Beyond Reproduction: Biological Mechanisms of Reproductive System Aging on Healthspan and Longevity (B-ReAL)

When beginning your next investigator-initiated application, consider the following NIH highlighted topic. The area of science described below is of interest to the listed NIH Institutes, Centers, and Offices (ICOs). This is not a notice of funding opportunity (NOFO).

Apply through an appropriate NIH Parent Funding Announcement or another broad NIH opportunity available on Grants.gov. Learn how to interpret and use Highlighted Topics.

Topic Description

Post Date: October 19, 2026

Expiration Date: October 19, 2028

This topic encourages a broad range of studies that identify and elucidate biological mechanisms whereby chronological aging of the reproductive system affects overall systemic aging, with the ultimate goal of improving healthspan and promoting healthy longevity in older adults.

A growing body of evidence suggests that aging of the reproductive system is not merely the end of reproductive capacity, but is also closely intertwined with—and impacts—overall aging, healthspan, and longevity.While reproduction itself ends relatively early in life (particularly in women), reproductive aging appears to both reflect and influence the aging trajectory of multiple organ systems—extending well beyond hormonal regulation alone.

Very little is known about the systemic effects of reproductive aging in men and women; however, in women, the transition to menopause is accompanied by changes that extend far beyond fertility. Declining ovarian function and changes in sex hormone production are associated with increased cardiovascular disease risk, bone and muscle loss, osteoporosis, metabolic dysfunction and insulin resistance, cognitive changes and increased risk of dementia, altered immune function and increased inflammation, and urogenital and skin aging. Notably, several of these age-related changes are also observed in men, but generally develop more gradually as age-related declines in testicular function and androgen production progress, in contrast with the abrupt endocrine transition that characterizes menopause.

Women who experience later natural menopause generally exhibit lower all-cause mortality and reduced cardiovascular mortality in observational studies, suggesting an association with longer health span and lifespan. However, later menopause is also associated with increased risks of certain hormone-sensitive cancers, and it remains unclear whether menopause timing is a causal determinant of longevity or a marker of slower biological aging. These observations suggest that the reproductive system functions as a regulator of whole-body physiology rather than solely as an organ for reproduction.

Given recent advances in reproductive aging research, this topic encourages applications seeking to understand the molecular mechanisms of reproductive system aging responsible for the aging of other organs, and the physiological implications on overall systemic aging in both sexes.

Participating ICOs

National Cancer Institute (NCI)

NCI seeks to study reproductive aging as a primary biological variable for cancer research, especially separate from hormone effects. Of interest:

  • How reproductive organ aging and involution alters distal microenvironments (ME) to prime cells for malignant transformation
  • How changes by reproductive aging in cell-of-origin, ME, inflammation, and post-menopausal tissue remodeling drive precancer initiation/progression
  • How reproductive aging, including altered androgen signaling, reprograms cellular and metabolic pathways, secreted factors, and extracellular vesicles to shape tumor initiation, evolution, and therapeutic response
  • Whether integrating reproductive aging status with tumor traits can guide treatment selection, sequencing, and resistance monitoring
  • Whether understanding treatment-induced reproductive aging can identify survivors at risk for accelerated aging, informing survivorship care
  • How reproductive aging affects response to cancer prevention/interception strategies
ICO Scientific Contact:
Toby Hecht (Cancer Treatment and Diagnosis)
[email protected]

National Institute on Aging (NIA)

Scientific questions of interest include, but are not limited to, identifying/understanding:

  • Mechanisms by which reproductive aging drives systemic aging beyond reproduction, and its impact on overall physiology, and age-related health outcomes
  • Molecular and cellular pathways through which reproductive interventions such as hormone therapies, surgical interventions, etc. may influence systemic aging and longevity
  • Mechanistic studies of how reproductive aging influences cellular and molecular mechanisms, including the hallmarks of aging, in systemic physiological networks (including the endocrine and immune systems) and/or individual organs and tissues (such as the brain, adipose tissue, liver, and kidney)
  • Whether mechanisms of accelerated reproductive aging indicate an individual's overall biological aging trajectory or causally contribute to systemic aging and age-related functional decline
  • Biological mechanisms underlying heterogeneity in the menopausal and andropausal transitions
ICO Scientific Contact:
Fei Wang, Ph.D.
[email protected]

National Institute of Allergy and Infectious Diseases (NIAID)

NIAID supports research on immune system development/function and infectious and immune-mediated diseases (e.g., allergy, asthma, autoimmunity, transplant rejection). Areas of research interest in reproductive aging include:

  • Immunologic changes associated with reproductive aging and how these changes impact responses, susceptibility to, or initiation, progression/severity, or recovery from infectious or immune-mediated diseases.
  • Age-related, hormonally induced changes in systemic and tissue-specific immunity that alter susceptibility to infection, or in development, progression of or symptomatic changes in immune-mediated diseases.
  • Impact of microbial dysbiosis of the reproductive system on susceptibility to infection, development or altered symptoms of immune-mediated diseases.
    • Effects of increased systemic inflammation that accompany reproductive aging on susceptibility to pathogenic infections or in the symptoms or trajectory of immune-mediated diseases.
       
ICO Scientific Contact:
B-ReAL_DAIT
[email protected]

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Interest areas include:

  • How variables in reproductive tract development and maturation affect healthspan
  • Mechanisms by which premature reproductive aging, loss of fertility, reproductive tract diseases/disorders, or interventions to treat them, affect overall systemic aging
  • How different trajectories of natural or altered perimenopause/andropause affect healthspan 
  • Effects of alignment or mismatch between chronological age and physiological age of the reproductive system on systemic aging
  • Molecular mechanisms for effects of contraceptive use on healthspan
  • Identification of aging-related semen or sperm parameters that impact healthy pregnancies and healthy offspring 

Applicants are strongly encouraged to contact an NICHD program official prior to submission.

ICO Scientific Contact:
NICHD Referral
[email protected]

Office of Research on Women's Health (ORWH)

Office of Research on Women’s Health (ORWH) interest areas:  

  • Evaluate the systemic health consequences of reproductive aging and menopause, including their role in chronic disease risk and progression.  



 

This office does not award grants. Applications must be relevant to the objectives of at least one of the participating Institutes or Centers listed in this topic.
ICO Scientific Contact:
Geetha P. Bansal, Ph.D.
[email protected]

For technical issues E-mail OER Webmaster