Lesion biomarkers of aging in B6C3F1 hybrid mice.

This study of B6C3F1 hybrid mice was designed to determine the effects of caloric restriction (CR) on age-related pathologic changes. These changes accompany and may, in part, account for the apparent effect of CR in slowing the rate of aging. The study also explored whether lesions observed in groups of animals killed at 6 month intervals can serve as biomarkers of aging. Approximately 30 mice of each sex and each of two diet groups--CR and ad libitum fed (AL)--and each of six age groups--6, 12, 18, 24, 30, and 36 months of age--from the Biomarkers of Aging Program of the National Institute on Aging were killed and all tissues from each were examined for the histological presence or absence of lesions. A total of 209 distinct lesions were observed, of which 51 occurred in at least 10% of the AL or CR mice. The average number of lesions per mouse increased linearly with age in all diet-sex groups except in male CR mice. This increase was significantly smaller in CR than in AL mice of both sexes. The number of distinct lesions also increased with age in both diet groups but much less rapidly in CR mice. Nearly all lesions, including neoplastic, and nonneoplastic proliferative and degenerative ones, occurred significantly less often in CR than in AL mice at all ages. Foci of leukocytes in the liver, however, occurred more frequently in CR mice. Lung adenomas in old female mice occurred with equal frequency in both diet groups. A parsimonious classification tree analysis showed that diet groups could have been distinguished at each age by an evaluation of relatively few lesions and tissues. Altogether, this study suggests strongly that the prevalence of many individual lesions, the total lesion burden, and the total types of lesions are good biomarkers of aging because they increase with age and reflect the effect of CR in slowing the aging process. The study also shows that lesions occur stochastically, randomly, and independently in genetically homogeneous mice raised in a nonvariable environment.