Slowing down the clock on ovarian aging-does the ovary hold the secret to the fountain of youth?

In the past century, the human Lifespan has doubled. However, this is not equivalent to Healthspan which refers to the number of years spent healthy and free from disease. Women have an additional level of complexity on the path to optimal healthspan where health resilience dramatically decreases following menopause and this is due to their ovaries aging by midlife. It still remains elusive on why and how the ovaries in women, albeit their distinct and vital reproductive functions, start to age before any other organs. Following menopause, women are at increased risks of age-associated chronic diseases such as cardiometabolic disease, osteoporosis, sarcopenia, frailty, and neurocognitive decline. By preserving reproductive longevity through targeting the ovary as the organ to rejuvenate in women, optimal healthspan could be obtained in women. Interestingly, population studies have shown that women who conceive naturally and give birth at advanced reproductive ages are demonstrated to have superior postmenopausal longevity. Correspondingly, men Lived longer with a sister reproducing after 45 years of age in natural fertility conditions, suggesting that late female fertility and slow somatic aging may be promoted by the same genetic variants. Causal inference analysis showed a link between increased reproductive lifespan (prolonged ovarian lifespan or later age at natural menopause) and a reduction of diseases such as diabetes and osteoporosis. Essentially, fewer ovarian follicles and shorter ovarian lifespan were associated with poorer health later in life. Therefore, innovative ways to understand and target the ovaries in women for gero-protection have the potential to avert aging diseases triggered by the female menopause. Our narrative review aims to integrate existing information from systemic and reproductive aging from preclinical and human studies to devise novel methodologies to avert ovarian aging which could potentially improve the health trajectory in aging women. Similar strategies can be applied to men to achieve healthy longevity in the population. While there are certain things one has little control over, such as genetics and the inevitable reduction of reproductive hormone levels over time, there are modifiable risk factors which can be targeted to preserve reproductive longevity by uniquely targeting the ovary especially in modifying and improving the ovarian microenvironment to ensure survival of the ovarian follicles which determine true reproductive lifespan and healthspan. This can be achieved by modifying diet, sleep patterns, and exercise and limiting toxin exposure to ensure optimal ovarian health, through healthy and functional ovarian follicles, which could bring us a step closer to enhancing women's healthspan and human longevity.