Pregnancy accelerates epigenetic aging in young women

Studies have found that pregnancy history influences the rate of epigenetic aging in young women, a hallmark of biological aging. Women who have had multiple pregnancies age faster. The study supports the theory that reproduction accelerates aging. The study was conducted in the Philippines with young people and controlled for social, environmental, genetic and other factors.

summary

One of the central predictions of evolution is that the energy used for reproduction will accelerate biological aging at the expense of the body's self-repair. The finding that supports this prediction is that high fertility rates in women predict that they will live shorter and have worse health in the future. However, biological aging is often thought to begin before age-related health decline, which limits the applicability of morbidity and mortality early in life for studying the aging process.

In this study, we examined the relationship between reproductive history and biological aging in young men and women (aged 20-22 years) from the Longitudinal Health and Nutrition Survey in Cebu, Philippines (n = 1735). We quantify biological aging using six measurements, collectively known as the epigenetic clock, which reflect various aspects of cellular aging, health, and mortality risk. In a female subsample, we tested whether longitudinal changes in the number of pregnancies between young women and early middle age (25-31 years) were associated with changes in timeline metagenetic aging.

The cross-cutting study found that the number of pregnancies was positively correlated with all six epigenetic accelerated aging measures in women (n = 825). In addition, a longitudinal increase in the number of pregnancies was associated with accelerated aging of both epigenetic clocks (n = 331). In contrast, male-reported fathers experienced an unrelated number of pregnancies to their epigenetic senescence (n = 910).

These effects are robust to socio-ecological, environmental, and immune factors, consistent with the hypothesis that pregnancy accelerates biological aging and that these effects can be detected in young women in high-fertility settings.

discuss

We used six epigenetic clocks to predict mortality risk, physiological dysregulation, and biological aging, and provided evidence that women who had at least one pregnancy showed faster biological aging than women who did not. We also found that women with more pregnancies in early adulthood showed faster biological aging.

These relationships persist under the influence of social, environmental, and genetic confounding factors, including socioeconomic status, degree of urbanization, smoking, and genetic variation. These relationships were also not diminished after adjusting for estimated differences in cell composition.

To minimize the confounding effects of social and environmental factors that cannot be measured over time, we conducted a longitudinal analysis. The results showed that women who experienced more pregnancies between baseline and follow-up showed a faster rate of biological aging, but this was limited to the measurement of the Horvath and Hannum clocks. In contrast, there is no evidence that the number of pregnancies in male fathers predicts epigenetic aging.

Taken together, these findings provide evidence that pregnancy accelerates biological aging in healthy young adult populations.

Our findings are broadly consistent with evolutionary-based pre-registration hypotheses and consistent with previous cross-sectional studies that have documented the relationship between reproductive effort and DNAm measurements of biological age. In a pilot sample of this population, we previously reported that aging can be accelerated using the Horvath clock, along with leukocyte telomere length, another molecular senescence measure. Similarly, Kresovich and colleagues found evidence that parity was associated with faster Horvath, Hannum, and PhenoAge clocks in a large number of American women who participated in the sister study. Notably, the normalized effect size for each additional pregnancy reported by Kresovich et al for Horvath and Hannum clocks was comparable to that reported here (Horvath b = 0.10 vs. 0.10; Hannum b = 0.12 vs. 0.08)。

These findings contrast with a recent cross-sectional study of young Finnish women, which did not report the relationship between nationally registered births and four epigenetic measures of aging. Since factors such as individual access to resources and health care may obscure trade-offs at the population level, social and economic differences between countries may partly explain these different findings. Most of the women in our study came from low- or middle-income families with limited social support and limited access to high-quality health care. In addition, our study is characterized by higher fertility rates and earlier reproductive ages. In the Philippines, the impact of reproductive costs on biological aging in this population supports the expectation that the trade-off between reproduction and somatic cell maintenance will be most pronounced when resources are limited and reproductive efforts are high.

In our cross-sectional analysis, each additional pregnancy was associated with the estimated effect of accelerated biological aging at 4.0 to 14.2 months, while each additional pregnancy was associated with the estimated effect of accelerated biological aging at 2.4 and 2.8 months in our longitudinal analysis. When women are younger, our cross-sectional analysis estimated higher pregnancy costs, which is consistent with the literature, which links earlier age at first childbearing to worse health outcomes later in life. Using the all-cause mortality hazard ratio from the large generation clock meta-analysis and the conservatively estimated effect size of our longitudinal analysis, we estimated the effect to be equivalent to an increase in all-cause mortality risk of 0.5% to 0.8% per pregnancy. Such a small effect may partly explain the inconsistent support for reproductive costs in some studies that employ measures with less clear links to long-term health and mortality risk. Although relatively small, the potential long-term effects of small deviations in the aging trajectory in early adulthood are unknown. In addition, these effects may accumulate with multiple pregnancies that often exceed live births.

