“Molecular Fountain of Youth” May Exist

Researchers have turned back the molecular clock by infusing the blood stem cells of old mice with a longevity gene and rejuvenating the aged stem cells’ regenerative potential. The University of California, Berkeley team says their discovery provides new hope for the development of targeted treatments for age-related degenerative diseases.

They found that SIRT3, one among a class of proteins known as sirtuins, plays an important role in helping aged blood stem cells cope with stress. When they infused the blood stem cells of old mice with SIRT3, the treatment boosted the formation of new blood cells, evidence of a reversal in the age-related decline in the old stem cells’ function.

“We already know that sirtuins regulate aging, but our study is really the first one demonstrating that sirtuins can reverse aging-associated degeneration,” says study principal investigator Danica Chen, Ph.D., assistant professor of nutritional science and toxicology.

“Studies have already shown that even a single gene mutation can lead to lifespan extension,” continiues Dr. Chen. “The question is whether we can understand the process well enough so that we can actually develop a molecular fountain of youth. Can we actually reverse aging? This is something we’re hoping to understand and accomplish.”

The importance of the sirtuin family of proteins to the aging process is becoming increasingly clear. SIRT3 in particular is found in a cell’s mitochondria, a cell compartment that helps control growth and death, and 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, which are responsible for maintaining and repairing tissue—but this function breaks down with age. They focused on hematopoietic, or blood, stem cells because of their ability to completely reconstitute the blood system, the capability that underlies successful bone marrow transplantation.

The researchers first observed the blood system of mice that had the gene for SIRT3 disabled. Among young mice, the absence of SIRT3 made no difference. But by the time the mice reached two years old, 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 are functioning well and have relatively low levels of oxidative stress, which is the burden on the body that results from the harmful byproducts of metabolism. At this youthful stage, the body’s normal antioxidant defenses can easily deal with the low stress levels, so differences in SIRT3 are less important.

“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 build up,” says Dr. Chen. “Under this condition, our normal antioxidative system can’t take care of us, so that’s when we need SIRT3 to kick in to boost the antioxidant 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.

It remains to be seen whether over-expression of SIRT3 can actually prolong life, but Dr. Chen pointed out that extending lifespan is not the only goal for this area of research. “A major goal of the aging field is to utilize knowledge of genetic regulation to treat age-related diseases,” she notes.

The findings were published online yesterday in the journal Cell Reports. The study is called “SIRT3 Reverses Aging-Associated Degeneration”.