In non-human species, the established theory (LHT: Life History Theory) is that the greater the reproductive effort, the more finite energy is expended; thus, females tradeoff life expectancy with reproductive effort (Hill and Kaplan, 1999). In humans, several large, population-based demographic studies of more than 140,000 women born between 1820 and 1920 in a preindustrial population in Utah, North America, have also shown that women who undertook more reproductive effort lived a shorter lifespan (Penn and Smith, 2007; Bolund et al., 2016). These results are largely in line with the LHT. However, according to Bolund et al. (2016), maternal life expectancy is shortened with four or more births, per the LHT; conversely, deliveries of less than four extended life expectancy (Bolund et al., 2016). Our current monogamous society no longer has an average of nine births (as was common in this previous era); for example, the number of childbirths in first-time married couples who had been married for 15–19 years in Japan was 1.94 in 2015 (The Fifteenth Japanese National Fertility Survey in 2015, 2017). A more recent large, North America-wide demographic study of more than 20,000 women was conducted (Shadyab et al., 2017), which better reflects the current average number of births. Shadyab et al. (2017) reported that the odds ratio (OR) of longevity in Caucasians was higher for mothers who gave birth more than once (two to four children; mean OR: 1.13) compared to that of those who gave birth once (OR: 0.91) or were nulliparous (OR: 1 as reference), even after adjusting for demographic characteristics, socioeconomic status, lifestyle behaviors, reproductive factors, and health-related factors (Shadyab et al., 2017). However, it was consistent with both the LHT and previous population demographics in most aspects, especially regarding having more children; the association between the number of deliveries and longevity was attenuated, and was certainly not higher in those with five or more children. Dior et al. (2013) reported a U-shaped and nonlinear, association between the number of deliveries and all-cause maternal mortality; the lowest risk was at two to three children (Dior et al., 2013). Therefore, while it may be true that having more than four children reduces life expectancy in women, the LHT may not be consistent with births of less than four children.

Hence, recent studies using molecular metrics have attempted to provide biological evidence for the effects of reproductive effort on women’s longevity. Telomere length was used as a molecular metric to reflect longevity in the initial study stages. The first study reported that mothers who had more children had shorter telomere lengths (Gray et al., 2014); by contrast, a study of the Mayan tribe in Guatemala reported that mothers who had more children had longer telomeres (Barha et al., 2016). In addition to telomere length, epigenetic age acceleration—which is obtained by calculating the deviation of DNA methylation age (mAge) from chronological age (Horvath, 2013)—has recently attracted attention, serving as a novel biomarker of aging. Using this metric, Ryan et al. showed that in 397 young, 20–22 year-old Filipino women, a higher number of pregnancies was associated with a greater mAge acceleration and shorter telomere length (Ryan et al., 2018). Kresovich et al. also retrospectively used this metric in more than 2,000 women aged 35–74 and living in the US, reporting that increased acceleration of aging was seen with more births (Kresovich et al., 2019). Nevertheless, the results of these studies cannot sufficiently explain why the influence of births of four or fewer children might be exceptionally non-linear. Moreover, the cause of this putative possibility might be difficult to elucidate in retrospective studies on generations that have already completed child-rearing. While the participants in the study by Ryan et al. were supposed to be rearing children, the mean age of childbearing in most developed countries is considerably higher, and was as high as 30.7 years old in Japan in 2016; therefore, while their results are applicable to younger mothers, it remains uncertain whether they can be applied to the general maternal population at present.

In addition to the phenomenon where reproductive effort affects aging and longevity, it has been affirmed that reproductive effort, including the experiences of pregnancy, delivery, and parenting, makes female brain structures more maternal and optimized for parenting (Nishitani et al., 2011; Nishitani et al., 2014; Kim, 2016). Hoekzema et al. (2017) conducted a longitudinal study that followed 25 first-time mothers from time of conception to 2 years after delivery; they found that at 10 months postpartum, the gray matter (GM) volume of the inferior and medial frontal gyrus, superior temporal sulcus, fusiform gyrus, precuneus, and hippocampus—involved in the theory-of-mind network—was reduced compared with during pregnancy (Hoekzema et al., 2017). Zhang et al. (2019) examined a similar longitudinal study and found that mothers showed changes in GM and white matter volumes, as well as the cortical thickness of several regions—including the superior and medial frontal gyrus, insula, limbic lobe, superior and middle temporal gyrus, and precentral gyrus—after 2 years of follow-up (Zhang et al., 2019). Luders et al. (2020) conducted a similar longitudinal study. They reported no decline in areas at 4–6 weeks postpartum compared with the immediate postpartum period (one to two days postpartum); however, there were increased GM volumes in certain regions, including the pre- and postcentral gyrus, thalamus, and precuneus, contrary to Hoekzema et al.’s results (Luders et al., 2020). These studies suggest that reproductive effort affects not only aging, but also elicits changes in brain structure. Contrasting with other species, humans do not reach the end of their life shortly after menopause; in fact, they live nearly twice as long as their age at menopause in this modern era. The grandmother hypothesis, explaining the existence of menopause in human life history by identifying the adaptive value of extended kin networking, has been proposed (Hawkes, 2004), as postmenopausal women have been found to have a great deal of biological and social activity (Kida et al., 2014; Hawkes and Finlay, 2018). This is unique to humans and is considered to be related to humans’ high sociability, owing to their highly evolved brains (Hawkes, 2020).

