Insulin Has Previously Unknown Effect That Has Role In Aging And Lifespan

The paper, published in the March 21st issue of Cell, reports that insulin inhibits a master gene regulator protein known as SKN-1, and that increased SKN-1 activity increases lifespan. SKN-1 controls what is called the Phase 2 detoxification pathway, a network of genes that defends cells and tissue against oxidative stress -- damage caused by elevated levels of free radicals (byproducts of metabolism) -- and various environmental toxins. The new finding was demonstrated in experiments on the digestive system of C. elegans, a microscopic worm often used as a model organism.

"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," said Dr. T. Keith Blackwell, senior investigator at Joslin and author of the paper. "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 idea down the line is that fine-tuning the activity of SKN-1 may lead to increased resistance to chronic diseases and influence longevity, he said. The work could be important as it relates to diabetes and the many problems associated with the disease, particularly vascular and renal complications.

But, today's finding may be most important for what it teaches about aging in general, he said.

"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," said Blackwell. "The implications go far beyond diabetes."

It has been known since the 1990s that insulin inhibits a gene regulator protein known as FOXO, important in diabetes metabolism, tumor suppression and stem cell maintenance. FOXO controls a number of genes, including many involved in stress resistance. Studies in C. elegans showed that reduced insulin signaling boosted activity of a FOXO protein known as DAF-16, leading to greater stress resistance and longer life.

The new work places SKN-1 alongside FOXO as a second master gene regulator that is inhibited by insulin signaling and adds to the body of knowledge about insulin and its effects on gene pathways, stress resistance and aging. According to the paper, insulin's effect on SKN-1 occurs independently of its effect on DAF-16.

"You can manipulate the expression of SKN-1 and the worms live longer," said Blackwell, an Associate Professor of Pathology at Harvard Medical School and faculty member at the Harvard Stem Cell Institute.

The experiments will have to be repeated in mammals, where insulin and insulin-like growth factor-1 have a complex array of effects in different tissues. But, according to Blackwell, other findings in the C. elegans model have generally turned out to be applicable to mice and humans.

Blackwell's lab at Joslin is focusing on mechanisms of free radical resistance and aging, and on gene regulation mechanisms in C. elegans stem cells with the idea of using this knowledge towards reprogramming human stem cells into insulin-producing cells.

The research was funded by the National Institutes of Health and The Iacocca Foundation, the Fonds der Chemischen Industrie, BMBF NGFN2, Qualitaetsoffensive BW and Deutsche Forschungsgemeinschaft CRC746 and EC Network of Excellence Lifespan, as well as an NRSA, an NIH training grant, KRF and MOST/KOSEF.

Other researchers involved in the paper were Jennifer M.A. Tullet, Joseph Baker and Riva P. Oliveira of Joslin; Jae Hyung An of Joslin and Yonsei University in Korea; Ji Yun Hwang of Yonsei University; and Shi Liu, Ralf Baumeister and Maren Hertweck of the University of Freiburg.