epigenetic ageing across tissues.

Biological aging is accelerated in people with multiple sclerosis, but whether such acceleration occurs during the pre-symptomatic phase or varies by organ system is understudied. We analyzed two independent proteomics datasets profiled using distinct platforms: the Johns Hopkins cohort profiled using the SomaScan platform (348 multiple sclerosis/49 age-matched controls) and the Department of Defense cohort profiled using the Olink platform (134 multiple sclerosis/79 age-matched controls), including 117 pre-symptomatic samples from people with multiple sclerosis (median lead time: 4.0 years), to estimate systemic and organ-specific proteomic age gaps using established clocks in pre-symptomatic and symptomatic phases, and assess their associations with severity. In the Johns Hopkins cohort, people with multiple sclerosis demonstrated acceleration of systemic ({beta}=2.2, 95% CI 1.2-3.2, P<0.001, FDR<0.001), brain ({beta}=1.7, 95% CI 0.6-2.7, P=0.003, FDR=0.01), muscle ({beta}=2.5, 95% CI 1.3-3.7, P<0.001, FDR<0.001), and immune age ({beta}=1.8, 95% CI 0.6-2.9, P=0.003, FDR=0.01), with findings reproduced in the Department of Defense cohort for systemic ({beta}=0.7, 95% CI 0.0-1.4, P=0.04, FDR=0.34) and brain age (3.2 years, 95% CI 2.1-4.3, P<0.001, FDR<0.001). Proteomic age acceleration was evident prior to symptom onset [systemic: ({beta}=1.0, 95% CI 0.4-1.7, P=0.002, FDR=0.02); brain: ({beta}=2.4, 95% CI 1.2-3.7, P<0.001, FDR=0.002)], whereas no immune age acceleration was detected before or after onset. Higher systemic age gap was associated with greater global Age-Related Multiple Sclerosis Severity Score ({beta}=0.14, 95% CI 0.05-0.24, P=0.005, FDR=0.03) and slower walking speed ({beta}=0.02, 95% CI 0.01-0.03, P=0.006, FDR=0.04), while higher muscle age gap was associated with greater global Age-Related Multiple Sclerosis Severity Score ({beta}=0.17, 95% CI 0.10-0.24, P<0.001, FDR<0.001), poorer manual dexterity ({beta}=0.28, 95% CI 0.04-0.52, P=0.03, FDR=0.30), slower walking speed ({beta}=0.02, 95% CI 0.01-0.03, P=0.002, FDR=0.02), lower peripapillary retinal nerve fiber layer ({beta}= -0.26, 95% CI -0.41 to -0.10, P=0.001, FDR=0.02) and ganglion cell-inner plexiform layer thicknesses ({beta}= -0.35; 95% CI -0.65 to -0.05; P=0.02, FDR=0.30). Higher brain age gap was associated with several imaging measures, including lower whole-brain ({beta}= -0.002, 95% CI -0.003 to -0.001, P=0.002, FDR=0.02), and lower peripapillary retinal nerve fiber layer thickness ({beta}= -0.21, 95% CI -0.39 to -0.03, P=0.02, FDR=0.10). Proteomic age acceleration in multiple sclerosis is detectable years before symptom onset and distinct organ-specific aging signatures are associated with disease severity. Proteomic aging may provide a biologically informative marker of early disease processes and a clinically relevant readout of disease heterogeneity.

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.

Glycosylation is a key structural modification of immunoglobulin G (IgG) that modulates its effector functions and has multiple roles in balancing inflammation. Altered IgG glycosylation has been reported in many diseases, often years before clinical manifestation, suggesting its causal role and biomarker potential. Here, we analyzed IgG glycome composition in 20,405 individuals from 42 different studies processed at the Genos Glycoscience Research Laboratory between 2008 and 2025. Across nearly all diseases, specific IgG glycome profiles reflected accelerated biological aging. Accelerated glycan aging was strongly associated with increased risk of all-cause mortality, independent of established clinical risk factors and potential confounders. Moreover, interventions known to reduce mortality risk, including hormone replacement therapy, therapeutic plasma exchange and caloric restriction, were associated with reversal of glycan aging. Given their role in modulating low-grade systemic inflammation, IgG glycans may represent a functional link between chronic inflammation, aging, disease susceptibility and all-cause mortality.

