The greatest risk factor for nearly all the neurodegenerative diseases is aging. The mechanisms for the age- dependent onset of neurodegeneration are unknown, which represents a fundamental problem both in the field. Studies in a variety of model organisms from yeast to rodents identify pathways that modulate aging. In mice, reduced somatotropic axis activity (or GHRH-GH-IGF1 pathway) leads to major increases in lifespan and healthspan. Murine mutant mice with slow rates of aging and murine AD disease models with varying phenotypic effects provide the opportunity to develop novel genetic models that will allow to study the interaction of aging and neurodegeneration. The long-term goal of our research is to understand the molecular basis of brain aging and the way in which aging contributes to pathological aging and neurodegenerative disorders. Our objective is to elucidate the role of the somatotropic axis in the age-dependent susceptibility to AD. Our hypothesis is that slowing aging by inhibiting the somatotropic axis will delay mortality and retard the development of behavioral and pathologic abnormalities secondary to A? toxicity in mice. This proposal, if successful, should lead to new models to study the interaction of aging with neurodegenerative diseases in the context of mutations that slow the aging process, and serve as a foundation for future work toward the development of interventions to prevent, retard, or treat neurodegenerative diseases. Our models would be also used to pursue mechanistic hypotheses about age-related processes that modulate AD and other late-life neurodegenerations.
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 hormonal signaling, cognitive aging and neurodegenerative 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-neurodegenerative 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 |
