University of Virginia scientists have identified a promising approach to delay aging by detoxifying the body of glycerol and glyceraldehyde, harmful by-products of fat that naturally accumulate over time.
The new findings come from UVA researcher Eyleen Jorgelina O’Rourke and her team. They are seeking to identify the mechanisms that drive healthy aging and longevity. Their new work suggests a potential way to do so by reducing glycerol and glyceraldehyde’s health-draining effects.
“The discovery was unexpected. We went after a very well-supported hypothesis that the secret to longevity was the activation of a cell-rejuvenating process named autophagy and ended up finding an unrecognized mechanism of health and lifespan extension,” said O’Rourke, of UVA’s Department of Biology and the UVA School of Medicine’s Department of Cell Biology.
O’Rourke said an exciting aspect of the discovery is that the keys to switch on the longevity mechanism are two enzymes that have been well studied because they detoxify the body of ethanol, the alcohol found in beer and bourbon.
“This existing knowledge greatly facilitates our search for drugs that can specifically activate this anti-aging process,” she said.
In their search for the secrets to slow aging, O’Rourke and her graduate student Abbas Ghaddar and postdoctoral student 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 were awarded to discoveries made using this worm exclusively.
Prior aging research in worms, mice and human cells made O’Rourke and other researchers suspect that the key to extending lifespan was to activate autophagy, a process that renews broken and old parts in our cells. But O’Rourke and her collaborators were surprised to find that wasn’t necessary. The scientists improved the worms’ health and lifespan by 50% with no increase in autophagy at all.
They did this by capitalizing on a mechanism they discovered and named AMAR, the Sanskrit word for immortality. AMAR, in this instance, stands for “Alcohol and aldehyde-dehydrogenase Mediated Anti-aging Response.”
The scientists found that they could prompt an anti-aging response by putting the spurs to a particular gene, called adh-1. Doing so prompted the gene to produce more of the enzyme alcohol dehydrogenase that prevents toxicity caused by glycerol and, indirectly, glyceraldehyde. The result was that the worms lived longer, healthier lives.
Findings in lab models such as worms and mice don’t always hold true in people, of course. So the researchers took several more steps to see if their lead was as promising as it appeared. First, they confirmed that the enzyme had similar beneficial effects on lifespan in another lab model, yeast.
Then they scoured through research looking at gene activity in creatures, including humans, who had undergone fasting or calorie restriction because both are known to extend health span and lifespan. Sure enough, the scientists found increased levels of the anti-aging enzymes in all the mammals tested, including humans.
The scientists suspect that human levels of glycerol and glyceraldehyde naturally increase over time because they are toxic byproducts of fat, which we store more of as we age. Thus, AMAR may offer a way to head off the fat-derived toxicity, extend the number of years we live in good health, and maybe help us shed some extra pounds, too.
“We hope to attract interest in developing therapeutics that target AMAR,” said O’Rourke, who is part of UVA’s Robert M. Berne Cardiovascular Research Center. “With age-related diseases currently being the major health burden for patients, their families and the healthcare system, targeting the process of aging itself would be the most effective way to reduce this burden and increase the number of years of independent healthy living for all of us.”
The researchers have published their findings in the scientific journal Current Biology. The team consisted of Ghaddar, 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 interests in the work.
The research was supported by the National Institutes of Health, grants RO1GM075240, RO1GM127394 and DK087928, and National Research Service Award F30AG067760. Additional funders include the Pew Charitable Trusts, the Jeffress Trust, the W.M. Keck Foundation, the Jefferson Scholars Foundation and UVA’s Society of Fellows, Medical Scientist Training Program and a cell and molecular biology training grant.
March 22, 2023