Detoxifying the body of two fat by-products can extend lifespan, researchers discover

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Scientists at the University of Virginia have found a promising approach to slowing 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, Ph.D., and her team, who are trying to identify the mechanisms that promote healthy aging and longevity. Their new work suggests a possible way to do this by reducing the health-depleting effects of glycerol and glyceraldehyde.

“The discovery was unexpected. We went after a very well-founded hypothesis that the secret to longevity was the activation of a cell-rejuvenating process called autophagy and finally found an unrecognized mechanism of health and lifespan extension,” said O’Rourke, of the Department of Biology at the UVA and the Department of Cell Biology at the UVA School of Medicine.

“An exciting aspect of the discovery is that the key to turning on this longevity mechanism is the activation of two enzymes that have been very well studied for their role in ethanol detoxification. [Ethanol is the alcohol contained in beer and bourbon]. This existing knowledge greatly facilitates our search for drugs that can specifically activate this anti-aging process.”

Discovery against aging

In their search for the secrets to slowing aging, O’Rourke and her graduate student Abbas Ghaddar and postdoc Vinod Mony turned to microscopic worms called C. elegans. These soil dwellers share over 70% of our genes and are invaluable for biomedical research; two Nobel Prizes in medicine were awarded to discoveries made exclusively with this worm.

Previous aging research in worms, mice and human cells led O’Rourke and others in the field to suspect that the key to extending lifespan was activating 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 health and lifespan of the worms by 50% without any increase in autophagy.

They did this by using a mechanism they discovered that they called AMAR, the Sanskrit word for immortality. AMAR in this case stands for “Alcohol and Aldehyde-Dehydrogenase Mediated Anti-aging Response.” Basically, the scientists discovered that they could trigger an anti-aging response by giving the trigger to 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. As a result, the worms lived longer and healthier lives.

Of course, findings in laboratory models such as worms and mice do not always apply to humans. So the researchers took several more steps to see if their lead was as promising as it seemed. First, they confirmed that the enzyme had similar beneficial effects on longevity in another lab model, yeast.

They then scoured research on gene activity in creatures, including humans, who had undergone fasting or calorie restriction, because both fasting and calorie restriction are known to increase health and longevity. Sure enough, the scientists found elevated levels of the anti-aging enzymes in all mammals tested, including humans.

The scientists suspect that our levels of glycerol and glyceraldehyde naturally increase over time because they are toxic by-products of fat, more of which we store as we age. So AMAR may provide a way to cope with fat-induced toxicity, extend the number of years we live in good health, and perhaps help us shed some 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.

“Given that age-related diseases are currently the largest health burden for patients, their families and the health care system, addressing the aging process itself would be the most effective way to reduce this burden and increase the number of years of independent and healthy living for all.” us.”

The researchers have published their findings in the scientific journal Current Biology.

More information:
Abbas Ghaddar et al, Increased Activity of Alcohol Dehydrogenase 1 Promotes Longevity, Current Biology (2023). DOI: 10.1016/j.cub.2023.01.059

Magazine information:
Current Biology

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