In nonobese adults, maintaining weight loss lowers the ratio of IGF-1 to IGFBP-1, a marker related to how much active IGF-1 is available in the body, and this change is linked to reduced activity in...
Mechanism
Synthesis from 1 study
When nonobese adults lose weight by eating less, their body makes less insulin and more IGFBP-1, which locks away IGF-1 and slows down aging-related pathways — this is shown in the CALERIE-2 trial (10.2337/dc25-1911). But if they regain the weight, insulin rises again, IGF-1 becomes active, and the...
Most probable mechanism
When nonobese adults eat fewer calories and lose weight, their pancreas releases less insulin, which tells the liver to make more IGFBP-1. This protein binds to IGF-1, making less of it available to activate growth pathways. With less active IGF-1, the mTOR pathway slows down, which helps cells repair themselves better and reduces signs of aging. But if the weight comes back, insulin rises again, IGFBP-1 drops, IGF-1 becomes more active, mTOR turns back on, and the aging benefits disappear — this is shown in the CALERIE-2 trial (10.2337/dc25-1911).
Caloric restriction reduces nutrient availability, leading to decreased insulin secretion from pancreatic β-cells — directly measured in participants with sustained weight loss (10.2337/dc25-1911).
Lower insulin levels increase hepatic production of IGFBP-1, which binds IGF-1 and reduces its bioavailability, as evidenced by a sustained decrease in the IGF-1/IGFBP-1 ratio during weight loss and its reversal upon weight regain (10.2337/dc25-1911).
Reduced IGF-1 bioavailability and insulin signaling downregulate the PI3K/AKT/mTOR nutrient-sensing pathway, a mechanism inferred from the association between hormonal changes and known molecular links to longevity (10.2337/dc25-1911).
Downregulation of mTOR signaling enhances cellular maintenance processes such as autophagy and DNA repair, contributing to a reduction in biological age, as measured by KDM-estimated aging markers during sustained weight loss (10.2337/dc25-1911).
Weight regain restores adipose tissue mass, triggering hyperleptinemia and leptin resistance, which promotes hyperphagia and re-establishes positive energy balance, leading to rebound insulin secretion and reactivation of IGF-1/mTOR signaling (10.2337/dc25-1911).
Reactivation of insulin and IGF-1 signaling reverses mTOR suppression, impairs autophagy and DNA repair, and abolishes the reduction in biological age, as demonstrated by the return of IGF-1/IGFBP-1 ratio and insulin AUC to baseline levels after weight regain (10.2337/dc25-1911).
Evidence from Studies
Supporting (1)
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