Scientists at the University of Virginia (UVA) have identified a promising approach to delay aging by detoxifying the body of glycerol and glyceraldehyde, harmful by-products of fats that naturally accumulate over time.
The new findings come from UVA researcher Eyleen Jorgelina O’Rourke, PhD, and her team, who seek to identify the mechanisms behind healthy aging and longevity. Their new work suggests a potential way to do this by reducing the adverse health effects of glycerol and glyceraldehyde.
“The discovery was unexpected. We went after a very well-supported hypothesis that the secret to longevity was the activation of a cellular rejuvenation process called autophagy and ended up finding an unrecognized mechanism for extending health and lifespan” , said O’Rourke, of UVA’s Department of Biology and Biology. the Department of Cell Biology at the UVA School of Medicine. “An exciting aspect of the discovery is that the key to activating this longevity mechanism is the activation of two enzymes that have been very well studied because of their role in the detoxification of ethanol. (Ethanol is the alcohol in beer and bourbon). This existing knowledge greatly facilitates our search for drugs capable of specifically activating this anti-aging process.
In their search for secrets to slow aging, O’Rourke and his graduate student Abbas Ghaddar and postdoc Vinod Mony turned to microscopic worms called C.elegans. These soil dwellers share more than 70% of our genes and are an invaluable tool for biomedical research; two Nobel Prizes in Medicine have been awarded for discoveries made exclusively using this worm.
Previous research on aging in worms, mice, and human cells led O’Rourke and others in the field to suspect that the key to extending lifespan was to activate autophagy, a process that renews the broken and old parts of our cells. But O’Rourke and his collaborators were surprised to find that it wasn’t necessary – scientists improved the health and lifespan of the worms by 50% without any increase in autophagy.
They did this by capitalizing on a mechanism they discovered and named AMAR, the Sanskrit word for immortality. AMAR, in this case, means “Aalcohol and aldehyde dehydrogenase Medited AAnti aging Ranswer. In short, scientists found that they could trigger an anti-aging response by putting the spurs on a particular gene, adh-1. This prompted the gene to produce more of an enzyme, alcohol dehydrogenase, which prevented the toxicity caused by glycerol and, indirectly, glyceraldehyde. The result was that the worms lived longer and healthier lives.
Findings in laboratory models like worms and mice don’t always hold true in humans, of course. So the researchers took several additional steps to see if their lead was as promising as it looked. First, they confirmed that the enzyme had similar beneficial effects on lifespan in another laboratory model, yeast. Next, they scoured research on gene activity in creatures, including humans, who had undergone fasting or calorie restriction, as both fasting and calorie restriction are known to prolong lifespan and length of life. of life. Indeed, scientists have found increased levels of anti-aging enzymes in all mammals tested, including humans.
Scientists suspect that our glycerol and glyceraldehyde levels naturally increase over time because they are toxic byproducts of fat, which we store more of as we age. So AMAR may offer a way to stave off fat-derived toxicity, extend the number of healthy years we live, and possibly help us shed a few extra pounds as well.
“We hope to generate interest in developing therapies that target AMAR,” said O’Rourke, who is part of UVA’s Robert M. Berne Cardiovascular Research Center. “As age-related diseases are currently the main burden for patients, their families and the healthcare system, targeting the aging process itself would be the most effective way to reduce this burden and increase the number of ‘years of healthy, independent living for all of us.’
The researchers published their findings in the scientific journal Current biology. The team consisted of Abbas Ghaddar, Vinod K. Mony, Swarup Mishra, Samuel Berhanu, James C. Johnson, Elisa Enriquez-Hesles, Emma Harrison, Aaroh Patel, Mary Kate Horak, Jeffrey S. Smith and O’Rourke. The researchers have no financial interest in the work.
Reference: “Increased activity of alcohol dehydrogenase 1 promotes longevity” by Abbas Ghaddar, Vinod K. Mony, Swarup Mishra, Samuel Berhanu, James C. Johnson, Elisa Enriquez-Hesles, Emma Harrison, Aaroh Patel, Mary Kate Horak, Jeffrey S. Smith and Eyleen J. O’Rourke, February 17, 2023, Current biology.
The research was supported by the National Institutes of Health, grants RO1GM075240, RO1GM127394, and DK087928, and National Research Service Award F30AG067760. Other funders include the Pew Charitable Trusts, the Jeffress Trust, the WM Keck Foundation, the Jefferson Scholars Foundation, and the Society of Fellows at UVA, the Medical Scientist Training Program, and a Cell Biology Training Grant and molecular.