Life expectancy and genes
Average and maximum life expectancy
Evgeny Rogaev, Post-science
Aging is a biological process that occurs in the body as it matures. Everyone is interested in why we age, what are the causes and mechanisms of aging. The most important thing is whether it is possible to reverse aging, because this issue is the focus of attention not only of scientists, but also of all other people. This is a very multifaceted problem, and many scientists are only dealing with part of this problem. I will start with what we are primarily interested in and what is important to isolate in this problem from the very beginning.
To begin with, about the history of why there is a process that we call aging. There are several theories and hypotheses on this score. The most well-known of them suggests that the pressure of natural selection occurs primarily before the reproductive period. Thus, after a living organism has left offspring, its individual function is exhausted. Mutations that accumulate in genes, or variants of genes that are expressed in the post-productive period, are already less significant and are not subject to selection, all kinds of diseases and aging processes arise from this. Another theory talks about the idea of selection for special genetic variants that promote reproduction. These options turn out to be harmful already in the post-productive period. This evolutionary theory explains why aging occurs.
I would single out a certain philosophical thread. The fact is that all people who live at the present time are evolutionarily successful beings. We all had ancestors, they survived and gave fertile offspring. In the process of evolution, a certain cell line is transmitted from generation to generation. To some extent, the germ cells do not age – otherwise the species would die out.
We are dealing with two questions: why the aging process of somatic cells occurs and why the cells of the germinal pathway do not age. The second question is very important, although it is not always singled out in this aspect. First, if we study why something ages, then we need to study why something doesn't age. Secondly, even in the recent history of man, there were completely different factors that influenced the duration of his life. Most often these were infectious diseases – they were the cause of most deaths. Any person who lives in a civilized modern society lives better than kings 200-300 years ago. We are talking about medical care and other benefits that affect life expectancy.
If we study the pedigrees of European royal families, we will see that out of 13-14 or more children, a maximum of 4 children survived. And even those who survived could be killed in the process of coups. Let's be honest, not a very attractive form of existence. But with the discovery of medicines, in particular antibiotics, immunostimulants, infant mortality has become lower. Despite the presence of many negative factors in medicines, which we are talking about in a civilized society, the average life expectancy of a person has increased to 80-83 years. In countries such as Japan, Switzerland, Canada, life expectancy among women has become higher than among men.
If we look at recent history, we will see that the maximum life expectancy has not changed at all. It is believed that a person can live up to 114 years. Cases in which it is described that someone lives to the age of more than 120 years, 99% false information. Including all known cases of the longest-lived people in the history of mankind. We have to separate the two concepts: what affects the average life expectancy and what affects the maximum life expectancy.
Now let's focus on genetic research. It was from them that they realized that life expectancy is plastic, it can really be influenced. If we study the epidemiological data, we will notice that the method of monozygotic twins is often used for research, since it is most convenient to trace the influence of genetic factors on human life expectancy using the example of a twin pair. In genetics, this is called "concordance of traits". We see that the genetic factor plays a role only in 20-30% of cases.
Already in the 1930s, according to animal studies, it became clear that calorie restriction is a very strict factor affecting life expectancy. Since the mid-1980s, research has begun on roundworms – C.elegans (free-living nematode). It is convenient to study it, because it has a known number of neurons, cells, it can be frozen and thawed. At first, we managed to get a result on the study of one gene, it was called age-1 (age-1). It turned out that if you turn off one gene, then life expectancy can be significantly increased. Not turning on the work of some gene, but turning off this gene. When they began to conduct a more systematic analysis of the mutants of such worms, two mutations were found. They were called daf-2, daf-16. It turned out that inactivation of two genes leads to an increase in life expectancy by 50%. And in combination of mutants of several genes, it is possible to increase the life of a roundworm by more than 5 times.
Since we know what these genes encode, similar genes, homologues, can be found in humans. It turned out that they belong to the family of genes of the insulin receptor pathway. All these genes are responsible for something close to nutrition, calorie restriction, diabetes, that is, metabolism. The genes that affect calorie restriction are involved in one way or another, and if they are turned off, then life expectancy increases.
