The translation initiation factor eIF2α regulates lipid homeostasis and metabolic aging

Aging is usually accompanied by excessive body fat gain, leading to increased susceptibility to comorbidities. This study aimed to explore an unexpected function for the eukaryotic initiation factor-2 alpha (eIF2 alpha) during aging. Reducing the eIF2 alpha dose led to a reconfiguration of the metabolic equilibrium, promoting catabolism, facilitating lipolysis, and decreasing body fat accumulation while maintaining healthy glucose and lipid metabolism during aging. Specifically, eIF2 alpha enhanced the expression of distinct messenger RNAs encoding mitochondrial electron transport chain proteins at the translation level. The mitochondrial respiration increased in eIF2 alpha heterozygotes, even during aging. Deceleration of translation was demonstrated as a conserved mechanism for promoting longevity across various species. Our findings demonstrated that the restriction of translation by reducing eIF2 alpha expression could fend off multiple tissue damage and improve metabolic homeostasis during aging. Hence, eIF2 alpha was a crucial target for benefiting mammalian aging achieving delayed mammalian aging.