Clinical implementation of neurofilament light chain (NfL), a biomarker of neurodegeneration, remains challenging due to absence of reliable cutoffs and influence of confounding factors, particularly age. We aimed to develop an age-adjusted, two-threshold classification framework to support clinical interpretation of NfL in the neurodegenerative dementia diagnosis. We retrospectively enrolled subjects with cognitive/behavioral disturbances and cognitively unimpaired controls (CTR). Participants underwent a baseline diagnostic workup, including at least a neuropsychological assessment, blood test, CSF and serum NfL measurement, and MRI, and were followed up for 2years. At follow-up, they were diagnosed with either a neurodegenerative dementia [Alzheimer's Disease (AD), Frontotemporal Dementia (FTD), or Lewy Body Dementia (LBD)] or a non-neurodegenerative condition [Other Etiology (OE)]. AD, FTD, and LBD were grouped as Neurodegenerative (NDG), while OE and CTR were grouped as Non-Neurodegenerative (non-NDG). Bayesian regression models assessed the effects of age, disease duration, renal function, and gender on NfL. A weighted support vector machine (SVM) with leave-one-out cross-validation defined age-adjusted cutoffs using a two-threshold strategy constraining sensitivity ≥ 85% and limiting the intermediate zone. We included 217 subjects (158 NDG, 59 non-NDG). Serum and CSF NfL levels were significantly higher in NDG. Age strongly increased NfL levels, particularly in serum where diagnostic separation declined beyond age 70. The SVM-based model applied to CSF NfL defined continuous, age-adjusted, two-threshold cutoffs, identifying low-risk, high-risk, and intermediate zones. The proposed framework for CSF NfL provides a clinically oriented decision-support tool to stratify the likelihood of underlying neurodegeneration and guide diagnostic workup in cognitive neurology settings, pending external validation.

Reducing activity of the mechanistic/mammalian target of rapamycin (mTOR) with rapamycin extends lifespan and healthspan in many species. The mechanisms by which mTOR regulates lifespan and healthspan, however, are still unknown. Understanding how mTOR signaling in different cell types regulates lifespan and aspects of healthspan is urgently needed if we are to harness the potential individual and societal benefits of healthspan extension by mTOR attenuation. mTOR kinase can form two complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The regulatory associated protein of mTOR (Raptor) is required for the assembly of mTORC1, the primary target of rapamycin. To define the role of mTORC1 and mTORC2 signaling during development in the regulation of healthspan we either ablated or reduced expression of Rptor (Raptor) or Mtor (mTOR) in neurons of mice. Developmental knock-down of Mtor (mTORKD) exclusively in neurons, had no significant impact on embryonic survival, but significantly increased adult mortality. In contrast, neuronal knockdown of Rptor (RaptorKD) during development reduced embryonic viability, but did not appear to impact adult survival, suggesting that reducing mTORC1 may confer a survival advantage after birth. Reduction of either Rptor or Mtor (mTORKD, RaptorKD) during development, however, significantly decreased growth rates, body weight, fat mass, resting and fasting blood glucose, and exercise capacity. Taken together, our studies indicate that neuronal mTORC1 plays a critical role in the determination of body size during development, as well as fat mass, metabolic states and exercise capacity during adulthood.

Vitality capacity (VC) reflects a physiological state and is a determinant domain of intrinsic capacity but has so far remained mainly theoretical. This study validates the vitality capacity domains 'energy and metabolism' and 'neuromuscular function' and examines its link to locomotor capacity and quality of life (QoL). Exploratory factor analysis (EFA) was performed on the combined dataset from the Fatigue Resistance AMErsfoort study (FRAME, n = 1000) and the Fatigue Plot study (FATPLOT,n = 620). Confirmatory factor analyses (CFA) were subsequently performed on data from the AMersfoort COhort study on functional decline, Healthy aging and Frailty (AMCOHF,n = 367) and the BrUssels sTudy on The Early pRedictors of FraiLtY (BUTTERFLY,n = 491), to validate VC in both middle-aged and older adults. Linear hierarchical regression analysis was used to investigate the relationship between VC, locomotor capacity, and QoL. EFA indicated a one-factor model and CFA validated this with good model fit in the dataset (BUTTERFLY) (Robust CFI; 0.960, SRMR: 0.040) and (AMCOHF) (Robust CFI; 0.942, SRMR: 0.055). This model validated maximal grip strength (GSmax), 30-s chair stand test (30CST), Multidimensional Fatigue Inventory (MFI-20) and Capacity to Perceived Vitality ratio physical (CPV-physical) to measure VC. Several assessments show a significant relationship with locomotor capacity and QoL. This study indicated that VC is a coherent domain and has a relationship with locomotor capacity and QoL.

