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Diet-related Metabolite TMAO Linked to Mortality in Older Adults

Jacob Fong-Gurzinsky | June 17, 2022
3 minutes to read

Trimethylamine N-oxide (TMAO) is a gut-derived metabolite that can serve as a biomarker for different aspects of human health, including diet, gut microbiome, and metabolism. Previous research has found that TMAO was associated with serious cardio-metabolic health outcomes. In a recent JAMA Network Open article, researchers found that TMAO and related metabolites are positively associated with a higher risk of death among older adults.

“While we understand that factors associated with mortality risks are concerning, TMAO is potentially modifiable,” emphasized the study’s lead author, Dr. Amanda Fretts, associate professor of epidemiology at the University of Washington. “TMAO is created from amino acids that can be found in meat, eggs, and fish, so diet can potentially affect TMAO levels. Now that we know more about the severity of risks associated with TMAO, we can explore effective approaches to change these levels in the body.” 

The prospective cohort study from the Cardiovascular Health Study (CHS)—a community-based longitudinal cohort of adults aged 65 years or older—evaluated 5,333 participants and investigated the associations of serial measures of TMAO and related metabolites with risk of death from cardiovascular disease and other causes. Participants with the highest levels of plasma TMAO, and specific members of its larger family of precursors (choline, carnitine, and butyrobetaine), had a 20–30% higher risk of death, when compared to those with the lowest levels of these metabolites. The level of risk did not change after considering whether the cause of death was related to cardiovascular disease versus other factors, though it was reduced after accounting for those with lower kidney function.

Previous research has focused on TMAO in people with comorbidities, such as diabetes, kidney disease, and heart disease. Those with comorbidities and high levels of TMAO in their bodies had higher risks of death than those with lower levels of TMAO.

“There have not been many studies of TMAO and risk of death in the general population. It is unclear if findings from previous studies among those with prevalent chronic diseases are generalizable to a wider group of people without underlying morbidity,” explained Dr. Fretts. “CHS is a population-based study that has been going on since 1989, so that gives a rich dataset to look at risk factors and outcomes, and also fluctuations in health behaviors over time.” 

More research is needed to understand how to effectively change levels of TMAO through therapies or behaviors. Promising candidates include clues for influencing diet, the gut microbiome, and metabolism.

The findings from this study may also help inform the future use of clinical tests for TMAO levels that can be ordered by a doctor. Dr. Stanley Hazen of Cleveland Clinic, one of the co-authors of the paper, developed the method of measuring TMAO over ten years ago, and he additionally developed the tests used for the other metabolites measured for the paper. So, to use these tests with a general population was an important advantage of using the CHS data.

“This paper adds to the body of evidence that TMAO is associated with poor health outcomes, but there is certainly hope that one’s risk of those health outcomes can change,” said Dr. Fretts.