Blood flow restriction training (BFRT) combines substantial metabolic stress with low mechanical loading, but its neurotrophic effects remain unclear. This study investigated the acute effects of BFRT and eccentric overload exercise (EOE) on neurotrophic biomarkers in healthy older men. Sixty-three healthy older men (60–78 years) were randomized to BFRT, EOE, or a non-exercising control group. Neurotrophic, metabolic, endothelial, and muscle damage biomarkers were measured before and after exercise. Responses were analyzed using repeated-measures ANOVA, Bonferroni-adjusted post hoc comparisons, and correlations. Significant time × group interactions were observed for plasma BDNF (p = 0.017, ηp2 = 0.151) and IL-6 (p = 0.001, ηp2 = 0.22), while a marginal time × group interaction was observed for serum IGF-1 (p = 0.050, ηp2 = 0.096). BFRT induced a significant increase in BDNF (mean change = 226.5 pg/mL, p = 0.006), with a greater change compared to CON (p = 0.014). IGF-1 increased significantly from baseline to 1 h post-exercise within the BFRT group (mean change = 29.2 ng/mL, p = 0.005); however, changes did not differ significantly between groups. IL-6 increased significantly following both BFRT (mean change = 8.26 pg/mL, p < 0.001) and EOE (mean change = 3.56 pg/mL, p = 0.013); however, the increase was greater only following BFRT compared to CON (p = 0.001), with no significant difference between BFRT and EOE (p = 0.123). BFRT elicited greater lactate accumulation than EOE and CON, and changes in BDNF correlated with changes in lactate (r = 0.367, p = 0.007). EOE elicited a greater CK increase than CON 48 h post-exercise, whereas syndecan-1 concentrations remained unchanged. Acute BFRT increased circulating BDNF and IGF-1 in healthy older men, and was accompanied by greater lactate accumulation, modest CK elevations, and no detectable increase in syndecan-1. The association between lactate and BDNF suggests that metabolic stress may contribute to the acute peripheral biomarker response; however, the neurological and clinical significance of these transient circulating changes remains to be established.
Cardiovascular disease and pneumonia are major causes of death in dementia, but cause-specific mortality has rarely been examined in clinically confirmed cognitive-impairment cohorts. In this nationwide retrospective cohort study, 116,563 individuals with clinically confirmed mild cognitive impairment or dementia in the Korean Dementia Relief Center registry (2016–2021) were linked to health screening and death registry data. Aerobic physical activity (APA) was quantified in metabolic-equivalent minutes per week (MET·min/week). Cox proportional hazards and Fine–Gray models estimated adjusted hazard ratios (HRs) and subdistribution HRs (sHRs). The Benjamini–Hochberg procedure controlled the false discovery rate (FDR) across 18 cause-specific comparisons. During 400,500 person-years of follow-up (mean, 3.4 years), 5022 participants (4.31
The growing evidence that existing cardio-renal-metabolic therapies, such as GLP-1 receptor agonists and SGLT2 inhibitors, confer all-cause mortality benefits has positioned them as the first wave of potential gerotherapeutics. However, repurposing these drugs for a lifespan extension indication remains constrained by trial duration, misaligned incentives, and the lack of a viable regulatory path. We highlight two parallel strategies to address these barriers: (1) identifying and validating precise surrogate endpoints, and (2) modifying the 505(b)(2) pathway to allow accelerated approval of already-approved drugs with demonstrated mortality benefit and favorable post-marketing safety. Veterinary medicine’s expanded conditional approval framework already applies these strategies, offering precedent for human gerotherapeutics development.
Loneliness is associated with cognitive decline and dementia risk, but the role of Alzheimer’s disease (AD) pathology in its associations with medial temporal lobe (MTL) morphology remains unclear. We examined whether loneliness was related to total hippocampal volume, hippocampal subfields, and entorhinal cortex (ERC) volumes, and whether plasma phosphorylated tau 217 (pTau217) moderated these relationships. We analyzed baseline data from cognitively unimpaired older adults aged 65–80 years enrolled in IGNITE. Loneliness was assessed using the revised UCLA Loneliness Scale. Structural 3 T MRI included a high-resolution T2-weighted hippocampal sequence. Hippocampal subfields and ERC volumes were extracted using ASHS, and FreeSurfer estimated total hippocampal volume and intracranial volume. Participants were classified as pTau217-positive or negative using an Aβ-PET-calibrated threshold (> 0.46 pg/mL). Covariate-adjusted linear regression models tested loneliness associations and loneliness×pTau217 interactions. We included 601 participants (69.8 ± 3.7 years; 72.2
