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. Author manuscript; available in PMC: 2015 May 1.
Published in final edited form as: Cytometry A. 2014 Feb 22;85(5):386–399. doi: 10.1002/cyto.a.22452

Figure 1.

Figure 1

Schematic presentation of the key pathways associated with cellular senescence and aging linking mTOR- and DNA damage-signaling as well as marking of sites for potential antiaging intervention. Signaling from several upstream pathways activated by insulin, IGFs, growth hormone (GH), or amino acids converges on, and activates, mTOR (raptor). mTOR stimulation triggers activation of S6K1 that results in phoshorylation of RP-S6 and 4EBP1, the factors indicative of activation of initiation and continuation of translation, This leads to cell growth, and particularly when cell division is postponed (e.g., because of replication stress), to growth imbalance (hypertrophy) characterized by the increased ratio of protein and RNA to DNA content, the hallmark of cellular senescence. As translation requires constant generation of energy (ATP), the oxidative phosphorylation in mitochondria persistently produces ROS. mTOR stimulation, thus, is inherently associated with generation of ROS. The oxidative DNA damage caused by endogenous ROS, when it occurs in sites coding for oncogenes or tumor suppressor genes, may lead to neoplasic transformation. Oxidative DNA damage of the telomeric DNA may cause telomere dysfunction and lead to replicative senescence, while lipid peroxidation is also a gero-promoting event, one of the typical features of the cellular senescence phenotype. The potential targets for antiaging modalities are marked with the Chinese symbol of longevity (see the text). One of the most attractive targets is AMPK whose activation inhibits mTOR signaling. Among AMPK activators that show gero-suppressive properties are metformin and berberine. The antioxidants, by scavenging ROS, have primarily chemopreventive properties but by preventing oxidative telomeric DNA damage and lipid per-oxidation they also attenuate the aging process. The gero-suppressive role of autophagy, which often is seen to be activated by inhibitors of mTOR, is also well recognized (86). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]