Monocyte Aging Links to Non-Somatic Depression Symptoms, With Nicole Perez, PhD

Depression heterogeneity may obscure biologically meaningful signals, but new data suggest monocyte-specific epigenetic aging could help differentiate symptom domains. In an interview with HCPLive, Nicole Beaulieu Perez, PhD, RN, PMHNP-BC, an assistant nursing professor at NYU Rory Meyers College of Nursing, said the findings reinforce a central clinical reality: "Depression is not a monolith,” with distinct symptom profiles potentially reflecting different underlying mechanisms.

“We see all the time in practice how patients present with a variety of presentations,” Perez said. “We know there's over 200 possible combinations of symptoms that get us that disorder of depression. What's been less clear is how those presentations have been linked differentially to underlying biology. What goes with that is that we see all the time that patients respond differently to medications that target different mechanisms, even though they have the same diagnosis. This study…is consistent with what we're seeing in that we found that the epigenetic aging and monocytes using this new clock monocyte age acceleration showed differential associations when we looked at symptoms of depression that were considered non-somatic.”

Non-somatic symptoms include profound hopelessness and anhedonia. Meanwhile, the study did not show a link between monocyte age acceleration and somatic symptoms, including fatigue and the inability to fall asleep.

“When we actually drill down and look at a symptom resolution lens of what symptoms people are experiencing, we see biological differences, and specifically in this study, having to do with the accelerated aging of monocytes,” she added.

The study analyzed 440 participants from the Women’s Interagency HIV Study, including 261 women with HIV (mean age, 43.7 years), evaluating associations between epigenetic age acceleration (EAA) and depressive symptoms measured by the Center for Epidemiologic Studies Depression Scale (CES-D). Investigators compared a monocyte-derived clock (MonoDNAmAge) with a multi-tissue clock (HorvathDNAmAge), focusing on symptom domains rather than total scores.

In adjusted models, monocyte EAA was associated with non-somatic depressive symptoms (P =.018), with particularly strong associations for anhedonia (P =.007) and hopelessness (P =.007). No associations were observed for somatic symptoms such as fatigue or sleep disturbance at the domain level. Horvath-based EAA was not associated with total or domain-specific depressive symptoms.

Implications for Clinical Assessment

Although the findings do not alter current diagnostic criteria for major depressive disorder (MDD), they support a more granular approach to symptom assessment. Perez noted that clinicians already differentiate symptom patterns in practice, but existing frameworks and tools may not adequately capture this heterogeneity.

She pointed to limitations of total scores from commonly used scales such as the CES-D. These instruments aggregate symptoms across multiple domains, despite depression being a multidimensional construct encompassing affective, cognitive, and somatic features.

“Someone could have the same score at 2 different time points but totally different symptoms,” Perez said. “It’s misleading to think that necessarily their symptoms are the same over time.”

Biomarker Potential and Biological Context

The study also advances interest in monocyte epigenetic aging as a potential biomarker for depression. However, its clinical role remains uncertain. Because the analysis was cross-sectional, it cannot determine whether monocyte EAA reflects a state marker of current symptom burden or a trait marker of vulnerability.

The findings may be particularly relevant for populations with elevated inflammatory burden. Women living with HIV experience greater rates of depression and chronic comorbidities, alongside social and structural stressors that may contribute to “biological weathering,” a process linking environmental adversity to accelerated aging.

Toward Precision Psychiatry

The selective association between monocyte aging and non-somatic symptoms supports emerging models of depression subtypes, including inflammation-related phenotypes characterized by anhedonia and affective disturbance. By contrast, the absence of associations with somatic symptoms highlights the importance of domain-specific analyses. Overall, the study suggests that aligning biological measures with specific symptom dimensions may improve signal detection and advance precision psychiatry.

“I don't think it's ready for prime time yet,” Perez said. “What we're seeing here is that folks [who] have distinct presentations are going to have different biological mechanisms at play.”

Perez has no reported disclosures.

References

Perez NB, Xu K, Xu Y, et al. Monocyte Epigenetic Age Acceleration is Linked to Non-Somatic Depressive Symptoms in Women with and Without HIV. J Gerontol A Biol Sci Med Sci. Published online March 24, 2026. doi:10.1093/gerona/glag083