Comprehensive study finds 238 genes that affect aging in yeast cells. 
 
 October 5, 2015/Novato, California Following an exhaustive, ten-year effort, scientists at the Buck Institute for Research on Aging and the University of Washington have identified 238 genes that, when removed, increase the replicative lifespan of S. cerevisiae yeast cells. This is the first time 189 of these genes have been linked to aging. These results provide new genomic targets that could eventually be used to improve human health. The research was published online on October 8th in the journal Cell Metabolism. 
 
 “This study looks at aging in the context of the whole genome and gives us a more complete picture of what aging is,” said Brian Kennedy, PhD, lead author and the Buck Institute’s president and CEO. “It also sets up a framework to define the entire network that influences aging in this organism.” 
 
 The Kennedy lab collaborated closely with Matt Kaeberlein, PhD, a professor in the Department of Pathology at the University of Washington, and his team. The two groups began the painstaking process of examining 4,698 yeast strains, each with a single gene deletion. To determine which strains yielded increased lifespan, the researchers counted yeast cells, logging how many daughter cells a mother produced before it stopped dividing. 
 
 “We had a small needle attached to a microscope, and we used that needle to tease out the daughter cells away from the mother every time it divided and then count how many times the mother cells divides,” said Dr. Kennedy. “We had several microscopes running all the time.” 
 
 These efforts produced a wealth of information about how different genes, and their associated pathways, modulate aging in yeast. Deleting a gene called LOS1 produced particularly stunning results. LOS1 helps relocate transfer RNA (tRNA), which bring amino acids to ribosomes to build proteins. LOS1 is influenced by mTOR, a genetic master switch long associated with caloric restriction and increased lifespan. In turn, LOS1 influences Gcn4, a gene that helps govern DNA damage control. 
 
 “Calorie restriction has been known to extend lifespan for a long time.” said Dr. Kennedy. “The DNA damage response is linked to aging as well. LOS1 may be connecting these different processes.” 
 
 A number of the age-extending genes the team identified are also found in C. elegans roundworms, indicating these mechanisms are conserved in higher organisms. In fact, many of the anti-aging pathways associated with yeast genes are maintained all the way to humans. 
 
 The research produced another positive result: exposing emerging scientists to advanced lab techniques, many for the first time. 
 
 “This project has been a great way to get new researchers into the field,” said Dr. Kennedy. “We did a lot of the work by recruiting undergraduates, teaching them how to do experiments and how dedicated you have to be to get results. After a year of dissecting yeast cells, we move them into other projects.” 
 
 Though quite extensive, this research is only part of a larger process to map the relationships between all the gene pathways that govern aging, illuminating this critical process in yeast, worms and mammals. The researchers hope that, ultimately, these efforts will produce new therapies. 
 
 “Almost half of the genes we found that affect aging are conserved in mammals,” said Dr. Kennedy. “In theory, any of these factors could be therapeutic targets to extend healthspan. What we have to do now is figure out which ones are amenable to targeting.” 
 
 Other Buck Institute researchers involved in the study include: Mark A. McCormick (first co-author), Mitsuhiro Tsuchiya, Scott Tsuchiyama, Arianna Anies, Juniper K. Pennypacker, Shiena Enerio, Dan Lockshon, Brett Robinson, Ariana A. Rodriguez, Marc K. Ting, and Rachel B. Brem. A full list of authors is included in the paper. 
 
 This research was supported by NIH grants R01AG043080, R01AG025549, R01AG039390 and P30AG013280, as well as NIH training grants T32AG000266, T32AG000057 and T32ES007032 and the Ellison Medical Foundation. 
 
 Citation: A comprehensive analysis of replicative lifespan in 4,698 single-gene deletion strains uncovers novel mechanisms of aging 
 
 About the Buck Institute for Research on Aging 
 
 The Buck Institute is the U.S.’s first independent research organization devoted to Geroscience – focused on the connection between normal aging and chronic disease. Based in Novato, CA, The Buck is dedicated to extending “Healthspan”, the healthy years of human life and does so utilizing a unique interdisciplinary approach involving laboratories studying the mechanisms of aging and those focused on specific diseases. Buck scientists strive to discover new ways of detecting, preventing and treating age-related diseases such as Alzheimer’s and Parkinson’s, cancer, cardiovascular disease, macular degeneration, osteoporosis, diabetes and stroke. In their collaborative research, they are supported by the most recent developments in genomics, proteomics, bioinformatics and stem cell technologies. For more information: www.thebuck.org ||||| “This shows the importance of replication in science,” Steven Austad, interim director of the Barshop Institute for Longevity and Aging Studies at the University of Texas Health Science Center in San Antonio . Dr. Austad, who was not involved with either study, said that the University of Wisconsin study “was not nearly as conclusive as it was made out to be” and that the new study casts further doubt on the belief that caloric restriction extends life. 
 
