Rapamycin suppresses brain aging in senescence-accelerated OXYS rats

Abstract

Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway andrapamycin extends life span in C elegans, Drosophila and mice. Herein, we investigated effects of rapamycin on brain aging in OXYS rats. Previously we found, in OXYS rats, an early development of age-associated pathological phenotypes similar to several geriatric disorders in humans, including cerebral dysfunctions. Behavioral alterations as well as learning andmemory deficits develop by 3 months. Here we show that rapamycin treatment (0.1 or 0.5 mg/kg as a food mixture dailyfrom the age of 1.5 to 3.5 months) decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. Inuntreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-foldincreased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the differencebetween OXYS and Wistar rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifestedby loci of demyelination. Rapamycin decreased the percentage of animals with demyelination and the number of loci.Levels of Tau and phospho-Tau (T181) were increased in OXYS rats (compared with Wistar). Rapamycin significantlydecreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. Importantly, rapamycintreatment caused a compensatory increase in levels of S6 and correspondingly levels of phospo-S6 in the frontal cortex,indicating that some downstream events were compensatory preserved, explaining the lack of toxicity. We conclude thatrapamyc in low chronic doses can suppress brain aging. © Kolosova et al.