The investigators are proposing to study the effects of early- and adult-onset caloric restriction (CR) on age-associated changes in cardiac function, structure, and mitochondrial abnormalities. CR is a robust and reproducible intervention capable of increasing both mean and maximum life span in a wide range of species. The mechanism by which a reduction in caloric intake exerts this effect is not known, however, there is increasing evidence that caloric restriction functions by decreasing oxidative stress and subsequent oxidative damage to cellular biomolecules. Mitochondrial genetic and enzymatic abnormalities have been linked to many inherited mitochondrial disorders, and there is increasing evidence for physiologically relevant accumulations of mitochondrial abnormalities in degenerative aging processes. These investigators and others have shown mtDNA deletions can accumulate to high levels in cells and that associated with this accumulation are mitochondrial electron transport system abnormalities. Their focal accumulation and mosaic distribution dictates the histologic approaches proposed. The use of the F344BNF1 strain is an important aspect of the proposed studies. This rat strain is less susceptible to many of the age-related pathologies commonly found in rat models (e.g., nephropathy) that can present confounding mechanisms for cardiac changes Rat hearts from animals of diverse ages will be first characterized by physiologic studies. The cardiac tissue will then be histologically assessed employing the quantifiable measures of LV function, changes in histological structure, abundance of cardiomyocytes exhibiting mitochondrial abnormalities and numbers of cardiomyocytes undergoing cell death. These physiological and histological studies will also be conducted on rats subjected to early- and, most germane to human aging, adult-onset CR.
| McKiernan, Susan H; Tuen, Victoria C; Baldwin, Katherine et al. (2007) Adult-onset calorie restriction delays the accumulation of mitochondrial enzyme abnormalities in aging rat kidney tubular epithelial cells. Am J Physiol Renal Physiol 292:F1751-60 |
| Hacker, Timothy A; McKiernan, Susan H; Douglas, Pamela S et al. (2006) Age-related changes in cardiac structure and function in Fischer 344 x Brown Norway hybrid rats. Am J Physiol Heart Circ Physiol 290:H304-11 |
| Pak, Jeong W; Vang, Fue; Johnson, Chad et al. (2005) MtDNA point mutations are associated with deletion mutations in aged rat. Exp Gerontol 40:209-18 |
| Bua, Entela A; McKiernan, Susan H; Wanagat, Jonathan et al. (2002) Mitochondrial abnormalities are more frequent in muscles undergoing sarcopenia. J Appl Physiol 92:2617-24 |
| Aiken, Judd; Bua, Entela; Cao, Zhengjin et al. (2002) Mitochondrial DNA deletion mutations and sarcopenia. Ann N Y Acad Sci 959:412-23 |
