An unusual model of aging
There are many similarities between pregnancy and aging
Polina Loseva, "Elements"
Israeli gerontologists, having carefully compared the changes occurring in the body during pregnancy and aging, came to the conclusion that these processes have a lot in common. Both pregnancy and aging are characterized by the same diseases and pathologies, hormonal background changes in a similar way, etc. This analogy, if accepted by the scientific community, may not just add another item to the list of models of accelerated aging, but also bring scientists closer to the search for rejuvenation technologies, because pregnancy is a way back and forth. In the meantime, another benefit can be derived from it – try to understand exactly what pregnancy does to a woman's body and how it affects life expectancy.
One of the branches of the evolutionary theory of aging is the theory of disposable soma, or "body for release" – assumes that the amount of resources of any organism is limited. Therefore, from the point of view of the life strategy, there is a choice on what to spend them: on repairs (on updating and repairing their own structures), or on reproduction (that is, to invest in a new generation).
It is known that this principle is carried out at the cellular level. The mTOR protein complex acts as a growth/repair switch. When it is active, the cell exists in the mode of reproduction or growth, produces a lot of substances, and therefore a lot of molecular debris, which reduces the time of its active life. When mTOR is blocked, the cell goes into self–preservation mode: instead of producing new molecules, it destroys or repairs old ones, starts the repair and autophagy systems - and gets a chance to live longer.
It is logical to assume that the same choice should arise before the body as a whole: you can endlessly engage in self–repair and live longer, but not leave offspring behind, or put your whole life on the production of descendants - and thereby shorten this life. In other words, if the theory of disposable catfish works at the level of organisms, then a person's number of children will affect life expectancy, since the time and resources that he could spend on repairs will be spent on bearing and raising children. In this case, mothers with many children will die earlier than women with 1-2 children, and childless mothers will have an increased chance of entering the list of super-long-livers.
However, attempts to identify this dependence have not yet led to unequivocal success (some examples are discussed in the review of E.Le Bourg, 2007. Does reproduction decrease longevity in human beings?). The results are very different depending on the study: somewhere children seem to shorten the mother's life, somewhere - on the contrary, prolong it, and somewhere they do not have a noticeable effect. This variation can be quite understandable if we consider that different researchers deal with different populations. If we are talking about modern developed countries, where women often resort to contraception, then we do not have so much data yet to judge life expectancy (since mass contraception appeared not so long ago). If we turn to populations with "natural" fertility, then another distortion arises: the number of children often depends on the physiological state of the mother. A healthy woman in such populations is the one who can bring a lot of offspring, and childless women are most often unhealthy, therefore they will hardly become centenarians.
Nevertheless, in many studies (mainly on modern European populations), similar results have independently emerged, which on the graph of the dependence of the chances of dying on the number of children look like a U- or J-shaped curve (Fig. 1): childless mothers live less than those with 1, 2 or 3 children. And then the risk of dying grows again, and the birth of 5 or more children has already adversely affected the mother's body (we will not consider fathers here for simplicity, although they also have similar dependencies – and also ambiguous – despite the fact that they do not participate directly in bearing children). And if there is nothing unexpected in the second part of the curve, then the first part directly contradicts the theory of disposable soma: the theory predicts that the birth of children should shorten life, and it, on the contrary, reduces the risk of dying. This fact suggests that in some cases the birth of a child becomes a blessing not only from an emotional, but also from a physiological point of view.
Fig. 1. Relative risk of dying (compared to childless people) depending on the number of children (only the birth of living children is taken into account). Data from meta-analysis of 18 works and almost three million people. The dotted lines show 95% confidence intervals. Graph from the article Y. Zeng et al., 2016. Parity and all-cause mortality in women and men: a dose-response meta-analysis of cohort studies.
The unevenness of this dependence can be explained in several ways.
Firstly, it may be that until recently society did not particularly encourage childlessness. And, despite contraception, women were still inclined to give birth to a small number of children, if their health allowed it. If so, then the U-shaped curve can be represented as the sum of two curves: one reflects the risk of death, which is often higher in childless and small-child women due to poor health, and the second reflects the wear and tear of the body, which is stronger with each child. In this case, three children is the point at which these two curves intersect. This idea is similar to the representation of the human mortality curve as the sum of the decreasing force of natural selection on mutations and the growing risk of dying "from old age" (see Infant mortality from inherited mutations masks the early onset of aging).
