2/15/2011 PERMALINK
Scientists uncover the 'core pathway' of aging, the root molecular cause of declining health in the old. "What we have found is the core pathway of aging connecting several age-related biological processes previously viewed as independent of each other," said Ronald A. DePinho, senior author of a report posted online by the journal Nature. The first author, Ergun Sahin, is a member of the DePinho Lab and an instructor in medicine at Harvard Medical School (HMS). DePinho, who is the director of Dana-Farber’s Belfer Institute for Applied Cancer Science and also a professor of medicine at HMS, said that although the studies were conducted in mice, "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."

The scientists found that the basic cause of age-related health decline is malfunctioning telomeres — the end caps on cells' chromosomes that protect them against DNA damage. As cells reach their predetermined limit of times that they can divide, the telomeres become shortened and frayed, making the chromosomal ends vulnerable to increased rates of unrepaired DNA damage.

Faced with this increasing reservoir of injured DNA, cells activate a gene, p53, that sounds an alarm and shuts down the cells' normal growth and division cycle, ordering them to rest until the damage can be repaired or, if not, to self-destruct.

Scientists previously had blamed this emergency shutdown and cell death for age-related deterioration of organs whose cells divide rapidly and are rejuvenated by reserves of adult stem cells. Such tissues include skin, intestinal lining, and blood cells, among others, which generate trillions of new cells each day of life.

However, left unanswered is how cells with less cell division, such as the heart or the liver, sustain equivalent levels of aging. The scientists felt if they could solve this mystery, they might gain new insights into how DNA damage could lead to age-related decline across all organs.

The new findings demonstrate that the telomere dysfunction and activation of p53 also trigger a wave of cellular and tissue degeneration that links telomeres to well-known mechanisms of aging that are not simply related to rapid growth and division. In other words, telomere dysfunction is not just one culprit in the declining health of advanced age. It's the kingpin, according to DePinho and his colleagues.