The ovary, along with the thymus, is one of the earliest organs to age into dysfunction. Studying the basis of ovarian aging may tell us something about aging more generally, an attractive prospect for researchers. For those who develop therapies, ovarian dysfunction may provide a somewhat easier point of intervention when assessing potential rejuvenation therapies that target underlying causes of aging, as the patients will be in better overall health, with fewer complicating comorbidities.
While those causes of aging are well catalogued at the present time, it remains challenging to understand their relative importance to any given age-related outcome. The web of cause, consequence, and interaction that lies between fundamental causes of aging and age-related conditions is very complex and little understood. The best way to find out whether a given cause of aging is important to give condition is to develop and test potential rejuvenation therapies that selectively target only that cause of aging. Here, for example, that would mean therapies targeting senescent cells, and assessing their effects on ovarian function.
Exploration of the mechanism and therapy of ovarian aging by targeting cellular senescence
Ovarian aging refers to the progressive decline in ovarian function with age, characterized by reduced follicle numbers, decreased quality of oocytes, changes of menstrual cycle, decreased fertility, and ultimately menopause. The decrease in estrogen levels due to ovarian aging can cause a series of clinical symptoms, such as vasomotor symptoms, osteoporosis, urogenital symptoms, neuropsychiatric dysfunction, cardiovascular diseases, endocrine diseases, and others. This aligns with the previous perspective that ovarian aging acts as a sensor for the overall aging of the female body. In humans, ovarian function typically begins to decline around 35 years of age, progressively deteriorates after 37, and ultimately ceases reproductive function around age 50. Notably, a growing number of women have been opting to delay childbearing to later stages of life, often influenced by social factors. Consequently, the diminishing fertility attributed to ovarian aging poses a significant challenge in the field of reproductive medicine, as no treatment modality has been proven to delay ovarian aging.
Cellular senescence refers to an irreversible cell cycle arrest caused by multiple stress responses, including accumulation of advanced glycation end products, oxidative stress, mitochondrial dysfunction, DNA damage, telomere shortening, and chronic inflammation. Cellular senescence exists throughout the life of multicellular organisms from development to death, and it also ubiquitously exists in both normal and senescent organs. Under physiological conditions, cellular senescence promotes organ differentiation and development by removing unwanted cells. With the accumulation of time or the degree of aging, cellular senescence further promotes organ aging through a variety of pathways, such as reducing the number of cells, decreasing cell quality, reducing metabolic level, accumulating metabolic waste, producing reactive oxygen species (ROS), thus damaging the organ and weakening the physiological function of the organ. Recently, cellular senescence was hypothesized to contribute to the age-related decline in ovarian function. Nevertheless, there remains a lack of a comprehensive theoretical framework concerning the role of cellular senescence in ovarian aging. Therefore, elucidating the role that cellular senescence may play in ovarian aging could lead to the development of novel therapies for reversing ovarian aging.
This review explores how cellular senescence may contribute to ovarian aging and reproductive failure. Additionally, we discuss the factors that cause ovarian cellular senescence, including the accumulation of advanced glycation end products, oxidative stress, mitochondrial dysfunction, DNA damage, telomere shortening, and exposure to chemotherapy. Furthermore, we discuss senescence in six distinct cell types, including oocytes, granulosa cells, ovarian theca cells, immune cells, ovarian surface epithelium, and ovarian endothelial cells, inside the ovary and explore their contribution to the accelerated ovarian aging. Lastly, we describe potential senotherapeutics for the treatment of ovarian aging and offer novel strategies for ovarian longevity.
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