There is also a number of data that show that if you use the drug rapamycin, which at one time was used as an antifungal, you can increase life expectancy. Genes called tor have been isolated, they are affected by rapamycin. It turned out that these genes also encode proteins that determine sensitivity to calorie restriction.
Another group of genes was discovered in the course of studies that began on yeast, on single-celled organisms, but what was obtained turned out to be true for more complex organisms. Sirtuins were found – genes that also encode proteins that regulate metabolism. Thus, these genes encode proteins that are some kind of modulators, modifiers of other proteins, deacetylases, they chemically alter other proteins. In this regard, such proteins are especially interesting from the point of view of the epigenetic theory of aging, which interests us, because it is the change in gene regulation that is probably the target in order to, if not reverse aging, then at least slow it down.
Naturally, when we move on to humans, a lot of the mechanisms that we have found in animals do not work as expected. First of all, many model animals have a completely different metabolism than humans. It is believed that the species duration depends very strictly on the level of metabolism. In particular, small animals, such as a laboratory mouse, live for two years at most, a house mouse – up to four years, their metabolism is very high. In large animals, the metabolism is somewhat lower, but there are exceptions. There are animals, say some species of bats, that live up to twenty years, but most of their lives they may be in a kind of semi–frozen state, lethargic - at this moment they do not have an active metabolism. If we exclude such periods, then their life expectancy is also very small. That is, chronological life expectancy, as well as metabolism, are very different in animals depending on the species. From the point of view of calorie restriction in humans, we get data from epidemiological studies that confirm that calorie restriction does increase life expectancy, but there are also data that do not directly confirm this.
We know that the daf-16 gene I mentioned is a gene encoding a protein called FOXO. In humans it is FOXO3, in C.elegans it is FOXO. This gene is a transcription factor operating downstream in the signaling pathway, determined by the insulin receptor and insulin–like growth factor. This is the same direction, but a different element of the structure. If we focus only on centenarians, we can trace a number of publications that show that centenarians in this gene have genetic variants that occur more often than in the general population. But the latest work, which was carried out on the basis of a large genetic database, showed that this genetic pattern is not repeated in large samples. That is, perhaps there is some factor affecting life expectancy.
Therefore, the question arises: how much do genetic factors affect the maximum life expectancy? If we break down a group of elderly people by age – before 60, after 60, after 90 years – it turns out that genetic factors have a particularly strong effect on life expectancy in a group of people over 90 years old. And until the age of 60, environmental factors still prevail. Therefore, our task and our scientific interest is to find an answer to the question why aging is a risk factor for many diseases.
Find, if possible, some protective factors that prevent diseases of late age. In particular, we are interested in centenarian people, because they usually have disorders such as atherosclerosis, hypertension, cancer risk, dementia, shift to a later stage, begin to develop later. Therefore, they have some factors that protect against such diseases. This is an interesting task with the analysis of the genomes of such people – to find protective factors from diseases, and not just to look for molecules that allow you to prolong late age, but not to treat diseases. In general, by various tricks we can increase life expectancy by 20%, by various factors or a combination of factors, and first of all, the average life expectancy. But it is unlikely that we will be able to influence the maximum life expectancy with the approaches that we now have in our hands.
It should be noted that there is a certain maximum species restriction. In this regard, it is interesting to study why different species have different life spans – to study not only the level of interindividual differences within the population, but also interspecific differences. Suppose, if we take only warm–blooded or mammals, we can see that large whales, such as sperm whales, live more than 200 years, an elephant - up to 86 years, while many small mammals live a little. If we talk about groups, primates live long enough, humans too, compared to other animals. Therefore, it is wrong to say that we live a little. But what mechanism lies behind the species limitation of life expectancy is completely unclear. It would be extremely interesting to investigate this particular issue.
About the author:
Evgeny Rogaev – Doctor of Biological Sciences, Corresponding Member of the Russian Academy of Sciences, Head of the Laboratory of Evolutionary Genomics of the N. I. Vavilov Institute of General Genetics, Head of the Department of Genetics of the Faculty of Biology of Moscow State University, University of Massachusetts Medical School.
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