"Compared to women who had never taken these hormones, the use of estrogen plus progestin was associated with a reduced risk of colorectal cancer," said Jill R. Johnson, M.P.H., a doctoral student at the University of Minnesota School of Public Health.

The largest risk reduction, approximately 45 percent, was seen among women who had completed use of estrogen plus progestin five or more years previously.

Johnson and her colleagues extracted data from 56,733 postmenopausal women who participated in the Breast Cancer Detection Demonstration Project follow-up study. Hormone therapy use and other risk factors were ascertained through telephone interviews and mailed questionnaires between 1979 and 1998. During an average 15 years of follow-up, Johnson and colleagues identified 960 new cases of colorectal cancer in this population.

Any use of estrogen therapy was associated with a 17 percent reduced risk in colorectal cancer. Among those who used estrogen, the largest reductions were seen among those who were current users (25 percent reduced risk) and users of ten or more years duration (26 percent reduced risk).

Researchers also found a 22 percent reduced risk among those who had ever used estrogen plus progestin in combination. They further found a 36 percent reduction in risk among those who had used progestin sequentially or less than 15 days per month. Past users of estrogen plus progestin, who had stopped at least five years ago, had a 45 percent risk reduction.

Although Johnson's study was not designed to look at biological mechanisms for the protective effect of estrogen therapy, she did say that previous research has suggested that hormones may play a role in decreasing levels of insulin-like growth factors, thereby reducing risk. "The biological mechanism will need to be explored in further studies," said Johnson.

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"It seems that an important job of SIRT6 is to restrain NF-kB and limit the expression of genes associated with aging," said 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. Tamping down 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 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 Chang. "We've tied together two previously separate pathways in aging. Now we'd like to better understand what regulates that pathway."

Chang and Chua's co-authors on the study include graduate students Tiara Kawahara and Mara Damian; research associate Eriko Michishita, PhD; postdoctoral scholars Adam Adler, PhD, and Ron McCord, PhD; research assistants Elisabeth Berber, PhD, Meihong Lin and Lisa Boxer; and Stanford undergraduate Kristine Ongaigui.

The research was supported by the National Institutes of Health, the Department of Veterans Affairs, the California Breast Cancer Research Program, the American Cancer Society and the Paul B. Beeson Aging Research Program.

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