The brain insulin receptor gene network and associations with frailty index

Global populations are aging, and aging is characterized by a gradual decline in physiological reserve. In frailty, this decline is accelerated, leading to increased vulnerability due to multisystem deterioration in reserve and function. This impairs the body's ability to cope with everyday stressors. While peripheral insulin and glucose regulation have been linked to frailty risk, the role of central insulin action in frailty remains less understood. In this study, we investigated the relationship between insulin signaling in the brain and Frailty Index (FI) progression over a 15-year period. Specifically, we used biologically informed polygenic risk scores (PRS) for the insulin receptor network in the hippocampus (hePRS-IR) and the mesocorticolimbic area (mePRS-IR) to explore their association with FI.

We analyzed 1,605 participants from the Helsinki Birth Cohort Study, measuring FI in late midlife (mean age 61.5 years) and again after 10 and 15 years. At baseline, higher hePRS-IR was associated with higher FI levels in women, but not in men. Women with moderate or high hePRS-IR had an increased risk of frailty (FI ≥ 0.25) compared to those with low hePRS-IR (OR for moderate hePRS-IR = 1.68, 95% CI 1.17–2.42, P = 0.005; OR for high hePRS-IR = 1.75, 95% CI 1.18–2.56, P = 0.005). Additionally, women with high hePRS-IR experienced a steeper increase in FI over time, particularly after the age of 73. However, no association was found between mePRS-IR and FI in either men or women.

Our findings suggest that women with greater individual variation in the hippocampal insulin receptor gene network exhibit higher frailty levels and faster frailty progression. These results extend existing evidence linking insulin metabolism to frailty and highlight potential novel drug targets for frailty prevention and intervention.

Original article:
The brain insulin receptor gene network and associations with frailty index.
Selenius JS, Silveira PP, Haapanen MJ, von Bonsdorff M, Lahti J, Eriksson JG, Wasenius NS. Age and Ageing.