Abstract
Rapamycin is known to extend lifespan. We conducted a randomized placebo-controlled study of enteric rapamycin-treatment to evaluate its effect on physical function in old low capacity runner (LCR) rats, a rat model selected from diverse genetic background for low intrinsic aerobic exercise capacity without genomic manipulation and characterized by increased complex disease risks and aging phenotypes. The study was performed in 12 male and 16 female LCR rats aged 16-22 months at baseline. The treatment group was fed with rapamycin-containing diet pellets at approximately 2.24mg/kg body weight per day and the placebo group with the same diet without rapamycin for six months. Observation was extended for additional 2 months. Physical function measurements include grip strength measured as maximum tensile force using a rat grip strength meter and maximum running distance (MRD) using rat physical treadmill test. The results showed that rapamycin improved grip strength by 13% (p=.036) and 60% (p<.001) from its baseline in female and male rats, respectively. Rapamycin attenuated MRD decline by 66% (p<.001) and 46% (p=.319) in females and males, respectively. These findings provide initial evidence for beneficial effect of rapamycin on physical functioning in an aging rat model of high disease risks with significant implication in humans.
Highlights
Co-existence of complex multiple chronic conditions is rather a norm than exception in older adults
None of the rapamycin-treated female rats or those in the placebo group showed any diabetic symptoms or had fasting glucose exceeding 100mg/dl over the course of the study. This randomized placebo-controlled study observed, for the first time, that enteric rapamycin-treatment led to improvement of grip strength and better maintenance of maximum running distance (MRD) over time in old Low capacity runner (LCR) rats, a rat model characterized by increased complex disease risks and aging phenotypes
Significant sex differences were noted in body weight, grip strength and MRD at the study entry, and these baseline differences might be due, in part, to differences in age as the male rats were 4-6 months older than the females
Summary
Co-existence of complex multiple chronic conditions is rather a norm than exception in older adults. Animal models with diverse genetic background suitable for the study of complex disease risks and aging may facilitate developing such strategies and are of immediate interest to the field of gerontology. While such ideal model systems with no genomic manipulation are scarce, a rat model of intrinsic aerobic exercise capacity can serve at least to some extent, as one. This rat model was developed from the genetically heterogeneous N:NIH out-crossed stock [3] through 2-way selective breeding using a rotational breeding scheme on the trait of running capacity measured by maximal distance run to exhaustion on a speed-ramped treadmill [4]. LCRs display increased complex metabolic and cardiovascular www.impactaging.com
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