Understanding Cytokine Shifts Driven by Hormonal Changes in the Elderly

The aging process is accompanied by a complex re‑wiring of the endocrine system, and these hormonal alterations exert profound effects on immune signaling networks. Among the most striking immunological hallmarks of older adults is a shift in cytokine production—often described as “inflamm‑aging”—characterized by elevated pro‑inflammatory mediators (e.g., IL‑6, TNF‑α, IL‑1β) and a relative decline in anti‑inflammatory cytokines (e.g., IL‑10, TGF‑β). While many reviews focus on the classic sex steroids or cortisol, a growing body of evidence points to a broader set of hormones—thyroid hormones, melatonin, adipokines, parathyroid hormone, ghrelin, and the secosteroid vitamin D—as pivotal drivers of these cytokine dynamics. Understanding how each of these endocrine factors modulates immune cell function helps to clarify why cytokine profiles change with age and opens avenues for targeted interventions that go beyond the well‑trod pathways of estrogen, testosterone, or glucocorticoids.

Hormonal Landscape in Aging

Aging is not a uniform decline in hormone production; rather, it is a mosaic of increases, decreases, and altered receptor sensitivity across multiple endocrine axes:

These hormones interact with immune cells through specific receptors (e.g., thyroid hormone receptors α/β, melatonin receptors MT1/MT2, leptin receptor Ob‑R, vitamin D receptor VDR) that trigger intracellular cascades influencing transcription factors such as NF‑κB, STAT3, and AP‑1. The net effect is a re‑balancing of cytokine output that can either amplify or dampen inflammatory signaling.

Thyroid Hormones and Cytokine Modulation

Mechanistic Overview

Thyroid hormones (TH) exert genomic effects via nuclear thyroid hormone receptors (TRα and TRβ) that bind thyroid response elements (TREs) on DNA, as well as non‑genomic actions through integrin αvβ3 on the plasma membrane. In immune cells, TH modulate:

• Monocyte/macrophage activation – T3 suppresses LPS‑induced NF‑κB translocation, reducing transcription of IL‑1β, IL‑6, and TNF‑α.
• Dendritic cell maturation – T4 promotes expression of co‑stimulatory molecules (CD80/CD86) and IL‑12, favoring Th1 differentiation.
• Natural killer (NK) cell cytotoxicity – Both T3 and T4 enhance perforin and granzyme B expression via the PI3K/Akt pathway.

Age‑Related Shifts

In older adults, the decline in free T3 (the biologically active form) diminishes the inhibitory tone on NF‑κB, contributing to higher basal levels of IL‑6 and CRP. Simultaneously, preserved T4 can still drive dendritic cell maturation, sustaining a pro‑inflammatory milieu despite reduced overall TH signaling. The net result is a skewed cytokine profile: elevated IL‑6/TNF‑α with a blunted anti‑inflammatory counterbalance.

Clinical Correlates

Subclinical hypothyroidism (elevated TSH, normal T4) is common in the elderly and has been linked to higher circulating IL‑6 and increased frailty scores. Conversely, modest T3 supplementation in carefully selected patients can lower IL‑6 and improve functional outcomes, underscoring the causal relationship between TH status and cytokine regulation.

Melatonin’s Role in Immune Regulation

Chronobiology Meets Immunology

Melatonin, secreted by the pineal gland in a circadian pattern, binds MT1 and MT2 receptors on lymphocytes, macrophages, and microglia. Its actions are twofold:

1. Antioxidant Defense – Scavenges reactive oxygen species (ROS), limiting oxidative activation of NF‑κB.
2. Signal Transduction – Activates the cAMP/PKA pathway, leading to increased expression of the anti‑inflammatory cytokine IL‑10 and suppression of IL‑1β and TNF‑α.

Impact of Age‑Related Decline

Aged individuals experience a 50‑80 % reduction in nocturnal melatonin peaks. This loss removes a critical brake on the innate immune system, allowing unchecked activation of inflammasomes (e.g., NLRP3) and heightened secretion of IL‑1β and IL‑18. Moreover, diminished melatonin impairs the circadian gating of cytokine release, resulting in a flattened diurnal rhythm of IL‑6 that correlates with poorer sleep quality and increased morbidity.

