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Monocyte Clock Detects Depression Signals, With Nicole Perez, PhD
Interview with Perez on how monocyte-derived epigenetic clocks outperform multi-tissue models in detecting symptom-specific depression signals.
In an interview with HCPLive, Nicole Beaulieu Perez, PhD, RN, PMHNP-BC, an assistant nursing professor at NYU Rory Meyers College of Nursing, discussed how a monocyte-derived epigenetic clock demonstrated greater sensitivity to depressive symptom domains than traditional multi-tissue models, with implications for biomarker development and precision psychiatry.
The study compared a monocyte-specific DNA methylation clock (MonoDNAmAge) with the widely used Horvath clock, a multi-tissue, multi-cellular epigenetic aging measure, among 440 participants from the Women’s Interagency HIV Study (261 women with HIV; mean age, 43.7 years). While both estimate biological age using DNA methylation patterns, they differ in design and biological specificity. Perez explained that this distinction likely underlies the observed differences in performance.
“[The Horvath clock] …has a lot of flexibility, but with that flexibility, there's not as much specificity, and we risk introducing a lot of noise from tissue and cell type heterogeneity that makes it difficult to find certain things,” Perez said.
This increased specificity was reflected in the findings. Monocyte epigenetic age acceleration was associated with non-somatic depressive symptoms (P =.018), particularly anhedonia (P =.007) and hopelessness (P =.007), while the Horvath clock showed no significant associations with symptom domains such as fatigue or sleep disturbance.
Biological Rationale for Monocyte Focus
Monocytes play a central role in inflammatory responses and are closely linked to both HIV pathophysiology and depression. In HIV, monocytes contribute to viral dissemination and serve as a long-term reservoir. In depression, prior research has identified shifts in monocyte subtypes, including increases in non-classical monocytes associated with inflammatory states.
This overlap is particularly relevant given the study population. Depression is the most common neuropsychiatric complication among individuals living with HIV, even among those with sustained viral suppression. Perez noted that shared immune mechanisms may help explain this co-occurrence.
By leveraging a monocyte-specific clock, investigators aimed to capture this intersection of inflammation, aging, and psychiatric symptoms more precisely than would be possible with a generalized aging metric.
Implications for Risk Stratification and Treatment
Although not yet ready for clinical use, these findings suggest potential applications in early detection and risk stratification. Perez highlighted a key limitation in current practice: depression is often identified only after symptoms become severe.
Perez addressed the importance of biomarkers to identify individuals at risk of depression earlier. Tissue-specific biomarkers could inform treatment selection. Current pharmacologic strategies rely heavily on trial-and-error, with 30% to 50% of patients failing to respond to first-line antidepressants such as selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. This process can delay effective treatment for months.
Path to Clinical Implementation
Despite promising findings, several steps remain before monocyte epigenetic age acceleration can be considered clinically actionable. Perez addressed the need for longitudinal studies to determine whether the marker predicts incident depression, tracks symptom changes, or responds to treatment. Standardization of measurement, validation across diverse populations, and integration with clinical workflows will also be necessary.
Ultimately, the study supports a shift toward more targeted approaches in psychiatric research. By aligning biological measures with specific cell types and symptom domains, investigators may improve the precision of both discovery and clinical translation.
“Not all depression is the same,” Perez said. “It doesn't necessarily all have the same mechanisms. It could be helpful with identifying folks early, with risk stratification and screening…and I think most importantly, help us to guide treatment decisions.”
Watch part 1 of the interview with Perez here: Monocyte Aging Links to Non-Somatic Depression Symptoms, With Nicole Perez, PhD
Perez has no reported disclosures.
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