Nutrient-Response Threshold Hypothesis

Core Proposition: Mild protein restriction extends lifespan through AMPK activation, while severe caloric restriction triggers catabolic stress and aging. The inflection point depends on baseline nutrient status, microbiome composition, and developmental timing.

Key Mechanisms: AMPK-mediated amino acid catabolism under mild restriction produces mitohormetic ROS bursts that enhance stress resistance. Methionine restriction reduces SAM availability, epigenetically regulating aging loci. However, exceeding the threshold — through greater severity, maladaptive timing (e.g., pre-weaning), or an unhealthy microbiome — flips AMPK signaling and activates maladaptive mTOR pathways.

Translational Implication: This hypothesis reframes CR as personalized, context-sensitive intervention rather than universal prescription, with CR mimetics offering alternatives where behavioral restriction becomes maladaptive.