Aging and menopause

Two population control programs

Yuri Deigin, Geektimes

What is aging? Programmed murder. And the menopause? Programmed castration. Two mechanisms of population control that genes have honed over billions of years. 

Why do genes treat us so cruelly? For the same reason they do everything else – to maximize the integral of their reproduction in time. That is, it is not the momentary maximum of the number of their copies that is important to them, but the area under the curve of the number of these copies in time. As wise economists, gene cartels do not strive for explosive growth, fraught with collapse, but for stable, long–term sustainable growth (sustainable growth - VM) to infinity. 

Why do genes need to copy themselves? Then, why does the electron "need" to the lowest possible orbital, and the free radical needs to oxidize someone. That's the way it is in our universe. And, by the way, the desire to maximize entropy seems to underlie the phenomenon of living systems (self–replicators) in general - at least if Jeremy England's calculations are correct. 

Anyway, let's go back two levels of abstraction higher – from physics to biology. It's somehow more familiar here. Why do genes need population control mechanisms? On an intuitive level, this is understandable even to a child. After all, it's not for nothing that almost any person who hears the proposal to stop aging for the first time immediately asks the question: "What about overpopulation?".

Yes, overpopulation threatens genes with extinction – if their replicators eat up all the nutritional resources, then they themselves will die of hunger, and the collective of the creator genes will sink into oblivion. And gene cooperatives that have not learned to control the population of their copiers, most likely, have been resting for a long time in this Summer. Either those who have mastered this skill (aging species), or those who have learned to wait out long periods of adverse conditions (plants, hydra, etc.) have survived to this day. Although many species can do both: for example, nematodes, are able to turn off aging at the larval stage if they feel a lack of nutrients in the environment.

Fortunately, thanks to the hypertrophied brain that gave us scientific and technological progress, overpopulation of the intelligent Human population is no longer threatened with extinction, but our unicellular ancestors have been very threatened for billions of years. I think overpopulation caused the extinction of many species due to the depletion of resources by an over-multiplied population, until cells invented apoptosis and telomeres, and the multicellular ones that appeared behind them did the same at the next level of fractality – they invented aging (phenoptosis) and menopause (replicative aging of the body). 

By the way, the female reproductive system is the shortest–lived system of our body. The term of its functioning is about 35 years (from 14-15 to 50 years), and the last 10-15 years (after 35) this functioning is very mediocre. Other body systems are also guaranteed to deteriorate with age, but not so rapidly:

By the way, with the onset of menopause, other negative processes also accelerate, for example, sarcopenia and osteopenia (loss of muscles and bone tissue):

There is an opinion that menopause is an exclusively human prerogative. They say that we are such good fellows, we have extended our lives so much that we have overtaken our physiological limit of the reproductive system. But this is not the case. Menopause (or, more precisely, the post-reproductive period of life) exists in many species – ranging from flies and worms, and ending with elephants, whales, cows, gorillas and macaques.

It is necessary to clarify that formally menopause is the termination of menstrual cycles, but in its meaning it is the loss of the body's ability to reproduce. And here lies the misunderstanding of how widespread this phenomenon is in nature. Menstrual cycles are observed only in some mammals (humans, chimpanzees, bats), but the "post-reproductive period of life", as I have already mentioned, is very many. Therefore, further, when I talk about menopause, it should be understood that I mean precisely the phenomenon of age-related sterilization (that is, loss of reproductive function), and not the narrow meaning of this term in the sense of stopping menstruation.

And, of course, menopause, like aging, is programmed. The reproductive system does not wear out due to use, but is purposefully destroyed. Which, from the point of view of population control, is absolutely logical: aging guarantees the outflow of new individuals from the population, and menopause limits the influx.

As I have already mentioned, this method of population control is not an invention of multicellular. Evolution, so fond of fractality, introduced it in unicellular organisms. And telomeres, which impose the Hayflick limit on the maximum number of cell divisions, are, in fact, exactly the same mechanism that limits the offspring of each individual cell.

What resets this limit in unicellular cells and builds up new telomeres? Sexual reproduction, that is, the exchange of genes, as a result of which a new individual is formed, which receives "permission" for the next ~ 50 divisions. As well as a new female individual in multicellular. By the way, males do not count, they do not participate in reproduction at all. Their role is only to give their partner a key in the form of a second set of chromosomes, which will open a casket with permission to reproduce a single-celled "host" of a female. This host is a sexual cell line, which, in order to replicate its genes, originally designed this female individual.

And this owner imposes very strict restrictions on reproduction for his creation. Even before the reproductive function of women turns off completely at 45-55 years, it begins to deteriorate actively from the age of 35. Not only does the risk of egg abnormalities increase from less than 0.1% in 35 years to 3.5% in 38-40 years, and the risk of fetal trisomy (for example, Down syndrome) increases from 5% in 38-40 years to 20% after 44 years, so also the risk of the mother herself dying from childbirth increases 10 times between 20 and 40 years old.

Who is in charge of this process of active destruction of the reproductive system? The same person who initially launches this system is our brain, or more precisely, the hypothalamus with the pituitary gland.

Here are the key findings from the research on the topic:

"More and more evidence suggests that there are several internal clocks that contribute to the onset of irregular cycles, decreased fertility and the onset of menopause. We present evidence confirming that a decrease in frequency and desynchronization of precisely tuned nerve signals lead to a deterioration in communication between the brain and the pituitary-ovarian axis, and that this combination of hypothalamic-pituitary-ovarian events leads to a deterioration in the regularity of cycles and the onset of menopausal transition."

