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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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Open field performance in 3.5 month old control and rapamycin-treated OXYS rats and Wistar rats. Treatment (0.1 or 0.5 mg/kg?day rapamycin) was started at 1.5 months. OXYS rats had reduced number of squares crossed (A), frequencies of rearing (B), and increased latency time to enter the centre (C), grooming frequency (D) compared to Wistar rats. In rapamycin-treated OXYS rats the number of squares crossed, frequencies of rearing increased, latency time to enter the centre and grooming frequency were decreased. 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 2: Open field performance in 3.5 month old control and rapamycin-treated OXYS rats and Wistar rats. Treatment (0.1 or 0.5 mg/kg?day rapamycin) was started at 1.5 months. OXYS rats had reduced number of squares crossed (A), frequencies of rearing (B), and increased latency time to enter the centre (C), grooming frequency (D) compared to Wistar rats. In rapamycin-treated OXYS rats the number of squares crossed, frequencies of rearing increased, latency time to enter the centre and grooming frequency were decreased. 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: Open field (OF) is a versatile test that assess anxiety-like, exploratory, and locomotor behavior. As shown in figure 2, locomotor and exploratory activities (numbers line-crossings and rearings) were significantly lower in OXYS rats compared to Wistar rats (F1,25 = 23.3, p < 0.0001 for crossings; F1,25 = 37.8, p < 0.0001 for rearings). Rapamycin treatment doubled the number of line-crossing in OXYS rats (mean ± SEM: control, 29±7.5, 0.1 mg/kg, 60±10.3, p=0.03 and 0.5 mg/kg, 59±8.2, p=0.013, Fig. 2A) and dramatically increased the number of rearings.


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)

Open field performance in 3.5 month old control and rapamycin-treated OXYS rats and Wistar rats. Treatment (0.1 or 0.5 mg/kg?day rapamycin) was started at 1.5 months. OXYS rats had reduced number of squares crossed (A), frequencies of rearing (B), and increased latency time to enter the centre (C), grooming frequency (D) compared to Wistar rats. In rapamycin-treated OXYS rats the number of squares crossed, frequencies of rearing increased, latency time to enter the centre and grooming frequency were decreased. 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 2: Open field performance in 3.5 month old control and rapamycin-treated OXYS rats and Wistar rats. Treatment (0.1 or 0.5 mg/kg?day rapamycin) was started at 1.5 months. OXYS rats had reduced number of squares crossed (A), frequencies of rearing (B), and increased latency time to enter the centre (C), grooming frequency (D) compared to Wistar rats. In rapamycin-treated OXYS rats the number of squares crossed, frequencies of rearing increased, latency time to enter the centre and grooming frequency were decreased. 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: Open field (OF) is a versatile test that assess anxiety-like, exploratory, and locomotor behavior. As shown in figure 2, locomotor and exploratory activities (numbers line-crossings and rearings) were significantly lower in OXYS rats compared to Wistar rats (F1,25 = 23.3, p < 0.0001 for crossings; F1,25 = 37.8, p < 0.0001 for rearings). Rapamycin treatment doubled the number of line-crossing in OXYS rats (mean ± SEM: control, 29±7.5, 0.1 mg/kg, 60±10.3, p=0.03 and 0.5 mg/kg, 59±8.2, p=0.013, Fig. 2A) and dramatically increased the number of rearings.

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