The ‘GrimAge’ Reaper: Accelerated mortality linked to major depressive disorder

by: Annika Pohlo

In addition to the most commonly known symptoms of major depressive disorder (MDD), this condition is also a risk factor for a number of issues associated with aging, such as cardiovascular disease and Alzheimer’s disease. Present in over 16.1 million Americans, MDD is a mood disorder tied to emotional and even physical symptoms. The association between MDD and premature mortality has been clear in the scientific community for years, with previous research concluding that those diagnosed with depression tend to live an average of 5 years less than those unaffected. However, despite these findings and our growing societal awareness, there are still many more research questions to pursue concerning the nature of the physiological processes involved. Recently, a DNA metric trained on time-to-death data, appropriately named ‘GrimAge’,  has proven itself an efficient and accurate means of predicting both morbidity and mortality. By conducting research comparing those affected by MDD to those unaffected, a group of scientists centered at the University of California, San Francisco were able to use GrimAge to predict premature mortality among those affected by MDD. This newfound metric of epigenetic age represents an important foundational step in studying the implications of factors and treatments involved in epigenetics, the study of how cells control gene activity without modifying the DNA sequence. 

On its own, depression hosts a plethora of complications, even excluding the role of epigenetics, including strained interpersonal relationships, chronic body aches, and increased chances of addictive tendencies, along with self-harm and suicide. According to a 1997 paper, depression is ranked second globally in terms of disease burden. While factors such as abuse, loss, or other major events can serve as causes of depression, there are also factors that leave some predisposed to depression – such as gender, genetics, age, and chronic illnesses. Certain members of these marginalized communities may already face issues concerning their respective conditions, including a lack of resources, so it is vital to create targeted treatments. It is also important to find the biological mechanisms involved in depression, in order to combat MDD, whether that be proactively or retroactively. Understanding the complexities of mental health conditions and their biological implications are an important step in improving approaches and accessibility. 

Recently, the topic of depression has been approached through the lens of epigenetics, a fascinating field that encompasses how behavioral and environmental factors alter gene expression. In general, epigenetic patterns within individuals can be affected by lifestyle habits such as diet, tobacco use, physical activity, sleeping habits, and stress. On a biological scale, epigenetic modifications result from DNA methylation and histone modifications (histone methylation and acetylation). DNA methylation occurs when a covalent bond forms between the methyl group and the 5-carbon of the cytosine ring, forming the ‘fifth base’ of DNA, at the subsets of the 28 million 5′-C-phosphate-G-3′ (CpG) sites on the genome. These methyl groups serve as both a protector and an inhibitor for the DNA by preventing transcription, which ultimately regulates gene activity.

Recently, scientists have made the connection between DNA methylation and accelerated aging. Prior to epigenetic analysis, scientists predicted mortality using other metrics in biological age—which quantifies the perceived age of cells, tissues, and organs. These units and systems were studied for their biochemistry based on certain factors, such as leukocyte telomere length, which is essentially the chromosomal ends of white blood cells. Recently, however, these methods have given rise to newer biomarkers of aging, also known as ‘epigenetic clocks’, which are more accurate in predicting mortality than prior measures of biological age. Over the past few years, epigenetic measures have been found to have a strong relation to all-cause mortality. This new metric also coincides with recent research findings, which determined that telomere length ultimately has a “weak or inconsistent association with all-cause mortality in previous epidemiological studies”. Instead, the ‘GrimAge’ clock, named after the Grim Reaper, identifies CpG sites with methylation states that are closely correlated with serum protein levels that predicted mortality; these ‘DNAm surrogates’ for serum proteins are then trained on large-scale time-to-death data. From there, GrimAge Acceleration is found via the residual from regressing epigenetic age on chronological age. When this age is greater than an individual’s actual, chronological age, this means they are experiencing ‘Epigenetic Age Acceleration’. Given these mechanisms and measurements, scientists predicted to be able to find an association between those with depression and those experiencing Epigenetic Age Acceleration.

In the researchers’ experiment, GrimAge was tasked with predicting the time to onset of a number of diseases, such as coronary heart disease, hypertension, early menopause, etc. The CpG sites are associated with proteins relating to health, so GrimAge was very accurate in describing associations between mortality and health as it relates to age. Overall, 113 individuals were studied, about half diagnosed MDD participants recommended by clinical sources, and half were found by various advertisements. Subjects went through multiple screenings to rule out potentially confounding variables, such as chronic illness and alcohol abuse.  While the groups did not differ much in terms of demographic categories, there was a difference in whether or not the individuals smoked; those with MDD were more likely to smoke. To account for this, the researchers created a sensitivity analysis within a sub-cohort of nonsmokers.

The participants had their blood drawn and collected in acid citrate dextrose. Using DNA purification kits, the DNA was extracted and the genomic DNA was treated with sodium bisulfite. This process involves the sulfonation, deamination, and desulfonation of DNA that converts unmethylated cytosines into uracil while the methylated cytosines remain cytosine.  Researchers profiled the genome-wide DNA methylation pattern using tools such as fluorescence and UCLA’s DNAm age website. To analyze the results, the researchers used two-tailed significance with an alpha value of 0.05. Ultimately, the researchers found that those with MDD seemed to, on average, have a median difference of 2 years of epigenetic age against those who were healthy in this aspect. Even when accounting for smoking, sex, and BMI this discrepancy remained. The researchers found a significant correlation between GrimAge and “chronological age in the combined cohort (Spearman Rho = 0.968, p < 0.001)”. These findings were the first that associated cellular aging and major depressive disorder using epigenetic markers to predict early mortality. Even after adjusting for other variables, MDD is a distinct factor that contributes to the Grim Age Acceleration, suggesting that there is much more to research concerning the relationship between the two. The researchers also noted other potential avenues to pursue such as the stability and reversibility of changes, the relationship between epigenetics and later illnesses, whether or not the GrimAge differences noted are specific to MDD or are also present in other psychiatric illnesses, and the biological mechanisms that link MDD to a shorter lifespan. In addition, epigenetic therapy is an emerging field of treatment that aims to target a series of epigenetic conditions, including those previously mentioned, extending beyond just mental illness. Understanding how epigenetic therapy can be used is also a means by which researchers can learn to treat other conditions; not just depression. Combined with the respective questions that have arisen as a result, this study is a major finding in the scientific community that allows for much more progress in the future, leading an era that values not only life but also the quality of life.

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