Why is the human ovary aging faster than other organs?

At essentially all scientific conferences focusing on human fertility, the impact of age is presented as the major cause of infertility in developed countries populations. It sounds like a plague, as if infertility was something abnormal in adult women. Then, when you look at the evidence, it becomes quite clear that the rate of infertility is tightly associated with the rate of aneuploidy (an abnormal number of chromosomes in the embryo) and the fact that this rate increases exponentially (instead of linearly) after the age of 35 (Franasiak et al. 2014). If fertility is still at an acceptable rate at 35, it is almost an exception after 40. Therefore, within a five-year period the ovary goes from functional to nonfunctional for making babies but remains essentially the same for its capacity to generate hormones and it continues to cycle until menopause one or two decades later. The scientific question that comes to mind is why?

Although chromosome segregation is a very complex and delicate process which happens close to the ovulation time once a month, the same process occurs more than 7000 times a minute during meiotic division in spermatozoa and carries on as long at the male lives (Donate et al. 2016). This same chromosome separation process has existed in yeast for 2 billion years and happens in all animal species both in males and females. The only species where it fails early is in humans and only in females. In most mammals, a high rate of aneuploidy is observed when hormones are used to stimulate the ovary and such phenomenon has been observed at all ages (mouse (Roberts et al. 2005) sheep (Veiga-Lopez et al. 2008) pig (Hazeleger et al. 2000) and humans (Baart et al. 2007). This phenomenon seems logical as nature (evolution) found a way to reduce the survival potential of oocytes when the number generated in a cycle largely exceeds the uterine capacity to bear such a number (Sirard 2011). If that was the case, only oocytes from superovulation would be affected; however, in women over 35, it seems to affect most oocytes regardless of the stimulation procedure (Franasiak et al. 2014).

The evolutionary perspective then suggests the hypothesis that the human ovary is made (has been selected) to lose the capacity to make babies after 40 (Sirard 2011). If you think about it, humans have the longest generation interval of all species. It takes approximately 12 years for a human infant to reach sexual maturity while it takes 6 months in pigs where birth and puberty weights are similar in proportion. In bovine, with a gestation time of 9 months, the offspring becomes puber at 12 months, 10 times faster than us. Generation interval is important because it defines the number of months/years required for the next generation to start reproducing and passing on the genes. In humans, it would be theoretically possible to have a baby every year from 12 onward, resulting in 23 babies born by the age of 35. Of course, breast feeding and other factors reduce that number to 10–12 which is already a major challenge knowing that the probability of survival is directly dependent on parental care in humans. To increase the chance of the already born infant to survive, a reduced maternity rate might be important also considering the birthing risk for the mother’s own survival. The risk of birthing complications increases with age for both the mother and the babies in humans (Leader et al. 2018). This is not observed in most mammals which can have babies until the end of their lifetime, sometime even longer in females than in males. If the mother dies, the probability for the remaining children to survive is reduced. Such phenomenon has only been observed in killer whales where sons stay with their mothers who stop reproducing to care for them to maximize the transmission of their genes to the next generation (Croft et al. 2017). Like humans, female killer whales stop giving birth at about 40 but can live into their 90s. When the mother whale dies, the survival of her son decreases (Croft et al. 2017).

This perspective is also supported by experts in evolution that recognize the value of having not only the mother but also the grandmother being present to share the burden of raising kids (Lumsden and Sassarini 2019). This is called the grandmother hypothesis and represents a rare exception where animals that are not reproducing anymore increase the survival of their next generation’s offspring by devoting energy to feed and protect them.

If it makes sense to reduce fertility past 35, why then not just program menopause at that age? Because that would be catastrophic to the maintenance of good health in aging women as ovarian hormones produced during the regular cycle of the ovary are very important for bone and cardiometabolic functions. So, infertility is beneficial but not menopause for the last decades of women’s lives. This becomes the logical explanation for the increase in aneuploidy-induced infertility beginning as the body clock hits 30 and the level of growth hormone decreases. The benefit of menopause, which occurs almost only in humans, is much harder to justify, as it reduces lifespan even if women are known to live longer than men. The timing of natural menopause is a clinically important indicator of longevity and risk of morbidity and mortality (Gold 2011).

A possible explanation could be that menopause may decrease sexual activity, allowing the male partner to continue reproducing with other cycling females. But this becomes highly speculative since monogamy may not have necessarily prevailed in the millenniums when humans initially evolved.

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