Alzheimers disease (AD) neuropathological changes can be detected with blood-based biomarkers during the long preclinical phase that precedes clinical diagnosis. Tau phosphorylated at threonine 217 (p-tau217) has been found to closely correlate with brain A{beta} burden. A recent large-scale cross-sectional study showed elevated p-tau217 concentrations in older individuals (Aarsland et al., 2025). This increase was higher in those with AD dementia and mild cognitive impairment (MCI), and lower in those with intact cognition and higher educational attainment. Thus, intact cognition and higher education may be associated with lower levels of AD neuropathological changes. Here we tested this hypothesis using longitudinal data from the population-based Betula study (n=1005; 1531 samples). The results revealed increases with increasing age over 10 years in p-tau217, where individuals with accelerated episodic-memory decline had the strongest increase. There were no differences in p-tau217 trajectories between individuals with lower or higher education or with well-maintained or age-typical decline in episodic memory. The lack of association with education was further replicated in the independent BioFINDER-2 cohort. These findings underscore the value of plasma p-tau217 for detecting early pathological changes in population-based settings but provide no support that individuals with well-maintained episodic memory or high educational attainment are spared from neuropathological changes.

Chronotype reflects individual circadian preference for timing of sleep, wakefulness, and peak performance and has been linked to variability in prefrontal cognitive function across the day. Whether chronotype independently relates to dual-task gait cost (DTC) and whether this relationship differs by cognitive task domain is unclear. Sixty-nine healthy young adults (37 female; mean age 21.3 years) completed the Morningness-Eveningness Questionnaire (MEQ). Spatiotemporal gait parameters were recorded with three-dimensional motion capture during single-task walking and three dual-task conditions: backward word spelling (5LWB; phonological), serial subtraction by seven (SS7; arithmetic), and reverse month recitation (RMR; sequential). DTC was calculated for eight gait parameters. Condition differences were assessed with nonparametric tests and post-hoc comparisons. Multiple linear regression, adjusting for age, sex, BMI, and baseline gait velocity, tested the independent association between MEQ score and mean velocity DTC; exploratory Spearman correlations examined other parameters. SS7 produced the largest mean velocity DTC (-12.76%), significantly greater than 5LWB (-7.95%; p = 0.002) and RMR (-9.57%; p = 0.021). MEQ score independently predicted mean velocity DTC in 5LWB ({beta} = -0.51, p < 0.001, R{superscript 2} = 0.269) and RMR ({beta} = -0.55, p = 0.004, R{superscript 2} = 0.222), indicating greater morningness associated with better gait-speed preservation under cognitive load; the SS7 association was not significant ({beta} = -0.33, p = 0.071). Exploratory correlations showed MEQ-DTC associations across 7/8 parameters in 5LWB, 4/8 in RMR, and 3/8 in SS7. Chronotype is independently associated with dual-task gait cost in a task-domain-specific manner, with stronger effects for phonological and sequential tasks than for arithmetic processing. The SS7 condition yielded the largest interference but weakest chronotype modulation, suggesting arithmetic dual-task disruption may be less sensitive to circadian arousal. Fixed testing time and cross-sectional design warrant within-subject, multi-timepoint studies to confirm chronotype effects separate from time-of-day confounds.

Background: Alzheimer's disease (AD) exhibits marked sex differences. While sex hormone levels across the lifespan likely contribute to this, little remains known about their causal impact and their relation to sex-biased genetic risk for AD. We therefore sought to identify potential shared genetic architectures, as well as causal genes and relationships, between sex hormone-related traits and AD risk. Methods: Large-scale AD sex-stratified genome-wide association study (GWAS) results were available from case-control, proxy-based, and population-based cohorts, including the Alzheimer's Disease Genetics Consortium, Alzheimer's Disease Sequencing Project, UK Biobank, and FinnGen. Sex hormone-related trait GWAS were available for age at menarche, menopause, and voice breaking, as well as testosterone, sex hormone-binding globulin (SHBG), progesterone, follicle stimulating hormone, luteinizing hormone, and estradiol levels. Cross-trait conjunctional analyses were conducted to identify pleiotropic overlap between sex-hormone traits and AD, followed by prioritization of candidate causal sex-biased AD genes through quantitative trait locus genetic colocalization analyses. The potential regulatory impact of sex hormones on these genes was assessed through transcription factor motif analyses. Finally, sex-stratified mendelian randomization analyses were used to infer causal effects of sex hormones on AD risk. Results: Genome-wide pleiotropy analyses demonstrated enrichment of AD with testosterone, SHBG, and age-at-menarche traits in women. We identified 12 high-confidence pleiotropic loci, 9 of which showed stronger AD effect sizes in women (3 in men) and 8 that were novel. Genes at these loci were often causally implicated in brain tissues and enriched for promoter-associated androgen receptor transcription factor binding motifs. Mendelian randomization indicated higher bioavailable testosterone in women (OR:0.88; 95%-CI:0.82-0.96) and higher SHBG levels in men (OR:0.86; 95%-CI:0.77-0.96) were associated with lower AD risk. Conclusions: Our findings reveal sex-specific shared genetic architectures between AD and sex hormone-related traits and nominate related genes that may drive sex-biases in AD risk. Several of the implicated female-biased genes are relevant to phosphatidylinositol and lipid metabolism, including Fatty Acid Desaturase 2 (FADS2). While we observed no causal effect of estradiol-related traits on AD risk, the protective effects of bioavailable testosterone in women and SHBG in men provide targets for sex-informed AD risk stratification and prevention strategies.

