Research in the major genetic model systems has revealed a strong and consistent association between dietary restriction, mutations that extend life span, and resistance to multiple stresses. Here we propose to investigate the mechanisms of aging with focus on starvation-dependent protection against oxidative damage and life span. We propose to continue our work to establish which combination of treatments and genetic manipulations causes the maximum resistance to toxins and identify the underiying mechanisms with focus on ER stress. We will continue and expand our mammalian cell and mouse studies to determine the role of short-term starvation on cellular senescence and aging in murine models and identify the mechanisms of starvation-dependent protection. We will also test the hypothesis that pathways analogous to those identified in yeast can protect normal but not cells with constitutively active pro-aging pathways (cancer cells) against oxidative damage and chemotherapy (Differential Stress Resistance, DSR) and study the mechanisms involved. Because older subjects are particularly sensitive to toxins, we will study DSR in young and old mice to identify interventions that can protect old organisms against cytotoxicity. The collaborations with Cohen and Lee will continue to introduce novel ideas, approaches, and research tools to our laboratory and provide the synergism necessary to accelerate our research. This collaborative biogerontology-based approach has the potential to identify new genetic pathways and mechanisms relevant to the basic biology of aging but also interventions that can be applied to the development of improved treatments and prevention of age-related diseases.
Research on age-related diseases focuses primarily on the damaged cells or tissues affected by the disease. Here we propose to take a biogerontology-based approach to instead focus on the mechanisms of protection of all the healthy cells ofthe organism. These studies will help identify strategies, genetic pathways and drug targets to protect the organism against the age-dependent damage and diseases caused by endogenous as well as exogenous toxins.
|Cohen, Pinchas; Weng, Wayne; Rogol, Alan D et al. (2014) Dose-sparing and safety-enhancing effects of an IGF-I-based dosing regimen in short children treated with growth hormone in a 2-year randomized controlled trial: therapeutic and pharmacoeconomic considerations. Clin Endocrinol (Oxf) 81:71-6|
|Lee, Amy S (2014) Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential. Nat Rev Cancer 14:263-76|
|Mirisola, Mario G; Taormina, Giusi; Fabrizio, Paola et al. (2014) Serine- and threonine/valine-dependent activation of PDK and Tor orthologs converge on Sch9 to promote aging. PLoS Genet 10:e1004113|
|Moody, Gordon; Beltran, Pedro J; Mitchell, Petia et al. (2014) IGF1R blockade with ganitumab results in systemic effects on the GH-IGF axis in mice. J Endocrinol 221:145-55|
|Lee, Changhan; Wan, Junxiang; Miyazaki, Brian et al. (2014) IGF-I regulates the age-dependent signaling peptide humanin. Aging Cell 13:958-61|
|Zhu, Genyuan; Wang, Miao; Spike, Benjamin et al. (2014) Differential requirement of GRP94 and GRP78 in mammary gland development. Sci Rep 4:5390|
|Mattson, Mark P; Allison, David B; Fontana, Luigi et al. (2014) Meal frequency and timing in health and disease. Proc Natl Acad Sci U S A 111:16647-53|
|Hu, Jia; Wei, Min; Mirzaei, Hamed et al. (2014) Tor-Sch9 deficiency activates catabolism of the ketone body-like acetic acid to promote trehalose accumulation and longevity. Aging Cell 13:457-67|
|Levine, Morgan E; Suarez, Jorge A; Brandhorst, Sebastian et al. (2014) Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab 19:407-17|
|Verghese, Joe; Annweiler, Cedric; Ayers, Emmeline et al. (2014) Motoric cognitive risk syndrome: multicountry prevalence and dementia risk. Neurology 83:718-26|
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