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

This longitudinal study of aging men demonstrates that lower serum total testosterone levels are independently associated with elevated levels of inflammatory markers C-Reactive Protein and Interleukin-6 over time, suggesting testosterone may serve as a useful biomarker for chronic inflammatory states.

Original authors: Sureshkumar, K., Grewal, M. R., Gurayah, A., Williams, A., Dubin, J., Masterson, T.

Published 2026-07-07

📖 5 min read🧠 Deep dive

CC BY 4.0

Original authors: Sureshkumar, K., Grewal, M. R., Gurayah, A., Williams, A., Dubin, J., Masterson, T.

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ⚕️ This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer

The Big Picture: The "Rust" and the "Engine Oil"

Imagine your body is a high-performance car. As the car gets older, two things usually happen:

The Engine Oil gets thin: In men, this is like Testosterone. It naturally decreases as you age.
The Engine gets Rusty: This is Inflammation. In the body, we measure this "rust" using markers called CRP and IL-6.

For a long time, doctors knew that older cars had less oil and more rust. But they weren't sure if the rust was just because the car was old, or if the lack of oil was actually causing the rust to spread faster.

This study asked a specific question: If we look at the same men over many years, does having lower testosterone levels predict more "rust" (inflammation), even if we ignore their age and other health problems?

How They Did It: The "Long-Term Road Trip"

Instead of taking a snapshot of 347 different men at one single moment (which is like taking a photo of a parking lot full of cars of different ages), the researchers took a "video" of the same men over time.

The Data Source: They used the Baltimore Longitudinal Study of Aging, a massive database where men have been checked up on every 1–4 years since 1958.
The Group: They picked 347 men who had blood tests done at least three times between 2004 and 2018.
The Filter: They made sure to only look at men who weren't taking testosterone supplements (so the numbers reflected their natural levels) and didn't have prostate cancer.
The Math: They used a special type of math (panel regression) that acts like a filter. It separates the "noise" of getting older or having diabetes from the specific relationship between testosterone and inflammation.

What They Found: The Connection Holds Up

The study found a clear, consistent pattern:

The Inverse Relationship: When a man's natural testosterone levels went down, his inflammation markers (CRP and IL-6) went up.
It's Not Just About Age: Usually, we think "older = more inflammation." However, in this study, age alone didn't predict the inflammation. A 70-year-old with high testosterone had less inflammation than a 70-year-old with low testosterone.
It's Not Just About Weight or Disease: The researchers checked for other culprits like obesity (BMI), heart failure, and diabetes. Even after accounting for these, the link between low testosterone and high inflammation remained strong.
- Analogy: Imagine two cars of the same age and weight. The one with the "thinner oil" (low testosterone) had more "rust" (inflammation) than the one with thicker oil, even if both were driven on the same roads.

The Specific Numbers:

CRP (The Rust Indicator): Higher testosterone was linked to lower CRP.
IL-6 (Another Rust Indicator): Higher testosterone was linked to lower IL-6.
Age: Interestingly, while getting older did increase IL-6 slightly, it did not increase CRP on its own. Testosterone, however, was a major driver for both.

What This Means (According to the Paper)

The authors conclude that low testosterone isn't just a passive side effect of getting old or getting sick. Instead, it seems to be tightly linked to the body's inflammatory state.

The Takeaway: Testosterone levels could act as a "warning light" or a biomarker for systemic inflammation in older men. If a man has low testosterone, he is statistically more likely to have a body that is "rusting" (inflamed) more than usual, regardless of his age or other diseases.

What the Paper Doesn't Say

It is important to stick to what the authors actually claimed:

No Causation Proven: The study shows a strong association (a link), but it does not prove that low testosterone causes the inflammation, or that inflammation causes the low testosterone. It's like seeing that clouds and rain happen together; you know they are linked, but this specific study doesn't prove which one makes the other happen.
No Treatment Advice: The paper does not say that giving men testosterone supplements will cure inflammation or prevent disease. It only suggests that testosterone levels are a useful piece of information to understand a man's inflammatory health.
No Generalization to Everyone: The study group was mostly white, middle-class men. The authors admit we don't know if this exact same "rust and oil" relationship applies to all races or social groups yet.

Summary Analogy

Think of your body as a house. Testosterone is the maintenance crew, and Inflammation is the peeling paint and rotting wood.
This study found that in houses of the same age, the ones with the weakest maintenance crew (low testosterone) tended to have the most rot and peeling paint (high inflammation), even if the house wasn't any older than the others. The study suggests that checking the strength of the maintenance crew might tell you a lot about the condition of the house, even before you see the rot.