Therefore, we hypothesized that reproductive effort would refine the brain structures involved in the sociability required for parenting, thereby influencing both mAge acceleration and longevity. In the present study, we examined the association between reproductive effort, mAge acceleration measured using salivary DNA, and brain structures evaluated by voxel-based morphometry (VBM), in mothers.

This study examined the relationship between reproductive effort, mAge acceleration, and brain structure in mothers of children in early childhood. Our results showed that their reproductive effort—regarding parity status, number of deliveries, motherhood period, and cumulative motherhood period—was associated with mAge deceleration, even after adjusting for potential confounders. Although previous studies have examined the relationship between mAge acceleration or telomere length and the number of deliveries as a representative variable, this is the first time that mAge acceleration has been simultaneously examined in relation to the other reproductive effort indices, also considering daily parenting stress. We also found that the precuneus GM volume increased as mAge deceleration occurred. We also observed a mediation effect of greater left precuneus GM volume on the relationship between parity status and mAge deceleration. This suggests that the precuneus—a central node in the human brain that supports complex cognition and behavior—may be associated with age deceleration in child-rearing mothers. This also suggests that multiparity between two to four births lead to maternal brain changes in the left precuneus, which contributes more to mAge deceleration than just one birth.

Our results were limited as we only included mothers who gave birth to one to four children; thus, we do not know how this would have affected women with more than four births. Still, among mothers who gave birth to one to four children, our results seemed to contradict the LHT (Hill and Kaplan, 1999). Our results suggest that mothers who gave birth to less than four children and have currently been rearing them have aged more slowly, depending on their reproductive efforts. Our findings are consistent with previous large demographic studies reporting that deliveries of less than four children extended, rather than diminished, life expectancy (Dior et al., 2013; Bolund et al., 2016; Shadyab et al., 2017). We speculate that this avoids a downward trend in the birth rate, since having only one offspring born to each couple would lead to a decline in population in a monogamous society. While childbearing certainly comes at the cost of energy based on the LHT, giving birth to two or more children while having fewer than four may benefit the mother’s lifespan, even accounting for the tradeoffs of childbirth.

One possible biological cause underlying this phenomenon could be due to maternal brain alteration. Human mothers’ brains undergo dynamic structural and functional changes during pregnancy and the early postpartum period to facilitate their psychological and behavioral adaptation to parenting (Kim, 2016; Hoekzema et al., 2017; Zhang et al., 2019; Luders et al., 2020). This transition to the maternal brain seems to particularly enhance the functioning of the reward, social information, and emotion regulation circuits (Ho et al., 2014). We identified that mAge deceleration associated with parity status was linked to an increase in precuneus GM volume in mothers, which is similar to the findings of the study by Luders et al. where an increase in precuneus GM volume was observed at 4–6 weeks postpartum, compared with 1–2 days postpartum (Luders et al., 2020). The precuneus is included in the social information circuit and is a hub for the default mode network (DMN), which involves empathy, as well as self-monitoring and reflection (Utevsky et al., 2014). In other words, becoming a mother of two or more children may have led to more complex social interactions, which may have contributed to a greater precuneus GM volume than in the past. It has also been found that patients with Alzheimer’s disease (AD) and in the prodromal stage of AD have decreased DMN functions and precuneus GM volume compared to controls (Goto et al., 2015). Using postmortem brains, a telomere length analysis of each brain region comprising the DMN showed that the precuneus telomere length was shorter in AD and the prodromal stage of AD than in controls, whereas there were no differences in the frontal, inferior temporal, posterior cingulate gyrus or visual cortex (Mahady et al., 2020). Furthermore, this telomere length reduction in the precuneus also correlated with cognitive task performance. One of the main symptoms of PTSD is an elevated rumination characterized by repetitive, negative self-focused cognition; it has been reported that reduced functional connectivity between the isthmus cingulate and the left precuneus within the DMN is linked to this high level of rumination (Philippi et al., 2020). Lifetime trauma burden and suffering from both current and lifetime PTSD have been reported to cause GrimAge acceleration (Katrinli et al., 2020). These studies support the notion that aging and mental stress that accelerates aging may affect the functional connectivity between the precuneus and the other brain network region. The sophistication of the social information and DMN functions involved in becoming a mother may have contributed to the mAge deceleration via enhancing precuneus function and volume; however, this finding is not related to the number of deliveries—which accounts for the major reproductive effort—but rather to parity status (whether a baby is born to a mother once or twice or more), and is not a model that is valid as the number of deliveries increases.

