In Europe we are having children later and later: the average age of mothers at the birth of their first child has reached 29.9 years in the EU, 31.9 in Italy. The reasons are cultural and economic. But while on the one hand freely choosing whether and when to start a family is certainly an achievement, for many women postponing the arrival of children to a more advanced stage of life means clashing with the inflexible laws of biology: becoming pregnant becomes increasingly complicated and risky as the years pass, and then becomes impossible (unless resorting to Pma) with the arrival of menopause.
The woman who became a mother at 57 years old
For this reason, many researches are trying to find a safe way to prolong female fertility and preserve the ovarian reserve beyond its natural time limit. This is what researchers at Huazhong University in China hope to do in a study published in Nature Aging have just described a molecular mechanism capable of slowing down the aging of the ovaries, and consequently delaying the onset of menopause.
The mechanism
The aging of the female reproductive system is characterized by a process of progressive fibrosis that alters the architecture of the ovaries. As we age, the extracellular matrix surrounding the follicles tends to accumulate collagen, becoming increasingly rigid and creating an unfavorable environment for the development of oocytes. This process is believed to be one of the main causes of the decline in female fertility that occurs with age, and the onset of menopause.
To understand which molecular signals activate this transformation, the researchers analyzed samples of ovarian tissue taken for medical reasons from pre-menopausal women between 18 and 52 years of age. Through RNA sequencing and proteomic analysis they identified the molecules responsible for the activation of fibroblasts, the cells that produce the extracellular matrix and induce its progressive stiffening.
The data highlighted that the overexpression of a cytokine known as interleukin 11 and its receptor, Il11ra1, represents the key element in the stiffening process. The secretion of this cytokine, in fact, increases steadily with age in mice, rats and the human species, but also occurs in the presence of pathological conditions such as endometriosis, polycystic ovary syndrome and following chemotherapy treatments.
The experiment
Having identified the possible culprit, the researchers then tested its functioning in the laboratory, with a series of experiments on mice, in which they inhibited the activity of interleukin 11 in the animals with two different approaches: first through direct genetic modification to deactivate the corresponding gene, then through the administration of nanoparticles loaded with silencing RNA.
The interventions produced a clear decrease in collagen deposits and a quantifiable reduction in ovarian stiffness. Functionally, aged female mice treated with the nanoparticles showed better preserved follicular reserve and higher blood levels of estrogen and other indicators of ovarian function, and produced more offspring per pregnancy than untreated animals of the same age.
From prevention to clinic
The results strengthen the hypothesis that the ovarian matrix does not constitute a simple inert structural support, but is rather a dynamic microenvironment whose state conditions the fate of the follicles. The possibility of acting on interleukin 11 therefore opens up new intervention perspectives for various clinical conditions. In the oncology setting, targeted therapy could be used before or during the administration of cytotoxic drugs to prevent therapy-induced premature ovarian failure.
Controlling the fibrotic response could offer new options for patients affected by polycystic ovary syndrome or severe endometriosis. And obviously, in the future it could lead to the development of strategies with which to prevent the aging of the ovaries and preserve female fertility even at an older age. The authors of the study underline, however, that the transition from animal testing to human application will require further investigations to verify the long-term safety of systemic inhibition of the protein and its actual clinical efficacy.