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Genetic and environmental factors both play a role in the occurrence of age-related disease. To examine the genetic contribution to the development of spontaneous lesions in aging animals, a complete range of tissues was comprehensively analyzed by histopathology from 180 individually housed ad libitum–fed or 40% calorically restricted 24-month-old male and female mice of 2 parental strains—DBA/2NNia (D2) and C57BL/6NNia (B6)—and the F1 cross B6D2F1/NNia. Several strain- and diet-dependent patterns of lesions were identified. Many lesions were genotype dependent and exhibited recessive phenotypic expression, defined as being common in 1 parental strain but infrequently observed in the F1 cross (eg, glomerulonephritis in B6 mice), while others were maintained from 1 parental strain to the F1 with similar frequencies (eg, reproductive tract leiomyoma in D2 mice). Other lesions were common regardless of genotype (osteoarthritis, periodontitis). Only rare lesions were more common in the F1 but underrepresented in the 2 parental strains. Furthermore, F1 mice had a lower number of overall total lesions and a lower number of tumors than either parental strain. Caloric restriction reduced the total number of lesions and neoplasms regardless of genotype but differentially affected genotype-dependent lesions in B6 and D2 mice, with B6 mice more sensitive to the effects of caloric restriction than D2 mice. In summary, genetics and environmental factors (eg, dietary restriction) both substantially contribute to the pattern of lesions that develop as animals age.

Strain- and Diet-Related Lesion Variability in Aging DBA/2, C57BL/6, and DBA/2xC57BL/6 F1 Mice