While we controlled for a range of potential social, environmental, genetic, and immune confounders in cross-sectional analyses, estimates of the effect of pregnancy on the epigenetic clock may be sensitive to residual confounding of variants not captured by our metrics. However, none of the epigenetic clocks in the same cohort we studied correlated with the number of pregnancies in young male fathers. This suggests that it is the direct input of pregnancy and lactation that drives the acceleration of epigenetic aging in our study, rather than socioeconomic factors associated with early childbearing (or sexual activity itself).

In addition, longitudinal approaches to predictors of changes in results over time minimize the effects of factors that vary due to individual differences but stabilize within individuals over time, such as birth weight, early growth and development, family socioeconomic class, or parental education. Longitudinal studies have found that women with more pregnancies between baseline and follow-up age age more quickly, according to the Horvath and Hannum clocks. This study correlates longitudinal changes in the number of pregnancies with longitudinal changes in epigenetic age, thus providing a stronger basis for causal inference. However, this finding was limited to the Horvath and Hannum clocks and did not appear in any of the other clocks associated with the number of pregnancies in our cross-sectional analysis, suggesting a more complex relationship between reproduction and epigenetic aging in this population.

It is unclear why the effect of pregnancy on longitudinal changes in epigenetic age is present in the Horvath and Hannum clocks, but not in the other epigenetic clocks we examined. One underlying factor is the foundation of different clocks, which differ in the prediction targets and data they use during development. Both Horvath and Hannum were trained using machine learning algorithms to predict age. In contrast, PhenoAge, GrimAge, and DunedinPACE were trained using measurements of blood chemistry, physiology, and organ system integrity.

The metabolic, immune, and inflammatory signatures prevalent in high-income Western settings trained at these clocks tend to differ from those observed in CLHNS and other non-Western settings. What's more, all of our follow-up samples were collected from pregnant women whose metabolic, physiological, and immune profiles, as well as methylomes, differed significantly from the non-pregnant population in the training dataset. While it is unclear how the physiological, metabolic, and immune changes that accompany pregnancy differ to the extent of variation in these states in nonpregnant populations, the clock built around these measures may be particularly sensitive to reproductive status. Since they are trained on precisely measured ages that have similar meanings in all cases, the Horvath and Hannum clocks may be more robust to biomarker differences between different populations and reproductive states.

However, the confounding of reproductive states at our second time point does not explain the apparent dose-dependent effects of pregnancy on the Horvath and Hannum clocks, which were not altered by our adjustments to the immune cell components. Additional work is required to examine the effects of socioecological environment (e.g., through exposure to infectious diseases) and reproductive status on the epigenetic clock.

Our findings should be interpreted in the context of some limitations. First, both our cross-sectional and longitudinal analyses focused on relatively young participants, with a shorter time span. However, if reproductive costs are cumulative, most pronounced in old age and at higher parities, then our analysis may not capture the full impact of pregnancy on epigenetic age. In fact, our work in a large representative sample of women in the United States suggests that the effects of reproductive effort on some biological aging measurements may not be fully apparent until later in life. If the same is true in the Philippines, our focus on young women may underestimate the impact of pregnancy on epigenetic aging.

Second, we limit our measure of reproductive effort to the number of pregnancies. While many of the metabolic, physiological, and immune changes associated with pregnancy overlap with those associated with aging, breastfeeding and parental care are also considered to be part of the long-term costs of reproduction. More work is needed to characterize these other forms of reproductive input, and in each child the frequency, duration, and intensity of lactation need to be documented in detail, as well as estimating their effects on biological aging.

Finally, we have not been able to correlate these DNAm biological age measurements with morbidity and mortality in later life in this population. While these links have now been demonstrated in older adults in the United States and Europe, the link between faster biological aging and morbidity and mortality in younger adults and individuals living in non-Western environments has yet to be validated in future social and ecological contexts more similar to Cebu.

conclusion

This large pre-registration study examines the reproductive costs of young men and women in high-fertility settings using state-of-the-art measures of biological aging. Our analyses controlled for a range of social, environmental, genetic, and immune confounders. We found evidence supporting the effect of pregnancy on epigenetic age, consistent with the theoretical trade-off between reproduction and aging, and supported by epidemiological findings that high fertility effort may increase the risk of a range of diseases and early death.

These findings suggest that pregnancy accelerates biological aging, especially early in a woman's reproductive life, and that these effects may be detectable from a relatively young age.