Sperm epigenetic clock sheds light on fertility timetable

A new technique to measure the biological age of male sperm has the potential to predict the success and time it takes to become pregnant, according to new research.

A new paper – Sperm epigenetic clock associates with pregnancy outcomes in the general population – published in the journal Human Reproduction, has found that sperm epigenetic aging clocks may act as a novel biomarker to predict time to pregnancy. The findings also underscore the importance of male fertility in reproductive success [1].

Longevity.Technology: We have written much about how individual organs, as well as individuals, age at different rates and therefore how important determining biological, rather than chronological age is. Now it would seem that sperm, which have a chronological age of 74 days in the testes and just 5 days once released in search of their destiny, have a biological age that can identified.

Understanding – and possibly manipulating – the biological age of sperm could have implications for improving fertility. As we strive for longevity – extending not only lifespan, but healthspan – there are wider ramifications to consider. Not only does society need to think about retirement options, pensions and working ages, it needs to consider the size of the population. Across the developed world, fertility rates have consistently been declining to below replacement level, so maintaining and improving fertility is a key concern, especially given that there is now widespread infertility and the need for assisted reproduction due to poor semen quality and/or oocyte failure. Add in reproductive health problems that are partially linked to increasing human exposures to chemicals originating directly or indirectly from fossil fuels [2], and the need to understand the rate of and factors affecting biological aging in sperm is paramount.

“Chronological age is a significant determinant of reproductive capacity and success among couples attempting pregnancy, but chronological age does not encapsulate the cumulative genetic and external – environmental conditions – factors, and thus it serves as a proxy measure of the ‘true’ biological age of cells,” said J Richard Pilsner, PhD, lead author of the study.

“Semen quality outcomes utilizing World Health Organization guidelines have been used to assess male infertility for decades, but they remain poor predictors of reproductive outcomes. Thus, the ability to capture the biological age of sperm may provide a novel platform to better assess the male contribution to reproductive success, especially among infertile couples [3].”

As we age, our epigenome – the chemical tags and markers applied to our DNA that revise, update or alter its instructions – changes too; these age-associated methylation alterations take place in the sperm as well [4] and studies investigating sperm epigenetics have found distinct and consistent alterations to the sperm epigenome associated with aging have the potential to impact offspring [5].

This new study found a 17% lower cumulative probability of pregnancy after 12 months for couples with male partners in older compared with younger sperm epigenetic aging categories. The study involved 379 male partners of couples who discontinued the use of contraception for the purpose of becoming pregnant.

The researchers at Wayne State University School of Medicine also found a higher epigenetic aging of sperm in men who smoked, which fits with existing research that demonstrates that cigarette smoke induces epigenetic alterations [6].

The results, Dr Pilsner said, indicate that higher sperm epigenetic aging is associated with a longer time to become pregnant in couples not assisted by fertility treatment, and among couples that achieved pregnancy, with shorter gestation.

The strong association between sperm epigenetic aging and pregnancy probability and its slowing or reversal through lifestyle choices and/or pharmacological interventions warrants further investigation. In addition, because older fathers have an increased risk of children with adverse neurological outcomes, it is important to understand the potential relation of sperm epigenetic aging on children’s health and development.

“There is a critical need for new measures of male fecundity for assessing overall reproductive success among couples in the general population,” Dr Pilsner said. “These data show that our sperm epigenetic clocks may fulfill this need as a novel biomarker that predicts pregnancy success among couples not seeking fertility treatment.

“While chronological age of both partners remains a significant predictor of reproductive success, our clocks likely recapitulate both external and internal factors that drive the biological aging of sperm. Such a summary measure of sperm biological age is of clinical importance, as it allows couples in the general population to realize their probability of achieving pregnancy during natural intercourse, thereby informing and expediting potential infertility treatment decisions [3].”

Dr Pilsner advised that because those studied were largely Caucasian, greater and more diverse cohorts are necessary to confirm the association between sperm epigenetic aging and couple pregnancy success in other races and ethnicities.

READ MORE: Unlocking ovarian aging could prolong fertility and delay menopause

[1] https://academic.oup.com/humrep/advance-article-abstract/doi/10.1093/humrep/deac084/6583111
[2] https://www.nature.com/articles/s41574-021-00598-8
[3] https://today.wayne.edu/medicine/news/2022/05/13/new-measure-of-sperm-age-may-be-predictor-of-pregnancy-success-47890
[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087840
[5] https://pubmed.ncbi.nlm.nih.gov/23809503/
[6] https://epigeneticsandchromatin.biomedcentral.com/articles/10.1186/s13072-019-0311-8

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