Although plasma pTau181 has been shown to accurately discriminate patients with Alzheimer's disease from healthy older adults, there are few studies of plasma biomarkers among middle-aged populations. Given the potential utility of plasma AD biomarkers such as pTau181 in screening for disease risk, examining pTau181 in a middle-aged cohort without AD is important for future implementation. The objectives of this studywere to characterise plasma pTau181 in a middle-aged birth cohort aged 45years and to investigate associations with early indicators of dementia risk. Participants were members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal study of 1037 people born in New Zealand in 1972-1973. Plasma pTau181, self-reported cognitive concerns, MRI-based brain structure, and DunedinPACE (an epigenetic biomarker of biological ageing) were measured at age 45; cognition was measured in childhood and age 45. Plasma pTau181 concentrations at age 45 (n = 854, 49% female) were associated with self-reported cognitive concerns (β = 0.09, p = .008); however, no significant associations were observed with objective cognitive decline, worse structural brain integrity, or biological ageing. Higher plasma pTau181 was associated with self-reported cognitive concerns at age 45, but not objective AD-related measures. The association of plasma pTau181 and self-reported cognitive concerns in this cohort suggests that AD pathology may begin to accumulate by age 45 and may be associated with subtle changes in cognition that are not at objectively measurable levels.

Chronic sympathetic nerve activity (SNA) to end organs plays a crucial role in the pathophysiology of obesity-induced hypertension. Oxidative stress and neuroinflammation in the rostral ventrolateral medulla (RVLM), a key brainstem region regulating sympathetic outflow, have been implicated in the sympathetic overactivity in obesity. However, the upstream mechanisms driving RVLM neuroinflammation remain unknown. We hypothesized that obesity inducescellular senescence, a stress response characterized by irreversible cell cycle arrest, in the RVLM and contributes to sympathoexcitation. To test this, C57BL/6J male mice were fed chow or a high-fat diet (HFD) for 16weeks, followed by treatment with Dasatinib (5mg/kg) and Quercetin (50mg/kg) (D + Q) to selectively eliminate senescent cells. Blood pressure was assessed by radiotelemetry in conscious, freely moving mice. SNA was indirectly measured through heart rate variability (HRV) analysis, depressor response to hexamethonium, and serum norepinephrine levels. The RVLM was microdissected for gene expression and protein analysis of senescence markers and DNA damage. Our results showed that HFD mice had a significant increase in mean arterial pressure and SNA compared to chow-fed controls. Obesity was associated with increased DNA damage and upregulation of cellular senescence markers in the RVLM. Senolytic treatment with D + Q selectively improved cardiac autonomic balance as assessed by HRV, without altering indices of global SNA or blood pressure. Collectively, our findings identify cellular senescence in the RVLM as a novel contributor to obesity-induced sympathoexcitation, and senolytic therapy could be a potential therapeutic avenue for obesity-associated autonomic dysfunction.

Cellular senescence is a multifaceted stress response marked by stable proliferative arrest and the secretion of diverse biologically active factors, collectively known as the senescence-associated secretory phenotype (SASP). The senescent phenotype is remarkably variable and subject to various regulatory influences. We previously demonstrated that mitochondrial dysfunction induced by diverse stimuli, including the loss of sirtuin 3 (SIRT3), leads to the hyperactivation of AMPK and p53, culminating in senescence while concurrently suppressing much of the proinflammatory SASP. Here, we extend our findings by revealing that the absence of SIRT3 can suppress segments of the SASP even in the absence of p53. Intriguingly, SIRT3 deficiency renders cells resistant to stimulation by exogenous cytokines, such as interleukin-1. Fibroblasts derived from Sirt3 knockout mice exhibit a diminished SASP, including reduced levels of Pdgfa, and these mice display impaired wound healing and a more expansive granulation area. Furthermore, aged Sirt3 knockout mice show disrupted patterns of senescence relative to wild type controls, including increases in senescence markers in adipose tissue, but surprisingly also decreases in liver and heart. Collectively, these data underscore a role for SIRT3 in orchestrating cellular senescence phenotypes, shedding light on its regulatory influence beyond the p53-dependent pathway.

