It’s not unusual to feel older than your years, but that might be more true for some people than they realize. There’s growing evidence that mental illnesses such as depression are somehow related to a sufferer’s brain resembling that of an aged person. But does depression cause a brain to age prematurely or does premature ageing precede the onset of disease?

Researchers use physical, cellular, and molecular markers to predict an individual’s ‘biological age’. With these tools, they are trying to understand why biological age differs from actual age in some people. Research into accelerated brain ageing is an offshoot of this line of investigation. An individual’s chronological age can be predicted by the metrics of their brain. As humans age past 30, their brain starts slowly deteriorating over the remainder of their life. These changes are both physical, such as grey matter atrophy, and functional, such as a decline in cognitive flexibility, memory, and visual processing speed. However, some things, such as vocabulary and some verbal skills, survive the ageing process.

With accelerated brain ageing, a person’s brain metrics belie their actual age. The changes may be slight, but a person’s brain looks and behaves closer to that of an older brain. Some researchers, such as Katharine Dunlop of Weill Cornell Medicine, are working to delineate the relationship between accelerated brain ageing and depression. In 2021, together with a team of researchers in the US and Canada, she published a paper on the subject in the journal Neuropsychopharmacology. They used images of more than 700 healthy adult brains to create a model that predicted age. When the model was used to predict the age of depressed patients, it predicted an age that was, on average, two years greater than the patients’ actual age.

Dunlop and her team also found that patients with older-looking brains were more likely to be impulsive, and males with older brains tended to have more severe symptoms. “We found that if you were more impulsive regarding financial decision-making, you tended to have an older-looking brain,” says Dunlop.

This finding echoes a much larger study from the ENIGMA major depressive disorder consortium. In this large, multinational study, led by Laura Han from Amsterdam UMC, the Netherlands, the ENIGMA consortium found structural variation in depressed patients’ brains that made them appear to be approximately one year older.

Dunlop says that prior to the ENIGMA MDD working group study, a few smaller studies showed “conflicting but not incompatible results” regarding whether brain ageing and depression were linked. Dunlop also remarks that although some conditions, such as schizophrenia and dementia, show “clear-cut” accelerated ageing, things are a “little fuzzier” when it comes to depression. The ENIGMA study goes some way to settling the debate, however, as the largest study to date on the topic.

In an effort to boost the study of accelerated brain ageing and depression, Han and her team also produced a web-based tool that allows other research groups to test their own data. “There are 77 structural brain features like thickness and surface area and volumes of the brain,” says Han. If another research team acquires these metrics and plugs them into the consortia’s web tool, it will offer up a prediction of brain age.

Dunlop says she believes that brain ageing research is a stellar example of collaborative research done right. “The spirit of collaboration is exemplified in a lot of the brain ageing work because it requires a lot of data from multiple sources. That ENIGMA paper is a really good example of that,” she says.

It’s too early to tell, says Han, if being able to detect or predict accelerated brain ageing will prove useful for patients. However, one of the “hopeful messages,” according to her, is that there’s a lot of variation and overlap between healthy controls and patients with depression, and the ENIGMA study found an average deviation of just over one year in those with accelerated brain ageing. Dunlop adds that other factors also greatly influence behavioural and structural metrics associated with brain ageing, such as sex and socioeconomic status.

Dunlop and her team also had access to outcome data in their study, as all participants underwent transcranial magnetic stimulation (TMS) therapy to treat their depression. “Earlier studies said ‘if you’re older, [TMS] doesn’t work,’” says Dunlop. Now it’s known that this isn’t the case. Instead, structural atrophy increases the distance from the stimulator to the brain — something that can be remedied by a simple equipment adjustment. Dunlop’s study found no significant link between accelerated brain ageing and TMS response. Interestingly, they found that older looking brains responded better to placebo stimulation.

But studies are ongoing—Han and her colleagues went on to publish a follow-up paper that showed a potential neuroprotective effect of antidepressants on brain age. For now, research efforts such as Han’s and Dunlop’s continue to try to untangle the relationship between depression and brain ageing. 

One key question, says Dunlop, is figuring out which happens first and which causes which – depression or brain ageing? “That’s the million-dollar question. I don’t think we have the answer to that just yet” she says. 

The link is more clear for some other conditions: a previous study tracked people with mild cognitive impairment and found that brain ageing predicted who would go on to develop full-blown dementia. There are examples of brain aging coming before certain diagnoses, but for psychiatric disorders, it’s a more complex story, and “probably not a unidirectional relationship,” Dunlop says. It’s likely that depression and brain ageing feed back into each other and involve mechanisms of chronic stress and inflammation. 

“The chicken and the egg discussion, it’s a real hurdle. And to answer these questions takes time and money,” Dunlop says.

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