{"id":1980,"date":"2009-06-24T00:00:00","date_gmt":"2009-06-24T07:00:00","guid":{"rendered":"https:\/\/vermont.salk.edu\/news-release\/climbing-the-ladder-to-longevity-critical-enzyme-pair-identified\/"},"modified":"2018-01-26T14:36:16","modified_gmt":"2018-01-26T22:36:16","slug":"climbing-the-ladder-to-longevity-critical-enzyme-pair-identified","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/de\/news-release\/climbing-the-ladder-to-longevity-critical-enzyme-pair-identified\/","title":{"rendered":"Climbing the ladder to longevity: critical enzyme pair identified"},"content":{"rendered":"<p>LA JOLLA, CA-Experiment after  experiment confirms that a diet on the brink of starvation expands  lifespan in mice and many other species. But the molecular mechanism  that links nutrition and survival is still poorly understood. Now,  researchers at the Salk Institute for Biological Studies have  identified a pivotal role for two enzymes that work together to  determine the health benefits of diet restriction.<\/p>\n<p>\n            When lacking  one enzyme or the other, roundworms kept on a severely  calorie-restricted diet no longer live past their normal lifespan, they  report in the June 24, 2009, advance online edition of the journal Nature.<\/p>\n<div class=\"imageCaption\"><img decoding=\"async\" src=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2015\/03\/dillin_hunter_20090624_363.jpg\" alt=\"enzyme WWP-1\" width=\"300\"\/><\/p>\n<p>The enzyme WWP-1, shown in green, is a key player in the signaling cascade that links dietary restriction to longevity in roundworms. Sensory neurons are shown in red.\n <\/p>\n<p>\nImage: Courtesy of Dr. Andrea C. Carrano, Salk Institute for Biological Studies<\/p>\n<\/div>\n<p>\n            &#8220;The  only other known factor regulating longevity in response to diet  restriction operates at the very end of the signaling cascade,&#8221; said  Howard Hughes Medical Investigator and senior author <a href=\"\/de\/faculty\/dillin.html\/\">Andrew Dillin<\/a>,  Ph.D., an associate professor in the Molecular and Cell Biology  Laboratory. &#8220;These two enzymes are further up the ladder, bringing us  closer to the receptor that receives the signal for throwing the switch  to promote a healthy lifespan.&#8221;<\/p>\n<p>\n            Identifying the receptor may  allow researchers to design drugs that mimic the signal and could lead  to new treatments for age-related diseases. This could enable us to  reap the health benefits of calorie restriction without adhering to  extreme diets in which the satisfying feel of a full stomach is  strictly off limits.<\/p>\n<p>\n            Although lifestyle factors such as obesity  clearly influence life expectancy, genetic factors are considered  central to the process of aging. To date, there are only three known  genetic networks that ensure youthfulness when manipulated. One centers  on the insulin\/insulin growth factor-1, which regulates metabolism and  growth; the second is driven by mitochondria, the cell&#8217;s power plants;  and the third is linked to diet restriction.<\/p>\n<p>\n            But first author  Andrea C. Carrano, Ph.D., a postdoctoral researcher in American Cancer  Society Professor Tony Hunter&#8217;s laboratory, hadn&#8217;t set out to unravel  the molecular connection between dietary restriction and increased  lifespan when she started to investigate the role of the mammalian  enzyme WWP-1. &#8220;I only knew that WWP-1 was a ubiquitin ligase and that  mammalian cells contain three copies, which would make it difficult to  study its function.&#8221;<\/p>\n<p>\n            Ubiquitin ligases work in tandem with so  called ubiquitin-conjugating enzymes to attach a chain of ubiquitin  molecules to other proteins. This process, called ubiquitination, flags  protein substrates for destruction but can also serve as a regulatory  signal.<\/p>\n<p>\n            Since the laboratory roundworm Caenorhabditis elegans  only contains one copy, Carrano teamed up with Salk researcher Dillin,  who studies aging and longevity in C. elegans. Initial experiments  revealed that worms without the WWP-1 gene seemed normal but were more  susceptible to various forms of stress. &#8220;This finding was the first  hint that WWP-1 might play a role in the aging process since mutations  that affect stress very often correlate with longevity,&#8221; she says.