In an article entitled, “SIRT3 Reverses Aging-Associated Degeneration” published online on 31st January, 2013 in the journal Cell Reports (DOI:10.1016/j.celrep.2013.01.005), Katharine Brown and eight other associates from the University of California, Berkeley report of a major advance in understanding the molecular mechanisms behind aging while providing new hope for the development of targeted treatments for age-related degenerative diseases. Researchers were able to turn back the molecular clock by infusing the blood stem cells of old mice with a longevity gene and rejuvenating the regenerative potential of aged stem cells. The biologists found that SIRT3, one among a class of proteins known as sirtuins, plays an important role in helping aged blood stem cells cope with the stress. When they infused the blood stem cells of old mice with SIRT3, the treatment boosted the formation of new blood cells, a piece of evidence of a reversal in the age-related decline in the function of old stem cells. Sirtuins have taken the spotlight in this quest as the importance of this family of proteins to the aging process becomes increasingly clear. Notably, SIRT3 is found in the mitochondria of a cell that helps control growth and death. Previous studies have shown that the SIRT3 gene is activated during calorie restriction, which has been shown to extend lifespan in various species.
To gauge the effects of aging, the researchers studied the function of adult stem cells. The adult stem cells are responsible for maintaining and repairing tissue, a function that breaks down with age. They focused on hematopoietic, or blood, stem cells because of their ability to completely reconstitute the blood system capable of successful bone marrow transplantation.
The researchers first observed the blood system of mice that had the gene for SIRT3 disabled. Surprisingly, among young mice, the absence of SIRT3 made no difference. It was only when time crept up on the mice that things changed. By the ripe old age of two, the SIRT3-deficient mice had significantly fewer blood stem cells and decreased ability to regenerate new blood cells compared with regular mice of the same age.
It appears that in young cells, the blood stem cells function well and have relatively low levels of oxidative stress burdening the body that results from the harmful byproducts of metabolism. At this youthful stage, the body’s normal anti-oxidant defenses can easily deal with the low stress levels, so differences in SIRT3 are less important. According to the principal investigator, Danica Chen, “When we get older, our system doesn’t work as well, and we either generate more oxidative stress or we can’t remove it as well, so levels harmful products build up. Under this condition, our normal anti-oxidative system can’t take care of us, requiring SIRT3 to kick in to boost the anti-oxidant system. However, SIRT3 levels also drop with age; so over time, the system is overwhelmed.”
To see if boosting SIRT3 levels could make a difference, the researchers increased the levels of SIRT3 in the blood stem cells of aged mice. That experiment rejuvenated the aged blood stem cells, leading to improved production of blood cells. According to the lead author Catharine Brown their results will pave the way toward developing rejuvenative therapy where one could increase a protein’s expression without increasing the risk of diseases like cancer. (summarized by Sumaiya Farah Khan of Plant biotechnology Laboratory, DU.)