Cells from individuals with Major Depressive Disorder
(MDD) were found to have higher than expected rates of methylation at specific
sites on their DNA, when compared to cells from healthy individuals without
MDD, according to a study by a multidisciplinary team of UC San Francisco
scientists, in collaboration with others. Methylation is a process by which DNA
is chemically modified at specific sites, resulting in changes in the
expression of certain genes.
Methylation of particular
sets of genes, called “DNA methylation clocks,” typically change in predictable
ways as people age, but the rate of these changes varies between people.
Methylation patterns in individuals with MDD suggested that their cellular age
was, on average, accelerated relative to matched healthy controls.
In the study, published April
6, 2021 in Translational Psychiatry, blood samples from
individuals with MDD were analyzed for methylation patterns using the ‘GrimAge’
clock – a mathematical algorithm designed to predict an individual’s remaining
lifespan based on cellular methylation patterns. Individuals with MDD showed a
significantly higher GrimAge score, suggesting increased mortality risk,
compared to healthy individuals of the same chronological age – an average of
approximately two years on the GrimAge clock.
The individuals with MDD
showed no outward signs of age-related pathology, as they and the healthy
controls were screened for physical health before entry into the study. The
methylation patterns associated with mortality risk persisted even after
accounting for lifestyle factors like smoking and BMI. These findings provide
new insight into the increased mortality and morbidity associated with the
condition, suggesting that there is an underlying biological mechanism
accelerating cellular aging in some MDD sufferers.
“This is shifting the way we
understand depression, from a purely mental or psychiatric disease, limited to
processes in the brain, to a whole-body disease,” said Katerina Protsenko, a
medical student at UCSF and lead author of the study. “This should
fundamentally alter the way we approach depression and how we think about it –
as a part of overall health.”
MDD is one of the most
prevalent health concerns globally. According to the World health Organization,
some 300 million people (4.4% of the population) suffer from some form of
depression. MDD is associated with higher incidence and mortality related to
increased rates of cardiovascular disease, diabetes, and Alzheimer’s disease
among sufferers.
“One of the things that’s
remarkable about depression is that sufferers have unexpectedly higher rates of
age-related physical illnesses and early mortality, even after accounting for
things like suicide and lifestyle habits,” said Owen Wolkowitz, MD, professor
of psychiatry and a member of UCSF’s Weill Institute for Neurosciences,
co-senior author of the study. “That’s always been a mystery, and that’s what
led us to look for signs of aging at the cellular level.”
The researchers collected
blood samples from 49 individuals with MDD who were unmedicated prior to the
study and 60 healthy control subjects of the same chronological age. They
analyzed the methylation rates of both groups using the GrimAge clock. While
there are numerous methylation-based longevity algorithms, GrimAge is the only
one based specifically on methylation patterns associated with mortality.
The researchers say that they
don’t yet know if depression causes altered methylation in certain individuals,
or if depression and methylation are both related to another underlying factor.
It is possible that some individuals may have a genetic predisposition to
produce specific methylation patterns in response to stressors, but this has
not been well-studied. Alterations in methylation patterns have previously been
observed in individuals with Post-Traumatic Stress Disorder.
Moving forward, the
researchers hope to determine whether pharmacological treatments or therapy may
mitigate some methylation changes related to MDD in hopes of normalizing the
cellular aging process in affected individuals before it advances. Although the
GrimAge methylation clock has been associated with mortality in other
populations, no studies have yet determined whether this methylation pattern
also predicts mortality in MDD.
“As we continue our studies,
we hope to find out whether addressing the MDD with anti-depressants or other
treatments alters the methylation patterns, which would give us some indication
that these patterns are dynamic and can be changed,” said Synthia Mellon, PhD,
professor in the Department of Ob/Gyn & Reproductive Sciences at UCSF and
co-senior author of the study.
Source: https://www.ucsf.edu/
Journal article: https://www.nature.com/articles/s41398-021-01302-0
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