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Can Pregnancy Effects be Used to Argue For Changes in Cell Signaling as an Effective Approach to Treating Aging?

Over the past decade, a few research groups have provided evidence to suggest that pregnancy can enhance regeneration in the mother. The proposed mechanisms have largely involved capable stem cells from the fetus acting as a mild form of stem cell therapy when they find their way into the mother's tissues. Since then, however, parabiosis research has taken off, in which an old and a young animal have their circulatory systems joined. This has a beneficial effect on the older animal, and researchers have spent a great deal of effort investigating signal molecules in the bloodstream that differ between old and young animals. The initial focus was on finding youthful signals that might help turn back some of the detrimental changes that take place in old tissues, such as loss of regenerative capacity and decline in stem cell activity.

Perhaps unfortunately, the latest update in this line of research puts something of a damper on the idea that young signals can rejuvenate old tissues, and proposes that the effect is achieved through dilution of harmful signals or waste in the old tissues and bloodstream. Still, now that everyone is as much focused on signals as they are on stem cells, it is perhaps time to look back at the evidence for pregnancy effects. Is there anything there that might be used to argue in one direction or another when it comes to the signal environment, aging, and potential therapies? From where I stand the existing evidence looks a little sparse to be building anything atop it, but it doesn't seem like an unreasonable angle to pursue further - at least for those researchers who are focused on slowing aging through forcing change on the signaling environment. That said, there is no necessary reason why these two situations, parabiosis and pregnancy, should in the end turn out to have much in common; it could just as easily be the case that the placental barrier rules out all of the interesting exchanges that take place in parabiosis.

Why does signaling change in old tissues? Those who see aging as an accumulation of molecular damage would say it is a consequence of increased levels of damage. Cells react to their environment, and it is unfortunately the case that some of those reactions go on to cause further harm. See, for example, cells becoming senescent. There is another viewpoint, that of programmed aging, which considers signaling changes a primary cause of aging, and altered cellular behavior then in turn leads to damage. After some years of reading around that area of theory, I still think its proponents have a tough hill to climb in order to make that case. Fortunately, the development of working rejuvenation theories will settle the right and wrong of things more rapidly than the slow battles over theory; practical efforts will come to an answer in the next ten to fifteen years, I'd say. Therapies based on damage repair and therapies based on alteration of signaling are both imminent; one approach will work far better than the other, and that will be that.

Molecular and Cellular Interactions between Mother and Fetus - Pregnancy as a Rejuvenating Factor

Prevention or even reversal of aging have become topics of numerous studies. The discovery of rejuvenating factors, if they exist and are of chemical nature, would become a breaking point in solving many problems in gerontology. Scientists periodically report a discovery of such factors; however, careful examination of their data and technical details of these studies raise doubts if the discovered factors indeed possess rejuvenating properties. In particular, when the circulatory systems of two animals of different ages are connected in a heterochronic parabiotic model, the older partner undergoes rejuvenation. Some recent studies aimed to identify the chemical factor that enters the older organism from the younger one suggested that this rejuvenating factor is GDF11, a differentiation growth factor that circulates in the common blood stream of parabiotic partners. However, more detailed studies failed to unambiguously confirm that GDF11 is responsible for the rejuvenating effect.

The rejuvenating effect of pregnancy remains a subject for discussion. We find it promising to view pregnancy as a parabiotic system in which organisms of different age (young fetus and mature mother) are functionally connected and exchange factors that affect both, in either positive or negative manner. Pregnancy is a great burden for the maternal organism and carries a risk of numerous complications. Hence, for many years, both clinical medicine and academic research have concentrated mostly on negative effects of pregnancy on the mother's health. However, recent studies have shown that pregnancy might have positive effects on the physiological state of many organs and on maternal longevity in general, especially in the absence of pregnancy-accompanying complications. Some studies even discussed the "rejuvenating" effect of pregnancy on the maternal organism.

The regenerative capacity of liver (estimated from the rate of liver regeneration after removal of 2/3 of its volume) in 10-12-month-old mice was four times lower than in young (3-month-old) animals. However, when old mice were in the third trimester of pregnancy, their rate of liver regeneration after hepatectomy was like that in young animals: in both young non-pregnant mice and aged pregnant mice, liver regenerated to its initial volume ~2 days after the surgery, while in old non-pregnant animals, liver volume remained less than 50% of the original one. Another common object for studying regeneration and its decline with age is a skeletal muscle. The regeneration index in 20-month-old mice was almost 10 times lower than in 3-month-old mice. The effects of pregnancy on skeletal muscles were like those observed in liver: pregnancy enhanced two-fold the regeneration of muscles in both aged (10-month-old) and young animals. The number of satellite cells (muscle stem cells) did not differ between the groups, which indicates that deterioration of the regenerative functions was not due to the exhaustion of the pool of these cells. The decline in the regenerative capacity of muscle tissue with aging is believed to be related to changes in regulation, in particular, to inactivation of the Notch signaling pathway. Pregnancy reverses these changes in aged animals and restores the activity of this pathway to the levels typical for young individuals.

The rejuvenating effect of pregnancy might be explained by the donation of fetal cells capable to differentiate. The regenerative properties of stem cells are well known, and therapeutic effects of stem cells injection after brain, liver, or kidney damage have been well described. Some fetal cells enter the maternal circulation and tissues - a phenomenon known as microchimerism. Fetal cells could be found in the mother's blood and tissues several decades after pregnancy. At present, there is no consensus on the mechanisms that would explain the effects of microchimeric cells on the maternal organism. Two main possibilities are discussed: the first one is regulatory interactions, and the second is direct differentiation of microchimeric cells into a type of cells required for the mother's regeneration. In the first case, a limited number of fetal cells act as coordinators of the regenerative process. For example, fetal cells are believed to regulate inflammatory response by downregulating TGF-β biosynthesis and by directing maternal regeneration toward scar-less fetal-like wound healing. A direct contribution of microchimeric multipotent cells to regeneration has been demonstrated in a damaged heart model. Fetal cells actively migrated into the damaged area of the mother's heart, where they differentiated into fully functional cardiomyocytes that contracted synchronously with surrounding cells. In the absence of damage, the number of fetal cells in the heart was 20-fold less.

A major question remains: what exactly is the contribution of each of the factors to the rejuvenating effect of pregnancy on the maternal organism? The answers to this question will allow to develop clinical approaches for protection of pregnant women and health improvement in the human population in general.

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