People with major depressive disorder may have a biological age as much as two years greater than their chronological age, according to a new study . The discovery provides a first step towards understanding the biological mechanisms that link depression to decreased lifespan.
A link between depression and aging
Depression is a serious global problem. The WHO calls major depressive disorder “the single largest contributor to global disability,” saying that it accounted for “7.5% of all years lived with disability in 2015” and is a major contributor to suicide deaths . Depression is a known risk factor for a range of diseases, many of which are also associated with aging, including cardiovascular disease and dementia.
The idea of a link between depression and aging isn’t new. Scientists were already speculating about a connection a decade ago, and researchers recently used fMRI to show that patients with major depressive disorder have brains that look older in terms of their functional connectivity. While those findings are compelling, they leave open the question of whether these patients also experienced increased cellular aging.
Refining the picture
To address that question, a research team used GrimAge to estimate the biological age of 50 patients with major depressive disorder along with 63 healthy controls. The measurements were taken using DNA extracted from blood samples rather than brain tissue.
Their analysis detected accelerated aging in the samples from patients with depression, with about two years of extra aging on average. This is approximately equivalent to the amount of extra aging detected in the fMRI study, which is an encouraging sign that researchers are on the right track.
However, the amount of increased aging didn’t correlate with depression severity, lifetime days of depression, days of untreated depression, or the duration of a current depressive episode. In other words, while the patients with depression showed accelerated aging, it’s not yet clear how to predict how much acceleration an individual patient would exhibit.
The researchers also weren’t able to pin down exactly which GrimAge markers contribute to the accelerated aging measure. Two groups of markers differed significantly between the patients and controls, but the statistical significance disappeared when they controlled for other factors, perhaps because of the small sample size. A site in one of the markers has also been suggested to play a role in post-traumatic stress disorder, so it’s tempting to think that there might be a link awaiting discovery.
Major depressive disorder (MDD) is associated with premature mortality and is an independent risk factor for a broad range of diseases, especially those associated with aging, such as cardiovascular disease, diabetes, and Alzheimer’s disease. However, the pathophysiology underlying increased rates of somatic disease in MDD remains unknown. It has been proposed that MDD represents a state of accelerated cellular aging, and several measures of cellular aging have been developed in recent years. Among such metrics, estimators of biological age based on predictable age-related patterns of DNA methylation (DNAm), so-called ‘epigenetic clocks’, have shown particular promise for their ability to capture accelerated aging in psychiatric disease. The recently developed DNAm metric known as ‘GrimAge’ is unique in that it was trained on time-to-death data and has outperformed its predecessors in predicting both morbidity and mortality. Yet, GrimAge has not been investigated in MDD. Here we measured GrimAge in 49 somatically healthy unmedicated individuals with MDD and 60 age-matched healthy controls. We found that individuals with MDD exhibited significantly greater GrimAge relative to their chronological age (‘AgeAccelGrim’) compared to healthy controls (p = 0.001), with a median of 2 years of excess cellular aging. This difference remained significant after controlling for sex, current smoking status, and body-mass index (p = 0.015). These findings are consistent with prior suggestions of accelerated cellular aging in MDD, but are the first to demonstrate this with an epigenetic metric predictive of premature mortality.
People with major depressive disorder have a shorter life expectancy on average. While changes in aging biology certainly aren’t the only possible explanation, it’s worth exploring how the two are linked, particularly given the association between depression and many age-related diseases. By showing accelerated cellular aging in these patients and correlating depression with epigenetic changes, this research brings us closer to understanding the biological mechanisms linking depression with decreased lifespan and healthspan.
 Protsenko, E. et al. “GrimAge,” an epigenetic predictor of mortality, is accelerated in major depressive disorder. Translational Psychiatry (2021), doi: 10.1038/s41398-021-01302-0
 World Health Organization. Depression and Other Common Mental Disorders: Global Health Estimates http://apps.who.int/iris/bitstream/handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf (2017).