The androgen clock is rewriting the science of aging, offering a precise way to measure hormone exposure and its profound effects on health, longevity, and biology.
Study: The androgen clock is an epigenetic predictor of long-term male hormone exposure. Image Credit: ivector / Shutterstock
In a recent study published in the journal Proceedings of the National Academy of Sciences, scientists investigated an innovative epigenetic marker called the "androgen clock," which accurately measures long-term exposure to male hormones. By focusing on deoxyribonucleic acid (DNA) methylation changes, they examined how hormonal levels influence this clock in both males and females and discussed its potential applications in aging research, medicine, and agriculture.
Epigenetic markers of aging
Aging involves gradual biological decline, marked by molecular changes such as DNA methylation alterations. DNA methylation is a key epigenetic mechanism and plays a critical role in regulating gene expression, with specific sites in the genome exhibiting consistent methylation changes over time.
This predictable behavior has led to the development of epigenetic clocks that estimate biological and chronological age. While these clocks provide insights into aging, their underlying mechanisms remain poorly understood. Prior research indicates a link between sex hormones and aging based on the observation that hormonal manipulation, such as gonadectomy, impacts lifespan and epigenetic aging rates.
Furthermore, emerging evidence has also suggested the development of sex-specific methylation patterns, particularly in androgen-sensitive regions. However, the precise role of androgens in driving these changes has not been thoroughly explored.
The current study
The researchers utilized advanced DNA methylation techniques to develop and test the androgen clock as an epigenetic tool for measuring cumulative androgen exposure in mammals. They collected tissue samples from sheep and mice under varied androgenic conditions. For sheep samples, the DNA was extracted from ear tissue of intact and castrated males and females and muscle tissue sourced from local butcheries and farms.
The study employed high-throughput methods such as barcoded bisulfite amplicon sequencing to measure methylation at androgen-sensitive cytosine-phosphate-guanine (CpG) sites, specifically targeting the methylation site cg21524116. This site was selected for its significant predictive capacity in prior studies.
The researchers also conducted androgen manipulation experiments in mice. These included genetic models such as androgen receptor knockout mice and chronic androgen exposure in females using dihydrotestosterone (DHT) implants. Subsequently, they analyzed DNA from tissues such as the tail, muscle, and kidney for methylation changes. Notably, tissues with high androgen receptor expression displayed significant methylation alterations, while those with minimal receptor expression, such as liver tissue, did not.
The study also validated the findings across platforms, using both sequencing and custom methylation arrays. Additionally, to ensure the accuracy of the findings, the researchers incorporated rigorous statistical modeling and leave-one-out cross-validation methods to evaluate the performance of the androgen clock in predicting androgen exposure. The model demonstrated remarkable predictive accuracy, with median absolute errors of 4.3 months in sheep and 1.4 months in mice, comparable to leading epigenetic age estimators.
Key findings
The study demonstrated that the androgen clock’s ticking depends on the presence of both androgens and functional androgen receptors, highlighting its potential for precise hormonal exposure assessments. The results indicated that the androgen clock serves as an accurate predictor of long-term androgen exposure in mammals.
In sheep, methylation at specific androgen-sensitive sites was strongly correlated with androgen exposure, with castration halting the clock entirely and supplementation accelerating it in females. In mice, chronic DHT treatment induced significant demethylation in tissues with high androgen receptor expression, including muscle, tail, and kidney, but not in the liver, where the receptor expression is minimal.
Furthermore, the androgen receptor knockout mice showed no methylation changes even when exposed to androgens, which confirmed the receptor's essential role in clock activation. Prenatal androgen exposure, however, did not alter methylation in adult mice, indicating that the sensitivity of the clock is limited to specific androgen levels and exposure contexts. This finding underscores the dose-dependent and tissue-specific nature of the androgen clock’s function.
The researchers also validated the clock's ability to predict androgen exposure across different tissue types and platforms and demonstrated accuracy levels comparable to existing epigenetic age estimators. Moreover, the cross-validation revealed minimal error margins. This cross-platform reliability is significant for potential applications in diverse biological systems. Importantly, the clock could differentiate between males and females and identify excessive androgen exposure beyond natural levels. These findings suggested that the androgen clock was an epigenetic marker that could be used to monitor androgen-related conditions, detect hormone abuse, and advance aging research.
Applications and limitations
The androgen clock offers exciting possibilities for medicine, agriculture, and aging research. For example, in agriculture, it could help assess meat quality by identifying androgen exposure in livestock and detecting steroid abuse. This may include distinguishing between high-quality meat and undesirable "ram taint," characterized by a strong odor and flavor in meat from intact male sheep. Similarly, in medicine, the clock could be applied to detect conditions such as polycystic ovary syndrome (PCOS), congenital adrenal hyperplasia, and anabolic steroid abuse in athletes. However, its current sensitivity to lower androgen levels, such as those associated with PCOS, remains limited and requires further refinement for broader clinical applications.
Despite its potential, the study acknowledged several limitations. The androgen clock’s performance across species, including humans, remains unexplored. Additionally, the relationship between androgen dose, exposure duration, and methylation changes is not yet fully understood. Further research is needed to address these gaps and optimize the clock for diagnostic use.
Conclusions
The study established that the androgen clock was a novel epigenetic tool capable of measuring androgen exposure with remarkable precision. The researchers also highlighted its potential applications in medicine, agriculture, and aging science by uncovering its reliance on androgen presence and receptor activity. They believe that the androgen clock offers a unique opportunity to explore the interplay between hormones and epigenetics, and can contribute valuable insights into aging mechanisms and hormonal regulation. Its unparalleled capacity for manipulation through androgen administration or receptor modulation provides a powerful experimental model for understanding epigenetic aging.
Journal reference:
- Sugrue, V. J., Prescott, M., Glendining, K. A., Bond, D. M., Horvath, S., Anderson, G. M., Garratt, M., Campbell, R. E., & Hore, T. A. (2025). The androgen clock is an epigenetic predictor of long-term male hormone exposure. Proceedings of the National Academy of Sciences, 122(3), e2420087121. DOI:10.1073/pnas.2420087121, https://www.pnas.org/doi/10.1073/pnas.2420087121