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Scientists Discover Link Between Stem Cells, Aging, and Cancer

Cell, October 21, 2008

Scientists at the University of Michigan have discovered that four genes which were already known to be involved in the control of cancer are also actively involved in the aging process and in stem cell regulation. The four genes, which are known to suppress tumor formation, also regulate the ability of endogenous adult stem cells to replace worn out tissue. When a person's own adult stem cells fail to replace such tissue, the aging process occurs.

As cells age, these four genes switch on and off in a coordinated fashion in order to reduce the risk of cancer, although such a process also hinders the capacity of stem cells to regenerate tissue. The findings illuminate the shared genetic pathways between natural stem cell regeneration, aging and cancer.

According to Dr. Sean Morrison, director of the University of Michigan Center for Stem Cell Biology, "All four of these genes had been implicated in the regulation of cancer, but only one of them had been implicated in the regulation of stem cells and aging. So this is a pretty significant expansion of our mechanistic understanding of the connections between these vital processes."

Commenting on the three-year study of mouse brain cells which led to the discovery, Dr. Morrison added, "The genes identified in this study work together to reduce the function of adult stem cells as they age. Embryonic stem cells offer the advantage of not aging, not turning on this pathway." In order to use embryonic stem cells as an actual medical treatment for something, however, the embryonic stem cells would have to undergo a certain degree of differentiation, which would therefore involve the aging of cells and the activation of these four genes. Meanwhile, the point is somewhat irrelevant at least for the foreseeable future since embryonic stem cells have never been used as a clinical therapy to treat any disease or injury, and the likelihood of embryonic stem cell technology advancing to the stage of a safe and effective clinical therapy is at least another decade away, if not further, by unanimous scientific consensus. By sharp contrast, adult stem cells have already been proven to be a viable treatment modality and have already been used in a wide range of clinical settings to treat a vast array of medical conditions for many years.

Specifically, the four genes under consideration are Ink4a, Arf, Hmga2 and let-7b, which were examined in this particular study by breeding mice that lacked combinations of these genes, and then measuring the effects of the missing genes on stem-cell function and brain-cell formation at different life stages. According to Dr. Jinsuke Nishino, a postdoctoral fellow in Dr. Morrison's lab, "We have now identified an entire pathway that changes gene expression within stem cells as they age, and that helps to explain why old tissues have less stem-cell function and less regenerative capacity."

In a 2006 publication in Nature, Dr. Morrison and his colleagues demonstrated that the Ink4a gene, which was already understood for its role as a tumor suppressor, becomes increasingly active with age, not only in the suppression of tumors but also in the suppression of stem cell replication, at least in mouse models. At that time, however, no one understood what it was exactly that causes Ink4a to become increasingly active with age. Now, Dr. Morrison and his colleagues have demonstrated that the activity of Ink4a is regulated by Hmga2, which in turn is controlled by let-7b. In light of these recent findings, the ability of the Ink4a gene to become activated with age would appear to be a type of defense mechanism against cancer-causing genetic mutations, which accumulate with the repeated cell division that is associated with aging. Although the studies were conducted with mice, the same molecular processes are believed to be at work in humans, who also possess the same four genes.

As Dr. Morrison explains, "The tumor-suppressor mechanisms ramp up with age. And the good news is that it allows us to get older before getting cancer. The bad news is that your tissues lose their regenerative capacity, making you older. The more we study this issue, the more we think that tissue aging exists as a by-product of mechanisms that were created to protect us against cancer."

As scientists understand more and more about the cellular, molecular and genetic processes of life, such discoveries will no doubt play a major role not only in the suppression and treatment of diseases such as cancer, but also in the development of increasingly precise medical tools, such as stem cells.



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