The objective of this proposal is to test the hypothesis that elevated levels of plasma high density lipoprotein cholesterol (HDL-C) are able to retard aging processes by slowing age-related physiological and pathological changes. Previously, only reduced caloric intake produced these effects in mammalian models. In humans, elevated HDL-C levels have been shown to be cardioprotective and to extend life expectancy. However, the increase in longevity is greater than what might be expected from protection against heart disease alone. Because human population studies are often complex and results difficult to interpret, we propose to test the effects of HDL-C on aging in a set of newly created mouse models which have widely differing HDL-C levels when fed a standard mouse diet. These models have been created in the same genetic background strain, B6 (C57BL/6J). Five mouse strains to be used, listed in the order of decreasing HDLC levels, are: (1) transgenic B6 mice with a human APOA1 gene, which expresses human apoA1 at twice normal mouse levels, thereby increasing HDL-C levels two-fold, (2) congenic B6.H Ath-lr, carrying an allele from strain C3H, which causes atherosclerosis resistance by increasing HDL-C levels, (3) B6, the standard aging inbred mouse model, (4) transgenic B6 mice carrying the CETP gene, which expresses cholesterol ester transfer protein (CETP), the carrier protein that transfers cholesterol from HDL to other lipoproteins thereby decreasing HDL-C levels, and (5) intercrossed transgenic B6 CETP and B6APOA1 mice. These strains have plasma HDL-C levels of 120, 90, 60, 30, and 15 mg cholesterol/dl, respectively. The specific hypothesis that we will test in these mice are as follows. Hypothesis 1: With higher HDL-C levels, longevity will increase and the rates of age-related changes in biological markers (e.g. immune system, collagen denaturation, renal function) will be retarded. Hypothesis 2: With higher HDL-C levels, incidences of tumors and other pathological biomarkers of age will be reduced. Males and females will be compared for both hypotheses 1 and 2, because of gender differences in tumor types and to shed light on whether higher HDL-C levels in human females contribute to their greater longevity. Hypothesis 3: Low calorie diets, which retard aging, act by mechanisms independent of the HDL-C effects. This hypothesis predicts that aging will be retarded to a similar extent in mice of high, medium or low HDL-C levels fed low calorie diets. Lifestyle changes and therapies which elevate HDL-C levels may result in a healthier old age, if HDL-C levels play a role in retarding aging processes.
