Proteins which prevent cancer in humans by ensuring that cells don't divide if they have chromosomal damage have been shown to determine lifespan in the nematode worm C. elegans. A Buck Institute study, appearing in the June 2nd issue of the journal Science, shows that checkpoint proteins, traditionally thought only to be functional in cells that divide, are also active in cells that no longer divide. The fact that the proteins appear to have dual functions opens a new way to study the connection between aging and cancer.
"Statistically, we know that aging is a huge risk factor for cancer," said Buck faculty member Gordon Lithgow, PhD, lead author of the study. "We don't know why that is. If we look at checkpoint proteins as a gear ï¿½ we've known for a long time that they drive the cancer gear, now we know that they also drive a longevity gear. This discovery has exciting potential as area of inquiry into a potential cellular link between aging and cancer."
The research carried out in the Buck Institute's Lithgow Laboratory, involved genetically eliminating checkpoint proteins in the microscopic worms. This caused a 15 ï¿½ 30% increase in their lifespan. Given the role that checkpoint proteins play in preventing the development of cancer (or in encouraging it when the proteins are defective), the findings raise the question of whether genetic variations in checkpoint proteins in humans may place some individuals at risk for cancer, but protect them against other age-associated diseases; or conversely, set a genetic course for a shorter life which would be free from cancer.
The intriguing discovery came from ongoing work in the Lithgow lab, during a screening for genes that determine stress resistance and longevity in the worm, an animal which has about 18,000 genes and does not undergo cell division once it reaches maturity. Lead researcher Anders Olsen, PhD, found an unfamiliar gene during his screening. "I typed the DNA sequence into an internet database, and up came this gene we had never heard of or ever imagined would be involved in lifespan determination," said Olsen. The scientist identified two other survival-controlling checkpoint proteins which are also included in the study. Olsen's work now involves identifying additional tumor suppressor genes that impact aging in both worms and human cells, as well as screening for compounds that mimic the genetic elimination of the checkpoint proteins that took place in the lab.
"We think there are many more checkpoint proteins -- in worms, in complex animals, in humans," said Olsen. "Some may be more attractive than others for developing therapies for cancer and aging. The job now is to catalogue the genes and find out which ones have these dual properties. There is lot of work to be done in many labs and by many people."
"This work brings a new richness and sophistication to the way we think about longevity interventions," said Dale Bredesen, MD, Buck Institute CEO and Scientific Director, who acknowledged that this area of research is in its infancy. "If we're smart about it, we might be able to design strategies where you could keep checkpoint proteins active in dividing cells and knock them out in cells that no longer divide, such as neurons. Increasing the survival of neurons could provide a new avenue of treatment for neurodegenerative diseases."
Joining Lithgow and Olsen as co-authors of the paper is Maithili C. Vantipalli, also of the Buck Institute. This work was supported by grants from the National Institutes of Health, the Ellison Medical Foundation, the Glenn Foundation for Medical Research, the Herbert Simon Family Medical Foundation, the Danish Research Academy, the Danish Cancer Society and the British Biotechnology and Biological Sciences Research Council.
The Buck Institute is the only freestanding institute in the United States that is devoted solely to basic research on aging and age-associated disease. The Institute is an independent nonprofit organization dedicated to extending the healthspan, the healthy years of each individual's life. The National Institute of Aging designated the Buck a "Nathan Shock Center of Excellence in the Biology of Aging," one of just five centers in the country. Buck Institute scientists work in an innovative, interdisciplinary setting to understand the mechanisms of aging and to discover new ways of detecting, preventing and treating conditions such as Alzheimer's and Parkinson's disease, cancer and stroke. Collaborative research at the Institute is supported by new developments in genomics, proteomics and bioinformatics technology. For more information: www.buckinstitute.org.
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