Limits...
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.

Show MeSH

Related in: MedlinePlus

Effect of rapamycin (0.5 mg/kg per day) on the levels and phosphorylation of S6 ribosomal protein in the hippocampus of OXYS and Wistar rats (n=6) measured by immunoblot. A: S6. B: pS6. C: Representative immunoblots of S6 and pS6 in the hippocampus of OXYS and Wistar rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3824413&req=5

Figure 4: Effect of rapamycin (0.5 mg/kg per day) on the levels and phosphorylation of S6 ribosomal protein in the hippocampus of OXYS and Wistar rats (n=6) measured by immunoblot. A: S6. B: pS6. C: Representative immunoblots of S6 and pS6 in the hippocampus of OXYS and Wistar rats.

Mentions: Next we measured levels of phospho-S6, as a standard marker on MTOR activity. In control, levels of S6 and pS6 in hippocampus were similar in OXYS and Wistar rats S6 (Fig. 4). Rapamycin had no significant effect on S6 and pS6 levels (F1,32=0.28, p<0.65 and F1,32 =2.31, p<0.13accordingly). Unexpectedly, we found that treatment with rapamycin increased levels of pS6 in the frontal cortex (Fig. 5). This can be explained by a corresponding increase of the S6 protein (Fig. 5 A), so that a ratio of phosphorylated and non-phosphorylated forms remained constant. This increase can be explained by compensatory reaction to chronic low doses of rapamycin, in order to spare protein synthesis. Noteworthy, some sites on S6 can be phosphorylated by other kinase pathways (such as the MEK/MAPK) pathway, independent from MTOR [41-43].


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)

Effect of rapamycin (0.5 mg/kg per day) on the levels and phosphorylation of S6 ribosomal protein in the hippocampus of OXYS and Wistar rats (n=6) measured by immunoblot. A: S6. B: pS6. C: Representative immunoblots of S6 and pS6 in the hippocampus of OXYS and Wistar rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Effect of rapamycin (0.5 mg/kg per day) on the levels and phosphorylation of S6 ribosomal protein in the hippocampus of OXYS and Wistar rats (n=6) measured by immunoblot. A: S6. B: pS6. C: Representative immunoblots of S6 and pS6 in the hippocampus of OXYS and Wistar rats.
Mentions: Next we measured levels of phospho-S6, as a standard marker on MTOR activity. In control, levels of S6 and pS6 in hippocampus were similar in OXYS and Wistar rats S6 (Fig. 4). Rapamycin had no significant effect on S6 and pS6 levels (F1,32=0.28, p<0.65 and F1,32 =2.31, p<0.13accordingly). Unexpectedly, we found that treatment with rapamycin increased levels of pS6 in the frontal cortex (Fig. 5). This can be explained by a corresponding increase of the S6 protein (Fig. 5 A), so that a ratio of phosphorylated and non-phosphorylated forms remained constant. This increase can be explained by compensatory reaction to chronic low doses of rapamycin, in order to spare protein synthesis. Noteworthy, some sites on S6 can be phosphorylated by other kinase pathways (such as the MEK/MAPK) pathway, independent from MTOR [41-43].

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