Therapeutic Insight

Chronotherapy with low‑dose melatonin (0.3–1 mg) administered in the early evening can restore the nocturnal IL‑10 surge and attenuate morning IL‑6 spikes, thereby re‑establishing a healthier cytokine rhythm without affecting the hypothalamic‑pituitary‑adrenal axis.

Adipokines: Leptin and Adiponectin as Immune Modulators

Leptin – A Pro‑Inflammatory Hormone

Leptin signals through the Ob‑Rb isoform, activating JAK2/STAT3, PI3K/Akt, and MAPK pathways. In immune cells:

• T‑cell polarization – Leptin favors Th1 and Th17 differentiation, up‑regulating IFN‑γ and IL‑17 production.
• Monocyte activation – Enhances expression of CD14 and TLR4, amplifying LPS‑driven IL‑6 and TNF‑α release.

In the elderly, leptin levels are often elevated due to increased adiposity, yet leptin resistance (impaired downstream signaling) can coexist. This paradox leads to a dysregulated cytokine output: basal pro‑inflammatory cytokine production remains high, while the capacity to mount an acute, regulated response is blunted.

Adiponectin – The Counterbalance

Adiponectin binds AdipoR1/R2 receptors, activating AMPK and PPARα pathways that suppress NF‑κB and promote IL‑10 synthesis. Although circulating adiponectin tends to rise with age, functional resistance (e.g., reduced receptor expression on macrophages) limits its anti‑inflammatory efficacy. Consequently, the protective “adiponectin shield” against cytokine overproduction weakens, contributing to the chronic low‑grade inflammation observed in seniors.

Integrated Perspective

The leptin/adiponectin ratio emerges as a robust predictor of cytokine imbalance. A high ratio correlates with elevated IL‑6 and CRP, whereas a lower ratio aligns with higher IL‑10 and better functional status. Interventions that improve leptin sensitivity (e.g., weight‑stable exercise) or augment adiponectin signaling (e.g., PPARγ agonists) can shift this balance toward a more anti‑inflammatory cytokine profile.

Parathyroid Hormone and Calcium‑Immune Interplay

Hormonal Crosstalk

Parathyroid hormone (PTH) regulates calcium homeostasis but also influences immune cells via the PTH1 receptor (PTH1R) expressed on monocytes and dendritic cells. PTH signaling activates the cAMP/PKA pathway, which can:

• Enhance IL‑6 production – Particularly in bone‑derived stromal cells, linking bone turnover to systemic inflammation.
• Modulate RANKL/OPG balance – Affecting osteoclastogenesis and, indirectly, the release of cytokines from the bone marrow niche.

Age‑Related Dynamics

Secondary hyperparathyroidism, driven by age‑related declines in vitamin D and renal function, leads to chronically elevated PTH. This persistent stimulation contributes to a “bone‑immune axis” where increased IL‑6 and TNF‑α promote both bone resorption and systemic inflammation, reinforcing the cytokine shift seen in frail elders.

Clinical Relevance

Targeted treatment of hyperparathyroidism (e.g., calcimimetics) has been shown to reduce circulating IL‑6 and improve markers of physical performance, highlighting the direct impact of PTH on cytokine regulation.

Ghrelin and the Gut‑Immune Axis

Hormone Overview

Ghrelin, primarily secreted by gastric oxyntic cells, binds the growth hormone secretagogue receptor (GHS‑R) on immune cells, especially regulatory T cells (Tregs) and macrophages. Its signaling cascades involve:

• AMPK activation – Suppressing NF‑κB and reducing pro‑inflammatory cytokine transcription.
• PI3K/Akt pathway – Promoting Treg survival and IL‑10 production.

Age‑Related Changes

Older adults often exhibit blunted post‑prandial ghrelin peaks and lower overall circulating levels. This deficit diminishes ghrelin’s anti‑inflammatory influence, leading to:

• Reduced Treg frequency – Lower IL‑10 and higher IFN‑γ/IL‑17 ratios.
• Enhanced gut permeability – Facilitating translocation of microbial products that trigger systemic IL‑6 and TNF‑α release.

Therapeutic Angle

Low‑dose ghrelin analogs (e.g., anamorelin) have demonstrated the capacity to restore IL‑10 levels and improve gut barrier integrity in animal models of aging, suggesting a potential avenue for modulating cytokine shifts via the gut‑immune interface.

