Genetics of longevity
Dream and reality
Yulia Chernaya, "Trinity Variant"
Life expectancy in the modern world varies greatly: in different countries, it ranges from 45 to 85 years. The five countries with the longest life expectancy predictably include Japan, Switzerland, the Republic of Korea, Singapore, and Spain. Russia ranks 98th in the list of 140 countries. We have all read about the benefits of a healthy lifestyle, the dangers of smoking and alcohol. But deep down we want to drink a magic pill and stay young and healthy for many years. Another open lecture at the Institute of Cytology and Genetics SB RAS (Novosibirsk) was devoted to the genetics of life expectancy. Yakov Tsepilov, art. sci. sotr. ICIG SB RAS, cand. biol. sci., told about the latest research in this field of genetics — that is, about how some manage to live long and stay healthy.
Many people do not see the difference between the genetics of aging and the genetics of longevity. But, as Tsepilov noted, the genetics of aging is a broader field that answers the questions of why organisms age, what evolutionary processes are behind it and what interspecific differences we observe. The genetics of life expectancy is trying to answer the question of why some individuals of the same species live longer.
Traditionally, it is believed that human longevity is inherited, moreover, there are populations with longer and shorter life spans. Studies conducted on twins have shown that the heritability of human life expectancy is approximately 25% (according to other data — less than 15%). To date, a huge number of genes are known, the deactivation or, conversely, the activation of which in model organisms leads to an increase in life expectancy. In 2013, it was possible to increase the life expectancy of experimental nematodes (roundworms) five times by disabling the work of a group of genes in them. In total, there are more than two thousand genes associated with life expectancy in model organisms.
But humanity, of course, is primarily interested in increasing human life expectancy.
In 2019, a group of researchers from the Institute of Biology of Aging named after Max Planck (Cologne, Germany), led by Joris Dylan, in partnership with other institutes, published the data of a genome-wide association study (PGIA, a method that allows to identify the relationship between allelic variants of genes and their manifestations). The researchers worked with various European countries, so it was decided not to designate a specific age of longevity: people aged 90 and 99 percentiles were considered as centenarians. Thanks to this approach, more than 11 thousand centenarians aged 90 percentiles participated in the study (90% of the country's residents do not live up to this age), almost 4 thousand — at the age of 99 percentiles and more than 25 thousand people — in the control group. Scientists have shown that two loci (areas of DNA on which a certain genetic determinant is located) are associated with life expectancy. One locus from this pair — rs429358 (apolipoprotein E (ApoE) e4) — is associated with lower chances of surviving to the age of 90 and 99 percentiles, while rs7412 (ApoE e2), on the contrary, significantly increases these chances.
— In reality, both genes were already known by the time the study was published. But this was the first study conducted on a large sample, with a large control group. It is noteworthy that the last of this pair of genes, APOE, is not only associated with a longer life expectancy — its presence reduces the risk of developing Alzheimer's disease. It is not surprising that this gene has become the hallmark of longevity genetics," the lecturer explains.
The results of another study important for the genetics of longevity were also published in 2019. An international group of scientists led by Paul R. H. J. Timmers conducted a PHIA on a sample of 500 thousand people. The researchers used data on the life expectancy of the parents of each of the project participants, so many media outlets wrote about the experiment with a million participants. The authors were able to identify 12 DNA sites that affect life expectancy. For 11 of the 12 loci found in this study, an association with a serious disease (autoimmune, cardiovascular diseases, Alzheimer's disease, etc.) is known. It turned out that the already mentioned APOE gene for heterozygotes (the gene is only on one chromosome inherited from one of the parents) increases the estimated life expectancy by one year, and for homozygotes (the gene is on both copies of the chromosome and inherited from both parents) — by 19! Two to three times more than any other locus.
— The authors of this study, — notes Yakov Tsepilov, — for the first time asked a very important question: do the loci they found increase life expectancy by themselves or do they increase it because they reduce the risk of a dangerous disease?
In the same year , an international group of scientists with the participation of our interlocutor published in the journal Communications Biology, the results of his research. At the center of their work was the duration of a healthy life — the expected life span from birth to the appearance of the first deadly disease. The case histories of more than 300 thousand people aged 37 to 73 years were taken from the British Biobank (UKB). Based on these data, eight diseases were selected that most often cause death after 40 years: cardiovascular diseases (some of which were considered separately), myocardial infarction (highlighted as a common cause of death), pulmonary diseases, stroke (also considered separately due to the frequency of occurrence), dementia, diabetes, cancer (all types of cancer are included in this category) and death by undetermined cause (all cases for which the cause of death was not specified fell into this group; there were quite a lot of them, and the authors of the study could not ignore this group). It turned out that the risk of any of these diseases increases exponentially with age. At the same time, all the obtained curves of the relationship between age and the risk of the disease are similar to the Gompertz curve (a mathematical function resembling a logistic curve in which growth deceleration does not occur as fast as its acceleration occurred) and doubling of probability occurs every seven to eight years. That is, every seven to eight years, the risks of dying from any disease are doubled.
