Depression

Depression and biological aging

Depression isn't just a mood problem. It's a measurable driver of accelerated biological aging. A 2023 study in Nature Communications analyzed 424,299 UK Biobank participants and found that people with older biological age (measured via DNA methylation clocks) had significantly higher rates of new-onset depression and anxiety over an 8.7-year follow-up ^[1]. The relationship works both ways: depression itself pushes biological age forward. A 2024 analysis using NHANES data showed that depressed mood increases the gap between biological and chronological age, and that accelerated aging partially mediates the link between depression and higher mortality risk ^[2].

The mechanisms are concrete. Depression elevates C-reactive protein (CRP) and interleukin-6 (IL-6), two inflammatory markers strongly associated with cardiovascular disease and cellular aging ^[3]. Chronic cortisol elevation suppresses immune function, impairs DNA repair, and shortens telomeres. For a longevity-focused person, untreated depression is as dangerous as smoking or a sedentary lifestyle.

How exercise compares to antidepressants

A landmark 2024 BMJ network meta-analysis pooled 218 randomized controlled trials with 14,170 participants and compared exercise directly against antidepressants and psychotherapy for major depressive disorder ^[4]. Walking, jogging, yoga, and strength training all produced clinically meaningful reductions in depressive symptoms. The effect sizes were comparable to, and in some analyses exceeded, those of SSRIs. Higher-intensity exercise produced larger benefits, and the dose-response relationship was clear: more vigorous activity meant greater symptom reduction.

This doesn't mean everyone should ditch medication. For moderate to severe depression, combining exercise with pharmacotherapy or psychotherapy tends to produce the best results. But for mild to moderate depression, 150 minutes of moderate aerobic activity per week is now backed by the same caliber of evidence as first-line drug treatments. The number needed to treat (NNT) for exercise was 2.78, meaning fewer than three people need to exercise for one to experience meaningful improvement.

The inflammation connection

Not all depression is the same biologically. Research published in Translational Psychiatry in 2024 identified that a subset of depressed patients have significantly elevated inflammatory markers, including CRP, TNF-alpha, and IL-6 ^[3]. This "inflammatory subtype" responds differently to treatment. Standard SSRIs often work poorly for these patients, while anti-inflammatory approaches, omega-3 supplementation, and exercise show more promise.

A 2025 review in the International Journal of Molecular Sciences confirmed that omega-3 fatty acids, particularly EPA, reduce depressive symptoms with moderate effect sizes, especially in people with measurable inflammation ^[5]. The dose that showed the most consistent benefit was 1-2 g/day of EPA-dominant fish oil. This isn't a replacement for clinical treatment, but it's a meaningful adjunct, particularly when blood markers show elevated CRP.

Sleep and depression feed each other

The relationship between sleep and depression is bidirectional, and understanding this matters for breaking the cycle. The HUNT study, a large prospective population study, found that people with insomnia at two consecutive time points had 6.2 times the odds of developing depression ^[6]. Meanwhile, depression disrupts sleep architecture, suppresses slow-wave sleep, and fragments REM patterns.

Treating sleep problems directly reduces depression severity. Cognitive behavioral therapy for insomnia (CBT-I) improves both sleep and mood, and a growing body of evidence suggests that fixing sleep can be as effective as antidepressants for the depressive symptoms that co-occur with insomnia. Prioritizing sleep hygiene, maintaining consistent sleep-wake times, and addressing sleep disorders like apnea should be part of any depression management plan.

Emerging treatments: psilocybin and ketamine

For treatment-resistant depression, two newer interventions are backed by growing clinical evidence. Psilocybin-assisted therapy has shown sustained remission in over 50% of patients at six months in clinical trials, with marked symptom reductions after just two sessions ^[7]. COMPASS Pathways reported positive Phase 3 results for their 25 mg psilocybin protocol in treatment-resistant depression.

Ketamine, available as the nasal spray esketamine (Spravato), produces rapid antidepressant effects within hours rather than the weeks required for SSRIs. A 2025 network meta-analysis found no significant differences in response rates between IV ketamine, transcranial magnetic stimulation, and electroconvulsive therapy, but ketamine had better acceptability with fewer people discontinuing treatment. These options are not first-line, but they represent a genuine advance for the 30% of depression patients who don't respond adequately to conventional treatment.

What actually works: a practical hierarchy

From a longevity perspective, start with a proper diagnosis using the PHQ-9 to establish a baseline. Address the foundations: regular exercise (150+ min/week moderate intensity), consistent sleep schedule, and social connection. Engage with evidence-based psychotherapy, particularly CBT. Consider pharmacotherapy when symptoms are moderate to severe. Test inflammatory markers (CRP, IL-6) and supplement with omega-3s if elevated. For treatment-resistant cases, discuss ketamine or psilocybin-assisted therapy with a qualified provider.