Lifestyle and psychosocial protective factors drive healthy aging and modulate inflammatory and metabolic pathways.

Lifestyle habits, cognitive reserve, and affective reserve (secure attachment, extraversion, psychological resilience) predict resilience in the oldest-old, though the underlying biological mechanisms remain unclear. This study explored relationships between these protective factors, 120 + NULISA CNS blood biomarkers, and multidimensional health outcomes (global cognition, mental health, walking speed) in 401 dementia-free participants (age 83-87) from the InveCe.Ab study. Using sparse partial least squares (sPLS) regression, eight biomarkers were stably associated with the protective factors: HBA1, DDC, IFNG, IL15, GOT1, ACHE, SNAP25, and SNCB. Structural equation modeling (SEM) showed that the three protective factors exerted an independent and domain-specific effect on health outcomes. Moreover, lifestyle habits were associated with ACHE (β = 0.26), IL15 (β = 0.22), and GOT1 (β = 0.28); affective reserve showed inverse associations with IFNG (β = -0.13) and IL15 (β = -0.31), and GOT1 (β = -0.18). Regarding health domains, SNAP25 was inversely related to global cognition (β = -0.10), while SNCB was associated with global cognition (β = 0.16) and walking speed (β = 0.13). Notably, no significant mediated effects were found, suggesting that the clinical benefits observed were not directly driven by the aforementioned biological pathways. The present study paves the way for further investigations on the biological mechanisms underlying resilient aging, while further demonstrating the key protective role of individual habits and psychosocial characteristics during the life course.