Genetic shifts in reproductive traits link to aging and health risks

Scientists uncover how genetic factors influence reproductive timing, aging, and health, shedding light on fertility trends and their impact on future generations.

A recent study published in the journal Nature Aging reviewed the genetics of human reproductive traits and their relationship with longevity, health, and offspring outcomes.

Human reproduction involves diverse genetic, biological, and socioeconomic factors. There has been a substantial reproductive shift in the past decades, including earlier ages at sexual debut and menarche, growing childlessness, lower number of children, and postponement of childbearing. First births in several countries now occur at age ≥ 30 when fecundity wanes.

In addition, parents often have longer birth intervals between children. One in six couples face infertility issues, with lifetime infertility prevalence estimated at 17.5%. Meanwhile, there is an increase in childlessness that includes both voluntary individuals choosing not to have children and involuntary infertile persons.

Various factors have been attributed to these shifts, such as contraception, economic uncertainty, health, legal abortions, inability to find a partner, and gender norms, among others. As the reproductive lifespan and childbearing shift to later ages, genetic factors that were previously unobserved may increasingly become important. In the present study, researchers reviewed the genetics of reproductive traits and behavior.

Genetics of Reproductive Traits and Aging

Genetic trade-offs: Later menopause, while linked to a longer lifespan, may increase the risk of hormone-sensitive cancers due to prolonged estrogen exposure, showcasing an evolutionary trade-off between longevity and disease risk.

Genome-wide association studies (GWASs) have driven the understanding of the genetics of reproductive aging and traits since the mid-2000s. Hundreds of GWASs have assessed the contribution of genetics to reproductive phenotypes, including age at first birth, testosterone levels, miscarriage, age at voice drop in boys, endometriosis, and the number of children.

These efforts have uncovered thousands of genotype-phenotype associations, revealing that multiple single nucleotide polymorphisms (SNPs) contribute to reproduction, which could be mapped to hundreds of genes. The authors used the GWAS Catalog to identify 37 genes or loci harboring association signals for at least four reproductive traits from 159 relevant studies.

Over half of these genes have been linked to rare Mendelian disorders, including 10 genes related to reproductive disorders. Follicle-stimulating hormone subunit β (FSHB) was the top reproductive trait gene, harboring GWAS signals for 11 reproductive phenotypes. The dynein axonemal heavy chain 2 (DNAH2) gene showed associations with uterine fibroids, age at menarche, testosterone, and sex hormone-binding globulin. The estrogen receptor 1 (ESR1) gene was also associated with multiple reproductive traits, such as age at first sex, age at first birth, testosterone, and sex hormone-binding globulin. The minichromosome maintenance 8 homologous recombination repair factor (MCM8) gene showed associations with anti-Müllerian hormone (AMH) levels, menopausal age, uterine fibroids, estradiol, and heavy menstrual bleeding.

The genetics of reproductive traits have also been linked to other traits and diseases, such as osteoporosis, breast cancer, cardiovascular disease (CVD), and psychiatric and behavioral traits. Further, there is substantial population variation in the age at the onset of puberty and menopause, the timing of which is associated with health outcomes in later life. An earlier age at menarche has been linked to an elevated risk of CVD, type 2 diabetes, and obesity.

Epidemiological studies have linked reproductive aging and traits to hormone-sensitive cancers, such as testicular, breast, prostate, ovarian, and endometrial cancers. Individuals with early puberty and delayed menopause have a greater risk of hormone receptor-positive breast cancer. Additionally, people with delayed menopause may have less efficient DNA damage response (DDR) mechanisms.

Reproductive Aging, Offspring Health, and Longevity

Parental age impact: Advanced parental age increases the risk of de novo mutations, contributing to conditions like autism, schizophrenia, and miscarriage, particularly through maternal chromosome errors and paternal point mutations.

Studies have linked reproductive lifespan and markers with longevity and aging. There are associations between early menopause and genes related to DDR; a recent study linked loss-of-function variants in DDR-related genes and diverse DDR processes to age at menopause. Loss-of-function mutations in checkpoint kinase 2 (CHEK2) have been reported to delay menopause and elevate the mosaic loss of the Y chromosome.

Further, later age at menopause has been associated with longevity and lower morbidity/mortality. In addition, there is an antagonistic pleiotropic relationship between longevity and cancer. A recent study observed that carriers of ovarian aging-related rare protein-coding variants have a higher cancer risk. Other studies have found that individuals with Werner syndrome or Hutchinson-Gilford progeria experience premature menopause or hypogonadism.

The timing of puberty onset, the reproductive window, and fertility are associated with longevity in various ways. A study found that a one-standard-deviation higher polygenic score for the timing of age at first birth was associated with a 2% to 4% decrease in mortality. Likewise, another study noted that one year later, puberty in males was associated with a nine-month longer life.

Further, the psychological stress of pregnancy may increase the biological age by up to two years. Parents’ age can have a direct biological effect on children through de novo mutations. For instance, large-scale genetic abnormalities, e.g., cell division errors, are associated with the mother's advanced age.

Evolutionary Insights and the Grandmother Effect

As human reproductive behavior shifts, the evolutionary theory of the "grandmother effect" has become increasingly relevant. It suggests that the extended post-reproductive lifespan, particularly in females, plays a crucial role in supporting offspring and subsequent generations through caregiving. This role in family dynamics and child-rearing further highlights the complexities of aging and reproductive longevity.

Concluding Remarks

Much of the research on reproduction and associated genetics has focused on females, and when males were included, samples were often smaller or involved select subjects. However, understanding the correlates, consequences, and causes of reproductive aging requires more data on male reproductive traits. Notably, GWASs have disproportionately focused on populations of European ancestry. As such, attaining greater diversity in reproductive research could accelerate scientific discoveries and augment translation efforts.

Journal reference:

• Benonisdottir, S., Straub, V. J., Kong, A., & Mills, M. C. (2024). Genetics of female and male reproductive traits and their relationship with health, longevity and consequences for offspring. Nature Aging, 4(12), 1745-1759. DOI: 10.1038/s43587-024-00733-w, https://www.nature.com/articles/s43587-024-00733-w