— We are not the first to discover such an addiction. This doubling was discovered back in 1830, and our research based on UKB data has once again confirmed it," says Yakov.
In the same work, the authors examined the data of 447 thousand Britons. For them, the duration of a healthy life was calculated based on the medical history of their parents and a PHIA was performed. As a result, 12 associated genomic loci (DNA sites) were identified, which showed high and significant genetic correlations with obesity, type II diabetes, coronary heart disease, metabolic disorders and death from unspecified causes (based on the medical history of parents).
— It is noteworthy that there is no APOE gene among the isolated loci. And this is one of the reasons why the article was not published in a journal with a higher rating, the question about the absence of this gene was one of the first that the reviewers asked," Tsepilov admits. — I see two possible explanations for the absence of this gene. Our genetic study involved relatively young people: there were few people over 70. Naturally, there were practically no cases of dementia in this sample. And in general, in our study, although we included dementia in the list of the eight most common diseases, it accounted for a small percentage of cases. And the second possible reason is the object of our research itself. It is possible that AROE increases life expectancy, but does not have a significant effect on the duration of a healthy life.
Of the 12 loci found, five were replicated (to find confirmation of the connection in independent studies), and three of them were named for the first time. Most of the genes identified in the study are somehow related to a predisposition to one of the selected groups of diseases.
— So in this work, we could not find any prerequisites for the development of the "longevity pill", — says Yakov. — You can look for ways to reduce the likelihood of contracting a single disease that can kill you, but it has not yet been possible to find a single gene or a single group of genes that would be responsible for life expectancy.
In 2022, Tsepilov's team published another work in which they again tried to find a single "genetic component of aging". The study used statistical data from various studies, including samples of sizes from ten thousand to 500 thousand Europeans. Scientists analyzed the self-assessment of health, the forecast of healthy life expectancy, data on the life expectancy of the father and mother; they also took into account longevity, the senility index (assessment of the depletion of physiological reserves of the body, which does not adequately respond to stressful effects), the epigenetic aging hours of Hannum and Horvath (methods for assessing the risk of death from various causes and a variety of pathologies), telomere length and mosaic Y-chromosome loss (indicates genome instability that appears in old age).
Genetic correlations were measured for all the studied traits, identifying 6 of the most genetically correlated traits.
— In 2020, we developed a method that allows us to take a large number of genetically similar traits and isolate a common genetic component. There is a lot of data accumulated to date, and we applied our method to 6 signs," says Tsepilov.
The common component was named by the authors GIP1 (genetically independent phenotypes 1). And the results, admittedly, are impressive. The resulting component was correlated with all the identified genetic traits, moreover, it correlated with other known diseases.
The paper identifies 27 loci exceeding the genome-wide threshold of significance. Many of these loci were already known, however, the group decided to send 23 new loci for replication (the well-studied APOE, HLA-DRB1/DQA1, LPA and CDKN2B/-AS1 were not sent). Based on data from two independent biobanks (Finland and Japan), two loci were replicated.
"It doesn't sound very impressive," the lecturer responds to our barely concealed disappointment. — But we must not forget that by this time only 18 replicated loci associated with longevity and aging were known. In fact, our work has increased the number of known longevity loci by 10%!
The study of the expression of the isolated genes showed that most of them are somehow connected with the nervous system — with the work of the brain in the first place — and lipid metabolism (important from the point of view of cardiovascular diseases).
The next part of the work concerned a new task — to establish a causal relationship between different concentrations of proteins in the blood and life expectancy.
— Finding a causal relationship is a non-trivial task. In epidemiology and pharmacology, it is solved with the help of randomized control studies (in which subjects are randomly assigned to groups and have an equal chance of receiving a drug or placebo). We were not interested in some new drug, but in the concentration of certain metabolites, lipids, proteins in the blood," says Yakov. — It is expensive to conduct randomized control trials. But there is the so-called Mendelian randomization (an analytical method that uses genetic variants as variables to determine whether any factor has an impact on the overall picture. — Yu. Ch.).
As a result, two proteins were found, a decrease in the concentration of which significantly increases life expectancy, while it does not increase the risks of other diseases! Both proteins, apolipoprotein (a), encoded by the LPA gene, and vascular cell adhesion 1, encoded by VCAM1, have been known for a relatively long time. The relationship of VCAM1 with cardiovascular and inflammatory diseases is being actively studied. There have been attempts to investigate its effect on the life expectancy of model animals. But the link with life expectancy and human aging has been proven for the first time.
