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Examining the link between depression and premature ageing

MDlinx Jan 31, 2024

It’s not unusual to hear people say they’re depressed about getting older. But they don’t typically say that depression is making them older. However, mounting evidence suggests that depression accelerates the aging process in multiple ways. 

Major depressive disorder (MDD) is associated with various signs of premature aging, including cardiovascular disease, dementia, and frailty, according to an article in Aging Research Reviews.

Lorenzo EC, Kuchel GA, Kuo CL, et al. Major depression and the biological hallmarks of aging. Ageing Research Reviews. 2023;83:101805.

Given that about 20% of people experience MDD in their lifetime, this association warrants a closer look. 


Here are some theories on how depression ages the body and mind on a cellular level, along with tips you can use to help your patients.


Measurable signs of accelerated aging


High inflammation is a common factor in aging and depression. Researchers writing in Translational Psychiatry note the overlaps between depression symptoms and the body’s response to fighting infections, including slower cognition, lethargy, and poor appetite.

Szymkowicz SM, Gerlach AR, Homiack D, et al. Biological factors influencing depression in later life: role of aging processes and treatment implications. Transl Psychiatry. 2023;13(1):160.

Adults with depression have elevated values for C-reactive protein, interleukin-6, and TNF-alpha. These proinflammatory cytokines are linked to more severe depression and poor response to treatment, as well as impairments to memory, executive function, and processing and motor speed. They’re also associated with gray matter and white matter losses.



The brains of depressed older adults appear 4 years older than their non-depressed peers based on structural MRIs. 

Scientists suspect that recurrent stress and depression impair neurotrophic function, increase regional brain atrophy, and promote cerebrovascular problems. In addition, longitudinal studies have associated depression with more significant reductions in hippocampal volume and greater white matter hyperintensities. While there appears to be a bidirectional relationship between depression and dementia, scientists have yet to identify clear genetic underpinnings.

Aging is also characterized by cellular senescence, as discussed in Aging Research Reviews. Features of cellular senescence include enlarged cells, accumulated beta-galactosidase, and lipofuscin in the cytoplasm. 


Cell cycle regulator markers, such as p16 and p21, are overexpressed in senescent cells. In addition, scenesent cells can’t initiate apoptosis, and they show signs of DNA damage and telomere shortening. 

Some of these markers of aging are also correlated with depression. For instance, p16 mRNA expression is higher in people with severe depression.



Physical and cognitive interventions


Preventing depression in older adults isn’t a one-size-fits-all proposition. 


Many seemingly promising prevention strategies, such as omega-3 supplementation, fail to stand up to scrutiny in randomized controlled trials.

Okereke OI, Vyas CM, Mischoulon D, et al. Effect of long-term supplementation with marine omega-3 fatty acids vs placebo on risk of depression or clinically relevant depressive symptoms and on change in mood scores. A randomized clinical trial. JAMA. 2021;326(23):2385–2394.



However, structured physical activity and social connections have well-established protective effects, per the authors writing in Translational Psychiatry. Exercise improves markers of cellular senescence, as does lithium carbonate, as noted in Aging Research Reviews. Because MDD raises the risk of diabetes, obesity, sarcopenia, and low grip strength, physical activity has significant potential benefit in older adults.

Once depression sets in, though, it is important to find effective treatment options, as this may help slow the cascade of accelerated aging and improve health and well-being later in life. 

Although antidepressants are more effective in younger adults, they nonetheless may help delay Alzheimer’s disease in older adults with mild cognitive impairment.

Alexopoulos GS. Mechanisms and treatment of late-life depression. Transl Psychiatry. 2019;9(1):188.

Patients who don’t respond to antidepressants can consider electroconvulsive therapy to treat depression later in life. Psychotherapies, including problem-solving therapy, cognitive behavioral therapy, and interpersonal therapy, are effective options with minimal adverse side effects. 


Novel therapies may be beneficial in certain cases and warrant further investigation. These include neurobiology-based psychotherapy, dopamine receptor D2/D3 agonists, computerized cognitive remediation, angiotensin receptor blockers, some calcium channel blockers, anti-inflammatory agents, and cytokine inhibitors. 

In addition to treating the depression itself, early screening and treatment for common comorbidities of MDD can help protect patients against depression-related health hazards.


What this means for you

Depression triggers cellular changes that age the brain and body prematurely. While some of the underlying genetic and molecular mechanisms aren’t fully understood, inflammation, oxidative damage, and lifestyle factors likely promote bidirectional, self-perpetuating damage. Recognizing the widespread risks of depression in your patient populations is the first step to intervening early and providing effective comprehensive care.


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