Aging reshapes the cellular and molecular landscape of mammalian tissues. These changes can be progressive, preceding linearly with age, or occur as abrupt transitions of the course of lifespan. To investigate the age-dependent cellular and molecular shifts we profiled matched proteomes and transcriptomes from male and female murine spleens across eight time points, from stable adults through late life. The spleen was chosen to integrate understanding of age-dependent changes associated with immune surveillance, inflammaging, and immune-related proteostasis. Male and female mice follow distinct aging trajectories particularly in protein-RNA correlation in late life, reflecting both compositional shifts and failure of post-transcriptional buffering. To investigate whether these changes could be attributed to specific cell-types within the spleen, we developed Celestial, a machine-learning framework to identify cell-type-specific changes in bulk tissue samples. We found that age-related bulk molecular changes could be attributed in part to compositional remodeling of cell-types--expansion of GZMK+ CD8+ T cells and C1Q+ macrophages alongside naive T cell and global B cell loss. These results demonstrate that cell-type-aware interpretation can inform bulk multi-omic data for accurate mechanistic inference in heterogeneous tissues undergoing complex molecular remodeling.

Qualitative models of Alzheimers pathology often posit that amyloid accumulation follows a sigmoid curve, indicating that the rate of deposition wanes over time. Longitudinal PET data now allow us to investigate amyloid accumulation trajectories with greater detail and over longer follow-up periods. We combine inferences from simulated amyloid trajectories, empirical PET data from the Alzheimers Disease Neuroimaging Initiative (ADNI), and the sampled iterative local approximation algorithm (SILA) to assess whether amyloid accumulation reaches a physiologic ceiling. We find that SILA reliably detects a ceiling, when present, across a range of simulated scenarios that impose a sigmoid shape. When fit to empirical data from ADNI, however, SILA does not appear to indicate the presence of a ceiling. Thus, we conclude that amyloid trajectories may not reach a physiologic ceiling during the stages of Alzheimers disease typically observed while patients remain under follow-up in cohort studies. Fits using SILA indicate that illustrative models of biomarker cascades, while useful tools for conceptualizing and interrogating pathologic processes, may not represent the shapes of amyloid trajectories accurately. Summary for General PublicAmyloid, a protein implicated in Alzheimers disease, is thought to reach a plateau in the brain, but methods that estimate how amyloid changes over time suggest it grows unabated. Gantenberg et al. use one such method and simulations to argue that amyloid does not reach a plateau during the typical course of Alzheimers.

Socioeconomic inequalities in health and well-being are a major public health concern, particularly in ageing populations. Education is a key determinant shaping multiple aspects of health outcomes. We used cross-sectional data from wave 9 of the German sample (n=4,148) of the Survey of Health, Ageing and Retirement in Europe (SHARE) to test whether formal education is associated with well-being in later adulthood, with health literacy, self-rated health, and preventive health behaviours as possible mediators. Our results showed that education was positively associated with greater well-being, but only via indirect pathways. Specifically, self-rated health, health literacy, and fruit and vegetable consumption mediated the relationship between education and well-being accounting for 54.7, 24.7, and 12.6 percent of the total effect, respectively. In addition, there were significant positive correlations between education and health literacy, as well as high-intensity physical activity, daily fruit and vegetable consumption, more preventive health check-ups, and less smoking. In contrast, alcohol consumption was more common among those with higher levels of education. All health behaviours and health literacy were correlated directly or indirectly (i.e., mediated by health) with well-being. These findings highlight the importance of examining indirect pathways linking education to well-being in later life. Interventions aimed at improving health literacy and promoting healthy behaviours may help reduce educational inequalities in quality of life among older adults.