Our results were partially inconsistent with previous studies. Ryan et al. reported mAge acceleration in mothers who had given birth to one to five children, as well as in nulliparous women (Ryan et al., 2018). However, their study participants were 20–22 years-old, which is relatively young compared with the average age of a primipara in modern, developed countries. Some reports suggest that a higher age at first birth is associated with longer telomere length (Fagan et al., 2017) and longer life expectancy (Shadyab et al., 2017). Thus, the association may be linear, rather than U-shaped, when the age at first birth is relatively young, as in this previous study. In addition, various environmental factors have been reported to influence mAge acceleration, most notably stress (Hoare et al., 2020; Katrinli et al., 2020). While Ryan et al. adjusted for socioeconomic status, they did not consider the effects of psychological aspects, such as parental stress; therefore, an analysis adjusting for these effects may also be necessary. In our results, higher parental stress, not only reproductive effort, was associated with the deceleration of aging. Conversely, Kresovich et al. reported accelerated aging in mothers who gave birth to one to four or more children, as well as in nulliparous women (Kresovich et al., 2019). However, their study was retrospective and included those who were currently out of the child-rearing phase (an average age of 55 years when the blood samples were collected), which is different from the present study, involving mothers of children in early childhood. Their results may thus be confounded by menopause (Gray et al., 2014) and the higher genetic risks for developing breast cancer, which is a unique characteristic of this cohort population (Sandler et al., 2017). By contrast, Barha et al. found longer telomeres in mothers who gave birth to one to six babies (Barha et al., 2016). Although this study did not measure mAge acceleration, telomere length results indicate that age deceleration may have occurred, perhaps akin to our findings. Additionally, our studies were similar in that the DNA was saliva-derived. Our method of estimating mAge by using Horvath’s multi-tissue clock should not be noticeably affected, even if the tissue from which the DNA was derived was different (Horvath, 2013). Still, the similarities regarding the type of sample may not be particularly relevant. Additionally, the participants in their study were, on average, 39.4 years old, premenopausal, and probably still rearing their children. This consistency in age and rearing young children may be related to the directional consistency of the two results. Although their results were linearly regressed, on closer inspection, an inverted U-shaped approximation with a peak at two to three births appears to be more appropriate.

There are at least six potential limitations concerning our study’s results. First, the small number of participants; we only had one participant with more than four children, limiting the ability to observe the U-shaped association that we hypothesized. Small group sizes may preclude drawing significant conclusions and limit generalizability of the results; thus, we will confirm these pilot results by increasing the sample size in future studies. Second, there were no nulliparous participants. Shadyab et al. (2017) reported that mothers had a longer life expectancy than nulliparous women (Shadyab et al., 2017). It is also known that changes in brain morphology and cognitive function occur when women become mothers (Hoekzema et al., 2017; Zhang et al., 2019; Luders et al., 2020); therefore, it is necessary to include nulliparous women to show the association between mAge acceleration and precuneus GM volume with brain materialization. Third, we used saliva DNA samples for mAge and mAge acceleration calculation. This limits the use of other newly developed blood DNA composite biomarkers, including: PhenoAge, which more effectively captures the epigenetic biomarkers of physiological age and discriminates between morbidity and mortality more definitively in individuals of the same chronological age (Levine et al., 2018); and GrimAge—named after the Grim Reaper—which predicts lifespan and healthspan in units of years (Lu et al., 2019). However, Horvath’s multi-tissue clock can be used for any type of tissues, enabling a direct comparison with most previous studies based on blood DNA (Ryan et al., 2018; Kresovich et al., 2019). Forth, there was a significant association that higher the PSI, the more age deceleration based on the multi-tissue clock (p = 0.003), but not for skin & blood clock (p = 0.31). Zannas et al. (2015) have reported that lifetime stress accelerates epigenetic aging since the multi-tissue clock has 85 probes located within glucocorticoid response elements (Zannas et al., 2015). Thus, these specific probes included in the multi-tissue clock might have affected the association with PSI. However, the effect directionality of our results was different. This may suggest that the age deceleration was not effortlessly obtained as it was also associated with the length of the motherhood period. Fifth, we do not have information whether these participants cohabit with their parent or parent-in-law. According to the public demographics, nuclear families in Japan were 82.7% (2016) (Graphical Review of Japanese Household, 2016) and this might have influenced the results. Finally, we have focused only on mAge acceleration, but it is necessary to explore the relationship with the genome-wide profile, which is a future research goal.

Despite these limitations, our results suggest that reproductive effort in mothers may refine the brain structures involved in the sociability required for parenting, conversely influencing mAge acceleration and longevity. Our results also suggest that the mAge deceleration associated with changes in the precuneus may be one of the phenomena linked to the maternalization of the brain.