Nicole Beaulieu Perez, PhD, RN, PMHNP-BC, an assistant nursing professor at NYU Rory Meyers College of Nursing

Nicole Beaulieu Perez, PhD, RN, PMHNP-BC

Monocyte Epigenetic Age Links to Depression Symptom Subtypes, With Nicole Perez, PhD

New data from the Women’s Interagency HIV Study (WIHS) suggest that monocyte-specific epigenetic aging may help distinguish biologically distinct subtypes of 

, particularly those characterized by non-somatic symptoms such as anhedonia and hopelessness. The findings contribute to a growing precision psychiatry effort aimed at moving beyond global diagnostic labels toward symptom-level biology.

The study included 440 participants, including 261 women living with HIV, with a mean age of 43.7 years. Investigators assessed epigenetic age acceleration (EAA) using 2 approaches: a monocyte-derived clock and a multi-tissue epigenetic clock (Horvath). Associations were evaluated across depressive symptom domains measured by the Center for Epidemiologic Studies Depression Scale (CES-D), rather than total scores alone.

Monocyte epigenetic age acceleration was significantly associated with non-somatic depressive symptoms (

 = .018), with the strongest signals observed for anhedonia (

 = .007). No associations were found for somatic symptoms, including fatigue or sleep disturbance, and the Horvath multi-tissue clock showed no significant associations with either total or domain-specific depressive symptoms.

In the third part of our interview, Nicole Beaulieu Perez, PhD, RN, PMHNP-BC, assistant professor at NYU Rory Meyers College of Nursing, described next steps before a marker like monocyte epigenetic age acceleration could be considered clinically actionable. She emphasized the need for replicated trials and to understand the dynamics of monocyte age acceleration in the monocyte-derived clock.

“Can we actually change it?” she wondered. “Is it more static? Is it more dynamic, and what is it actually going to take? Is it something that we can reasonably do with pharmacology or with lifestyle behavioral interventions? How malleable is it?”

Perez added that while epigenetics is often considered more malleable than genetic sequence and known to change over the course of life in response to environmental influences, its clinical manipulation remains unclear. It is not yet known how malleable epigenetic marks are or what the appropriate timing or dosing would be to meaningfully manipulate them.

“This is not a study that is going to change practice today,” Perez said. “We hope that it will offer a roadmap for other precision mental health studies and for us to really start thinking differently about these very broad diagnostic categories.”

Watch parts 1 and 2 of the interview with Perez here: 

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

Monocyte Clock Detects Depression Signals, With Nicole Perez, PhD

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. 

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Perez discusses the next steps before a marker like monocyte epigenetic age acceleration could be considered clinically actionable for precision psychiatry in depression.

, 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 

 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 (

 =.007), while the Horvath clock showed no significant associations with symptom domains such as fatigue or sleep disturbance.

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.

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: 

Interview with Perez on how monocyte-derived epigenetic clocks outperform multi-tissue models in detecting symptom-specific depression signals.


Depression heterogeneity may obscure biologically meaningful signals, but new data suggest monocyte-specific epigenetic aging could help differentiate symptom domains. In an interview with 

, 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 (

=.018), with particularly strong associations for anhedonia (

=.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.

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.

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.”

In this interview, Perez discusses data linking monocyte epigenetic age acceleration to non-somatic depressive symptoms.


Nicole Beaulieu Perez, PhD, RN, PMHNP-BC

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