Clozapine Treatment Reduces Epigenetic Age in Male Psychiatric Patients

Researchers are beginning to apply epigenetic clocks to known cases in which drug treatment is associated with a longer life expectancy, even less unusual ones, such as this case. Patients treated with the antipsychotic drug clozapine exhibit a longer life expectancy, and epigenetic clock data now shows that male patients in addition experience a lowered epigenetic age. Whether any of this data proves useful at the end of the day is an open question. The challenge in the use of epigenetic clocks is that researchers don't yet understand how specific epigenetic marks connect to the underlying mechanisms of aging. Therefore clocks become unreliable in the context of interventions that address a given mechanism of aging: the clock may be biased towards or against that mechanism, and without calibrating the therapy against the clock in life span studies, it is impossible to draw conclusions from the data.

Long-term studies have shown significantly lower mortality rates in patients with continuous clozapine (CLZ) treatment than other antipsychotics. We aimed to evaluate epigenetic age and DNA methylome differences between CLZ-treated patients and those without psychopharmacological treatment. The DNA methylome was analyzed in 31 CLZ-treated patients with psychotic disorders and 56 patients with psychiatric disorders naive to psychopharmacological treatment. Delta age (Δage) was calculated as the difference between predicted epigenetic age and chronological age. CLZ-treated patients were stratified by sex, age, and years of treatment. Differential methylation sites between both groups were determined using linear regression models.

The Δage in CLZ-treated patients was on average lower compared with drug-naive patients for the three clocks analyzed; however, after data-stratification, this difference remained only in male patients. Additional differences were observed in Hannum and Horvath clocks when comparing chronological age and years of CLZ treatment. We identified 44,716 differentially methylated sites, of which 87.7% were hypomethylated in CLZ-treated patients, and enriched in the longevity pathway genes. Moreover, by protein-protein interaction, AMPK and insulin signaling pathways were found enriched. CLZ could promote a lower Δage in individuals with long-term treatment and modify the DNA methylome of the longevity-regulating pathways genes.


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