**8. Summary**

GH and IGF-1 are pleotropic hormones a ffecting multiple cellular functions, including cell proliferation, di fferentiation, metabolism, and cell survival. Both hormones activate many signaling cascades implicated in regulation of mitochondrial proteins expression and function. Most evidence indicates that the e ffects of GH on mitochondrial mass and function are indirect and mostly mediated by IGF-1. IGF-1 a ffects mitochondrial mass via increased transcriptional activities of key factors involved in mitochondrial biogenesis such as PGC-1 α. Additionally, it appears that the e ffects of IGF-1 on mitochondrial respiration are indirect and coincide with enhanced synthesis of mitochondrial proteins such as Cyt c and UCP. With respect to oxidative stress, the literature is divided and studies showing either positive or negative e ffects of GH or IGF-1 have been published. While congenital mouse models with life-long decreases in GH/IGF-1 axis signaling indicate mostly protection from oxidative stress, models of age-induced decreases in GH/IGF-1 signals, as seen in humans, associate with increased oxidative stress.

Finally, it is widely accepted that GH/IGF-1 are involved in cell senescence and apoptosis. The molecular mechanisms involved in GH/IGF-1-mediated cellular senescence are still poorly understood. Both hormones exert a dual function and promote, on one hand, cell proliferation and, on the other hand, cellular senescence. Therefore, it is conceivable that the dose and duration of GH/IGF-1 exposure might regulate senescence, and that the e ffects of GH/IGF-1 on senescence are tissueand cell type-specific. On the other hand, the protective roles of IGF-1 from mitochondrial-mediated apoptosis have been better defined. Studies of numerous cell types and animal models have

shown that IGF-1-mediated activation of the PI3K-AKT/FOXO pathway upregulates transcription of antiapoptotic genes.

**Funding:** Financial support was received from National Institutes of Health Grant R01AG056397 to S.Y. and from the United States-Israel Binational Science Foundation gran<sup>t</sup> (2013282) to S.Y. and H.W.

**Conflicts of Interest:** The authors declare no conflict of interest.