Secondly, it may be that with the birth of a child, not only the state of health changes, but also the lifestyle of a woman. They often give up bad habits and switch to the same healthy food that they feed their children. It can be assumed that these changes linger in a woman's life the longer the more children she has. But at some point, again, the wear and tear of the body from pregnancies outweighs.
This assumption is supported by statistics on Swedish families with their own and adopted children (Fig. 2). The shape of the curve for parents with adopted and born children is somewhat similar: the first children in both cases reduce the risk of dying. It is logical to assume that the point here is just a change in lifestyle. Then, however, discrepancies begin: the risk of dying in foster parents with many children does not grow as sharply and not as reliably as those who raise their own children. Perhaps a lack of data plays a role here: few people take on many children at once (in this study, four foster children turned out to be the maximum). But the fact that foster parents, on average, are at risk of dying less than biological ones, the authors of the work explain by third-party factors: foster parents are selected in advance according to the level of well-being and lifestyle.
Fig. 2. Relative risk of death depending on the number of children – biological or adopted. The blue lines are biological children, the red lines are foster children. The dark shades of both colors correspond to the data, taking into account the education, social status and well-being of the parents. Image from an article by K. Barclay, M. Kolk, 2018. Parity and mortality: an examination of different explanatory mechanisms using data on biological and adoptive parents.
Thirdly, one can imagine that pregnancy can affect a woman's body in a positive way, bringing with it not only wear, but also some favorable physiological changes. For example, during pregnancy, there are often more estrogens in the blood than in normal life – and they have many useful functions (A.M. Horstman et al., 2012. The Role of Androgens and Estrogens on Healthy Aging and Longevity): among other things, they protect cells from oxidative stress, slow down the development of certain types of cancer and inhibit the formation of adipose tissue from stem cells (A. Ahmed et al., 2017. Effect of aging on stem cells).
In light of this last assumption, a recent article by Israeli researchers led by Gil Atzmon looks particularly interesting, in which scientists propose to consider pregnancy as a process somewhat similar to aging.
Such works, generally speaking, come out quite often: every now and then some disease from Down syndrome (C. Franceschi et al., 2019.Accelerated bio-cognitive aging in Down syndrome: State of the art and possible deceleration strategies) to COVID-19 (A. Mueller et al., 2020. Why does COVID-19 disproportionately affect older people?) gerontologists find characteristic features and equate it with accelerated aging. And there is a reason for this: since most researchers consider aging to be a natural and inevitable process, and they cannot fight it directly (because it has not yet been recognized as a disease), they have to work out potential rejuvenation strategies on those analogues that are officially considered pathology.
However, the comparison of aging with pregnancy is a little more complicated, since pregnancy is a reversible condition and ends sooner or later. And if it is possible to find signs of aging in it, then there must be traces of rejuvenation somewhere, which the body uses to return to its original state - and they can give the most favorable physiological effect.
How to prove that any condition is similar to aging? There is no single criterion here (not least because aging still does not have a strict definition), so Atzmon and colleagues decided to go from several sides at once.
To begin with, they compared the characteristic sets of diseases inherent in aging and pregnancy. Aging is accompanied by a set of age–related pathologies (and according to some scientists, it even comes down to them, see B. Kennedy et al., 2014. Geroscience: linking aging to chronic disease), which include cardiovascular diseases, autoimmune diseases, cancer, diabetes, dementia. Some of them occur in pregnant women as temporary conditions: for example, hypercoagulation, that is, a tendency to form blood clots. The body of a pregnant woman has to produce fewer anticoagulants to cope with postpartum bleeding. But this leads to the fact that pregnant women have a higher risk of heart attack and rupture of the coronary artery than ordinary women. In addition, during pregnancy, the pulse and cardiac output increases, which leads to an increase in pressure, which researchers liken to senile hypertension.
Another illustrative example is diabetes. Approximately every tenth pregnancy, according to the authors, brings with it gestational diabetes. This is also a consequence of normal processes: the mother's body needs to share glucose with the growing fetus, so the mother's cells become more resistant to insulin, and the blood sugar level increases. In some cases, this leads to an abnormal increase in the concentration of glucose in the blood, and gestational diabetes develops, which in many ways is similar to type II diabetes mellitus (insulin-independent, not associated with the destruction of the pancreas).
