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 and rapamycin 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 and memory deficits develop by 3 months. Here we show that rapamycin treatment (0.1 or 0.5 mg/kg as a food mixture daily from the age of 1.5 to 3.5 months) decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. In untreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-fold increased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the difference between OXYS and Wistar rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifested by 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 significantly decreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. Importantly, rapamycin treatment 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 that rapamycin in low chronic doses can suppress brain aging.

Deletion of Nuclear Factor kappa B p50 Subunit Decreases Inflammatory Response and Mildly Protects Neurons from Transient Forebrain Ischemia-induced Damage

“…BCCAo also induced a reduction in spontaneous locomotion specifically in the Nfkb1-deficient female mice. Similarly, a strain of senescenceaccelerated OXYS rats has been reported to exhibit a dramatic decrease in open field rearing [50].…”

Comparative study of perception and processing of socially or sexually significant odor information in male rats with normal or accelerated senescence using fMRI

“…Although neurodegenerative changes were also observed in OXYS rats even at the young age of 3 months [37,38], they were localized mainly in the cortical area while the size of hippocampus was even increased. The latter may evidence compensatory mechanisms that explain the absence of significant changes in olfactory function.…”

Targeting Unselective Autophagy of Cellular Aggregates

“…Rapamycin causes a brain area-dependent reduction of sarkosyl insoluble tau levels, and a marked increase of autophagy markers [80]. Rapamycin, when given at a low dosage between 1.5 and 3.5 months of age, reduces total tau levels and p-Ser181 tau levels in OXYS rats, and increases total S6K1 and p-S6K1 levels [81].…”