AGING PPAR AND HEPATIC PEROXISOMES

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DESCRIPTION (Adapted from applicant's abstract and specific aims): Several isoforms of the peroxisome proliferator-activated receptor (PPAR) have recently been discovered and implicated in the process of peroxisome proliferation. It is reported that while PPAR-alpha (PPAR-a) is responsible for the pleiotropic effects of peroxisome proliferators, PPAR-delta (PPAR-d) and PPAR-d may play a repressive role in this process. Tissues which are most responsive to peroxisome proliferators express high amount of PPAR-a and low amounts of the other two isoforms. Studies also show that fenofibrate, a peroxisome proliferator, enhanced the expression of hepatic PPAR-a. Preliminary data show a decline in basal and inducible levels of hepatic peroxisomal enzymes in aged animals. The investigators hypothesize that aged animals have lower levels of PPAR-a and/or higher levels of PPAR-a and PPAR-d, compared to young animals, and the expression of PPAR-a is not enhanced in livers of aged rats by peroxisome proliferators, to levels observed in young animals. The investigators will test this hypothesis by: (1) quantitating hepatic constitutive levels of the various PPAR isoforms in young (4,10 wk), mature (20 wk) and aged (50,100 wk). (2) determining the level of inducibility of PPAR-a in response to several structurally dissimilar peroxisome proliferators (WY-14,643, DEHP, clofibrate, PFOA) in these animals groups, (3) correlating levels of individual PPAR isoforms with peroxisomal enzyme activities in livers of various age group rats untreated and treated with peroxisome proliferators. The purpose of these experiments will be to investigate the relationship between levels of expression of the various PPAR isoforms and constitutive levels of peroxisomal enzyme activities as well as the extent of the pleiotropic response to peroxisome proliferators in the livers of young and aged animals. Recent published findings showing that inhibiting peroxisomal enzyme activities shortened the animal longevity and the fact that aged animals have reduced peroxisomal activities, necessitates an urgent evaluation of the possibly that the decline in these activities may contribute to the process of aging.