The long-term objective is to understand how the nutritional modulation, food restriction, retards mammalian aging rates. It is widely thought to act by retarding the decline with age in immune responses or by reducing life-long metabolic activity. However, some recent data contradict both hypotheses. To evaluate the contributions of the immune and metabolic systems, food restriction will be studied in many groups of genetically defined mice varying in rate of immune aging and in metabolic rate. An absence of direct correlations between effects on aging (biomarkers, longevity, pathological leisons) and effects on immunological decline would rule out the immune system as a mediator of the age-retarding effects of food restriction. The presence of such correlations would direct attention to the immune system. The same is true for the metabolic system. Mice of the following four types provide a wide range of immunological aging rates and life-long metabolic rates: B6CBAF1, B6, B6-ob/+ and B6-ob/ob. In the latter, food restriction fails to retard immune aging, but reduces metabolic rates, separating the two hypotheses. The range of immune aging and metabolic rates will be broadened by initiating food restriction at 1, 6, or 12 months of age. Effects of food restriction on aging will also be studied in D2 and BALB mice so that detailed genetic analyses of differences with B6 can be planned. Immune aging rates will be directly measured with standard tests of T and B cell functions, and antigen-containing cells, in aging mice, plus testing whether declines with age result from declines in numbers of T- helper and killer precursor cells. Metabolic rates as the caloric value of O/2 consumed will be derived from measuring long-term O/2 consumption, and production of CO/2 and urinary nitrogen. Effects of food restriction on aging will be defined by longevities and pathological lesions. In addition a series of biomarkers - changes with age assessed in a variety of systems without harming the mouse - will be used. These are important because declines with age in many different biological systems are not consistently related to longevity. Thus the biomarkers will be used to determine whether immune aging or metabolic rate can be ruled out as mediators of the beneficial effects of food restriction in biological systems not related to longevity in the particular group tested.
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