A New Precise Epigenetic Biomarker of Male Aging: The "Androgenic Clock"
The aging process is associated with modifications in DNA methylation across the genome. By determining the methylation levels of specific genomic loci, scientists have developed so-called epigenetic clocks capable of estimating biological age. According to the findings published in Science, a unique DNA site was identified where methylation levels are influenced by the presence of androgens and their receptors, reflecting the biological age exclusively in males. This discovery allows for highly accurate determination of the age of male mice and sheep.
Researchers from scientific institutions in New Zealand and the United Kingdom identified a single site where methylation serves as an accurate indicator of male age in sheep and mice. Project participant Steve Horvath, known for developing state-of-the-art epigenetic clocks, made a significant contribution to this discovery. The new aging biomarker was named the “androgenic clock.”
Aging is determined by a multitude of factors, including biological sex, which plays a crucial role in the process. It is well established that females tend to live longer, and manipulations involving reproductive organs, such as castration, often influence lifespan, highlighting the importance of sex hormones in aging.
Earlier studies by the same authors demonstrated that a set of CpG dinucleotides present in male sheep, mice, and bats undergo demethylation with age. Female individuals maintain high methylation levels at these sites throughout their lives, while castrated males also retain relatively high methylation. These regions are referred to as androgen-sensitive differentially methylated probes (asDMPs).
The study identified an asDMP site where the most significant methylation differences were observed between intact and castrated rams. This site, known as the CpG site cg21524116 in the Muskelin 1 (MKLN1) gene, exhibits decreased methylation with age. To assess methylation levels, researchers employed barcoded bisulfite amplicon sequencing (BBA-seq), enabling precise analysis of a large number of samples.
The researchers tested the method on meat samples purchased from stores, confirming that meat from older rams shows lower methylation levels compared to lamb meat. This finding could aid in verifying the authenticity of products in the market. During testing, one sample showed unusual results, but without complete information, it remains unclear whether this was due to an error.
The researchers established that methylation of the CpG site in DNA effectively predicts the biological age of males, with the inclusion of additional asDMPs reducing accuracy. This underscores the high predictive power of cg21524116, allowing age estimation with precision within a few months.
In experimental settings, female mice were exposed to high levels of androgens, leading to demethylation of cg21524116 in several tissues but not in liver cells. Knockout of androgen receptors in males confirmed the necessity of these receptors for the functioning of the “androgenic clock.”
Thus, the “androgenic clock” has become a new tool in aging research. It provides high accuracy in measuring biological age under the influence of androgens, opening opportunities for in-depth analysis of aging processes and changes in DNA methylation.
Publication date: 14.01.2025
Source:
Sugrue V.J. et al. The androgen clock is an epigenetic predictor of long-term male hormone exposure. Proc Natl Acad Sci U S A. 2025 Jan 21;122(3):e2420087121. doi: 10.1073/pnas.2420087121. Epub 2025 Jan 13. PMID: 39805019; PMCID: PMC11760496. https://www.pnas.org/doi/10.1073/pnas.2420087121
Researchers from scientific institutions in New Zealand and the United Kingdom identified a single site where methylation serves as an accurate indicator of male age in sheep and mice. Project participant Steve Horvath, known for developing state-of-the-art epigenetic clocks, made a significant contribution to this discovery. The new aging biomarker was named the “androgenic clock.”
Aging is determined by a multitude of factors, including biological sex, which plays a crucial role in the process. It is well established that females tend to live longer, and manipulations involving reproductive organs, such as castration, often influence lifespan, highlighting the importance of sex hormones in aging.
Earlier studies by the same authors demonstrated that a set of CpG dinucleotides present in male sheep, mice, and bats undergo demethylation with age. Female individuals maintain high methylation levels at these sites throughout their lives, while castrated males also retain relatively high methylation. These regions are referred to as androgen-sensitive differentially methylated probes (asDMPs).
The study identified an asDMP site where the most significant methylation differences were observed between intact and castrated rams. This site, known as the CpG site cg21524116 in the Muskelin 1 (MKLN1) gene, exhibits decreased methylation with age. To assess methylation levels, researchers employed barcoded bisulfite amplicon sequencing (BBA-seq), enabling precise analysis of a large number of samples.
The researchers tested the method on meat samples purchased from stores, confirming that meat from older rams shows lower methylation levels compared to lamb meat. This finding could aid in verifying the authenticity of products in the market. During testing, one sample showed unusual results, but without complete information, it remains unclear whether this was due to an error.
The researchers established that methylation of the CpG site in DNA effectively predicts the biological age of males, with the inclusion of additional asDMPs reducing accuracy. This underscores the high predictive power of cg21524116, allowing age estimation with precision within a few months.
In experimental settings, female mice were exposed to high levels of androgens, leading to demethylation of cg21524116 in several tissues but not in liver cells. Knockout of androgen receptors in males confirmed the necessity of these receptors for the functioning of the “androgenic clock.”
Thus, the “androgenic clock” has become a new tool in aging research. It provides high accuracy in measuring biological age under the influence of androgens, opening opportunities for in-depth analysis of aging processes and changes in DNA methylation.
Publication date: 14.01.2025
Source:
Sugrue V.J. et al. The androgen clock is an epigenetic predictor of long-term male hormone exposure. Proc Natl Acad Sci U S A. 2025 Jan 21;122(3):e2420087121. doi: 10.1073/pnas.2420087121. Epub 2025 Jan 13. PMID: 39805019; PMCID: PMC11760496. https://www.pnas.org/doi/10.1073/pnas.2420087121