The coupling between lifespan and energy metabolism is well documented, and caloric restriction was shown to extend the lifespan of a wide spectrum of organisms. Genetics studies in nematodes and flies showed that impaired insulin signaling through PI3K and its downstream effector, the serine/threonine kinase, Akt, is associated with a decline in energy metabolism and an extended lifespan. In C. elegans, the most distal effector of insulin signaling that determines lifespan is the forkhead transcription factor, DAF- 16, which is inactivated by Akt via phosphorylation. Thus, reduced Akt activity increases DAF-16 activity and thereby increases lifespan. Another conserved downstream effector of Akt, the target of rapamycin (TOR), was recently implicated in the regulation of lifespan both in nematodes and flies. However, the contribution of the PISK/Akt signaling pathway to longevity in mammals has not been thoroughly explored. In particular, there is no extant genetic evidence supporting a role for this pathway in mammalian lifespan. This may be due, in part, to the association of this pathway with an array of processes including, apoptosis, glucose metabolism, and differentiation, which complicate evaluating its role in modulating mammalian longevity. Our long-term goal is to determine whether Akt can regulate lifespan and sensitivityto oxidative stress in mice. The mouse has three Akt isoforms encoded by distinct genes (aktl, akt2, and akt3). We propose to take advantage of the availability of genetically engineered Akt-deficient mice generated in our laboratory. These animals lack individual akt genes, alone and in combination. They provide excellent genetic models for examination of the contributions of Akt activity and individual Akt isoforms to longevity and oxidative-stress-dependent aging and senescence. At the cellular level, we will expand on our initial observations that cells derived from Akt (knockout) KO mice exhibit lower basal levels of intracellular reactive oxygen species (ROS) than their wild-type counterparts, whereas cells expressing activated Akt generate higher ROS levels. These changes are associated with corresponding changes in both energy metabolism and oxygen consumption. We will elucidate the mechanisms whereby Akt activity regulates intracellular ROS abundance and the role of Akt in the regulation of cellular senescence. At the organism level, we will determine whether partial ablation of Akt activity caused by the loss of individual isoforms, alone or in combination, is sufficient to extend normal lifespan and confer resistance to oxidative stress in the mouse.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Velazquez, Jose M
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University of Illinois at Chicago
Schools of Medicine
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Hay, Nissim (2016) Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nat Rev Cancer 16:635-49
Guzman, Grace; Chennuri, Rohini; Chan, Alexander et al. (2015) Evidence for heightened hexokinase II immunoexpression in hepatocyte dysplasia and hepatocellular carcinoma. Dig Dis Sci 60:420-6
Nogueira, Veronique; Hay, Nissim (2013) Molecular pathways: reactive oxygen species homeostasis in cancer cells and implications for cancer therapy. Clin Cancer Res 19:4309-14
Jeon, Sang-Min; Chandel, Navdeep S; Hay, Nissim (2012) AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485:661-5
Xu, P-Z; Chen, M-L; Jeon, S-M et al. (2012) The effect Akt2 deletion on tumor development in Pten(+/-) mice. Oncogene 31:518-26
Nogueira, Veronique; Sundararajan, Deepa; Kwan, Jennifer M et al. (2012) Akt-dependent Skp2 mRNA translation is required for exiting contact inhibition, oncogenesis, and adipogenesis. EMBO J 31:1134-46
O'Brien, Kelly A; Gartner, T Kent; Hay, Nissim et al. (2012) ADP-stimulated activation of Akt during integrin outside-in signaling promotes platelet spreading by inhibiting glycogen synthase kinase-3?. Arterioscler Thromb Vasc Biol 32:2232-40
Tzivion, Guri; Hay, Nissim (2011) PI3K-AKT-FoxO axis in cancer and aging. Biochim Biophys Acta 1813:1925
Hay, Nissim (2011) Interplay between FOXO, TOR, and Akt. Biochim Biophys Acta 1813:1965-70
O'Brien, Kelly A; Stojanovic-Terpo, Aleksandra; Hay, Nissim et al. (2011) An important role for Akt3 in platelet activation and thrombosis. Blood 118:4215-23

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