Transient caloric restriction in early adulthood hastens disease endpoint in male, but not female, Cu/Zn‐SOD mutant G93A mice

Abstract

Long-term caloric restriction (CR) prolongs the lifespan in healthy insects, rodents, and nonhuman primates. We previously reported that long-term CR improves motor performance but hastens clinical onset of disease in an animal model of amyotrophic lateral sclerosis (G93A mice). G93A mice overexpress the mutant human Cu/Zn-SOD gene and show progressive lower motor neuron weakness and increased oxidative stress. To study short-term (15 days) CR in the same animal model, we investigated the effect of transient caloric restriction (TCR) on paw grip endurance, clinical onset, disease progression (time from clinical onset to endpoint), and lifespan. Starting at age 40 days, 32 separately caged G93A mice were randomly divided into two groups: ad libitum (AL, n = 17; 10 females, 7 males) and TCR (n = 15; 6 females, 9 males) with a diet equal to 60% of AL. When the TCR mice lost 30% of their weight they were offered food AL until endpoint, otherwise all TCR mice were provided food AL from age 55 days until endpoint (i.e., range of TCR = 13-15 days). Paw grip endurance started to decrease significantly at age 96 days compared with baseline values for all the groups. TCR males reached clinical onset 5 days sooner than TCR females. Disease progression was 8 days faster in TCR mice than AL mice and 6 days faster in male mice than female mice. The probability of survival was significantly different between the groups, with the TCR males having a faster rate of reaching endpoint than TCR females, AL males, and AL females. We conclude that TCR hastens clinical onset of disease and shortens the lifespan in male, but not female, G93A mice. Moreover, TCR hastens progress of disease but has no effect on paw grip endurance. The female sex is protective against the detrimental effects of short-term CR in G93A mice. Assuming we can extrapolate these results to humans, short-term CR should be avoided in patients with amyotrophic lateral sclerosis, especially men.