Accelerated cell aging associated with mortality seen in depressed individuals

The cells of healthy individuals with major depressive disorder were found to have higher-than-expected methylation rates at specific sites on their DNA, compared to cells of healthy individuals without MDD, according to research by the Walter Reed Institute of the Army’s multidisciplinary team and scientists at the University of California, San Francisco, in collaboration with others.

Methylation is a process by which DNA is chemically modified at certain sites, resulting in changes in the expression of certain genes. Methylation of certain sets of genes, called “DNA methylation clocks,” usually changes in predictable ways as people age, but the rate of these changes varies among people. Methylation patterns in individuals with MDD suggest that their cellular age of DNA methylation is on average accelerated compared to matching healthy controls.

In a study published in Translational psychiatry, blood samples from 49 people with MDD were compared with 60 healthy control subjects of the same chronological age using a ‘GrimAge’ clock – a mathematical algorithm designed to predict an individual’s remaining lifespan based on cell methylation patterns. Individuals with MDD showed a significantly higher GrimAge score, indicating an increased risk of mortality compared to healthy individuals of the same chronological age – averaging approximately two years on a GrimAge watch.

Individuals with MDD were not treated prior to the study and did not show external signs of age-related pathology because they and healthy controls were examined to determine physical health prior to entering the study. Methylation patterns associated with the risk of mortality persisted even after lifestyle factors such as smoking and BMI were taken into account. These findings provide new insights into the increased mortality and morbidity associated with this condition, suggesting that there is a basic biological mechanism that accelerates cellular aging in some MDD patients.

“This shifts the way we understand depression, from a purely mental or psychiatric illness, limited to brain processes, to a whole-body illness,” said Katerina Protsenko, a medical student at UCSF and lead author of the study. “This should basically change the way we approach depression and how we think about it – as part of overall health.”

MDD is one of the most prevalent health concerns globally. According to the World Health Organization, about 300 million people (4.4% of the population) suffer from some form of depression. MDD is associated with higher incidence and mortality due to increased rates of cardiovascular disease, diabetes, and Alzheimer’s disease among sufferers.

“One of the things that is remarkable about depression is that sufferers have an unexpectedly higher rate of physical illness associated with aging and early mortality, even after considering things like suicide and lifestyle habits,” said Dr. Owen Wolkowitz, professor of psychiatry and a member of the UCSF’s Weill Institute of Neuroscience, co-senior author of the study. “It’s always been a mystery and it has led us to look for signs of aging at the cellular level.”

Researchers say they do not yet know whether depression causes altered methylation in individuals or whether depression and methylation are related to another underlying factor. It is possible that some individuals may have a genetic predisposition to create specific methylation patterns in response to stressors, but this has not been well studied. Changes in methylation patterns have previously been observed in individuals with posttraumatic stress disorder.

“These findings will allow us to better understand the link between behavioral disorders – for example, 60% of PTSD cases are comorbid with MDD. Clarifying these mechanical and biochemical bases will improve efforts to develop targeted diagnostic and medical strategies, ultimately improving patient care, “said Dr. Marty Jett, Chief Scientist of WRAIR. Previous research from the group used GrimAge to study men with combat PTSD.

Moving forward, researchers hope to determine if pharmacological treatments or therapy can alleviate some of the methylation changes associated with MDD in hopes of normalizing the cellular aging process of affected individuals before it progresses. Also, although the “GrimAge” methylation clock is associated with mortality in other populations, no study has yet prospectively determined whether this methylation pattern also predicts MDD mortality.

“As we continue our studies, we hope to find out if the pattern of MDD changes with antidepressants or other treatments to methylation patterns, which would give us some indication that these patterns are dynamic and can change,” said Dr. Synthia Mellon, Professor in the Department of Obstetrics, Gynecology and Reproductive Sciences at UCSF and co-senior author of the study.

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About the Walter Reed Research Institute:

The Walter Reed Institute for Military Research (WRAIR), part of the U.S. Army Medical Research and Development Command, provides unique research opportunities and innovative medical solutions to a range of health care and force readiness challenges currently facing U.S. service members, along with anticipated threats during future operations. WRAIR has created a model of vaccine development and therapy that is unique, agile, and responsive to dynamically evolving infectious diseases of military importance. Using its expertise, capacity and international network, the Institute has helped develop many vaccines and drugs used today in military and civilian medicine around the world. In 2018, the New Infectious Diseases Branch (EIDB) was established with an explicit mission to investigate, anticipate, and combat the growing threat of new infectious diseases of critical importance to U.S. forces at home and abroad.

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