The primary aim of this proposal is to investigate the cellular and molecular mechanisms underlying the remarkable anti-aging action of dietary restriction. Intensive research endeavors from the past two decades have firmly established that dietary restriction is the most efficacious, and in fact the only, means available to gerontologists of intervening in the aging processes in mammals. Therefore, we propose that the mechanistic delineation of the action of dietary restriction is the most logical approach leading to a better understanding and probing of the complex biological aging processes. The central theme of the proposed project is built on the concept that aging processes involve the loss in the ability of organisms to maintain cellular homeostasis due to deterioration of self-regulatory mechanisms at various levels. Therefore, it is our hypothesis that dietary restriction exerts its anti-aging action by maintaining in optimal condition the integrative and self regulatory capacities of critical intracellular and extracellular biochemical processes. Project I tests the hypothesis that the modulation of free radical activity and attenuation of the resulting oxidative alterations are mechanisms by which dietary restriction retards aging and its disease processes. Project II explores the cellular mechanisms by which dietary restriction enhances the efficiency of DNA repair in specific genes. Project IV examines the proteolytic processes which degrade abnormal and altered proteins and their modulation by dietary restriction. Project VI explores the age-related alterations in cellular calcium regulation and the mechanisms by which dietary restriction maintains calcium homeostasis. Project VII tests the hypothesis that dietary restriction retards aging processes by modifying the cellular characteristics of fuel utilization. Project VIII investigates the mechanism underlying mild hyperadrenocorticism associated with dietary restriction and tests the hypothesis that the hyperadrenocorticism potentiates cellular homeostasis and contributes to its life-prolonging action. These studies will permit a broader understanding and knowledge of the molecular and cellular mechanisms responsible for te anti-aging action of dietary restriction and provide new insights into the mechanisms underlying the biological aging processes.
