Contact: Alexander Shtifman
Phone: 617-713-8989
alex...@childrens.harvard.edu

This story, entitled "Mice may provide clues to aging process", recently aired on New England Cable News.

In a new paper in Cell, appearing January 27, 2006, the Sirt6 gene has been linked to acute degenerative processes associated with aging - potentially establishing a genetic connection to the familiar signs of aging in mammals, and raising the possibility that Sirt6 may be instrumental among the factors that determine lifespan.

Scientists found that deletion of the Sirt6 gene in mice resulted in aging-related breakdowns such as wasting, colitis, spinal curvature, low glucose levels, an impaired immune system, and loss of bone mineral density akin to osteoporosis. See comprehensive list of abnormalities at bottom of this article. Photos of affected mice are available.

This discovery from the laboratory of Frederick Alt, Ph.D., at the Immune Disease Institute in Boston and the Howard Hughes Medical Institute at Children's Hospital Boston, represents a step forward in research into the genetics of aging, a booming field that includes studies of the Sirt 1-7 genes. These genes are the mammalian analogs to the Sir2 gene which has been seen to influence lifespan in studies with yeast and worms.

Alt worked with colleagues at several research centers, including Howard Hughes Medical Institute, Stanford University School of Medicine, Harvard Medical School, Brigham & Women's Hospital in Boston, and the Jackson Laboratory.

Previously, the Sirt 1 gene has been linked to caloric restriction, which in turn is one means for increasing lifespan. However, this study in Cell is the first to provide concrete data about aging degeneration experienced by "knockout" mice with one of the Sirt 1-7 genes deleted.

According to Raul Mostoslavsky, M.D., Ph.D., the paper's first author and research fellow at the Immune Disease Institute and the Children's Hospital. "This is the first mammalian analog for Sir2 that may affect longevity. We got very excited when we analyzed the first set of mutant mice."

Explains Fred Alt: "Although these kinds of abnormalities are interesting in that they correlate with those seen in aging, they could be due to some other mechanism entirely."

"The sirtuin genes greatly extend the lifespan of simple organisms, but precisely what they do in mammals is unclear," states David Sinclair, Ph.D., an associate professor of pathology at Harvard Medical School who has made key discoveries about the Sir2 and Sirt1 genes. This new study, he asserts, "shows that one of these genes is crucial for the prevention of DNA damage that seems to be required to have a healthy lifespan."

The Cell study shows that deletion of the Sirt6 gene results in a dramatic breakdown in DNA repair and genomic stability - processes that play a far-ranging role in immune system regulation and the development of cancer. Specifically, Sirt6 interacts with the BER pathway, which is crucial for repairing oxidative stress damage. Oxidative stress is believed to be related strongly to cellular senescence.

Alt states that while Sirt6-deficiency is a good model for studying BER at the cellular level, its value as an animal model remains unknown. "We have a lot more work to do to confirm the value of the model in whole animals," he said. "We have seen defective BER in two types of cells in such mice, but we don't know that this repair process is defective in every tissue. At this point, we can't conclude that all of the effects we see in the mice are due to defective BER. As we have found in our studies of Sirt1, it's quite possible that Sirt6 regulates more than one process or pathway."

A mouse model of the potential effects of BER on aging would be especially useful, said Alt, because other known mutations that affect BER are either lethal or have no obvious effect. Thus, Alt and his colleagues are working toward establishing the value of a Sirt6-knockout mouse model of BER. For example, they are testing the effects of knocking out Sirt6 only in specific tissues of the mice, to distinguish the multitude of effects caused by a complete loss of the gene.

The Alt lab has produced knockout mice for all seven Sirt genes and is now investigating their attributes. Sirt6, states Dr. Alt, "will likely become the focus of many new studies aimed at understanding potential roles of the Sirt genes in processes related to aging."

Because many compounds have been developed that modulate the activity of Sirt proteins, the Sirt6 findings will likely put it alongside Sirt1 as a potential disease target, particularly given the finding of its role in influencing metabolic processes.

The following is a list of degenerative abnormalities associated with aging which Fred Alt and his team discovered in Sirt6-deficient mice. Photographs of these mice, in comparison to normal mice, are available.

  • Reduced body size apparent early after birth;
  • Otherwise normal development until day 18, then advent of "progeroid" pathologies (progeria is a disease in which young people appear old) and multiple degenerative processes associated with aging:
  • Wasting -- loss of subcutaneous fat,
  • Breakdown in DNA repair,
  • A form of colitis,
  • Spinal curvature/humpback (lordokyphosis),
  • Ostopenia - loss of bone mineral density similar to osteoporosis,
  • Low glucose levels and metabolic imbalance,
  • Low levels of Insulin-like Growth Factor, which protects lymphocytes/immune system(insulin signaling is critical for regulating lifespan),
  • Atrophy of thymus and spleen,
  • Lymphopenia - greatly reduced numbers of lymphocytes in spleen and B cells in bone marrow after day 18,
  • And early death of entire population of mice by day 24.