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Insulin, Aging and Lifespan

Cell, March 21, 2008

Affiliated with Harvard Medical School, the Joslin Diabetes Center is the world's largest research center and clinic devoted exclusively to the study and treatment of diabetes. Similarly, the Harvard Stem Cell Institute is one of the leading organizations in the world dedicated to scientific collaboration in stem cell biology. Now, researchers from both organizations have discovered that insulin plays a much greater and more important role, in many other physiological processes, than previously realized.

Primarily, insulin is well known for its importance in carbohydrate metabolism, and an insufficiency of insulin in diabetes has been understood for decades to cause a number of life-threatening problems. Additionally, since the 1990s it has been known that insulin inhibits a specific gene regulator protein known as FOXO, which is active not only in diabetes metabolism but also in tumor suppression, in the maintenance of stem cells, and in the control of a variety of genes that are involved in stress resistance.

Now, as the result of experiments conducted on the digestive system of C. elegans, a microscopic worm that is widely used as a research model in laboratories throughout the world, Harvard researchers have discovered that insulin inhibits a master gene regulator protein known as SKN-1, increased activity of which is known to increase lifespan. Additionally, SKN-1 is recognized as controling what is known as the Phase 2 detoxification pathway, which is a network of genes that collaborate to defend cells against oxidative damage such as that caused by free radicals and environmental toxins. As a result of these studies, a reduction in insulin signaling was found to trigger increased activity of both the FOXO and the SKN-1 proteins, thereby increasing resistance to stress and increasing longevity of life.

According to Dr. T. Keith Blackwell, a senior investigator at the Joslin Diabetes Center, associate professor of pathology at Harvard Medical School, a faculty member at the Harvard Stem Cell Institute, and the primary author of the paper, "We've found something new that insulin does and it has to be considered when we think about how insulin is affecting our cells and bodies. This has implications for basic biology since under some circumstances insulin may reduce defense against the damaging effects of oxidative stress more than we realize. The major implication is that we have found something new that affects lifespan and aging, and an important new effect that insulin and/or a related hormone called insulin-like growth factor-1 may have in some tissues. The implications go far beyond diabetes."

Indeed, the work relates not only to diabetes but also to other diseases which are often secondary complications that result from diabetes, such as vascular and renal problems. Additionally, the findings also have much broader implications for health, stress, lifespan and longevity. According to Dr. Blackwell, "You can manipulate the expression of SKN-1 and the worms live longer." Currently, Dr. Blackwell's lab is focused on further delineation of the precise molecular mechanisms that regulate free radical resistance and aging.

Certain types of adult stem cells have already been shown to differentiate into the insulin-producing beta islet cells of the pancreas. Combined with Dr. Blackwell's recent discovery, stem cells once again enter the realm not merely of disease treatment but also of longevity and extended lifespan.



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