The Good, the Bad, and the Ugly of ROS: New Insights on Aging and Aging-Related Diseases from Eukaryotic and Prokaryotic Model Organisms

Figure 4

Crosstalk between mTOR and other longevity pathways. mTORC1 responds to a variety of environmental cues, including oxygen and nutrients, and communicates with several other known longevity factors in a complex network of interactions. Rapalogs inhibit mTORC and decrease its activity. Sensing of low oxygen levels stimulates mTORC1 to activate the hypoxic response by enhancing translation of HIF-1, which inhibits FOXO family members and increases longevity. mTORC1 inhibits the stress response transcription factor SKN-1/Nfr2, resulting in extended lifespan. Inhibition of the mTOR downstream effector ribosomal protein S6 kinase (S6K), involved in the regulation of protein translation, also results in extended lifespan. Caloric restriction can lower mTORC1 signaling partly through activation of AMPK, resulting in enhanced longevity, potentially via PGC1α-mediated increase in mitochondrial metabolism. Calorie restriction also inhibits IGF1-dependent signaling via PI3K/PDK1/Akt which inhibits FOXO, blocking the expression of antioxidants and autophagy. Calorie restriction leads to increased NAD⁺/NADH ratio, which activates sirtuins, that in turn induce mechanisms to enhance cell protection, including enhanced antioxidant production and autophagy. Calorie restriction can also block inflammation via the effects of sirtuins on NF-κB. cAMP response element binding proteins (CREB) can also upregulate the transcription of sirtuins, slowing aging.