Technical Summary: Longitudinal Associations Between Endogenous Testosterone, C-Reactive Protein, and Interleukin-6 in Aging Men

Problem Statement
The pathophysiology of hypogonadism in aging men is complicated by the concurrent rise in chronic inflammation. While cross-sectional studies have suggested an inverse relationship between total testosterone (TT) and inflammatory markers such as C-Reactive Protein (CRP) and Interleukin-6 (IL-6), it remains unclear whether this association is a direct biological link or merely a reflection of aging and the accumulation of chronic comorbidities (e.g., diabetes, congestive heart failure, obesity). Existing literature lacks robust longitudinal evidence to determine if declining endogenous testosterone is independently associated with increasing inflammatory burden over time within individuals.

Methodology
This study utilized a longitudinal panel regression analysis on data from the Baltimore Longitudinal Study of Aging (BLSA), covering the period from 2004 to 2018.

Cohort: The final analytic cohort consisted of 347 male participants who contributed a total of 698 study visits. Inclusion criteria required at least three visits with documented serum TT measurements.
Exclusions: Participants were excluded if they had fewer than three visits, missing data, used testosterone replacement therapy (TRT), had a history of prostate cancer, or possessed biologically implausible laboratory values (e.g., <0 or >3 standard deviations from the mean).
Variables:
- Outcomes: Serum CRP and IL-6 levels.
- Predictors: Total testosterone (TT), age, Body Mass Index (BMI), High-Density Lipoprotein (HDL), triglycerides, and binary comorbidity indicators (Diabetes Mellitus, Congestive Heart Failure, Cancer).
- Testosterone Measurement: Assessed via high-performance liquid chromatography-tandem mass spectrometry (Esoterix/LabCorp), certified by the CDC-HoSt Program.
Statistical Analysis: Linear mixed-effects regression models were employed to analyze repeated measurements within individuals. This approach controlled for unbalanced and heterogeneous data, allowing for the assessment of independent associations between testosterone and inflammatory markers while adjusting for age and comorbidities.

Key Results

Demographics: The median age of participants was 70 years (IQR = 18), with an average follow-up of 6.7 ± 3.2 years. Median baseline levels were 1.0 mg/dL for CRP, 3.6 pg/mL for IL-6, and 446 ng/dL for TT.
Testosterone and CRP:
- Univariable Analysis: Increasing TT and HDL were associated with decreased CRP. High BMI, Diabetes, and increased triglycerides were associated with increased CRP. Age showed no association with CRP.
- Multivariable Analysis: Increasing endogenous TT levels were independently associated with a decline in CRP levels ( $p = 0.018$ ). Increased BMI remained a significant predictor of higher CRP ( $p = 0.001$ ). Age, CHF, Diabetes, HDL, and triglycerides were not significant predictors of CRP in the multivariable model.
Testosterone and IL-6:
- Multivariable Analysis: Increasing TT levels were independently associated with lower IL-6 levels ( $p = 0.03$ ). Increased HDL was also associated with lower IL-6 ( $p = 0.020$ ). Conversely, increased age was independently associated with higher IL-6 levels ( $p < 0.001$ ). BMI, CHF, diabetes, and triglycerides were not significant predictors of IL-6.

Significance and Claims
The authors conclude that lower levels of serum total testosterone are associated with an increase in CRP and IL-6 in older men over time, independent of age and major chronic inflammatory diseases.

Novelty: Unlike prior cross-sectional investigations, this study provides longitudinal evidence that the inverse relationship between testosterone and inflammation persists within individuals as they age and accumulate comorbidities. The findings suggest that testosterone decline is not solely a passive consequence of aging or chronic disease but is linked to inflammatory processes.
Clinical Implication: The study proposes that total testosterone may serve as a biomarker for systemic inflammation in aging men. The authors suggest that profiling testosterone levels could offer additional insight into inflammatory risk beyond traditional clinical factors.
Future Directions: The paper calls for further investigation into the mechanistic relationship between androgen status and inflammation, specifically whether addressing testosterone deficiency could influence inflammation and downstream chronic disease risk.

Limitations Acknowledged by the Authors
The authors note that the study demonstrates association rather than causation. Limitations include the inability to include certain biomarkers (e.g., SHBG, TNF-alpha) due to data availability in the BLSA protocol, potential residual confounding from unmeasured lifestyle factors (smoking, diet, physical activity), and a study population that was predominantly white and middle-class, limiting generalizability. Additionally, the study did not account for disease severity or concurrent treatment status for comorbidities.