Can lifespan be extended by point of view?
Tricking the roundworm, Caenorhabditis elegans, into a state of calorie restriction can extend the worm's lifespan by 50 percent — which suggests such diet "tricks" might work for humans too.
Researchers at the Buck Institute based in Novato, California, have shown a surprise affect on aging through a small molecule which can alter the perception of food in the nematode (roundworm) called c elegans for short. The Buck Institute is an independent research organization devoted to Geroscience, the study of the connection between normal aging and age-related diseases.
Published in Aging Cell, Buck researchers "tricked" the worm's metabolism into a state of caloric restriction — reducing calorie intake without becomming malnutritioned. The result was the worm's lifespan was extended by 50 percent.
Such results are encouraging new research around the world attempting to develop human drugs that mimic this "trick".
"This small molecule [NP1] blocks the detection of food in the worm's mouth. The worm senses that its mouth is empty even when it is full of food, tricking the animal's body into shifting its physiology into a caloric restricted-state even when it is eating normally.
"Our study suggests that primary sensory pathways represent new targets for human pharmacology."
Gordon Lithgow PhD, Buck faculty and senior author.
Lead author Mark Lucanic PhD, postdoctoral researcher in Lithgow's lab, screened 30,000 synthetic, drug-like compounds in nematodes to identify several related to caloric restriction. One small molecule, NP1, changed the worm's food perception pathway by stimulating glutamate signaling in the throat of the animal. Glutamate works as a point-to-point transmitter of synapses — in this instance, activating a neuro signal transmissions.
"The chemical activated a neurotransmitter [controlling a] food deprivation signal, this altered the animal's normal metabolism into a caloric restriction state."
Mark Lucanic PhD, Postdoctoral Research Fellow, Lithgow lab.
Lithgow thinks exploring sensory pathways for potential drug targets might help mimick caloric restriction and extend health/lifespans. Lucanic: "The mechanisms involved in sensory pathways may be more specific than secondary pathways to detect energy levels or absorbed nutrients at the cellular level." Current scientific interests are in intracellular pathways — such as mTOR and AMPK — being studied in many labs around the world.
"Targeting sensory pathways may lead to a more rapid response in changing diet. Also, altering these higher level and specific response mechanisms may have fewer effects on other systems in the body."
Gordon Lithgow PhD
Lucanic will now work to identify specific molecules that NP1 activates in c elegan's sensory pathways. He'd also like to explore the 59 other synthetic compounds that "hit" c elegan's known aging pathways. "Aging researchers have found scores of both natural and synthetic compounds that affect aging in simple animals. I tell people we have at least 100 of those compounds in our freezer and that any one of them could hold the key to extending human health/lifespan."
Model organisms subject to dietary restriction (DR) generally live longer. Accompanying this lifespan extension are improvements in overall health, based on multiple metrics. This indicates that pharmacological treatments that mimic the effects of DR could improve health in humans. To find new chemical structures that extend lifespan, we screened 30 000 synthetic, diverse drug-like chemicals in Caenorhabditis elegans and identified several structurally related compounds that acted through DR mechanisms. The most potent of these NP1 impinges upon a food perception pathway by promoting glutamate signaling in the pharynx. This results in the overriding of a GPCR pathway involved in the perception of food and which normally acts to decrease glutamate signals. Our results describe the activation of a dietary restriction response through the pharmacological masking of a novel sensory pathway that signals the presence of food. This suggests that primary sensory pathways may represent novel targets for human pharmacology.
Citation: Chemical Activation of a Food Deprivation Signal Extends Lifespan Doi: 10.1111/acel.12492
Other Buck researchers involved in the study include Theo Garrett, Ivan Yu, Azar Asadi Shahmirzadi, Aaron Miller and Robert E. Hughes. Other collaborators include Matthew S. Gill, Scripps Research Institute, Jupiter, FL; along with Fernando Calahorro and Lindy Holden-Dye, Center for Biological Sciences, Institute for Life Sciences, University of Southampton, United Kingdom;. G.J.L. is supported by National Institutes of Health grants T32 AG000266, UL1024917, RL1 GM084432 and 1RO1AG02963-01A1 as well as the Ellison Medical Foundation/American Federation of Aging Research and a Larry L. Hillblom Foundation grant. R.E.H. is supported by RL1 GM084432.
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: http://www.thebuck.org
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May 30, 2016 Fetal Timeline Maternal Timeline News News Archive
(Left) Young C Elegans. (Right) Old C Elegans.
Aging is a universal phenomenon associated with many functional disabilities and
susceptibility to diseases such as cancers, neurodegenerative diseases and diabetes.
Image Credit: Dr. Arjumand Ghazi laboratory