Abstract
Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway and rapamycin extends life span inC 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 Wister 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.
Highlights
MTOR is activated by nutrients, insulin and other hormones, growth factors, inflammatory cytokines and in turn stimulates cellular growth and functions [1,2,3,4]
OXYS rats had reduced the number of entries to open arms (A), time spent in open arms (B), frequencies of rearing (C), and increased grooming frequency (D) in comparison with Wistar rats
In agreement with our previous reports, here we described that 3-months-old OXYS rats displayed lower locomotor and exploration activities in the open field (OF) and a higher level of anxiety in the elevated plus maze (EPM) tests in comparison with Wistar rats
Summary
MTOR (mechanistic Target of Rapamycin) is activated by nutrients, insulin and other hormones, growth factors, inflammatory cytokines and in turn stimulates cellular growth and functions [1,2,3,4]. Aging is associated with a slow deterioration of cognitive performance, of learning and memory as well as with an increased risk of neurodegenerative diseases. Aging and age-associated neurodegeneration lead to behavioral impairments: impaired neuromuscular coordination and reduced exploratory activity. In a mouse model of Alzheimer's disease, rapamycin reduces amyloid-beta levels and abolishes cognitive deficits [23]. Lifelong rapamycin administration ameliorates age-dependent cognitive deficits [24]. Inhibition of MTOR with everolimus (rapamycin analog) causes significant cognitive and affective improvement in humans (in heart transplant recipients) [26]
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