 But other researchers still think that it does, and one of the authors of the new study, Julie A. Mattison, said it was still possible that some benefit would be revealed. The study is continuing until the youngest monkeys are 22 years old. While the data pretty much rule out any notion that the low-calorie diet will increase average life spans, there still is a chance that the study might find that the diet increases the animals’ maximum life span, she said. 
 
 Meanwhile, some others said that the Wisconsin study made them reluctant to dismiss the idea that low-calorie diets result in longer life. 
 
 “I wouldn’t discard the whole thing on the basis of one study, when another study in the same species showed an increase in life span,” said Eric Ravussin, director of the nutritional obesity research center at the Pennington Biomedical Research Center in Louisiana . “I would still bet on an extension of life.” 
 
 The idea that a low-calorie diet would extend life originated in the 1930s with a study of laboratory rats. But it was not until the 1980s that the theory took off. Scientists reported that in species as diverse as yeast, flies, worms and mice, eating less meant living longer. And, in mice at least, a low-calorie diet also meant less cancer. It was not known whether the same thing would hold true in humans, and no one expected such a study would ever be done. It would take decades to get an answer, to say nothing of the expense and difficulty of getting people to be randomly assigned to starve themselves or not. 
 
 Researchers concluded the best way to test the hypothesis would be through the monkey studies at the University of Wisconsin and the National Institute on Aging, although the animals would have to be followed for decades. 
 
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 It was a major endeavor. The National Institute on Aging study involved 121 monkeys, 49 of which are still alive, housed at a facility in Poolesville, Md. Those that got the low-calorie diet did not act famished, Dr. de Cabo said. They did not gobble their food, for example, but ate at the same speed as the control animals, even though their calories had been cut by 30 percent. 
 
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 As the studies were under way, some human enthusiasts decided to start eating a lot less, too. 
 
 In those same years, though, studies in mice began indicating there might not be a predictable response to a low-calorie diet. Mice that came from the wild, instead of being born and raised in the lab, did not live longer on low-calorie diets. And in 2009, a study of 41 inbred strains of laboratory mice found that about a third had no response to the diets. Of those that responded, more strains had shorter life spans than had longer ones when they were given less food. 
 
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 The response to that study was “absolute disbelief,” Dr. Austad said. “Even though the authors are well-respected calorie restrictors, people said the result was not interesting, that there was something weird about the mice.” 
 
 Now, with the new study, researchers are asking why the University of Wisconsin study found an effect on life span and the National Institute on Aging study did not. 
 
 There were several differences between the studies that some have pointed to as possible explanations. 
 
 The composition of the food given to the monkeys in the Wisconsin study was different from that in the aging institute’s study. 
 
 The University of Wisconsin’s control monkeys were allowed to eat as much as they wanted and were fatter than those in the aging institute’s study, which were fed in amounts that were considered enough to maintain a healthy weight but were not unlimited. 
 
 The animals in the Wisconsin study were from India . Those in the aging institute’s study were from India and China , and so were more genetically diverse. 
 
 Dr. de Cabo, who says he is overweight, advised people that if they want to try a reduced-calorie diet, they should consult a doctor first. If they can handle such a diet, he said, he believes they would be healthier, but, he said, he does not know if they would live longer. 
 
 Some scientists still have faith in the low-calorie diets. Richard Weindruch, a director of the Wisconsin study, said he was “a hopeless caloric-restriction romantic,” but added that he was not very good at restricting his own calories. He said he might start trying harder, though: “I’m only 62. It isn’t too late.” 
 
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 Then there is Mark Mattson, chief of the laboratory of neurosciences at the National Institute on Aging, who was not part of the monkey study. He believes there is merit to caloric restriction. It can help the brain, he said, as well as make people healthier and probably make them live longer. 
 
 Dr. Mattson, who is 5-foot-9 and weighs 130 pounds, skips breakfast and lunch on weekdays and skips breakfast on weekends. 
 
 “I get a little hungry,” he acknowledged. “But we think being hungry is actually good.”
– Ten years into research they call "exhaustive," scientists at the University of Washington and the Buck Institute for Research on Aging are reporting in the journal Cell Metabolism that they've isolated 238 genes linked to aging in yeast cells. After working with undergrads to painstakingly delete a single gene from each of 4,698 yeast strains, they say that when any of these 238 genes are not present, the yeast's life span goes up—and that 189 of these genes hadn't before been linked to aging. One gene, LOS1, produced "particularly stunning results," the institute reports—deleting LOS1 alone helped extend life span by 60%. LOS1 is influenced by a genetic "master switch" that's already associated with reduced caloric intake; switching it off seems to mimic the positive health benefits of fasting. Will these findings in yeast have any bearing on humans? "Almost half of the genes we found that affect aging are conserved in mammals," says lead author Dr. Brian Kennedy. "In theory, any of these factors could be therapeutic targets to extend healthspan. What we have to do now is figure out which ones are amenable to targeting." The findings come on the heels of research out of the University of Southern California finding that a five-day-a-week diet designed to mimic fasting with an up to 50% reduction in caloric intake also slows aging, improves the immune system, and reduces heart disease and cancer, reports the Telegraph. (This test can predict when you'll die.)