Fusing aging theories: Telomere shortening causes mitochondrial dysfunction

New research is adding insight and linking three theories of aging—one that suggests telomere shortening governs lifespan, and two others that suggest dysfunctional mitochondria or oxidative stress leads to aging.

At Harvard-affiliated Dana-Farber Cancer Institute, scientists have gathered data suggesting telomere shortening is the cause of mitochondrial dysfunction and diminished antioxidant defenses. Together, they decrease the body’s energy and diminish organ function, both characteristic of old age.

As telomeres—protective caps at the end of cell chromosomes—shorten with age and begin to fray, cells activate the p53 gene, which signals an “emergency shutdown” chain of events that turns off normal cell growth and division and compromise antioxidant defenses. Going one step further, data from the carefully orchestrated mouse study, published in Nature, show that the p53 gene also represses PGC1-alpha and PGC1-beta. These PCGs are considered the master regulators of metabolism and mitochondrial function.

Repressing PCGs increases the number of dysfunctional mitochondria (with mutated mitochondrial DNA) and leads to a decrease in functional mitochondria distributed throughout in muscles and organs. The dysfunctional mitochondria in aged tissues leak greater amounts of reactive oxygen species and the lack of functional mitochondria hinders normal energy production from cell respiration (the body’s main producer of ATP energy).

“What we have found is the core pathway of aging connecting several age-related biological processes previously viewed as independent from each other,” said Ronald A. DePinho, M.D., a cancer geneticist and senior author of the paper, in a press release.

“Because telomere dysfunction weakens defenses against damage by free radicals, or reactive oxygen species,” Dr. DePinho said, “we think this exposes telomeres to an accelerated rate of damage which cannot be repaired and thereby results in even more organ deterioration. In effect, it sets in motion a death spiral.”

In an article also published in the same issue Nature, Daniel P. Kelly, M.D., scientific director and professor at Burnham Institute for Medical Research-Lake Nona, Orlando, Florida, said that the “intriguing study… unveils a potentially unifying mechanism for cellular ageing.”

Mitigating the Toll of Aging

The new study further supports current thinking that the best defense against aging is to reduce the adverse affects of overproduction of free radicals produced from dysfunctional mitochondria, which cause additional oxidative stress.

Dr. DePinho said, “The findings bear strong relevance to human aging, as this core pathway can be directly linked to virtually all known genes involved in aging, as well as current targeted therapies designed to mitigate the toll of aging on health.”

Those current targeted therapies include boosting the human body’s antioxidant defenses by eating a healthy diet, reducing calories (by around 25 percent), and supplementing with antioxidant vitamins C and E, as well as with green tea, CoQ10 and resveratrol. These practices not only help to protect against oxidative stress, thereby protecting against telomere shortening, but also help boost generation of new, healthy mitochondria.

When we asked telomere biologist Bill Andrews, Ph.D., to comment on the new study, he answered that it was “tremendous news,” as it supports the need for more research into management of telomeres by activating the genetic expression of the enzyme telomerase, which re-lengthens telomeres.

Dr. Andrews wrote, “It’s the best support ever for the fact that telomere elongation’s role in aging far exceeds the roles played by mitochondria and oxidative stress.” In effect, telomere shortening is the root cause of the others.

Mitochondria become dysfunctional when telomeres shorten and fray, a new study suggests. In an article to be published in a forthcoming issue of IsaNews magazine, Dr. Andrews writes, “Mitochondrial dysfunction causes aging—but telomere shortening has turned out to be the primary cause of mitochondrial dysfunction. And humans’ natural defenses against oxidative stress are really quite exceptional (for example, our cells produce ten times more superoxide dismutase, a potent natural antioxidant, than mice)—until telomere shortening begins to degrade those defenses inside our bodies.”

He added that while “anti-aging therapies of years past merely treated the symptoms of aging. New research is devoted to identifying a new class of therapies that treat aging at its root cause, and hold great promise of one day allowing us to feel young and healthy at 120 years of age and beyond.”

An earlier study, of which Dr. DePinho was also the senior author, gives testimony to the benefits of telomerase, as found in mice that were genetically engineered to produce the enzyme. The study found that when the telomerase was restored in the mice, their age-related symptoms disappeared and several organs including the brain were rejuvenated.

References:

Kelly DP. Cell biology: Ageing theories unified. Nature 2011;470:342-3.

Sahin E, Colla S, Liesa M et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 2011;470:359-65.

Sahin E, DePinho RA. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 2010;464:520-8.

Jaskelioff M, Muller FL, Paik JH et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 2011;469:102-6.