<\/p>\n<p>\n            Prompted  by the findings, Carrano&#8217;s next set of experiments focused on WWP-1&#8217;s  potential role in the regulation of lifespan. When she genetically  engineered worms to overexpress WWP-1, well-fed worms lived on average  20 percent longer. Deleting PHA-4, which was discovered in Dillin&#8217;s lab  and so far is the only gene known to be essential for lifespan  extension in response to diet restriction, abolished the life-extending  effects of additional WWP-1 placing the ubiquitin ligase as a central  rung on the same genetic ladder as PHA-4. Without WWP-1, cutting down  on calories no longer staved off death.<\/p>\n<p>\n            When a study by others  found that UBC-18 interacts with WWP-1, Carrano wondered whether it  could play a role in diet-restriction-induced longevity as well. She  first confirmed that the UBC-18 functions as an ubiquitin-conjugating  enzyme and gives WWP-1 a hand. She then tested whether it played a role  in lifespan regulation. &#8220;Overexpression of UBC-18 was not enough to  extend the lifespan of worms but depleting it negated the effects of  caloric restriction,&#8221; says Carrano, who is busy looking for potential  substrates of the UBC-18-WWP-1 ubiquitination complex. <\/p>\n<p>\n            &#8220;The  WWP-1 pathway is highly conserved between worms and mammals and could  play a role in the human aging process,&#8221; says senior author <a href=\"\/de\/faculty\/hunter.html\/\">Tony  Hunter<\/a>, Ph.D., a professor in the Molecular and Cell Biology  Laboratory. &#8220;We didn&#8217;t expect that this protein would be involved in  the regulation of lifespan but it is very exciting when experiments  lead you in a surprising direction.&#8221;<\/p>\n<p>\n            For information on the commercialization of this technology, please contact the Salk Office of Technology Management and Development at (858) 453-4100, Ext. 1278.<\/p>\n<p>\n            This  work was supported by the National Institutes of Health, the Ellison  Medical and Glenn Medical Foundations, the American Cancer Society and  the Rossi Endowment.<\/p>\n<p>\n            Zheng Liu, Ph.D., a research associate, in the Dillin Laboratory also contributed to the work.<\/p>\n<p><strong> About the Salk Institute   for Biological Studies:<\/strong><br \/>\n                The Salk   Institute for Biological Studies is one of the world&#8217;s preeminent basic research   institutions, where internationally renowned faculty probe fundamental life   science questions in a unique, collaborative, and creative environment. Focused   on both discovery and mentoring future generations of researchers, Salk   scientists make groundbreaking contributions to our understanding of cancer,   aging, Alzheimer&#8217;s, diabetes, and cardiovascular disorders by studying   neuroscience, genetics, cell and plant biology, and related   disciplines.<\/p>\n<p>\n                Faculty   achievements have been recognized with numerous honors, including Nobel Prizes   and memberships in the National Academy of Sciences. Founded in 1960 by polio   vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit   organization and architectural landmark.<\/p>","protected":false},"featured_media":0,"template":"","faculty":[72],"disease-research":[],"class_list":["post-1980","disclosure","type-disclosure","status-publish","hentry","faculty-tony-hunter"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.3 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Climbing the ladder to longevity: critical enzyme pair identified - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/de\/news-release\/climbing-the-ladder-to-longevity-critical-enzyme-pair-identified\/\" \/>\n<meta property=\"og:locale\" content=\"de_DE\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Climbing the ladder to longevity: critical enzyme pair identified - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"LA JOLLA, CA-Experiment after experiment confirms that a diet on the brink of starvation expands lifespan in mice and many other species. 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