Decreased metabolic rate (MR) is widely believed to play a major role in the anti-aging effects of caloric restriction (CR). Such a role is consistent with the Rate of Living theory and with evidence demonstrating reduced MR in response to CR. However, studies of whole animal metabolism indicate the reduced MR is transient and does not persist over the lifespan. These studies do not exclude sustained reduction in MR of specific tissues. This is important because homeothermic animals must expend energy to maintain body temperature. The two most robust models of extended longevity in mammals (calorie restriction of rodents and dwarfism in mice) both involve high rates of heat loss associated with high surface/volume ratios. Thus is it possible that MR of key tissues such as the brain is reduced while MR of tissues regulating body temperature such as brown fat or skeletal muscle is increased. Technical limitations have thus far prevented measurement of MR of specific rodent tissues in vivo. The recent development of micro Positron Emission Tomography (PET) devices now makes it possible for the first time to establish MR of specific rodent tissues non-invasively. Using PET measurements together with magnetic resonance imaging and indirect calorimetry, we propose to provide the first test of the Hypothesis: The extended longevity of caloric restriction and of dwarfism in laboratory rodents is associated with altered metabolic rates of specific tissues. In particular, specific metabolic rates of key maintenance tissues such as the brain are decreased and specific metabolic rates of heat generating tissues such as skeletal muscle are increased. The hypothesis will be tested by executing the following Specific Aims: 1. To measure specific metabolic rates of skeletal muscle, brown adipose tissue, brain, heart, kidneys, liver and of the whole animal in male Fischer 344 rats fed ad libitum and fed 40 percent less than ad libitum. 2. To measure specific metabolic rates of skeletal muscle, brown adipose tissue, brain, heart, kidneys, liver and whole body in male C57BL/6 mice fed ad libitum or fed 40 percent less than ad libitum. 3. To measure the specific metabolic rates of skeletal muscle, brown adipose tissue, brain, heart, kidneys, liver and whole animal in male Ames dwarf mice fed ad libitum. The measurements will provide a definitive test of the involvement of reduced metabolic rate in the mechanism by which CR retards aging processes.
