‘AMAR’ Is Latest Addition To The List Of Anti-Aging Hopefuls

By Deborah Borfitz 

April 4, 2023 | Using “genetic trickery,” scientists at the University of Virginia (UVA) have hit on a means to detoxify the body of fat byproducts and, with that, extend the healthy lifespan of the model organism C. elegans. The specific trick was to boost the activity of two enzymes involved in alcohol detoxification, according to cardiovascular researcher Eyleen Jorgelina O’Rourke, Ph.D. 

The link between fat detox and alcohol detox is that stored fats in the body are mostly triglycerides, and triglycerides are composed of two parts: fatty acids and a special type of alcohol known as glycerol. Those components are released into circulation when fats are metabolized, damaging cells and tissues, she points out. 

People are accustomed to having their doctor regularly check the levels of triglycerides and fatty acids in their blood, says O’Rourke. However, the biomedical community “tends to forget” about glycerol and glyceraldehyde, another toxic byproduct of fat that naturally accumulates in the body over time.  

Superactivating the two enzymes that detoxify glycerol increased the health and lifespan of microscopic worms and yeast by 50%. O’Rourke and her team named this new anti-aging mechanism AMAR (alcohol and aldehyde-dehydrogenase mediated anti-aging response), a Sanskrit word for immortality. Promisingly, mining previous studies, researchers found increased levels of the anti-aging enzymes in mammals undergoing fasting or calorie restriction—both known to extend life.  

The study, published recently in Current Biology (DOI: 10.1016/j.cub.2023.01.059), was originally intending to focus on the well-supported hypothesis that the secret to longevity is activating autophagy. Autophagy is a cell-rejuvenation process that normally kicks in when food is scarce or lacking, says O’Rourke, and is thought to underlie all anti-aging treatments.  

Fasting or caloric restriction don’t need to be constant to positively impact human health, she continues. Periodic, 12-hour fasting during the daytime has likewise been shown to have significant positive effects on certain measures of health, including improved insulin sensitivity, reduction in circulating fatty acids, and better overall metabolic health. Humans, however, don’t live in a controlled laboratory environment but a real world where they are perpetually tempted by and can readily access hyper-caloric foods. 

After a decade of working in the aging field, O’Rourke says, “this is the closest we have gotten to finding something we feel can be translated to the clinic.” But, as with any medication that succeeds in delaying the onset of age-related diseases, it will come with a slew of broad societal and regulatory questions that will require serious discussion. 

Only two drugs are currently being tested to promote healthy aging—rapamycin and metformin. While the biomedical community is “very excited to learn the results of those studies,” she says, success would not preclude the need for other options. 

Most of the genes known to have strong effects on lifespan are “central hubs of information within cells” with a lot of downstream effects, says O’Rourke. By contrast, AMAR is a downstream effector with a much narrower function, yet able to impact aging across the body. In addition, the two enzymes executing AMAR are well characterized; thus, screening for or designing activators is expected to be feasible, she adds. 

Bigger Questions  

Years of genetics and biochemistry research has revealed that hyperactivation of certain genes and pathways can either extend or shorten lifespan, O’Rourke says, but most of these play central roles in altering cellular and tissue function. “If you touch them in a lab environment, you can achieve this extension of health and lifespan, but they don’t work in natural environments [of humans].” 

In their latest experiment, the UVA team mimicked these environmental challenges and the animals with superactivated AMAR seemed to be resilient to the stresses. “It seems, so far, that there is no big compromise in hyperactivating these alcohol detoxifying enzymes,” says O’Rourke. 

The bigger unknown is how society will embrace anti-aging medicine more generally—by tackling aging and simultaneously delaying the onset of age-associated diseases such as Alzheimer’s, cancer, and stroke, or by tackling each disease one at a time, she continues. The case for the full-swoop approach is it could result in a healthier population and less burden on health systems, but at the price of clinical trials in mostly young and healthy people who would ultimately be taking the anti-aging drugs.  

With delayed onset of these chronic and acute diseases, lifespan itself will be extended such that people might aspire to live healthier possibly to the age of 120 or 150, says O’Rourke, but with an assortment of unconsidered societal consequences. “How are we going to sustain Social Security? Are we going to work until we are 100 years old?” 

The best of all options may be to live an average of 90 years, she offers. “But at age 85 or 87, we’re still dancing on the floor and going on hikes and living a healthy life.” 

Measuring Age 

The research team is now planning new studies of AMAR-activating agents in a mouse model and cultured human cells, O’Rourke reports. “If we find the right [industry] partners, those could be done in a couple of years... to decide if this is worth pursuing in human testing.” 

Rapamycin as well as metformin, used for decades in diabetic patients, are already in clinical trials “to reduce the prevalence or delay the onset of age-related disease,” says O’Rourke. While possibly precedent-setting, society and regulatory agencies still need to decide if this is the best path forward. 

With human cells in culture, the UVA team will be using a battery of biological aging clocks—including global gene expression, epigenetics, DNA methylation, mitochondrial function, and senescence—all purporting to have the best biomarkers for measuring biological age, O’Rourke says. The instruments will be used to determine the age of cells after they’re manipulated to hyperactivate AMAR. Researchers will also be on the lookout for any “tradeoffs” in terms of undesirable secondary effects.