Rapamycin – only for healthy
Rapamycin does not increase life expectancy in mice with impaired DNA repair and with a knockout of the telomerase enzyme gene, although normal mice treated with rapamycin have an increase in life expectancy. According to the author, this proves that neither DNA damage nor telomere shortening reduce the average life expectancy.
In the experiment, the life expectancy of mice with artificial telomerase deficiency was 18% lower than the average while taking rapamycin, while in wild-type mice rapamycin increased life expectancy by 39% and healthy life expectancy by 58%.
Thus, rapamycin, by increasing life expectancy in normal mice, does not help animals with delayed cell growth that die at a young age.
One of the theories of aging connects this process with hyperfunctionation of cells, the other – with the gradual accumulation of molecular damage and shortening of telomeres.
(A) Wild-type mice. Hyperfunctional aging (green-yellow-red arrow) progresses from growth (green arrow) to the appearance of diseases (red), reaching death and shortening life expectancy. The accumulation of molecular damage (gray arrow) occurs slowly and does not reach the death mark during the life of the animal. In other words, it will take longer to die due to the accumulation of molecular damage. Treatment with rapamycin (RAPA) increases life expectancy by slowing down aging caused by mTOR.
(B) Progeroid mice with telomerase deficiency or impaired DNA repair. The accumulation of molecular damage (gray arrow) is artificially accelerated and shortens life. Treatment with rapamycin (RAPA) cannot affect this process.
Blagoslonny writes that he has found new evidence that normal aging is not caused by the accumulation of molecular damage or shortening of telomeres: rapamycin increased life expectancy in normal mice, but could not do this in mice dying from the accumulation of molecular damage.
Previously, other evidence has been obtained that molecular damage does not accelerate aging, some of them are presented below.
In most studies, overexpression of damage-reducing enzymes did not increase life expectancy. Similarly, antioxidants did not prolong the life of animals. Moreover, even the data that confirm the theory of damage can be explained by other mechanisms. For example, N-acetyl-L-cysteine, a commonly used antioxidant, is able to inhibit mTOR.
According to calculations, animals do not live to see the moment when molecular damage, especially mitochondrial DNA mutations and telomere shortening, can reach the fatal threshold.
Knockout of signaling pathways can increase life expectancy without touching molecular damage. Similarly, pharmacological interventions can prolong life without affecting the accumulation of damage.
Significant intraspecific and interspecific differences in life expectancy are poorly correlated with the rate of molecular damage.
Nuclear transfer and nuclear reprogramming exclude DNA damage as a cause of aging. After the transfer of the nucleus of an adult somatic cell, the cloned animals become healthy with a normal lifespan.
A low level of molecular damage can increase life expectancy. This phenomenon is known as hormesis. Regardless of the mechanistic explanations, this proves that molecular damage does not shorten life even with moderate magnification.
Rapamycin increases life expectancy in all healthy animals studied, which indicates that mTORC1-dependent hyperfunctional aging limits life.
Thus, the accumulation of damage should eventually lead to death, but hyperfunctional aging makes it faster. Molecular damage can limit life expectancy if artificially accelerated or, potentially, if hyperfunctional aging is slowed down.
The article by M.V.Blagoslonny DNA- and telomere-damage does not limit lifespan: evidence from rapamycin is published in the journal Aging-US.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on Aging: DNA- and telomere-damage does not limit lifespan: evidence from rapamycin.