Although life expectancy has increased, many of the added years are lived in poor health, highlighting growing inequalities in ageing trajectories. Despite the increasing need for ageing-related health strategies, non-EU European countries remain underrepresented in comparative research, leaving limited evidence on healthy ageing disparities between EU and South-Eastern European (SEE) nations. This study explored variations in key health and socioeconomic indicators of societal ageing and age-related disease burden among individuals aged 70 and older across European countries, with a focus on EU and non-EU SEE nations. Data for 33 European countries were extracted from Global Burden of Disease 2021 study. Indicators included mortality, years lived with disability (YLD), healthy life expectancy (HALE), current health expenditure (HE), and Human Development Index (HDI). Hierarchical cluster analysis was used to classify EU countries, and SEE countries were analysed separately. Trends in mortality, YLD rates, and HALE were analysed using Joinpoint regression. Spearman's rank correlation was used to assess relationships between health, socioeconomic factors, and disease burden. Western and Northern European countries showed the most favourable values for indicators, while SEE countries exhibited the highest all-cause and cardiovascular mortality and the lowest HALE and HDI values. Across all countries, strong negative correlations were observed between HE, HDI, HALE, and total mortality (r = -0.81, -0.82, and -0.92, p < 0.001; respectively). Regionally adjusted and coordinated policies are needed to reduce inequalities and promote healthy ageing across Europe. Such strategic integration is essential to narrowing the gaps in ageing trajectories and socioeconomic development between EU and SEE countries.

Aging is associated with progressive deterioration of vascular function and cardiovascular risk. Cardiorespiratory fitness (CRF) isclosely associated with cardiovascular health, yet longitudinal data in healthy older adults remain limited. This study examined 3-year changes in vascular and echocardiographic parameters in older adults and their associations with CRF and muscle strength. Forty-nine participants (mean age 63.8 ± 3.8years) underwent vascular assessments (brachial/central blood pressure (BP), pulse wave velocity (PWV), augmentation index), echocardiography, CRF testing via spiroergometry to determine VO2peak, muscle strength testing, and carotid sonography at baseline and after 3 years. Participants were grouped by carotid plaque status: no atherosclerosis, existing atherosclerosis, or newly developed atherosclerosis. Over 3 years, CRF and muscle strength (grip strength, leg flexion) declined significantly (all p < 0.005), while systolic BP (p = 0.042), brachial-ankle PWV (p = 0.006), and echocardiographic parameters including aortic root diameter and ventricular dimensions increased (all p < 0.001). Participants with newly developed atherosclerosis showed the greatest CRF decline (p = 0.012). Changes in CRF were inversely associated with changes in systolic, diastolic, and central BP (all p < 0.01). Declines in leg flexion strength were also linked to larger BP increases. Participants maintaining > 90% of baseline VO2peak had significantly smaller BP increases. These results indicate that vascular aging progresses measurably within a few years in clinically healthy older adults and isassociated withdeclines in CRF and muscle strength.Preservation of CRF is linked to more favorable vascular aging profiles and a lower prevalence of newly developed atherosclerosis.

Age is a well-known risk factor to develop severe viral respiratory infections, including severe COVID-19. This study aimed to identify the biological alterations linked to severe disease in elderly patients with COVID-19. For this purpose, we employed a derivation cohort with 450 SARS-CoV-2 infected and unvaccinated patients admitted to hospital wards and a validation cohort with 244 SARS-CoV-2 infected and unvaccinated patients admitted to hospital Intensive CareUnit (ICU). Twenty-one biomarkers were measured in plasma samples from patients upon admission, including SARS-CoV-2 RNA, IgG antibodies, and protein biomarkers. Patient cohorts were divided into two groups based on age: adult (≤ 70years old) and elderly (> 70years old) patients. In the derivation cohort, 90-day mortality rate observed in the adult group was 6.0% whereas in the elderly group it rises to 31.6%, same trend was noticed regarding the validation cohort, with 11.2% versus 40.3% 90-day mortality rates for adult and elderly groups, respectively. The machine-learning framework XGBoost-SHAP, fed with the plasma biomarkers information, was used to profile an age-related host response to SARS-CoV-2 infection. Based on SHAP plot, elderly patients had a strong thrombo-inflammatory response profile (significantly elevated plasma levels of: lipocalin-2, endothelin-1, D-dimer) combined with deficient adaptive and cytotoxic antiviral responses. Model performance evaluated with the validation cohort confirmed the robustness and generalizability of the model developed (AUC = 0.710). In conclusion, the machine learning approach we built allowed us to identify the presence of a deranged host response in elderly patients with COVID-19 linked to poor viral control and increased mortality.