— If living organisms have genes or a group of genes that can be turned off to prolong life, why did these genes not turn off during evolution? — asked the speaker at the end of the lecture, its organizer, Professor Pavel Borodin.
— I do not know the exact answer to this question. But I would venture to suggest that longevity is a neutral sign for evolution: it is not important how many years you have lived, but how many offspring you have left.
Another wonderful question came from the audience:
— Does stupidity count as a deadly disease in any studies?
— You can argue for a long time whether stupidity is fate or illness. But in numerous studies, they tried to take into account and find a connection (or refute it) with the level and duration of education. This connection is undoubtedly there: the longer you study, the higher your expected life expectancy. Another question is whether this long duration is explained by the fact that educated people simply have a higher standard of living, or there are biological reasons related to the characteristics of people who are more inclined to study. Recent studies indicate the veracity of the second version.
I also could not deny myself the pleasure of asking a number of questions to Yakov Tsepilov:
— You have already published two articles this year. One is related to the genetics of longevity, and you talked about it in detail at the lecture. And the other, quite unexpectedly, is with the genetics of sheep.
— My specialization is quantitative and statistical genetics. The focus of my attention is the genetics of longevity and the genetics of chronic back pain (the most common cause of disability in Europe), the genetics of cardiovascular diseases (the most common cause of death) and genomic selection in animal genetics. All this is quantitative genetics used to solve various problems.
— Tell us about the most interesting results of your work on the genetics of back pain.
— About a quarter of all my scientific articles are devoted to this topic. The sign is complex, heterogeneous. We were interested in chronic back pain: when the back hurts continuously for more than three months. This is the reason for almost half of the appeals of elderly people to a therapist in Of Russia. Of course, back pain is not always associated with spinal disease, but if we talk specifically about the spine, one of the main risk factors is degeneration of intervertebral discs. Chronic back pain has been studied for a long time, as well as other chronic pains. By the way, they are all genetically related to each other. We conducted a study at the time, found loci associated with this trait. We also conducted epidemiological studies of the association of risk factors with chronic back pain. In such complex diseases, it is difficult to identify cause-and-effect relationships. For example, it is well known that an increased body mass index is associated with back pain. But what is primary: problems with the spine arise because of excess weight or a person is overweight because it hurts him to move? We were able to prove that body weight gain is the cause. But it turned out that weight has a small contribution to the problem. This conclusion was completely unexpected for the medical community. The advice to lose weight is the first thing people with back pain hear. And our research has shown that weight loss may not have such a big effect. In fact, back pain is not treated in any way today. These pains are definitely, but very difficult to relate to depression. Paradoxically, antidepressants help with some types of back pain. We were also engaged in repurposing medicines. If there is information about genetics, we can assume that some medications for other diseases can be used for back pain. In fact, in this area we are doing the same as in the genetics of longevity. But the study of back pain and medications has not yet been completed, so it's too early to talk about the results.
In general, both the genetics of longevity and the genetics of chronic pain are being actively investigated. Although research is usually very expensive, firstly, because of access to data, and secondly, because of the complex design. That is why such studies are always carried out within the framework of large collaborations, with a large number of specialists from different institutes. Many countries have collected their biobanks, phenotyped them and opened access to them for their scientists. First of all, such a measure improves the quality of life of the citizens of this country. When scientists began working with the British biobank, they tried to check the data obtained on other samples, but first of all the conclusions were made for the British population. In Russia, the organization of a federal biobank is not yet planned.
— In your opinion, is it possible to find the genes responsible for longevity? Is the "longevity medicine— a reality? — I ask the most childish question in the end.
— As for your first question: based on a lot of experiments on animals, I would consider it very likely. In a sense, the APOE gene can be considered such a gene. You can argue with me by pointing out that this gene is primarily associated with neurodegenerative diseases, and it is still necessary to live up to them. But I think there are other, similar genes. In addition, if it is possible to increase the life expectancy for model organisms, why should it not work with humans? I am optimistic.
How close science is to the appearance of "rejuvenating medicine" is up to the readers to decide. It's funny, but even if you invent a pill for old age, you won't be able to register it. Old age is not considered a disease, which means there can be no cure for it. So in pharmacology, the concept of "geroprotector" appeared — a tool that helps to increase life expectancy. Geroprotectors are registered not as medicines, but as biologically active additives. On the website geroprotectors.org a huge database of drugs has been collected that increase the life expectancy of model organisms with varying degrees of reliability. According to Yakov Tsepilov, this site presents more than 300 substances that have increased the life of mice, nematodes, fruit flies, yeast, etc.
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