Progranulin (PGRN) is a neurotrophic and anti-inflammatory factor produced mainly by neurons and microglia in the central nervous system. Progranulin haploinsufficiency causes frontotemporal dementia (FTD). In a previous study we showed that transgenic restoration of progranulin in neurons in progranulin knockout mice (NestinGrn KOBG knockout background) did not prevent the dementia-like phenotype. Here, we assessed if pharmacologic microglia depletion via PLX3397-diet (CSF1R-antagonist) had therapeutic value in these mice. Microglia depletion and spontaneous repopulation was confirmed in immunofluorescence and rtPCR studies. There was no difference in depletion or repopulation efficiency between NesGrn KOBG, PGRN KO and heterozygous (het) PGRN mice, but microglia repopulated faster than in control Grn-flfl mice, and the morphology of primary PGRN deficient microglia during repopulation was closer to homeostatic microglia, and it was accompanied by a remarkable restoration of dendritic spines and synaptic structures. Regardless of these positive effects, NesGrn KOBG and PGRN het mice experienced serious side effects during microglia depletion which peaked around the microglia nadir. Overactivity and excessive grooming escalated and caused serious skin lesions. Bulk transcriptomic and metabolomic studies in the brain taken 8 weeks after the end of PLX-diet clearly revealed differences between genotypes but mostly no lasting impact of PLX-diet, except for a further increase of proinflammatory genes, cathepsins and complement factors in PLX-treated groups. Cell type specific lipidomic studies revealed a time dependent switch not only in microglia but also astrocytes upon PLX3397 treatment. While nadir-microglia were triglyceride-laden, repopulated microglia returned to normal TG levels but were enriched in ether-bound phosphatidylcholines (PC-O) and lysophosphatidylglycerol species which are pro-inflammatory lipids; and astrocytes overtook the TG burden during repopulation. Our data suggest that microglia depletion may cause a deterioration in progranulin-deficiency.

BackgroundTau aggregation is the defining feature of tauopathies, however, the mechanisms by which distinct tau strains drive disease-specific responses remain unclear. Existing models largely rely on recombinant tau seeding or tau overexpression, which fail to capture the biochemical diversity of pathological tau. The aim of this study was to develop a robust and reproducible human cell-based model of disease-specific tau pathology and to use this model to determine how tau from unique diseases impact tau accumulation and lysosomal dysfunction. MethodsPatient-derived tau aggregates were enriched from post-mortem brain tissue obtained from sporadic Alzheimers disease (AD), Picks disease (PiD), progressive supranuclear palsy (PSP), and control cases using phosphotungstic acid precipitation. Patient-derived tau preparations were biochemically characterised by immunoblotting and mass spectrometry and normalised for tau content prior to seeding. Patient-derived tau aggregates were seeded into multiple human immortalised cell lines (SH-SY5Y, M03.13, U-87 MG, and U-118 MG cells) and iPSC-derived astrocytes. Tau seeding efficiency, aggregate morphology, and integrity of the autophagy-lysosomal pathway was assessed using quantitative imaging approaches. ResultsPatient-derived tau seeds retained disease-specific phosphorylation patterns and isoform composition and led to reproducible, dose-dependent insoluble tau accumulation in all cell lines tested. Despite equivalent tau input and similar background protein composition, PiD-derived tau had the most aggressive pathological signature, showing the highest number of tau aggregates per cell and inducing system wide disruptions in the autophagy lysosomal system including increased SQSTM1 puncta and lysosomal damage markers. Seeding with AD-derived tau led to a high number of tau aggregates per cell and more specifically depleted the lysosomal protease CTSD and uniquely co-seeded A{beta} pathology. Seeding with PSP-derived tau resulted in only a moderate number of tau aggregates per cell and uniquely caused increased lysosomal biogenesis. ConclusionsTogether, these results demonstrate that intrinsic properties of human tau strains drive disease-specific cellular responses and establish a scalable, physiologically relevant platform for dissecting tau-cell interactions and screening therapeutics across tauopathies.