In principle, leading gerontologists had an understanding that menopause does not occur due to the deterioration of the reproductive system or depletion of egg stocks back in the 1950-70 years. Dilman, Everitt, Frolkis, Aschheim wrote about this more than half a century ago. Here is a quote from my beloved 1977 book "Hypothalamus, pituitary gland and aging":

Ashheim, by the way, was one of those who set up a key experiment that showed that transplanting young eggs into an old rat does not restore its estrous (ovulation) cycles. But if you transplant old, post-reproductive eggs into a young rat, which had previously had its own removed, then these old eggs do not cause the termination of cycles in such rats. That is, the role of eggs in the termination of cycles is secondary:

And in general, we have a strange story with eggs (oocytes). 90% of them are killed before puberty: the embryo has more than 6 million of them, and at the time of the first menstruation there are less than 500 thousand. Although this is a thousandfold excess. In a woman's entire life, no more than 500 ovulations occur. And eggs are being killed constantly, and with age, faster and faster, and exponentially:

Why should nature create 6 million eggs if she is going to use no more than 500 of them? One of the hypotheses is to increase the chances of genetic mutations. Yes, yes, it is for magnification. Because only mutations in the germ cells will be inherited. And mutations are the driving force of evolution. After all, they are the ones who create new gene variants. Although it is difficult for women to compete with men who create hundreds of millions of new sperm every day, that is, the risk of mutations in men is 4-5 orders of magnitude higher.

There is another theory about why the female body produces so many oocytes – in order to minimize mitochondrial mutations in these very eggs. Presumably, when there are a lot of eggs, it will be possible for each ovulation cycle to somehow choose the one where "mitochondria are better". But this theory seems to me to be erroneous for several reasons.

First of all, mitochondrial respiration is generally turned off in oocytes, so no free radicals are formed in them, and their mitochondria do not "break down" over time, unlike other cells. Secondly, if the goal was to minimize mutations, no system would repeat the mutagenic process of creating new oocytes 6 million times, when it would be enough to repeat it only 500 times.

And, finally, the probability of mutation of mitochondrial DNA during the division of each oocyte is significantly less than the probability of mutation in nuclear DNA: mtDNA contains only 16 thousand pairs of nucleotides against 3 billion. in nuclear DNA. At the same time, each oocyte has as many as 100 thousand independent mitochondria, and mutation of mtDNA in one or more of the mitochondria will not affect mtDNA in all the others.

The protection of mitochondria in oocytes during the life of an individual could have been the original goal in separating the germ and somatic cell lines of our ancestors millions of years ago, as well as in disabling the function of mitochondrial respiration in the germ line (so that free radicals are not formed in them), but it hardly plays any role in the dynamics of destruction oocytes during their programmed destruction during the female reproductive period.

Well, in conclusion, I can't help but mention that the existence of menopause in such a large number of different species refutes the hypothesis of a trade-off of a certain finite "resource" that the body can spend either on reproduction or on maintaining somatic cells (that is, on prolonging life). After all, from the point of view of individual selection, a post-reproductive individual is completely useless for evolution, so spending a valuable "resource" on the post-reproductive period of her life would be a waste of it.

Therefore, there is no resource, but there is an aging program. Or rather, even several independent programs: a program of reproductive aging, or, roughly speaking, programmed castration, and a program of delayed killing of the individual itself, also divided into several subprograms (shutdown of the immune system, atrophy of muscles, bones, brain, deterioration of hearing, vision, heart, lungs, kidneys, teeth, etc., and etc.).

And yes, it seems obvious to me that aging is a program. Like everything else in the body. Starting from the first day of embryogenesis, when a colony of trillions grows out of one cell at a breakneck speed, and ending with puberty, a regular 28-day cycle (program!), turning off sexual function, etc. It would be very strange if all these processes in the body were programmed, but aging is not. After all, organisms are the most accurate programs, honed by billions of years of debagging.

The key question, of course, is how to turn off this subroutine, and where does it have a button. Urri, Urri? Does not give an answer… What do I personally think about this at the moment? That the central mechanism for the implementation of the aging program is epigenetics, that is, the gradual shutdown of some genes and the inclusion of others. It is clear that this process must be synchronized, which we empirically observe in the "methylation clock" of different tissues, which show very similar values at an early age and only begin to desynchronize with age.

The next logical question is whether there is a central synchronization center in the body that sets a certain clock frequency to all cells, and whether it can be overclocked. Well, or underclocking, to be precise. I see such a center in the hypothalamus, and the clock frequency in circadian rhythms. Is it possible to deceive our body by making its internal "day" last not 24, but 48 or even 240 hours? I'm not sure, but it would be interesting to try.

And the best thing would be, of course, to learn how to centrally roll back our epigenetic clock. That is, to adjust exactly the mechanisms that our genes trigger during fertilization, giving a 30-year-old egg permission to reset its age and become a new individual. Of course, it is impossible for us to completely reset, but it would not hurt to learn how to slowly move this clock back a few years at all. The successful experiments of the Belmonte group from the Salk Institute on the use of Yamanaki factors to roll back the epigenetic clock give us hope that this is possible.

In the meantime, unfortunately, modern science has no radical means of combating these programs of our murder and castration. But they will definitely be. Breakthroughs in the understanding of epigenetics give me great hope that within 25-30 years we will learn to stop and reverse all these harmful congenital pathologies. And then we can finally throw off the yoke of genes and stop being slaves to our biology.

Portal "Eternal youth" http://vechnayamolodost.ru  14.06.2017