Long lifespan inhibits tumors

Mutations that lengthen a worm's lifespan also inhibit tumor growth, according to a study in this week's Science. The authors found that mutant Caenorhabditis elegans worms that live twice as long show increased cell death and decreased cell division in tumor cells. The finding is the latest in a string of phenotypes that have been linked to longevity mutants, including resistance to memory loss, muscle deterioration, and pathogenic microorganisms."I think that these longevity pathways are allowing cells to protect themselves better against damage," said senior author Cynthia Kenyon, director of the Hillblom Center for the Biology of Aging at the University of California, San Francisco. "There's something about this more stress-resistant state that seems to increase lifespan and also disadvantage a tumor," she said.Previous work in mice has shown that calorie reduction or mutations in the insulin/insulin-like growth factor-1 (IGF-1) signaling pathway confer both a long lifespan and tumor resistance, said Kenyon, also a founder of Elixir Pharmaceuticals in Cambridge, Mass, which uses aging research to develop therapies. However, other work has found that mutations that inhibit tumors actually decrease life expectancy. "It's been a little bit confusing," she said. Kenyon's group, led by Julie Pinkston at UCSF, examined the relationship between aging and tumor development in a panel of C. elegans longevity mutants. In each strain, they mutated a tumor-suppressor gene called gld-1. Worms with mutations in this gene normally die early in life from germ cell tumors.When the researchers mutated gld-1 in worms with mutations in daf-2 -- part of the insulin/IGF-1 pathway -- the authors found that the animals' lifespans were not shortened at all by the changes in gld-1. In addition, daf-2 mutations reduced germ cell number in the worms, which the authors show resulted from both decreased cell division and increased cell death."With reduced growth factors, you'd expect reduced tumor growth," according to Wayne Van Voorhies from New Mexico State University in Las Cruces, who was not involved in the study. "The thing that was really surprising, though, was that it seems those daf-2 mutants have increased rates of apoptosis in the tumor cells," Van Voorhies said. "That's not an anticipated result."The researchers found that apoptosis was upregulated in both normal and cancerous daf-2 cells, but decreased cell division was specific to tumor cells. "I was really surprised by that," Kenyon told The Scientist. "I expected to see [reduced cell division] in normal cells and we didn't."The researchers also analyzed C. elegans with mutations that increase longevity through caloric restriction or reduced mitochondrial activity. These mutations did not affect apoptosis of germ cells but did reduce germ cell division. As in the daf-2 mutants, this reduction in cell division was specific to tumor cells.Normal worms do not usually develop tumors, so tumor inhibition alone cannot explain why longevity mutants survive so long, Kenyon said. Instead, pathways that control both longevity and tumor development likely interact, according to the authors.Mutations that increase an animal's longevity make cells resistant to stress, Kenyon told The Scientist. They found that the transcription factor DAF-16 -- already known to be essential for daf-2 mutant longevity -- is required for daf-2 mutations to increase apoptosis in germ cells. They also found that DAF-16 is required for an increase in germ cell apoptosis, which occurred after the animals were exposed to gamma irradiation, suggesting "that you can activate the same pathway either with gamma rays or by mutating the insulin/IGF-1 receptor," Kenyon said.According to Thomas Johnson of the University of Colorado at Boulder, who was not involved in the study, researchers have thought for some time that longevity was simply a "secondary effect" of a normal body process. However, nematodes are "not an accurate model of what goes on in mammalian tumor formation," Johnson added."In mammals, it's exactly backwards, where tumor formation and longevity seem to be traded off with respect to p53 levels," Johnson noted. Indeed, several studies have shown that mutations in mice that increase the activity of the tumor suppressor p53 reduce tumor development but shorten lifespan.Kenyon, however, countered that another study found that a different mutation in p53 also suppresses tumors but doesn't alter lifespan. "It has to do with the functions of p53, which may be more specialized or somehow not as basic and fundamental as these lifespan pathways," she said. In other words, the relationship between aging and cancer may not be clear-cut. "There can't be a fixed tradeoff between aging and cancer."Melissa Lee Phillips mphillips@the-scientist.comLinks within this articleS.J. Olshansky et al., "The longevity dividend," The Scientist, March 1, 2006. http://www.the-scientist.com/2006/3/1/28/1/J.M. Pinkston et al., "Mutations that increase the life span of C. elegans inhibit tumor growth," Science, 313:971-975, August 18, 2006. http://www.sciencemag.orgK. Lee, "Genes controlling longevity," The Scientist, March 13, 2001. http://www.the-scientist.com/article/display/19519/H. Murakami et al., "Aging-dependent and -independent modulation of associative learning behavior by insulin/insulin-like growth factor-1 signal in Caenorhabditis elegans," Journal of Neuroscience, November 23, 2005. PM_ID: 16306402C.F. Glenn et al., "Behavioral deficits during early stages of aging in Caenorhabditis elegans result from locomotory deficits possibly linked to muscle frailty," The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, December 2004. PM_ID: 15699524D.A. Garsin et al., "Long-lived C. elegans daf-2 mutants are resistant to bacterial pathogens." Science, June 20, 2003. PM_ID: 12817143Cynthia Kenyon http://wormworld.ucsf.edu/S.D. Hursting et al., "Calorie restriction induces a p53-independent delay of spontaneous carcinogenesis in p53-deficient and wild-type mice," Cancer Research, July 15, 1997. PM_ID: 9230186M.M. Ramsey et al., "Growth hormone-deficient dwarf animals are resistant to dimethylbenzanthracine (DMBA)-induced mammary carcinogenesis," Endocrinology, October 2002. PM_ID: 12239127Elixir Pharmaceuticals http://www.elixirpharm.com/S.D. Tyner et al., "p53 mutant mice that display early ageing-associated phenotypes," Nature, January 3, 2002. PM_ID: 11780111R. Francis et al., "Analysis of the multiple roles of gld-1 in germline development: interactions with the sex determination cascade and the glp-1 signaling pathway," Genetics, February 1995. PM_ID: 7713420 Wayne Van Voorhies http://darwin.nmsu.edu/~molbio/mbfaculty/vanvoorhies.htmlC. Kenyon et al., "A C. elegans mutant that lives twice as long as wild type," Nature, December 2, 1993. PM_ID: 8247153 Thomas Johnson http://ibgwww.colorado.edu/tj-lab/B. Maier et al., "Modulation of mammalian life span by the short isoform of p53," Genes and Development, February 1, 2004. PM_ID: 14871929P. Smaglik, "Taking aim at p53: Researchers are targeting the tumor suppressor with vectors, viruses, and small molecules," The Scientist, January 18, 1999. http://www.the-scientist.com/1999/1/18/6/1/I. Garcia-Cao et al., "'Super p53' mice exhibit enhanced DNA damage response, are tumor resistant and age normally," EMBO Journal, November 15, 2002. PM_ID: 12426394

Long lifespan inhibits tumors

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