Geroscience Approaches to Women’s Health in an Aging World

The U.S. population is aging. By 2034, for the first time in U.S. history there will be more people over the age of 65 years old than under the age of 18. This means that 77.0 million people will be over the age of 65 years, half of which are women (United States Census Bureau, 2019) (1). This trend is not unique to the United States, as the global population is also experiencing unprecedented changes in its age structure due to longer life expectancies and decreasing birth rates. In 2020, the United Nations Department of Economic and Social Affairs reported 727 million people worldwide at or over the age of 65 years and projected that in the next 3 decades this age group will increase from 9% of the total population to representing approximately 16.0% in 2050 (2). Focusing on women’s aging processes will be critically important as in most areas of the world women live longer than men, and so comprise the majority of older persons, especially at more advanced ages. As a result, many conditions related to reproductive aging contribute to significant health care costs including menopausal symptoms and its associated comorbidity risks, cancers of the ovaries, uterus, breast, and vulvar region, urinary incontinence, pelvic floor disorders as well as fertility preservation. Indeed, along with shifts in the aging population is the concomitant decrease in birth rates. The decline in U.S. birth rates has occurred gradually over many decades with births below replacement level since 1971 (3) and recently, the Center for Disease Control National Center for Health Statistics reported that the United States hit a record low with another 4% drop in birth rates in 2020 from 2019 (4). These trends, which are occurring worldwide are contributing to lifestyle, socioeconomic influences, and other environmental changes leading women to have children at later ages. For example, in 1970 the average age of women in the United States when their first child was born was 21 years old for mothers and 27 years of age for fathers, but by 2017 these averages rose to 27 and 31 years of age for mothers and fathers, respectively (5,6). Most importantly, between 2017 and 2019, almost half of all births in the United States were from women past the age of 30 years including 3.46% born by mothers over the age of 40 years (6). Thus, a geroscience approach to understanding how the female reproductive system ages is critical in the need to develop treatments that significantly affect a woman’s health, fertility, and quality of life for this growing population of aging women. In women, signs of normal aging in the reproductive system begin in their 30s resulting in gradual declines in fecundity from 30 to 35 years of age followed by more rapid declines by 37 years old. This is much earlier compared to men whose reproductive capabilities decline around 45 years of age, as demonstrated in studies of older men with younger partners showing increased risks of miscarriage and mental health issues in their progeny. The decline in female reproductive organs is associated with declines in hormone levels, reduced ovulation, and dysregulated menstrual cycles. While menopause defined by the cessation of menstruation occurs on average for most women around the age of 51 years old, many women experience early menopause between the ages of 41 and 45 years while about 1% of women experience premature menopause before the age of 40 years. Menopause for which there are no effective treatments significantly affects women’s health lending to increased risk of osteoporosis, cardiovascular disease, stroke, urinary incontinence, and other conditions covered in this issue that significantly affect quality of life. For example, in this issue Labandeira-García and colleagues (7) show in animal models how estrogen regulates the renin–angiotension system in the gut and its potential impact in menopause-associated increases in age-related disorders involving gut motility, permeability, and inflammation. To date, an important contributor to these afflictions, preservation of steroidogenic functions of the ovaries and other tissues and optimizing hormone therapies to maximize their benefit to risk ratio have been met with limited or no success. Understanding the gaps in the basic mechanisms that control aging in these tissues will provide important targets for therapeutic strategies to counter reproductive aging and its impacts on the aging population. The following articles will discuss how the aging reproductive system intersects with reproductive fitness and overall health. While these tissues which include the ovaries, oviducts, uterus, vagina, and vulvar region have been well-studied and appreciated for their importance in the health of young women, the aging of these tissues has been primarily focused on pathways associated with disease, like cancer and menopause while aging is a major risk factor for these afflictions. As a result, there are fundamental gaps in our understanding of the pathways that control healthy aging. Identification of the mechanisms underlying the aging reproductive system has the potential to provide interventions or treatments for age-related decline and promote a healthier life span. For example, it is known that genitourinary afflictions caused by menopause result from effects of low estrogen on the female genitourinary tract, including the vagina, labia, urethra, and bladder. While it was known that vaginal microbiota, particularly Lactobacillus spp., are beneficial to the female genital tract, in this issue Shardell and colleagues (8) show that their abundance declines with age in women from 35 to 60 years old, and this decrease in microbiota is associated with vulvar-vaginal atrophy and dryness and sexual dysfunction along with an overall self-reported quality of life suggesting a potential avenue for novel treatments. To understand aging in the female reproductive system it is also necessary to understand that these ti