The portions of adult human physiology that age most rapidly are the ovaries and the thymus/ Both are targets of interest for the research community. They represent not only ways to learn more about aging, by comparing these rapidly aging organs with those that sustain function further into old age, but also an easier point of intervention, in which rejuvenating or age-slowing therapies could in principle be deployed in mid-life or earlier and still produce benefits.
In today’s open access paper, the authors discuss what is known of the role of cellular senescence in ovarian aging. The important question at the end of the day is whether senolytic drugs that selectively clear senescent cells are likely to produce an impact on fertility and menopause. As the researchers note, little has been published on this topic, and one might suspect that this is because the sort of unpublished exploratory work that happens behind the scenes has so far produced results that were not that promising.
On the one hand we might think, based on the evidence to date, that senescent cells start to accumulate in earnest throughout the body only after ovarian aging is well advanced, and thus do not play a major role in the ovaries. This point can certainly be argued, and the researchers here do so, pointing out lines of evidence that suggest that senescence occurs in the ovaries somewhat in advance of the rest of the body. On the other hand, even if senescent cells are harming the ovaries earlier in life than is the case in other organs, we might think that once the damage is done, there is no regenerative process that operates to restore lost ovarian function. Thus clearance of senescent cells after losses have occurred will do little to reverse ovarian aging. But this is all very much hand-waving and theorizing. More research is needed.
The role of cellular senescence in ovarian aging
The aging process differs from tissue to tissue. The primary feature of aging in most tissues is the accumulation of senescent cells. Cellular senescence is a state of permanent cell cycle arrest triggered in response to numerous stressors, aiming to inhibit the proliferation of aged and/or damaged cells. Despite this, senescent cells are metabolically active and secrete inflammatory cytokines, chemokines, growth factors, and matrix metalloproteinases. These factors are commonly referred to as the senescence-associated secretory phenotype (SASP). The SASP allows senescent cells to modulate pathways in neighboring and distant cells and tissues and has been widely used as a marker of cellular senescence. The SASP recruits immune cells, thereby creating a pro-inflammatory microenvironment in injured or aging tissues. The chronic accumulation of senescent cells with advancing age results in detrimental effects on health, increasing age-related diseases.
There is limited data on senescence cell accumulation and their function in the ovary. Although there is no well-defined panel of biomarkers for cellular senescence, some have been widely used in the ovary, including markers of pro-inflammatory stress, double-strand DNA breaks, and lipofuscin. Corresponding with reduced ovarian function, there is also a significant increase in markers related to senescence in the ovaries of mice between 3 and 12 months of age, along with the accumulation of lipofuscin aggregates. Similar accumulation of senescent cells in other organs is observed much later in life, around 18-20 months of age. Additionally, the ovarian transcriptomic profile indicates a positive regulation of genes related to pro-inflammatory stress and cell cycle inhibition, while genes involved in cell cycle progression were negatively regulated, which is characteristic of senescent cells. Increased SA-β-Gal and p21 levels were detected in the ovarian stroma of mice at 8-10 months of age, indicating senescent cell accumulation. Thus markers of senescence in ovarian tissue can be observed before 12 months of age in mice. Similar observations were made in human tissue. Expression of p21 was elevated in ovarian of middle-aged women (older than 37 years) compared to young controls (younger than 33 years). Other senescence and fibrosis related genes were also up-regulated in stromal cells of middle aged compared to younger women.
There are few studies using senolytics in young reproductive age mice available in the literature, which suggest that the compounds currently used have few beneficial systemic benefits at this age window. Even fewer studies evaluated the effects of senolytics in the ovary. These suggest that senolytics may prevent ovarian reserve loss, but cannot reverse the damage to the ovarian reserve after senescence is established. The activation of primordial follicles is an irreversible process, which means that the damage promoted by senescent cells in the ovarian reserve would not be able to be reverted by senolytics. This may indicate the direction for future studies, focusing on preventing accumulation of senescent cells in the ovaries in order to prevent declines in fertility. Additionally, the inflammation generated by senescent cells through the SASP itself can contribute to irreversible follicular activation. Therefore, it is possible that other senolytic compounds with greater efficacy in the ovary need to be tested. Compounds with senomorphic activity, i.e. able to decrease SASP secretion, may be considered to prevent the negative pro-inflammatory environment generated by senescent cells in the ovary. Therefore, the path to validating the use of senotherapies in female reproductive aging is still open. A better understanding of ovarian senescence biomarkers and the role of senescent cells on female fertility is still necessary in order to define how to promote targeted elimination of these cells without negative impact on other organs in young females.
