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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG006232-02
Application #
3117171
Study Section
Nutrition Study Section (NTN)
Project Start
1987-09-30
Project End
1992-08-31
Budget Start
1988-09-01
Budget End
1989-08-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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Erway, L C; Willott, J F; Archer, J R et al. (1993) Genetics of age-related hearing loss in mice: I. Inbred and F1 hybrid strains. Hear Res 65:125-32
Harrison, D E; Zhong, R K (1992) The same exhaustible multilineage precursor produces both myeloid and lymphoid cells as early as 3-4 weeks after marrow transplantation. Proc Natl Acad Sci U S A 89:10134-8
Harrison, D E (1992) Evaluating functional abilities of primitive hematopoietic stem cell populations. Curr Top Microbiol Immunol 177:13-30
Harrison, D E; Lerner, C P (1991) Most primitive hematopoietic stem cells are stimulated to cycle rapidly after treatment with 5-fluorouracil. Blood 78:1237-40

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