Vitamin D (Calcitriol) as a Hormone and Cytokine Crosstalk Hub

Endocrine Functions

The active form of vitamin D, 1,25‑dihydroxyvitamin D₃ (calcitriol), binds the nuclear vitamin D receptor (VDR) present on virtually all immune cells. VDR‑mediated transcription regulates:

• Antimicrobial peptide genes (e.g., cathelicidin) – Enhancing innate defense.
• Cytokine balance – Up‑regulating IL‑10 and down‑regulating IL‑6, IL‑12, and TNF‑α via inhibition of NF‑κB and MAPK pathways.

Decline with Age

Cutaneous synthesis of cholecalciferol falls by ~50 % after age 70, and renal 1α‑hydroxylase activity wanes, leading to lower calcitriol levels. This deficiency removes a critical checkpoint on pro‑inflammatory cytokine production, contributing to the characteristic “inflamm‑aging” profile.

Biomarker Implications

Serum 25‑OH‑D concentrations <20 ng/mL correlate with a 2‑3‑fold increase in IL‑6 and CRP in community‑dwelling seniors. Supplementation to achieve >30 ng/mL can modestly reduce IL‑6 and improve vaccine responsiveness, underscoring the hormone’s role in shaping cytokine landscapes.

Integrated Signaling Pathways and Cellular Mechanisms

These pathways intersect at several nodal points—most notably NF‑κB, STAT3, and AMPK—creating a network where the net cytokine output reflects the cumulative hormonal milieu. Age‑related shifts in hormone concentrations, receptor density, and downstream signaling fidelity collectively tip the balance toward a pro‑inflammatory state.

Clinical Implications and Biomarker Considerations

1. Composite Hormone‑Cytokine Indices – Combining measurements of free T3, melatonin nocturnal peak, leptin/adiponectin ratio, PTH, ghrelin, and 25‑OH‑D with cytokine panels (IL‑6, TNF‑α, IL‑10) improves risk stratification for frailty, cardiovascular events, and infection susceptibility in seniors.
2. Targeted Hormone Modulation – Selective interventions (e.g., low‑dose T3, timed melatonin, PTH antagonists, ghrelin mimetics) can recalibrate specific cytokine axes without broadly suppressing immunity.
3. Receptor Sensitivity Assessment – Functional assays (e.g., STAT3 phosphorylation after leptin challenge, VDR transcriptional activity) may uncover hormone resistance that static hormone levels miss, guiding personalized therapeutic choices.

Future Directions and Research Gaps

• Longitudinal Multi‑Omics – Integrating hormone metabolomics, transcriptomics of immune cells, and epigenetic profiling will clarify causal pathways linking endocrine drift to cytokine reprogramming over the lifespan.
• Sex‑Specific Analyses – While this article avoids classic sex steroids, emerging data suggest that sex chromosomes modulate receptor expression for thyroid hormone, melatonin, and adipokines, potentially influencing cytokine trajectories differently in men and women.
• Microbiome‑Hormone Interactions – Gut microbes can convert bile acids into ligands for nuclear receptors (e.g., FXR) that intersect with cytokine regulation; the interplay with ghrelin and melatonin warrants deeper exploration.
• Therapeutic Window Optimization – Determining the optimal timing (chronotherapy) and dosing of hormone supplementation to align with circadian immune rhythms could maximize anti‑inflammatory benefits while minimizing adverse effects.

Summary

The cytokine shifts observed in the elderly are not merely a by‑product of immune senescence; they are actively sculpted by a constellation of hormonal changes that extend far beyond the classic sex steroids and cortisol. Declines in thyroid hormone activity, melatonin, ghrelin, and vitamin D, together with alterations in leptin, adiponectin, and PTH, converge on shared intracellular pathways—chiefly NF‑κB, STAT3, and AMPK—to tilt the cytokine balance toward chronic, low‑grade inflammation. Recognizing these endocrine drivers provides a mechanistic framework for interpreting inflamm‑aging, offers novel biomarkers for risk assessment, and opens targeted therapeutic avenues that restore a more youthful cytokine milieu without compromising essential immune defenses.