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
