"Earlier is not better": how early menstruation and childbirth are linked to accelerated aging and disease

A team from the Buck Institute and UCSF has tested in human data an old evolutionary idea called antagonistic pleiotropy: that what helps early reproduction may speed up aging later. In eLife, they show that the later menarche and first birth occur, the more favorable the “aging route”—even to the point of slower epigenetic clocks and lower risks of diabetes and heart disease. It’s one of the largest human tests of the theory using genetic tools.

Background of the study

Why does nature "pay" for early reproduction with accelerated aging? The classical theory of antagonistic pleiotropy suggests that alleles that provide advantages in youth (height, early puberty, early birth) may worsen health later - when the force of natural selection weakens. This has long been shown in model organisms, but in humans, causal evidence has been sketchy: observational links are easily confused with social and behavioral factors.

To avoid confounding, the authors rely on Mendelian randomization (MR), an approach in which randomly distributed genetic variants serve as a “natural randomizer.” If SNP markers associated with earlier menarche or earlier first birth are also associated with accelerated epigenetic aging and age-related diseases, this would support the idea of an “early birth ↔ earlier aging” causal tradeoff. The team is also validating their findings in ~200,000 UK Biobank participants, testing whether genetic signals are replicated in real-world health trajectories.

The context of this topic is applied. Early menarche and early childbirth have already been associated with a higher risk of obesity, type 2 diabetes, hypertension, and heart failure, but it was unclear how much of these associations were “biological” and how much were environmental (family income, education, nutrition, smoking). If part of the effect is indeed genetically determined and passes through known “long-term” pathways (IGF-1/GH, AMPK/mTOR), then this is a strong argument to consider reproductive chronology as an early marker of age-related risks and to adjust prevention (monitoring weight, glucose, blood pressure) in women with very early reproductive events.

Finally, the work adds a bridge between the evolutionary theory of aging and the clinic: testing with “hard” markers – the epigenetic clock (GrimAge), the frailty index, the age of menopause and a panel of age-related diseases – allows us to assess not only individual outcomes, but also the rate of biological aging as a whole. This provides a basis for more “gender-sensitive” health strategies, where a woman’s reproductive biography is not a separate chapter, but one of the main predictors of her health lifeline.

How the study was conducted

The authors used Mendelian randomization (MR), a method that uses the random distribution of genetic variants as a “natural randomizer.” They collected SNP markers associated with age at menarche and age at first birth, correlated them with dozens of aging and disease outcomes, and then tested the results in regressions in ~200,000 UK Biobank participants.

• Exposures: age at menarche and age at first birth.
• Outcomes: parental life expectancy, frailty index, epigenetic aging (GrimAge), age at menopause, “fascial/facial” aging; diseases - T2DM, coronary heart disease/heart failure, hypertension, COPD, ALC-Gamer, etc.
• Genetic pathways were analyzed using Ingenuity Pathway Analysis; mediators were analyzed separately (e.g., BMI).

Main results

Genetically determined later menarche and first birth were associated with: longer parental life expectancy, lower frailty, slower epigenetic ageing, later menopause, less "facial ageing" and a lower risk of T2DM, cardiovascular disease, hypertension, COPD and late Alzheimer's disease. Validation in the UK Biobank showed that menarche before 11 years or first birth before 21 years were associated with an accelerated set of risks - almost a twofold increase in the odds of diabetes and heart failure and a fourfold increase in obesity.

• 158 significant SNPs were found, some of which lie in the “long-lived” pathways: IGF-1/GH, AMPK, mTOR.
• BMI partially mediated the association of early reproductive events with T2DM and heart failure (but did not fully explain it).

What's New in Aging Biology

The paper provides direct human evidence for the idea: genetic tweaks that speed up early reproduction come at a cost to health later. This is antagonistic pleiotropy in action - a trade-off between "having children earlier" and "living longer without disease." eLife rating: the evidence is "solid," the conclusions are important and cross-disciplinary.

How it was measured (example of outcomes)

To make it clearer what we were looking at:

• General markers of aging:
  • age at death of parents (proxy for longevity),
  • Freilty Index,
  • acceleration of GrimAge (epigenetic clock).
• Specific age-related diseases:
  • T2DM, heart disease/CHF, hypertension, COPD, ALC disease, osteoporosis, cirrhosis, CKD.
• Reproductive and "external" signs:
  • age of menopause,
  • "facial aging" by GWAS traits

Why it might work (mechanisms)

Genes and regulatory networks that accelerate puberty and early fertility often tweak growth/metabolic axes:

• IGF-1/GH - acceleration of growth and maturation, but in the long term - the price in the form of metabolic and cardiovascular risks.
• AMPK/mTOR - the "build vs. fix" balance: a shift toward youthful anabolism may reduce "repair" in adulthood.
• Body fat component (BMI) is a partial mediator: excess weight increases diabetes/heart risks at early menarche/childbirth.

Practical meaning (and what it doesn't mean)

These findings are not about individual guilt or “universal recipes.” This is a genetic-population picture that suggests where and how to reduce modifiable risks in women with early reproductive events.

• For whom monitoring is more important: women with menarche <11 years and/or first birth <21 years - a group where it is worth monitoring glucose, blood pressure, weight, and lipids earlier and more actively.
• Gender-sensitive prevention: the trajectory of women's reproductive health is part of the age-related risk map, not a separate chapter.
• Risk environments ≠ fate: BMI, lifestyle, pressure, sleep, stress - “levers” that can still be pushed.

Strengths and Limitations

Pros: genetic design (reduces confounding), wide panel of outcomes, and validation on UK Biobank. Cons: classic for MR: assumption of absence of horizontal pleiotropy and that genetically predicted exposure is not equal to the real life of a single person. Also, most GWAS are in European populations; transferability to other ethnic groups requires verification. Nevertheless, the eLife assessment is “solid evidence”.

Conclusion

• Later menarche/first birth - slower aging and fewer age-related diseases (according to MR and UK Biobank).
• Early reproductive events are a “biomarker” that the risks of accelerated aging are higher, and prevention should begin earlier and more targeted.

Source: Xiang Y. et al. Early menarche and childbirth accelerated aging-related outcomes and age-related diseases: Evidence for antagonistic pleiotropy in humans. eLife 13:RP102447 (12 August 2025). https://doi.org/10.7554/eLife.102447.4