The Role of Estrogen in Modulating Inflammatory Responses in Older Adults

Estrogen, traditionally celebrated for its central role in reproductive physiology, exerts profound effects on the immune system that become especially relevant as individuals age. In older adults, the gradual decline in circulating estrogen—most notably after menopause in women and a more subtle reduction in men—coincides with a shift toward a pro‑inflammatory milieu often termed “inflamm‑aging.” This article explores the molecular pathways through which estrogen modulates inflammatory responses, the age‑related alterations that reshape these pathways, and the clinical implications for maintaining immune health in later life.

Estrogen Receptors and Signaling Pathways Relevant to Inflammation

Estrogen signals through three principal receptor families: the classical nuclear receptors estrogen receptor‑α (ERα) and estrogen receptor‑β (ERβ), and the membrane‑bound G‑protein‑coupled estrogen receptor (GPER, also known as GPR30). While ERα and ERβ function primarily as ligand‑activated transcription factors, GPER mediates rapid, non‑genomic signaling cascades. All three receptors are expressed on key immune cells—including monocytes, macrophages, dendritic cells, neutrophils, T lymphocytes, and B lymphocytes—allowing estrogen to influence both innate and adaptive immunity.

• Genomic actions: Upon binding estrogen, ERα/ERβ dimerize, translocate to the nucleus, and bind estrogen response elements (EREs) on target genes. This can directly up‑regulate anti‑inflammatory genes (e.g., IL‑10, TGF‑β) or repress pro‑inflammatory genes through interaction with transcription factors such as NF‑κB and AP‑1.
• Non‑genomic actions: GPER activation triggers intracellular second messengers (cAMP, Ca²⁺) and kinase pathways (PI3K/Akt, MAPK/ERK). These rapid signals can modulate the activity of inflammasomes, phagocytic capacity, and cytokine release within minutes of estrogen exposure.

The balance between these pathways determines whether estrogen exerts a net anti‑inflammatory or, under certain conditions, a pro‑inflammatory effect.

Mechanisms by Which Estrogen Attenuates Pro‑Inflammatory Signaling

1. Inhibition of NF‑κB Translocation

NF‑κB is a master regulator of inflammatory gene expression. Estrogen‑ER complexes can sequester the p65 subunit of NF‑κB in the cytoplasm, prevent its DNA binding, or recruit co‑repressors such as NCoR and SMRT to NF‑κB target promoters. This results in reduced transcription of IL‑6, TNF‑α, and IL‑1β—cytokines that are typically elevated in older adults.

2. Modulation of the NLRP3 Inflammasome

The NLRP3 inflammasome drives the maturation of IL‑1β and IL‑18, cytokines implicated in age‑related chronic inflammation. Estrogen, via GPER‑mediated activation of the PI3K/Akt pathway, enhances the expression of autophagy‑related proteins (e.g., Beclin‑1) that facilitate the clearance of damaged mitochondria—a key trigger of NLRP3 activation. Consequently, estrogen dampens inflammasome assembly and downstream cytokine release.

3. Promotion of Anti‑Inflammatory Cytokine Production

ERα binding to EREs in the promoter regions of IL‑10 and TGF‑β genes up‑regulates their transcription. These cytokines act in autocrine and paracrine fashions to suppress macrophage activation and limit Th1‑type immune responses, fostering a more regulated inflammatory environment.

4. Regulation of Chemokine Expression and Immune Cell Trafficking

Estrogen reduces the expression of chemokines such as CCL2 (MCP‑1) and CXCL10 (IP‑10) on endothelial cells and resident macrophages, limiting the recruitment of monocytes and neutrophils to sites of sterile inflammation—a process that becomes dysregulated with age.

Age‑Related Changes in Estrogen Signaling

• Decline in Circulating Estradiol

Post‑menopausal women experience a 70–80 % reduction in serum estradiol, while men exhibit a more gradual decline (~1 % per year after age 40). This reduction diminishes ligand availability for all estrogen receptors, weakening the anti‑inflammatory signaling cascade.

• Altered Receptor Expression

Studies of peripheral blood mononuclear cells (PBMCs) from older adults reveal a down‑regulation of ERα and a relative increase in ERβ expression. Since ERα is more potent in suppressing NF‑κB activity, this shift may tilt the balance toward a pro‑inflammatory state.

• Epigenetic Reprogramming

Age‑associated DNA methylation of ERα promoter regions and histone modifications can further suppress receptor transcription. Moreover, microRNAs such as miR‑221/222, which target ERα mRNA, are up‑regulated in senescent immune cells, compounding the functional deficit.

