Sir2: scrambling for answers: researchers have yet to solidify links for the proposed longevity lynchpin.

The Scientist, Dec 6, 2004 v18 i23 p20(2)
(Research) Maria W. Anderson.
Full Text: COPYRIGHT 2004 Scientist Inc.

Low-calorie diets extend lifespan in almost every model tested, but scientists can't yet agree on what controls this phenomenon. biologist Leonard Guarente at Massachusetts Institute of Technology, contend that Sir2 is dependent on nicotinamide adenine di-nucleotide (NAD) and that CR activates Sir2 by reducing glucose metabolism, which increases the ratio of NAD to its reduced version, NADH. (2) Others, such as Harvard Medical School pathologist David Sinclair, hold that nicotinamide, not NAD, is the control switch for Sir2, and that the deaminase PncI converts nicotinamide to nicotinic acid, which in turn increases Sir2 activity.

"I think it's a push and a pull system," explains Sinclair. Work by Guarente and Shin-Ichiro Imai, a molecular biologist at Washington University, St. Louis, showed that increases in NAD activate yeast Sirz in vivo, while Sinclair's studies indicated that removing nicotinamide, a Sir2 inhibitor, can pull the reaction forward. "So we've got them pushing and us pulling, and [these mechanisms] probably work in concert with each other," says Sinclair.

In September, a group of researchers from Stan Fields' lab at the University of Washington (UW), Seattle, published a paper offering evidence that CR may work through a pathway not involving Sir2. In yeast lacking Sir2, CR did not extend lifespan

Matt Piper, a biologist at University College London, says he sees a role for Sir2 in lifespan extension by CR but notes that an organism's diet influences its physiology in multiple ways that might affect its lifespan. "Because diet is so complex, you have many different signaling pathways in the organism determining many different physiological processes, which result in lifespan extension or shortening," says Piper. "To put it all down to one gene in one pathway is a very big call." He explains that both the insulin-signaling pathway, which responds to sugar, and the TOR-signaling pathway, which is affected by dietary protein, probably play a role in CR-mediated longevity. Having at least two different signaling pathways for lifespan extension in flies and worms, Piper adds, "would suggest that there's probably a number of different feed-ins to get lifespan extension."

References
(1.) L.P. Guarente, "Forestalling the great beyond with the help of SIR2," The Scientist, 18:34-5, April 26, 2004.
(2.) S.J. Lin et al., "Calorie restriction extends yeast life span by lowering the level of NADH," Genes Dev, 18:12-6, 2004.
(3.) R.M. Anderson et al., "Nicotinamide and PNCl govern lifespan extension by calorie restriction in Saccharomyces cerevisiae," Nature, 423:181-5,2003.
(4.) M. Kaeberlein et al., "Sir2-independent life span extension by calorie restriction in yeast," PLoS Biology, 2:1381-87, September 2004.
(5.) H. Tissenbaum, L. Guarente, "Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans," Nature, 410:227-30, 200l.
(6.) K. Houthoofd et al., "Life extension via dietary restriction is independent of the Ins/IGF-1 signaling pathway in Caenorhabditis elegans," Exp Gemntol, 38:947-54, 2003.
(7.) B. Lakowski, S. Hekimi, "The genetics of caloric restriction in Caenorhabditis elegans," Proc Nat/Acad Sci, 95:13091-6, 1998.
(8.) B. Rogina, S.L. Helfand, "Sir2 mediates longevity in the fly through a pathway related to calorie restriction," Proc Natl Acad Sci, 101:15998-16003, Nov. 9, 2004.
(9.) D. Secko, "'Longevity' gene, diet linked," The Scientist Daily News, June 18, 2004, available online at www.biomedcentral.com/news/2005540618/01.
Maria W. Anderson (manderson@the-scientist.com)