Atzmon and colleagues cite other examples, although they look less convincing. So, according to their data, at least half of women complain of a decrease in cognitive functions during pregnancy, which can be considered an analogue of dementia.
The second level of comparison is a characteristic set of processes that lead to the development of typical pathologies. At the cellular level, this is oxidative stress. According to the free radical theory of aging, organisms owe a lot of intracellular and extracellular problems to active forms of oxygen (free radicals) that appear in mitochondria as a byproduct of cellular respiration, and then attack proteins, lipids and DNA. During pregnancy, stress also increases: first, because there is not enough oxygen in the placenta, and then because she is breathing too actively and spending too much energy. Increased levels of free radicals are associated with the risk of pregnancy complications (for example, preeclampsia and miscarriage).
Another process that is inherent in aging is inflammation. Aging cells accumulate mutant proteins and turn into strangers for their own immune system, and fraying tissues only add fuel to the fire by releasing pro-inflammatory proteins. Pregnancy is also a collision with a stranger who has settled in the uterine wall: during the first trimester, the immune system reacts aggressively to him, trying to expel a foreign body from the body.
Another reason for age–related changes is hormonal shifts. Aging is associated with a deficiency of insulin-like growth factor-1 (IGF-1), which the liver secretes under the action of growth hormone. In the first trimester of pregnancy, the liver becomes resistant to the action of growth hormone, and the concentration of IGF-1 drops by at least a third.
Finally, the third level at which pregnancy and aging could be compared is markers of biological age, that is, changes at the molecular level. But here, unfortunately, the data turned out to be insufficient, since few people have ever thought of measuring the biological age of pregnant women. The only marker that has been tested in any way is the length of telomeres. However, the results differ here: some researchers write that telomeres shrink with each pregnancy, while others, on the contrary, find longer telomeres in women with many children. This may mean that pregnancy does not have a direct effect on telomeres, or that the dependence here is nonlinear (for example, also U-shaped), or that telomere length is not the best marker of aging, and you need to use some other, for example, epigenetic clocks.
Nevertheless, all these processes and pathological conditions that allowed Atsmon and colleagues to liken pregnancy to aging are reversible. Some of them return to a state of equilibrium already in the last trimester, when, for example, placental cells begin to actively produce antioxidants, reducing the level of oxidative stress, and also secrete growth hormone, compensating for its deficiency at the beginning of pregnancy. In some processes, the rollback happens after childbirth (for example, then the traces of hypertension and gestational diabetes disappear). And since pregnancy is a reversible condition, it can be assumed that the recovery process after it may be delayed, and then the body will not only return (at least partially) to the biological age that it would have had without pregnancy, but will also become even a little younger than it should be. This effect could explain the U-shaped curve phenomenon we discussed above and the decrease in maternal mortality after the birth of the first few children.
The works in which this "restoration with overlap" has been documented are still very rare. However, in a recent study, it was noticed that the brains of mothers look younger than the brains of unborn women (for this, researchers previously collected MRI scans of the brains of many women and trained a neural network to determine their age by the shape and size of different areas, see A. de Lange et al., 2019. Population-based neuroimaging reveals traces of childbirth in the maternal brain). At the same time, according to their calculations, the first children "gave" 0.4 years of life to their mothers' brains, the second – 0.5, the third – 0.75, but after the fifth child, the effect disappeared. The authors of the work proposed to explain this phenomenon by "overlap": during pregnancy, the brain volume decreases, and after childbirth returns to its original state, and may even exceed the original size (A. Oatridge et al., 2002. Change in Brain Size during and after Pregnancy: Study in Healthy Women and Women with Preeclampsia).
The comparison of pregnancy and aging has, of course, many subtle and controversial places, and will hardly ever become full-fledged. Do not expect that pregnancy will be included in the list of conditions of accelerated aging along with progeria, Down syndrome or oncological diseases. Nevertheless, such a comparison gives an unexpected angle from which you can look at both problems separately.
On the one hand, if we consider pregnancy as a path to aging and back, it becomes clear exactly how it can be beneficial for the body – and this allows us to explain the first half of the U-shaped curve. On the other hand, if we consider the end of pregnancy as a way out of the state of aging, then we can discover natural mechanisms by which the body reverses age–related changes and overcomes many pathologies - the very ones that we now consider inevitable and irreversible.
A source: Giller et al., Pregnancy as a model for aging // Ageing Research Reviews. 2020.
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