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Rapamycin suppresses brain aging in senescence-accelerated OXYS rats.

Kolosova NG, Vitovtov AO, Muraleva NA, Akulov AE, Stefanova NA, Blagosklonny MV - Aging (Albany NY) (2013)

Bottom Line: Rapamycin decreased the percentage of animals with demyelination and the number of loci.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cytology and Genetics SB RAS, Acad. , 630090, Novosibirsk, Russia. gorislavna@mail.ru

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.

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EPM performance in 3.5 month old control and rapamycin-treated OXYS rats and control Wistar rats. Treatment (0.1 or 0.5 mg/kg?day rapamycin) was started at the age of 1.5 months. 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 rapamycin-treated OXYS rats, the of rearing was increased. Legend: #p < 0.05 as the difference between the rat strains and *p < 0.05 as compared of Rapamycin-treated to the control OXYS rats.
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Figure 1: EPM performance in 3.5 month old control and rapamycin-treated OXYS rats and control Wistar rats. Treatment (0.1 or 0.5 mg/kg?day rapamycin) was started at the age of 1.5 months. 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 rapamycin-treated OXYS rats, the of rearing was increased. Legend: #p < 0.05 as the difference between the rat strains and *p < 0.05 as compared of Rapamycin-treated to the control OXYS rats.

Mentions: In agreement with previous results, 3.5-month-old OXYS rats had higher scores of anxiety-like behavior compared to the age-matched Wistar rats, namely, decreased number of entries into open arms (F1,25 = 6.6, p < 0.02), the tendency to spend less time in open arms (F1,25 = 3.9, p = 0.06, Fig. 1), as well as a higher number of grooming frequency (F1,25 = 7.5, p < 0.02). Rapamycin treatment did not affect these indexes in OXYS rats (p < 0.05).


Rapamycin suppresses brain aging in senescence-accelerated OXYS rats.

Kolosova NG, Vitovtov AO, Muraleva NA, Akulov AE, Stefanova NA, Blagosklonny MV - Aging (Albany NY) (2013)

EPM performance in 3.5 month old control and rapamycin-treated OXYS rats and control Wistar rats. Treatment (0.1 or 0.5 mg/kg?day rapamycin) was started at the age of 1.5 months. 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 rapamycin-treated OXYS rats, the of rearing was increased. Legend: #p < 0.05 as the difference between the rat strains and *p < 0.05 as compared of Rapamycin-treated to the control OXYS rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824413&req=5

Figure 1: EPM performance in 3.5 month old control and rapamycin-treated OXYS rats and control Wistar rats. Treatment (0.1 or 0.5 mg/kg?day rapamycin) was started at the age of 1.5 months. 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 rapamycin-treated OXYS rats, the of rearing was increased. Legend: #p < 0.05 as the difference between the rat strains and *p < 0.05 as compared of Rapamycin-treated to the control OXYS rats.
Mentions: In agreement with previous results, 3.5-month-old OXYS rats had higher scores of anxiety-like behavior compared to the age-matched Wistar rats, namely, decreased number of entries into open arms (F1,25 = 6.6, p < 0.02), the tendency to spend less time in open arms (F1,25 = 3.9, p = 0.06, Fig. 1), as well as a higher number of grooming frequency (F1,25 = 7.5, p < 0.02). Rapamycin treatment did not affect these indexes in OXYS rats (p < 0.05).

Bottom Line: Rapamycin decreased the percentage of animals with demyelination and the number of loci.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cytology and Genetics SB RAS, Acad. , 630090, Novosibirsk, Russia. gorislavna@mail.ru

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.

Show MeSH
Related in: MedlinePlus