Lifespan and Lesions in Genetically Heterogeneous (Four-way Cross) Mice: A New Model for Aging Research

Abstract

Abstract. Genetically heterogeneous animal models provide many advantages for research on aging but have been used infrequently. We present here lifespan and lesion data from a study of mice bred as a cross between (AKR/J x DBA/2J)F, females and (C57BL/6J x SJL/J)F, males. In such a four-way cross population, each mouse is genetically unique, but replicate populations of essentially similar genetic structure can be generated quickly, at low cost, and of arbitrary size from commercially available, genetically stable hybrid parents. We employed a protocol in which mice judged to be severely ill were euthanatized to obtain tissue in optimal condition for necropsy, and we were able to infer a likely cause of illness in 42 of 44 animals. Malignant lymphoma, including at least four histopathologically distinct subtypes, was the most common cause and was also a frequent incidental finding in mice dying of other causes. Neoplastic disease, benign or malignant, was the sole or a contributing cause of illness in 90% of the mice for which a cause could plausibly be assigned. A wide range of lethal and nonlethal degenerative lesions was also noted. The coefficient of variation for lifespan in these genetically heterogeneous mice was 26%, similar to that seen in analyses of recombinant inbred mouse lines. Baseline lifespan and pathology data on four-way cross mice is a useful prelude to the exploitation of this rodent model in tests of genetic and mechanistic hypotheses about aging.

Monitoring Tumorigenesis and Senescence In Vivo with a p16INK4a-Luciferase Model

“…Likewise, the rate of change in luminescence activity at any age was not predictive of death (Figures 2F and S2H–S2J). Consistent with previous assessments of mortality in several strains of inbred as well as outbred mice (Chrisp et al, 1996; Miller et al, 2011; Wilkinson et al, 2012), all autopsied animals from the study showed signs of advanced cancer. Moreover, no significant decrease in median survival was observed between p16 +/+ and p16 +/LUC animals (Figure S2K).…”

The Pathology of Aging 129S6/SvEvTac Mice

“…Figs. [6][7][8]. Based on these findings, the frequency of epithelial hyalinosis affecting extrapulmonary sites was significantly higher in 129S6/SvEvTac females than males.…”

Pathobiology of Aging Mice and GEM

“…151,156 Hematopoietic tumors were the primary cause of death in 4WC mice and found in 55% of male and 43% of female mice when pathology was evaluated. 53 Frequency of tumors (or of other pathology phenotypes) has been defined as the proportion of mice with tumors in animals submitted for necropsy. The data may be skewed if some strains are maintained and studied to later ages than others (eg, aging nulliparous research populations vs younger breeding populations).…”