It is well accepted that early developmental events can have profound long-term effects on health and diseases. For example, Intrauterine growth retardation, maternal nutrition deficiency represent risk factors for development of diseases including cardiovascular diseases, type 2 diabetes and metabolic syndrome. However, it is unknown whether (or to what extent) these early life events also influence mammalian aging and longevity. On the basis of most recent findings, we hypothesize that the first few weeks of postnatal life represents a critical """"""""developmental window"""""""" in which the rate of aging is set by a combination of factors including hormonal levels and nutritional signals. To uncover mechanisms responsible for these early life events, we will try to understand when and how early hormonal signaling can have a profound effect on aging rate, lifespan and age-associated metabolic changes. We will also examine the effects of calorie restriction (CR) during early postnatal life. Moreover, we will compared the early life CR effects on the GH-deficient and resistant mice. The results will begin to fill the gap in the present understanding of the developmental influences on aging and metabolism and set the stage for addressing broader questions of major public health significance. To ensure the success of this career development grant, I have assembled a team of experts in the areas that are proposed to be studied in this proposal. All of the mentors have considerable experience in writing and evaluating grant proposals, as well as in researching diverse areas of mammalian aging. We have also developed a complete plan for enhancing my research skills and pushing my career forward.
The proposed research is aim to address a crucial public health issue in a cost-effective manner because the aging of the Baby Boomer generation is resulting in a massive increase in the absolute number and proportion of elderly Americans. Age is the biggest risk factor for many diseases, leading to increased cost of healthcare. This project will develop new models to study early hormonal signals, lifespan, and age-related diseases in the context of mutations that slow the aging process, and serve as a foundation for promising novel approach for the development of counter-aging therapy.
|Fang, Yimin; Hill, Cristal M; Darcy, Justin et al. (2018) Effects of rapamycin on growth hormone receptor knockout mice. Proc Natl Acad Sci U S A 115:E1495-E1503|
|Sun, Liou Y; Fang, Yimin; Patki, Amit et al. (2017) Longevity is impacted by growth hormone action during early postnatal period. Elife 6:|
|Fang, Yimin; McFadden, Samuel; Darcy, Justin et al. (2017) Differential effects of early-life nutrient restriction in long-lived GHR-KO and normal mice. Geroscience 39:347-356|
|Darcy, Justin; Fang, Yimin; Hill, Cristal M et al. (2016) Original Research: Metabolic alterations from early life thyroxine replacement therapy in male Ames dwarf mice are transient. Exp Biol Med (Maywood) 241:1764-71|
|Hill, Cristal M; Fang, Yimin; Miquet, Johanna G et al. (2016) Long-lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high-fat diet on metabolic function and energy expenditure. Aging Cell 15:509-21|
|Darcy, Justin; McFadden, Samuel; Fang, Yimin et al. (2016) Brown Adipose Tissue Function Is Enhanced in Long-Lived, Male Ames Dwarf Mice. Endocrinology 157:4744-4753|
|Bartke, A; Sun, L; Fang, Y et al. (2016) Growth hormone actions during development influence adult phenotype and longevity. Exp Gerontol 86:22-27|
|Koopman, Jacob J E; van Heemst, Diana; van Bodegom, David et al. (2016) Measuring aging rates of mice subjected to caloric restriction and genetic disruption of growth hormone signaling. Aging (Albany NY) 8:539-46|
|Spadaro, Olga; Goldberg, Emily L; Camell, Christina D et al. (2016) Growth Hormone Receptor Deficiency Protects against Age-Related NLRP3 Inflammasome Activation and Immune Senescence. Cell Rep 14:1571-1580|
|Camell, Christina; Goldberg, Emily; Dixit, Vishwa Deep (2015) Regulation of Nlrp3 inflammasome by dietary metabolites. Semin Immunol 27:334-42|
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