How to cheat the genes of old age
Eternal youth
Scientists have identified more than a thousand genes associated with the aging process. Exposure to them allows you to prolong life. While in laboratory animals
Alexey Moskalev, Forbes
The genetics of aging and life expectancy is one of the fundamental disciplines in the study of aging processes. Actually, it was with her that success in the biology of aging began, since in the early 1990s Cynthia Kenyon from the University of Southern California (USA) showed that a mutation in only one gene in a model animal - the nematode roundworm C. elegans – leads to an increase in its life expectancy by 2 times. This fact has allowed many researchers to believe that aging can really be significantly slowed down and it can be done here and now.
Since then, research has continued, other model animals have been added to the nematodes: fruit flies of drosophila (a favorite and well-studied object by geneticists) and mice. Thanks to the use of transgenesis methods, all of them have also become actively used in research on the genetics of aging. If in the experiment of Cynthia Kenyon there was a mutation that turns off the activity of the product of a certain gene, then transgenesis allows us to investigate how, on the contrary, the activation of additional copies of certain genes can affect life expectancy and the rate of aging.
And here the fruit flies of drosophila turned out to be the most convenient model system, since their life expectancy is very short.
Experiments with them have made it possible to discover dozens of genes for life expectancy.
It turned out that the genes associated with aging are mostly associated with the regulation of metabolism and the cell's response to a lack of nutrients. Nutrients are nutrients, such as amino acids, which are needed to build cellular proteins that ensure our vital activity. The genes associated with the detection of nutrients encode, first of all, various kinases (a kind of enzymes. – Forbes), which activate the processes of cell growth and division, but at the same time, due to the intensification of metabolism, the number of errors increases, the cell ages faster, and the body as a whole, too. Therefore, mutations in genes involved in the regulation of metabolism and accelerating it lead to a slowdown in aging and an increase in life expectancy.
A well-known example is the mTOR kinase. It is located in the center of metabolic pathways that, in response to the presence of amino acids in the cell, trigger the processes of protein synthesis, and ultimately cell growth and division. But at the same time, this kinase turns off the mechanisms of cell purification from intracellular debris as unnecessary. Autophagy is a phenomenon when a cell begins to digest itself, primarily destroying damaged mitochondria and protein aggregates. This slows down aging. And when the cell has enough nutrients, it does not need to include the energy-consuming process of self-digestion. Therefore, the aging process is accelerated.
Deactivation of the mTOR kinase by mutation or pharmacological inhibition (deceleration) leads to activation of autophagy and slowing down of aging. An inhibitory effect means the suppression of the functions of a particular gene or protein encoded by this gene. We can turn off the activity of the product of a given gene pharmacologically when the substance binds to some enzyme, blocks its activity or sharply reduces it. And if this gene product was involved in the aging process, then we get a slowdown in aging.
Genes that can be attributed to longevity genes, on the contrary, are involved in reparative (restorative) processes in the cell, for example, genes of heat shock proteins. When a cell is stressed, the proteins in it get knocked into aggregates, which does not allow them to perform any function. As a result, the vital activity of the cell slows down (this is bad for the cell and leads to accelerated aging), and heat shock proteins are activated, which pull these aggregates apart or send them for disposal (autophagy).
If transgenesis used to be actively used on simple model animals, such as drosophila, nematode, now more and more expensive and lengthy studies are being conducted when transgenesis is carried out on mice. Mice are already mammals, they are evolutionarily close to humans, so such studies are especially valuable. But experiments with mice last for years. But the results of such studies, in fact, are preclinical tests, the results of which can be tried to be applied in medical practice.
If we know the target gene, we can try to regulate its activity during normal aging, including in the human body.
This can be either pharmacological regulation, when substances are selected that inhibit the function of the product, for example, aging-associated gene, or, conversely, turn off the inhibitor of the longevity gene. This is a pharmacological pathway that ultimately leads to the creation of geroprotectors – pharmacological drugs that slow down aging.
However, gene therapy is already on the way, when we will be able to control the function of the gene in the human body, for example, by introducing an additional copy and activating it in some target tissue. With the help of a gene-therapeutic approach, we will be able to slow down the aging of blood vessels in order to overcome atherosclerosis, slow down heart failure, and fight Alzheimer's or Parkinson's disease. It is cardiovascular, metabolic and neurodegenerative age-related diseases that are the main causes of mortality today.
The genetics of aging and life expectancy over the past couple of decades has revealed more than a thousand target genes associated with aging and longevity. And a number of these target genes encode proteins for which pharmacological regulators are known. For example, the already mentioned mTOR kinase has a substance called rapamycin as an inhibitor. And it has been shown that the addition of rapamycin can lead to an increase in life expectancy in mice by up to 25%. In addition, Cynthia Kenyon's experiments once showed that mutations in the P3K kinase gene can lead to a doubling of life expectancy. And our experiments on drosophila have already revealed that pharmacological inhibitors of P3K kinase lead to a 20% increase in life expectancy. This, of course, is not an increase by several times, but, nevertheless, our pharmacological effects reproduce the genetic approach, which gives hope for their use in future medicines.
Cyclooxygenase inhibitors (enzymes that are involved in inflammation processes), such as aspirin, ibuprofen, are also, apparently, potential geroprotectors and, slowing down the aging process, increase life expectancy in model experiments. The geroprotective effect of ibuprofen was revealed by an international team of researchers from the University of Washington, the Buck Institute of Aging and our group simultaneously on three model organisms, which gives hope for the universality of this effect and its application in medicine. The range of such drugs is now significantly expanding.
Unfortunately, pharmacologically not all targets are accessible, not all are regulated by some substances, but gene therapy can help here. There are already two studies on mice, when with the help of gene therapy, their life expectancy increased by 22%. And another experiment showed that the introduction of the telomerase gene (an additional copy of the gene of the enzyme that completes the ends of chromosomes) it also significantly prolonged the life of mice. That is, those targets that are pharmacologically inaccessible, we will be able to regulate in the future already with the help of gene therapy.
About the author:
Alexey Moskalev is a Doctor of Biological Sciences, Head of the Laboratory of Genetics of Life Expectancy and Aging at MIPT.
Portal "Eternal youth" http://vechnayamolodost.ru 28.03.2016