Mathematical modelling of ageing acceleration of the human follicle due to oxidative stress and other factors

Abstract

There is a gradual telomere shortening due to the inability of the replication machinery to copy the very ends of chromosomes. Additionally, other factors such as high levels of oxidation (free radicals or reactive oxygen species (ROS)), e.g. due to cumulated stress, inflammation or tobacco smoke, accelerate telomere shortening. In humans, the average telomere length is about 10–15 kb at birth and telomeres shorten at a pace of 70 bp per year. However, when cells are exposed to ROS, telomere attrition happens at a faster pace, generating a wide variety of telomere size distribution in different length percentiles, which are different to what is expected just by age. In this work, the generational age of a cell is associated with its telomere length (TL), from certain maximum to the minimal TL that allows replication. In order to study the accumulation of aged granulosa cells in human follicles, from preantral to preovulatory size, a mathematical model is proposed, regarding different degrees of accelerated telomere shortening, which reflect the action of ROS in addition to the telomere shortening that happens after cell division. In cases of cells with TL shorter than cells with average TL, with low telomerase activity and accelerated telomere shortening, the mathematical model predicts an aged outcome in preovulatory follicles. The model provides a plausible explanation for what has been observed in oocytes from older women, which have been exposed to ROS for a longer period of time and have bad outcomes after in vitro fertilization.

Individual Differences in Relative Telomere Length in Mentally Healthy Subjects: The Effect of TERT Gene Polymorphism and Urban Residency

“…The influence of age on telomere length has been discussed for a long time [ 2 , 18 ]. It is known that telomere length is diminished in normal cells with age until telomeres become too short to perform their role and preserve their ability to divide.…”

“…Telomeres (telomeric repeats) are heterochromatin structures located at the ends of chromosomes, necessary to maintain their integrity and stability [ 1 ]. It is known that telomeres consist of 5'-TTAGGG-3' tandem repeats with a length of 10–15 kb in humans, which inevitably decrease at a rate of 50 to 200 bp during each replication cycle owing to the so-called “terminal underreplication problem” and the action of specific nucleases [ 2 ]. Nevertheless, this problem is solved in cells by a compensating effect of telomerase—ribonucleic reverse transcriptase.…”

“…It should be noted that men, compared to women, and individuals of European origin, compared to individuals of other ethnicity, are characterized by shorter telomere length [ 19 ]. The accumulation of age-dependent reactive oxygen species and free radicals in the cells, which is associated with the effects of stress factors, inflammatory reactions, and unhealthy lifestyle (smoking, excessive alcohol intake, low physical activity), results in shortening of telomeres [ 2 , 18 ]. Considering a possible effect of the aforementioned environmental factors on the emotional state [ 20 , 21 ] and cellular aging of the body, the study of a large array of sociodemographic characteristics in the context of their effect on telomere length is of relevance.…”

Ovarian Telomerase and Female Fertility

“…Mathematical models were used to predict infertility with aging according to TL and TA in granulosa cells. Predicted infertility was associated with either low levels of telomerase activity and short telomeres in GCs or with cumulative exposure to oxidative stress [101,102]. The conclusion of these models is the important role of sustained ovarian TA to preserve fertility in aging.…”