For treatment of GAD on top of reducing “brain aging” associated with it in my personal case - I’m more personally biased toward psilocybin. I had a poor individual response to SSRIs with the usual sexual side effects, then switched to nighttime low-dose mirtazapine in an attempt for hitting insomnia as well (so I didn’t have to rely on gabapentin off-label as there are tolerance buildup issues). Mirtazapine made me feel weird and groggy in the morning, so I was pretty bummed. Ended up doing CLIA-certified whole genome sequencing and took a look at SLC6A4, HTR1A/2A/3B, TPH, and BDNF specifically (well also some of the CYPs) and found a few drug-gene interactions and low predicted remission rates for SSRIs. It also pointed me to suggestive evidence towards other pharmacotherapy targets.
Although there is pretty weak evidence on SSRI efficacy/toxicity predictions, I have a 5-HTTLPR short-form genotype - which appears to suggest a decreased response to SSRIs and an increase in the reactivity of the human amygdala - which may be contributory to GAD. Since psilocybin appeared to be better at maladaptive rumination/repetitive self-critical thoughts even with short-form genotype and decreased blood flow to the amygdala, according to fMRI study (PMID 29030624) - I ended up settling on it via clinical trial - but I can’t say that it will necessarily apply to others, nor does the pharmacogenetics side have strong enough evidence yet for SSRIs - not to mention, WGS is generally not shown to be cost-effective. Now I get psilocybin from a brick-and-mortar Canadian store that sells it openly (dry whole shroom - I’m a stickler for avoiding adulteration ie even a tiny risk of NBOMe) at an estimated ~25 mg psilocybin equivalent every 4 weeks - but I prefer to pre-convert it to psilocin and reduce the time I’m out - it seems to work well.
As for how that relates to “brain aging” - rumination/HPA axis activation from chronic stressors/anxiety appears to be associated with shortening telomeres and DNN hyperactivity (PMID 19735238) which psilocybin reduces. Psilocybin increases BDNF, synaptic neurogenesis, and neuroplasticity as well. Seems long-term safety is likely high with such a long cultural use. And especially since it is intermittent use and non-addictive, it would seem unlikely to pose significant safety concerns assuming supervision, although there can be rare serious side effects like HPPD.
An interesting update is psilocybin appears likely for FDA approval soon (probably the end of 2023 if not 2024) and there are licensed Oregon centers now: DocumentCloud
As for some other “brain aging” interventions:
I take microdose lithium 1mg - don’t really feel anything and it’s hard to tell if it’ll pan out since a trial on ALS failed before - the likelihood of harm seems minimal - it slowed cognitive decline in AD patients in a poorly done study. (PMID 22746245)
Been looking at Circadin (melatonin prolonged release) vs eszopiclone vs lemborexant (I’m indicated since I already tried CBT-I and sleep hygiene) for a while. Sleep architecture alteration is a long story and not going to get into it - the basic principle is don’t mess with it on your own, since it’s really complex with a lot of knowledge gaps.
Some other notables besides diet/sleep/exercise etc - dietary astaxanthin, green tea, morning coffee, mushroom/dark berries intake, dental health, high-quality high-dose fish oil, and reducing toxin exposure (particularly indoor air pollution/PM 2.5 exposure, lead/other heavy metals, organophosphates, too high manganese, mitochondrial toxins) may be helpful. This is assuming A1c or HOMA-IR/lipids/visceral fat already looks perfect and no nutritional deficiencies.