Fig. 1.

GH/INS/IGF signaling-dependent metabolic pathways that impact aging in all somatic cells and stem cells. A highly caloric diet and low levels of physical activity enhance GH/INS/IGF signaling in somatic cells in mTOR/mTORC1-dependent manner, including stem cells. The main role of mTORC1 is to activate and control translation of proteins and to exert this function TORC1 functions as a nutrient/energy/redox sensor that requires adequate energy resources, nutrient availability and oxygen abundance. However, over time, this leads to damaging, mTOR-activated intracellular processes due to e.g., ROS-mediated telomeric DNA oxidative damage, lipid peroxidation, inhibition of autophagy. The beneficial effects of AMPK activators that inhibits mTORC1 (e.g., metformin and berberine) and direct mTOR inhibitors (e.g., rapamycin) are indicated. As will be demonstrated in Fig. 2, due to epigenetic changes in methylation state of some parentally imprinted genes VSELs, similarly as PGCs are more resistant to GH/INS/IGF signaling as compared to other TCSCs and somatic cells