I The insulin like-growth factor (IGF) system is well recognized to control mulfiple processes including growth, differentlafion, cancer and aging. Our preliminary data includes evidence that genefic variations in the GH- IGF system is involved in human longevity and that the IGF-IGFBP system is a potent modulator of cancer progression in vitro and In vivo. In this project, we propose to utilize an array of unique cell lines and mouse models we have established with focus on IGFBP-deficient mice to determine if they exhibit altered life span or altered stress responsiveness and survival in response to oxidative stress and chemotherapy and to see if fasting results in an additive or antagonistic stress response to toxins. We will also investigate the mechanisms responsible for IGFBP-dependent effects on stress resistance and will examine the differential stress response (DSR) effect in murine genetic models of prostate cancer mated into IGF/IGFBP modified strains. Finally, we plan to invesfigate if IGF modulafing drugs mimic or complement the DSR effects of fasting and diet on stress resistance and longevity in these models. The ulfimate goal of this project is to test the hypothesis that lGF-1 and IGFBPs play central roles in the modulafion of stress resistance as it relates to aging and diseases of aging. This knowledge can be applied to develop pharmacologic and nutrifional intervenfions that will protect older pafients against cancer, chemotherapy and radiotherapy, and other age- dependent diseases caused by endogenous toxins. We will therefore pursue the following specific aims: 1) Invesfigate the mechanism and differenfial action of IGFBPs on protection and sensifizafion of normal and transformed cells in vitro. Our hypothesis is that IGFBPs confer a differential stress resistance effect between primary and cancer cell lines through a dual mechanism involving both IGF-inhibition and direct cellular acfions. 2) Define the role of IGFBPs in longevity and in vivo stress resistance through the use of the IGFBPS and IGFBPl knockout mice. 3) Examine the effects of IGF-modulafing drugs including IGF-1 receptor blocking-anfibodies on stress resistance and longevity in mice. 4) Determine the effects of IGF and IGFBPs on survival in prostate cancer models by mafing IGF/IGFBP altered mice into genefic prostate cancer models, testing the progression of prostate cancer. Together, these studies will develop new strategies to understand the molecular mechanisms of cellular protection and apply them to differential protection of normal and cancer cells and the development of strategies to enhance healthy aging.

Public Health Relevance

; The insulin-like growth factor (IGF) system is a complex biological pathway that controls cellular and organismal growth and differenfiation;and has been linked to aging and longevity on one hand and to cancer progression on the other. We will address important implicafions of potenfial therapies that target IGF activity and examine their effects on lifespan and on cancer development in mouse models. Our work will have direct relevance to the health of elderly Americans, as it will pave the way towards safe and effective approaches to enhance lifespan and health-span extension and healthy aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-5)
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University of Southern California
Los Angeles
United States
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Brandhorst, Sebastian; Harputlugil, Eylul; Mitchell, James R et al. (2017) Protective effects of short-term dietary restriction in surgical stress and chemotherapy. Ageing Res Rev 39:68-77
Lee, Amy S; Brandhorst, Sebastian; Rangel, Daisy F et al. (2017) Effects of Prolonged GRP78 Haploinsufficiency on Organ Homeostasis, Behavior, Cancer and Chemotoxic Resistance in Aged Mice. Sci Rep 7:40919
Cheng, Chia-Wei; Villani, Valentina; Buono, Roberta et al. (2017) Fasting-Mimicking Diet Promotes Ngn3-Driven ?-Cell Regeneration to Reverse Diabetes. Cell 168:775-788.e12
Okada, Alan K; Teranishi, Kazuki; Lobo, Fleur et al. (2017) The Mitochondrial-Derived Peptides, HumaninS14G and Small Humanin-like Peptide 2, Exhibit Chaperone-like Activity. Sci Rep 7:7802
Nashiro, Kaoru; Guevara-Aguirre, Jaime; Braskie, Meredith N et al. (2017) Brain Structure and Function Associated with Younger Adults in Growth Hormone Receptor-Deficient Humans. J Neurosci 37:1696-1707
Hine, Christopher; Kim, Hyo-Jeong; Zhu, Yan et al. (2017) Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production. Cell Metab 25:1320-1333.e5
Ayers, Emmeline; Shapiro, Miriam; Holtzer, Roee et al. (2017) Symptoms of Apathy Independently Predict Incident Frailty and Disability in Community-Dwelling Older Adults. J Clin Psychiatry 78:e529-e536
Balasubramanian, Priya; Longo, Valter D (2016) Growth factors, aging and age-related diseases. Growth Horm IGF Res 28:66-8
Mirzaei, Hamed; Raynes, Rachel; Longo, Valter D (2016) The conserved role of protein restriction in aging and disease. Curr Opin Clin Nutr Metab Care 19:74-9
Marini, Cecilia; Ravera, Silvia; Buschiazzo, Ambra et al. (2016) Discovery of a novel glucose metabolism in cancer: The role of endoplasmic reticulum beyond glycolysis and pentose phosphate shunt. Sci Rep 6:25092

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