Almost 12 years ago, an evolutionary theory based on intergenerational telomere erosion was introduced [8] and was widely covered by the press [11, 12]. In 2011, based on published data on human telomere length inheritance, I refined my theoretical framework and located the source of human intergenerational telomere erosion in the female germline [6, 7, 10]. According to this model, telomeres in the testes of elderly males are longer than those in young males because the seniors are members of a previous generation (=birth-cohort effect) and therefore skipped, on average, one female-based intergenerational telomere loss. In 2014, I further developed the model of telomere-driven macroevolution and presented a complete biological framework for the old European model of saltatory evolution of nonadaptive characters [6].
In agreement with this theoretical model, a high-profile study, published in the August issue of Aging Cell in 2015, finally confirmed the long-awaited birth-cohort effect on leukocyte mean telomere length in humans [9, 10]. The authors found clear evidence that newborns of previous generations must have had longer telomeres, but could not explain the phenomenon. They just speculated that intergenerational telomere erosion could be the consequence of some kind of environmental factor, but it must be a recent phenomenon. Interestingly enough, Holohan et al. found evidence of intergenerational telomere erosion in all the human birth-cohorts they looked at, back to 1920 [9]. Thus, I think it is time that we face the unthinkable, namely that biological evolution is not only about survival of the fittest, but every species becomes unfit after some time, due to an intrinsic cause [6–8].
As already introduced in 2011 and 2014, I propose that the paradoxical findings of longer telomeres in the testes of very old men are the result of transgenerational telomere erosion in the female germline, causing a significant birth-cohort effect in sperm telomere length [6, 7]. Replicative telomere erosion is thought to take place during embryogenesis, when the female primordial germ cells multiply, according to the production-line hypothesis [13]. Starting at puberty, there is a hierarchy with long-telomered oocytes ovulating first [14, 15]. This contrasts with the constantly high telomerase levels in the testes, which ensure lifelong telomere length stability in male germ cells per generation [6, 7]. For a detailed explanation and figure of the proposed patterns of telomere dynamics in the germline of both sexes I refer readers to my previous publications [6, 7, 10]. In the following, I just want to highlight two important observations/study results, on which I initially based my theoretical model and explain them in more detail.
The majority of oocytes of women aged 40 years and older may be aneuploid [16]; this is by far the highest aneuploidy rate of all human cell types during aging [17], with the exception of cancerous cells. Critically short telomeres are known to result in telomere associations/fusions and subsequently in numerical and/or structural chromosomal aberrations in dividing eukaryotic cells (=aneuploidy). Thus, the widely known strong positive correlation between the mother’s age at conception and trisomic pregnancies (e.g. Down’s syndrome) [18] seems to be a clear indication of telomere erosion in the female germline [7], and even more so since the father being of an advanced age does not increase the incidence of chromosomally abnormal offspring, despite lifelong germ cell divisions [18]. Although, David L. Keefe had already introduced the telomere theory of reproductive senescence in women in 2006, he has since insisted on an embryonic telomere reset between generations, neglecting any possible intergenerational telomere loss [19].
Further critical evidence, on which I based my model, came from a large human study spanning three healthy generations, published in PNAS [20]. Eisenberg and colleagues found that the positive telomere effect of older fathers (age at conception) is cumulative between generations. In the paternal line, older grandfathers (advanced age when the father was born) contributed as much to longer leukocyte telomeres in grandchildren as older fathers did. However, it was found that a grandfather’s positive effect on grandchildren’s telomere length diminished in the maternal line, which clearly supports my concept of female-based transgenerational telomere erosion in the human germline [6, 7]. Accordingly, in this multigenerational study grandfathers’ chromosomes underwent female-based telomere erosion in the maternal line only, because in the paternal line they do not go through female germ cell divisions. Therefore, the positive age effect on telomere length could only be stably transmitted to the grandchildren of the paternal line [6].