MIDI MOUSE AS A NOVEL MODEL FOR INVESTIGATING IGF-1 IN AGING

Open Access
Author:
Motch, Susan Marie
Graduate Program:
Physiology
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
June 24, 2010
Committee Members:
  • Roger John Mccarter, Dissertation Advisor
  • Roger John Mccarter, Committee Chair
  • Michael Henry Green, Committee Member
  • Ramesh Ramachandran, Committee Member
  • Wesley Craig Hymer, Committee Member
  • Joseph Tobias Stout, Committee Member
Keywords:
  • physical activity
  • metabolism
  • heat shock proteins
  • midi mouse
  • aging
  • IGF-1
  • stress
Abstract:
Health in late life is the net result of a complex interplay of biological, psychosocial and environmental factors occurring over a lifetime. One factor modulating this interplay is the hormone Insulin-Like Growth Factor-1 (IGF-1). The focus of this dissertation is to examine the physiological status over the lifespan of mice genetically modified to exhibit low levels of IGF-1 throughout their bodies with the goal of evaluating the use of these mice for testing theories of aging. These mice have been termed "midi mice". Midi mice attained a longer median lifespan, defined as the point in time at which 50% of the population had died. Female midi mice (n=26) achieved a median lifespan of 768 d which was longer (p < 0.01) than that attained by control female mice (725 d, n = 22). Male midi mice (n = 22) attained a median lifespan of 778 d, which was longer than the median lifespan attained by male control mice (721 d, n = 30). Male midi mice also showed an increased maximum lifespan (897 d), defined as tenth percentile survivors, compared to male controls (813 d) (p <0.05). There was no difference in maximum lifespan between female midi mice (813 d) and female controls (822 d), p = 0.11. We found increased weight in male and female controls from 100 d to 495 d of age, while male and female midi mice maintained approximately the same body weight. At 100 d of age, energy expenditure was approximately twice that of 495 d old mice. Control mice did not vary in physical activity by sex or age, in contrast all midi mice showed a significant increase in physical activity with age. Core body temperature increased with age in all groups except male midi mice, which remained lowest throughout life. Diurnal patterns of energy expenditure, physical activity, and core body temperature were similar across all groups throughout the lifespan although actual values were different. At 100 d of age, BMD was lower (p<0.0001) in midi mice compared to controls, with no effect between sexes of either genotype (p = 0.321). At 495±5 d, BMD was lower in midi mice (p<0.0001) compared to controls. Sex also influenced BMD (p=0.010), with males of both genotypes exhibiting lower BMD in older animals. All groups maintained lean body mass and fat mass in the region of interest, defined as the area from the cranial portion of the scapulas to the 100 d to 495 d, p <0.05. Total protein was extracted from liver of mice (n= 36, 9 per sex and genotype). There was no difference in liver total protein content by sex or genotype (p>0.05). All mice expressed similar non-stress levels of liver HSP70 and liver HSP90, both of which are ubiquitously expressed. Following hyperthermia, male midi and male control mice produced the highest levels of liver HSP90, followed by female midis. Female control mice produced the lowest level of liver HSP90 following the hyperthermia stressor. Following hyperthermia, midi mice expressed slightly higher levels of liver HSP70 than controls. Following hyperthermia treatment, liver CRP levels were significantly lower in female midi mice than both male and female control mice. Liver CRP levels were lower in male midi mice than all other groups. Of unique interest, oxidative damage, measured as nmols carbonyls per mg liver protein in post-hyperthermia treatment mice was higher in midi mice compared to control mice (p < 0.02, n = 36, 9 per group). Mouse common cytokines were also examined, however, no differences were found in liver between control and midi mice for IL1A, IL1B, IL2, IL4, IL6, IL10, IL12A, IL13, IL17A, G-CSF, GM-CSF (n=6 per genotype; 3 males and 3 females per genotype). These experiments provide a broad starting point, showing that the midi mouse model could be useful in healthspan studies involving inflammation, metabolism, osteoporosis, nutrition, exercise, and innumerable others as was the intention of this project.