AGING OF THE LIVER - AGE-ASSOCIATED MITOCHONDRIAL DAMAGE IN INTACT HEPATOCYTES

Mitochondrial damage may be a major cause of cellular aging. So far, t his hypothesis had only been tested using isolated mitochondria. The a im of this study was to investigate the involvement of mitochondria in aging using whole liver cells and not isolated mitochondria only. Usi ng now cytometry, we found that age is associated with a decrease in m itochondrial membrane potential (30%), an increase in mitochondrial si ze, and an increase in mitochondrial peroxide generation (23%). Intrac ellular peroxide levels were also increased. The number of mitochondri a per cell and inner mitochondrial membrane mass did not change. Gluco neogenesis from glycerol or fructose (mitochondrial-independent) did n ot change with age, whereas it did from lactate (mitochondrial-depende nt). The change in the rate of gluconeogenesis was not accompanied by changes in any of the following parameters: phosphoenolpyruvate carbox ykinase or pyruvate carboxylase activities or mitochondrial ATP/ADP or cytosolic NADH/NAD(+) ratios. This was caused by a decreased rate of malate export (to 20% of the controls) from mitochondria. The impairme nt of the mitochondrial malate transporter is posttranscriptional beca use its expression in Xenopus oocytes using polyadenylated RNA from li vers of young or old animals did not change. Ketogenesis from oleate a lso fell in hepatocytes from old rats. Our results show, for the first time in intact cells, a correlation between age-associated impairment of cell metabolism and specific changes in mitochondrial function and morphology, supporting the hypothesis that mitochondrial damage plays a key role in aging.