• Impaired GPER Signaling

Membrane fluidity and lipid raft composition change with age, potentially affecting GPER localization and its ability to couple with G‑proteins. Reduced GPER signaling may blunt the rapid anti‑inflammasome effects of estrogen.

Collectively, these alterations create a permissive environment for heightened basal inflammation and exaggerated responses to stressors in older adults.

Clinical Evidence Linking Estrogen to Inflammatory Markers in Older Populations

These data consistently demonstrate that higher estrogenic activity—whether endogenous or pharmacologically induced—associates with lower circulating pro‑inflammatory cytokines and attenuated inflammasome activity in older adults.

Therapeutic Implications and Considerations

1. Hormone Replacement Therapy (HRT) in Post‑Menopausal Women
• Potential benefits: Restoration of estradiol levels can re‑engage ERα‑mediated NF‑κB inhibition, lower systemic CRP, and improve endothelial function, thereby reducing cardiovascular inflammation.
• Risks and contraindications: HRT may increase the risk of thromboembolic events, breast cancer, and certain hormone‑sensitive malignancies. Individual risk assessment, timing of initiation (the “window of opportunity” hypothesis), and formulation (transdermal vs. oral) are critical.

2. Selective Estrogen Receptor Modulators (SERMs) and Tissue‑Selective Estrogen Complexes (TSECs)

SERMs such as raloxifene and bazedoxifene act as ER agonists in bone and immune cells while antagonizing estrogenic activity in breast and uterine tissue. Their ability to dampen inflammasome activation without systemic estrogen exposure makes them attractive candidates for older adults at higher cancer risk.

3. Phytoestrogens and Dietary Approaches

Isoflavones (genistein, daidzein) from soy and lignans from flaxseed exhibit modest ERβ affinity. While their anti‑inflammatory potency is lower than endogenous estradiol, regular consumption can modestly reduce IL‑6 and CRP levels, offering a low‑risk adjunct strategy.

4. Targeting GPER

Emerging GPER‑selective agonists (e.g., G‑1) have shown promise in preclinical models for suppressing NLRP3 activation and improving macrophage phagocytosis. Clinical translation remains early, but GPER activation may provide a pathway to harness estrogen’s rapid anti‑inflammatory effects without stimulating nuclear receptors.

5. Personalized Dosing Based on Biomarkers

Monitoring serum estradiol, ERα/ERβ expression ratios on immune cells, and inflammatory markers (CRP, IL‑6) can guide titration of estrogenic therapies. Adjustments can be made to achieve a therapeutic window where anti‑inflammatory benefits are maximized while minimizing adverse events.

Future Research Directions

• Deciphering Sex‑Specific Immune Aging

While estrogen’s anti‑inflammatory actions are evident, the interplay with other sex hormones and genetic factors warrants deeper investigation, especially in older men where estradiol is derived from aromatization of testosterone.

• Longitudinal Multi‑Omics Studies

Integrating transcriptomics, epigenomics, and proteomics of immune cells across the aging trajectory will clarify how estrogen signaling networks evolve and identify novel downstream effectors amenable to therapeutic targeting.

• GPER‑Centric Drug Development

Designing selective, orally bioavailable GPER agonists with favorable safety profiles could unlock rapid anti‑inflammatory pathways without the risks associated with systemic estrogen exposure.

• Inflammasome‑Focused Clinical Trials

Trials that specifically measure NLRP3 activity, caspase‑1 cleavage, and IL‑18 levels in response to estrogenic interventions will provide mechanistic validation of the preclinical findings.

• Interaction with the Microbiome

Estrogen metabolism is partially mediated by gut microbial enzymes (e.g., β‑glucuronidases). Understanding how age‑related dysbiosis influences estrogen bioavailability and immune modulation could open avenues for combined probiotic‑estrogen strategies.

Practical Take‑Home Messages

• Estrogen exerts a multi‑layered anti‑inflammatory influence through genomic (ERα/ERβ) and non‑genomic (GPER) pathways, chiefly by dampening NF‑κB signaling, restraining NLRP3 inflammasome activation, and promoting anti‑inflammatory cytokine production.
• The age‑related decline in circulating estradiol, coupled with altered receptor expression and epigenetic silencing, contributes to the heightened inflammatory tone observed in older adults.
• Clinical evidence supports that restoring estrogenic activity—via HRT, SERMs, or phytoestrogens—can lower key inflammatory biomarkers, though therapy must be individualized to balance benefits against potential risks.
• Emerging therapeutic concepts focus on selective receptor modulation, especially GPER activation, and biomarker‑guided dosing to optimize immune health in the elderly.
• Ongoing research into the molecular aging of estrogen signaling, its interaction with the microbiome, and targeted drug development promises to refine strategies for mitigating inflamm‑aging and enhancing overall resilience in later life.