Identifying and Implementing Endpoints for Geriatric Mice

Abstract

The types of changes in physical appearance and behavior that occur in elderly people similarly develop in elderly animals. Signs and symptoms that might cause concern in younger people or mice may be normal in their elderly but generally healthy counterparts. Although numerous scoring methods have been developed to assess rodent health, these systems were often designed for young adults used in specific types of research, such as cancer or neurologic studies, and therefore may be suboptimal for assessing aging rodents. Approaches known as frailty assessments provide a global evaluation of the health of aged mice, rats, and people, and mouse frailty scores correlate well with the likelihood of death. Complementing frailty assessment, prediction of imminent death in aged mice can often be accomplished by focusing on 2 objective parameters-body weight and temperature. Before they die, many (but not all) mice develop marked reductions in body weight and temperature, thus providing signs that close monitoring, intervention, or preemptive euthanasia may be necessary. Timely preemptive euthanasia allows antemortem collection of data and samples that would be lost if spontaneous death occurred; preemptive euthanasia also limits terminal suffering. These approaches to monitoring declining health and predicting death in elderly research mice can aid in establishing and implementing timely interventions that both benefit the research and reduce antemortem suffering.

Figure 1.

Comparison of mouse frailty assessment scales. Modified and expanded from reference with permission.

Figure 2.

Comparison of CFI values in adult humans (male and female) and male mice of 3 age groups

Figure 3.

Kaplan–Meier survival plots of AKR/J, C57BL/6J, and BALB/cByJ mice. The horizontal dashed line indicates the point at which 50% of the mice remained alive. Reproduced from reference with permission.

Figure 4.

Body weight, temperature, and temperature×body weight during the final weeks of life in AKR/J, C57BL/6J, and BALB/cByJ mice. For all panels, values of temperature, body weight, and the product of temperature and body weight (T×BW) were aligned with regard to the day of collection prior to death. The left panels show the mean of actual measured values for male (filled circles) and female (open circles) AKR/J mice. The horizontal lines represent the average of all values collected during weeks 9 through 12 prior to death for male (solid line) and female (dashed line) mice and were considered to be the baseline. Stars denote values significantly (P value < 0.05) different from the baseline value for female (open stars) and male (filled stars) mice. In the center panels, values for individual AKR/J mice were normalized with regard to each animal's individual baseline values, defined as the mean of values collected during weeks 9 through 12 prior to death for that mouse (circled values). For body weight and T×BW, data at each time point were converted to a ratio of the baseline value for that mouse; the horizontal solid and dashed lines on those panels respectively indicate ratios of 1.0 and, as a visual benchmark, 0.95. For temperature, data were expressed as a difference from the baseline value for that mouse; the horizontal solid and dashed lines on that panel respectively indicate normothermia and, as a visual benchmark, hypothermia of 1 °C. In the right panels, data from C57BL/6J and BALB/cByJ mice are displayed in a similar manner to those of AKR/J mice in the center panels. However, for the C57BL/6J and BALB/cByJ mice, values for individual animals were normalized with regard to each animal's individual mean baseline values during weeks 13 through 16 prior to death (circled values). For body weight and T×BW, data at each time point were converted to a ratio of the baseline value for that mouse; the horizontal solid and dashed lines on those panels respectively indicate ratios of 1.0 and, as a visual benchmark, 0.95. For temperature, data were expressed as a difference from the baseline value for that mouse; the horizontal solid and dashed lines on that panel respectively indicate normothermia and, as a visual benchmark, hypothermia of 1 °C. Open and filled stars denote values significantly (P < 0.05) from the baseline value for BALB/cByJ and C57BL/6J mice, respectively. Modified from reference with permission.

Figure 5.

Body weight and temperature in the last weeks of life of Hsd:ICR mice. The panel represents the average of the calculated values of temperature×body weight (T×BW) for individual mice. The circle highlights values that were averaged to generate the 100% value for each mouse, represented by the upper horizontal dashed line. In the last 2 wk of life, values fell to below 90% of the 100% benchmark (indicated as the lower dashed line). Reproduced from reference with permission.