Impact of FGF21 on healthspan and lifespan

Yale University, New Haven CT

Investigators

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Abstract

This is an administrative supplement request (PA-18-591) in response to NOT-AG-18-008 Disease focused 1P01 AG051459-02 entitled ?FGF21 and hypothalamic control of aging (Dixit, Kliewer, Mengelsdorf PDs)?. The administrative supplement request relates to Project 4 of the PPG (Horvath TL, PI) titled ?FGF21 and hypothalamic control of aging?. The goals of Project 4 of this Program Project is to determine the role of the hypothalamus in mediating FGF21's action on systemic aging. There are no Alzheimer's Disease-related studies proposed in this grant. Numerous studies in various models, including worm, fruit fly, mice rats and non-human primates showed that moderate calorie restriction prolongs health-span and can also prolong mean and maximal lifespan [for review see 1]. To date, this is the only physiological intervention that has consistent and predictable effects to prolong life and health in all species studied. In humans, prospective experiments are underway, and preliminary data show that similar shifts in metabolic profiles and overall tissue health are also associated with calorie restriction in men and women [1]. Because of the above, increasing efforts have been made to identify mimetics of calorie restriction to attempt pharmacological enhancement of health- and lifespan. Among these, the effects of the growth factor, fibroblast growth factor 21 (FGF21), emerged as a promising lead candidate with therapeutic potential. FGF21 is generated and secreted by the liver to the circulation during negative energy balance and acts on target cells expressing its mandatory co-receptor, ?- Klotho, in various tissues, including the brain. FGF21 in this context evokes adaptive responses of the body to energy shortage (i.g., calorie restriction) [1]. Because cellular signaling evoked by FGF21 overlaps with that necessary for activation hypothalamic AgRP neurons, cells that are crucial in promotion of hunger-related behavioral and autonomic adaptations, we hypothesize that hypothalamic AgRP neurons play a key role in mediating central and peripheral actions of FGF21. We seek to determine if FGF21 can alter the trajectory of cognitive aging and actually ?rejuvenate? critical aspects of learning and memory in elderly primates. (Alzheimer's and its related Dementias (AD/ADRD)-focused Administrative supplements for NIH grants that are not on Alzheimer's disease) to our ongoing program project grant NIH grant circulating development published pathology impact hippocampal response to NOT-AG-18-008, we request funds test the hypothesis that geronic peptides, substances with contrasting levels in young and aged animals, impact the onset of phenotype in a murine model of AD (directly relevant to Aim 3 of Project 4 of the parent grant). We recently that changes in brain oscillations (EEG) in this rat model of AD ( precedes brain and behavioral changes in rats carrying human mutations predictive of AD [2; see below for details] goal of our proposed studies is to determine whether circulating substances that are thought to chronological aging, specifically fibroblast growth factor 21 (FGF21), alters the onset of cortical and oscillatory abnormalities identified in In to TgF344-AD rats) . The TgF344-AD rats. 1