Chronic inflammation is a common feature of aging and is observed across various age-related neurodegenerative diseases, including Alzheimers disease (AD). It has, however, been challenging to develop measurements of brain structure directly linked to peripheral measures of neuroinflammation. This cross-sectional study examined whether plasma levels of markers related to inflammation are associated with diffusion magnetic resonance imaging (dMRI) measures of white matter microstructure: mean diffusivity (MD) and Neurite Orientation Dispersion and Density Imaging (NODDI) free water fraction (FWF) and orientation dispersion index (ODI). Participants included 457 dementia-free individuals (mean age=63.82, SD=7.63). Blood plasma markers related to inflammation included two measures of systemic inflammation, (1) high-sensitivity C-reactive protein (CRP), and (2) a composite of pro-inflammatory cytokines (IL-1, IL-1{beta}, IL-2, IL-6, IL-8, TNF-, TNF-{beta}), as well as (3) glial fibrillary acidic protein (GFAP), a measure of astrocytic activation. Higher cytokine composite levels were associated with higher values of all three measures (FWF, ODI, MD) in cerebral white matter, and with higher ODI in the cerebellar peduncles. Higher CRP levels were associated with higher ODI in cerebral and cerebellar white matter. Associations with GFAP were not significant after adjusting for multiple comparisons. Results were consistent after accounting for plasma biomarkers of AD pathology (p-tau181/A{beta}42). Thus, higher levels of peripheral pro-inflammatory markers are associated with white matter microstructure (higher FWF, ODI, and MD), supporting the view that these dMRI-based metrics are sensitive to inflammatory processes. Additionally, the sensitivity of dMRI-based measures to inflammation may differ by inflammatory marker types.

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.

BackgroundChronic exposure to high-altitude hypoxia imposes sustained cardiovascular stress, yet hemodynamic adaptation among healthy high-altitude dwellers is heterogeneous and remains poorly characterized. This study aimed to identify distinct hemodynamic phenotypes in a healthy high-altitude population using unsupervised machine learning and to evaluate their association with multi-system subclinical target organ damage. MethodsThis cross-sectional study enrolled 694 healthy adults permanently residing at [&ge;]3300 m on the Qinghai-Tibet Plateau. Unsupervised K-means clustering was performed on nine hemodynamic variables, including peripheral and central blood pressures, augmentation index (AIx), pulse pressure amplification ratio (pPP/cPP), and systolic pressure amplification (pSBP-cSBP). Differences across phenotypes in carotid intima-media thickness (IMT), estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMI), and pulse wave velocity (PWV) were assessed using one-way ANOVA with Bonferroni-corrected post-hoc tests. ResultsThree distinct hemodynamic phenotypes were successfully identified. The C2 (Balanced Adaptation) phenotype (n = 245) demonstrated the most favorable hemodynamic profile, characterized by the lowest blood pressure and augmentation index (AIx) values, along with the highest peripheral-to-central pulse pressure ratio (pPP/cPP). The C1 (Vascular Stress) phenotype (n = 267) presented with normal peripheral systolic blood pressure (125.9 {+/-} 11.3 mmHg) but exhibited markedly elevated wave reflection indices, including the highest heart rate-adjusted augmentation index (AIx@HR75: 31.9 {+/-} 9.7%) and the lowest pPP/cPP ratio (1.29 {+/-} 0.08). The C3 (High-Load Decompensation) phenotype (n = 182) displayed significantly elevated blood pressures and the greatest overall hemodynamic load. Regarding target organ damage, a clear gradient was observed across the three phenotypes. The C3 phenotype showed the highest carotid intima-media thickness (IMT: 1.162 {+/-} 0.23 mm) and left ventricular mass index (LVMI: 69.18 {+/-} 40.73 g/m{superscript 2}). Conversely, the C2 phenotype exhibited the highest estimated glomerular filtration rate (eGFR: 97.38 {+/-} 16.38 mL/min/1.73m{superscript 2}) and the lowest IMT (0.994 {+/-} 0.26 mm). The C1 phenotype consistently displayed intermediate values for all organ damage indicators. After Bonferroni correction, all pairwise comparisons for LVMI and pulse wave velocity (PWV) reached statistical significance (all P < 0.05). ConclusionsHealthy high-altitude individuals manifest three distinct hemodynamic phenotypes arrayed along a cardiovascular risk continuum. The novel Vascular Stress (C1) phenotype represents a "masked" high-risk state characterized by normal peripheral blood pressure but elevated arterial stiffness and wave reflection, challenging sole reliance on brachial pressure for risk assessment. This phenotype-based stratification provides a framework for precision prevention and early intervention in high-altitude populations.

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.