Link Between Aging Pathways in Mice Uncovered

Derailing or suppressing this molecular treachery, although still far in the future, may enable investigators to one day add years on human lives--or at least delay the appearance of that next wrinkle. "There is a genetic process that has to be on, and enforced, in order for aging to happen,” said Howard Chang, M.D., Ph.D., associate professor of dermatology at the Stanford University School of Medicine (CA, USA; http://med.stanford.edu) and a member of Stanford's Cancer Center. "It's possible that those rare individuals who live beyond 100 years have a less-efficient version of this master pathway, just as children with progeria--a genetic aging disease--may have components of this pathway that are more active.”

The study, which was published in the January 9, 2009, issue of the journal Cell, came out of a three-year collaboration between Dr. Chang and Katrin Chua, M.D., Ph.D., assistant professor of endocrinology, gerontology, and metabolism at Stanford and a member of the Stanford Cancer Center. Drs. Chang and Chua are co-senior authors of the research.

The researchers focused their investigation on two seemingly separate pathways connected to aging. One involved a molecule known as SIRT6--a member of the sirtuin family of proteins that modulate life span in organisms such as yeast and worms--that Dr. Chua's laboratory has been studying for several years. She and her lab members have previously shown that SIRT6 is involved in genomic stability and the protection of chromosomal ends called telomeres. Telomeres, which grow shorter with each cell division, are thought to function as a sort of internal molecular clock associated with aging. Furthermore, mice lacking SIRT6 are born normally but die within a few weeks because of a rapid, multi-organ degeneration that somewhat resembles premature aging.

"Sirtuin family members have been implicated in aging and age-related diseases,” said Dr. Chua, "but very little was known about how SIRT6 worked on a molecular level until recently. Our new study reveals that SIRT6, in addition to its role in genomic stability and telomere protection, also regulates gene expression.”

The other pathway involved a better-known protein called NF-kappa B (NF-kB), which binds to and regulates the expression of many genes, including those involved in aging. The expression of many of these genes increases with age, and blocking the activity of NF-kB in the skin cells of elderly mice causes them to look and act like younger cells.

The researchers speculated if NF-kB and SIRT6 somehow work together to help cells age properly. They discovered that, in human and mouse cells, SIRT6 binds to a subunit of NF-kB and modifies components of a nearby DNA packaging hub, called histones. This modification makes it more difficult for NF-kB to trigger the expression of the downstream gene--possibly by causing the DNA to twist in such a way to kick off the protein.

"It seems that an important job of SIRT6 is to restrain NF-kB and limit the expression of genes associated with aging,” said Dr. Chang. "We've been interested in the activity of regulatory genes such as NF-kB during aging for several years now, and we were quite happy to find this very clear biochemical connection between these two pathways.”

Young mice lacking the SIRT6 protein displayed elevated levels of NF-kB-dependent genes involved in immune response, cell signaling, and metabolism--all potentially involved in the uniformly fatal aging-like condition that killed them within four weeks of birth. Suppressing the expression of the gene for NF-kB's SIRT-binding subunit allowed some of the mice to escape this fate.

"Mice lacking SIRT6 seem to hit some kind of a wall at around four weeks of age,” said Dr. Chua, "when their blood sugar drops to a level barely compatible with life. Reducing NF-kB activity somehow allows the mice to get over this critical period and to live much longer. These mice provide a great new tool to study the effect of SIRT6-deficiency in much older animals than was possible before.”

The researchers are now working to understand how NF-kB knows when and to what extent during an organism's lifetime to initiate the degenerative process and what role SIRT6 may play. "It's a very provocative question,” said Dr. Chang. "We've tied together two previously separate pathways in aging. Now we'd like to better understand what regulates that pathway.”

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