Men over 45 have 31% more genetic mutations than those under 30

Historically we have heard that only women have to worry about their biological clock when it comes to having children, meaning that the sooner they get pregnant, the better. The classic biological argument was based on the finite ovarian reserve and the cellular aging of the oocytes. But the evidence has been warning for years that the clock is ticking for men.

A new study presented by the IVI Foundation during the 42nd Annual Meeting of the European Society of Human Reproduction and Embryology has put a figure specific to male reproductive aging. This indicates that men over 45 years of age have 31% more mutations in their sperm compared to men under 30.

A cell factory. Unlike oocytes, which are formed during female embryonic development and remain in a state of latency until ovulationsperm are produced continuously from puberty. This implies that the stem cells from which the sperm come are constantly dividing, causing even a seventy-year-old man to continue producing sperm.

In cell biology, each division is an opportunity to make a copying error in DNA. And although cellular repair mechanisms are amazingly efficient, they are not perfect. Over the decades, errors accumulate and these genetic alterations that were not present in the parents but appear in the offspring are known as de novo mutations.

They warn you. Science has been documenting this phenomenon for more than a decade and we have an example in an article published in Nature in 2012 that already established that approximately 80% of mutations of note They come from paternal genetics. Furthermore, the researchers estimated that the offspring’s genome acquires between 1 and 2 additional de novo mutations for each year that the father’s age increases. Now the new study confirms these data.

Selection of sperm. The 31% increase in mutations is not solely due to a passive failure in DNA repair due to the simple wear and tear of age. This is where a fascinating, microscopic evolutionary mechanism operating in the testes called “selfish spermatogonial selection” comes in.

In this case, some of the mutations that occur in sperm stem cells are not neutral, but rather confer a proliferative advantage to the cell itself. Specific mutations, such as those that occur in the gene FGFR3 or in the RAS signaling pathway, cause these mutated stem cells to divide faster and survive better than neighboring healthy cells. Over time, these mutated “clones” end up dominating large areas of the testicle, producing an increasing proportion of sperm carrying the mutation.

Relative risk. The mutations de novo associated with advanced paternal age are strongly linked to the appearance of rare diseases of monogenic origin in offspring, such as achondroplasia, Apert syndrome or Costello syndrome, in addition to showing complex genetic correlations with neurodevelopmental disorders.

However, the absolute risk of a father over 45 years of age conceiving a child with one of these severe pathologies remains statistically very low, specifically less than 0.5% in those over forty years of age. All of this means that the mutational increase is undeniable at the genomic level, but the probability that these mutations directly impact a critical gene and result in a congenital syndrome remains rare.

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