Longitudinal Associations Between Endogenous Testosterone, C-Reactive Protein, and Interleukin-6 in Aging Men: Findings from the Baltimore Longitudinal Study of Aging

  1. Keerthana Sureshkumar
  2. Meghan R. Grewal
  3. Aaron A. Gurayah
  4. Adam Williams
  5. Justin M. Dubin
  6. Thomas Masterson
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Abstract

Background

Elevated C-Reactive Protein (CRP), interleukin-6 (IL-6) and testosterone deficiency are associated with advanced age and chronic inflammatory diseases; while normal testosterone levels have been shown to decrease inflammation through several mechanisms. Cross-sectional studies have shown an inverse relationship between CRP, IL-6 and total testosterone (TT) levels, yet mixed findings have been reported when individual components of metabolic syndrome are considered. We evaluated the relationship between CRP, IL-6 and TT levels in men from 2004-2018 using the Baltimore Longitudinal Study of Aging to determine if low testosterone status is associated with a high inflammatory profile.

Methods

Participants were selected from the Baltimore Longitudinal Study of Aging. Male participants with serum TT level measured during at least three visits were included in our cohort. Common measures of inflammatory disease such as CRP, High-Density Lipoprotein (HDL) and Triglyceride levels were collected via blood specimens. Comorbidity data were documented at each visit. Panel regression was used to analyze the relationship of a series of independent variables collected in pooled cross-sectional observations over time with a dependent variable for modeling.

Results

A total of 347 patients were included in this study (median age = 70, IQR = 18, average follow up time = 6.7 ± 3.2 years). Participants had a median CRP level of 1.0 mg/dL, median IL-6 level of 3.6, a median TT level of 446 ng/dL. On univariable analysis, increasing TT and HDL levels were associated with a decline in CRP, while high Body Mass Index (BMI), congestive heart failure (CHF), Diabetes, and increased serum triglycerides were associated with increased CRP. Age was not associated with CRP. On multivariable analysis, we found that increasing TT level was associated with a decline in CRP levels, independent of comorbidities (p = 0.018; Table 1). As expected, increased BMI was associated with a significant increase in CRP (p = 0.001, Table 1). Age, CHF, Diabetes, HDL, and Triglycerides were not significant predictors of CRP on multivariable analysis. Similarly, on multivariable analysis, increasing TT levels were independently associated with lower IL-6 levels. Higher HDL cholesterol levels were also associated with lower IL-6 levels, whereas increasing age was associated with higher IL-6 levels. BMI, CHF, diabetes, and triglycerides were not significant predictors of IL-6 (Table 2).

Conclusions

Lower levels of serum total testosterone are associated with an increase in CRP in older men over time, independent of chronic inflammatory disease. Given the importance of CRP in pathogenesis of chronic disease, we highlight the potential benefits of using total testosterone as a biomarker of chronic inflammatory states.

Key findings

  • In this longitudinal analysis of 347 men from the Baltimore Longitudinal Study of Aging, lower endogenous total testosterone levels were independently associated with higher levels of the inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6). These associations persisted after adjustment for factors such as age, body mass index, and major chronic comorbidities. Interestingly, age alone was not independently associated with CRP, while testosterone remained a significant predictor of inflammatory burden over time.

What is known and what is new?

  • Prior cross-sectional studies have suggested an inverse relationship between testosterone and inflammatory markers, but findings have been both inconsistent and variable, and it has remained unclear if this relationship reflects aging or the accumulation of chronic disease. Additionally, longitudinal evidence addressing this question has been limited.

  • This study provides longitudinal trends indicating that declining total testosterone is independently associated with increases in CRP and IL-6 over time, even after accounting for aging and common comorbidities. The findings suggest that a decline in testosterone is not simply a passive consequence of aging but may be linked to inflammatory processes that extend further than diagnosed chronic disease.

What is the implication, and what should change now?

  • These results support total testosterone as a biomarker of systemic inflammation in older men. It suggests that profiling of testosterone levels may offer additional insight into inflammatory risk beyond traditional clinical factors. Our findings support the need for further investigation into the mechanistic relationship between androgen status and inflammation and whether addressing testosterone deficiency could influence inflammation and downstream chronic disease risk in older male populations.

Article activity feed

  1. Version published to 10.64898/2026.06.25.26356580 on medRxiv