Biomarkers of aging
Biomarkers of aging are measurable indicators of vital activity that reproducibly change, quantitatively and qualitatively, with the age of the organism. They can take place at various levels of the organization of a living system: they can be systemic, for example, changes in the immune system, in the blood system, in neuropsychic functions, in kidney function; they can be at the cellular level, for example, the so-called cellular aging, when normally dividing cells refuse to divide, go into a state of rest and do not return to division; they can be at the molecular level, for example, chromosome breakdowns or so-called genetic instability, when DNA is damaged with age, these damages accumulate in cells, and they can be detected and the age of tissues or specific cells can be determined by these indicators.
Why is it important? The fact is that if, let's say, we have a geroprotector (a drug that prolonged the life of some model animal), then how can this drug be applied to a person? A person lives for a very long time, clinical studies using a person's life expectancy are too time-consuming and financially expensive. We need something measurable, reliable, related to aging, but at the same time working for shorter periods of time, say, several years, so that we can measure some indicators and understand that, indeed, under the influence of this drug, aging is already slowing down in humans, otherwise we will never get a geroprotector applicable to a person.
There are a sufficient number of developed approaches here when we know what really correlates with aging in humans. For example, the vital capacity of the lungs changes with age. We can measure it – we can measure forced exhalation and, let's say, judge the aging of the respiratory system. We can measure the stiffness of the vascular wall and assess the state of the cardiovascular system: indeed, the vessels become more rigid, less elastic with age, and, for example, by the speed of the pulse wave propagation, we can estimate how much our vessels have aged. Autofluorescence of the skin: the fact is that during aging, crosslinking occurs between proteins, including connective tissue protein, collagen, and eventually the end products of glycation are formed, which autofluoresce – under certain lighting, we can detect this glow and determine, for example, the rate of skin aging.
When modern research methods came to medicine, in the laboratory, it allowed, for example, to establish that with age there is a change in the pattern of methylation of certain DNA sequences. A methyl label on DNA turns off the activity of certain genes. The change in the methylation pattern with age turned out to be one of the most accurate indicators of the age of a given person, that is, by measuring, for example, the level of methylation of blood cells of a certain person, with an accuracy of plus or minus three years, we can tell how old he is.
How does the biological age differ from the passport age? We can no longer change the passport age, this is our given, and the biological age is how much the vital signs of our body deviate from the norm characteristic of this age. And here it turns out that someone, for example, at the age of thirty has a biological age according to the indicators of different systems of forty years or, conversely, twenty years, that is, this person is either slowly or rapidly aging. What does this give us? We can look for intervention: lifestyle changes, diets, taking pharmaceuticals, and then observe how these changes affect the biological age in order to correct it: if a person has accelerated aging, how to slow it down, return it to the age norm, or even unscrew the biological age and make a person functionally younger than he is at the moment.
The MARK-AGE project was implemented in Europe, where human metabolism indicators and the activity of certain genes were analyzed – we have more than 20 thousand protein-coding genes. It turned out that the activity of hundreds and in some tissues even thousands of genes changes in a specific way with age, and this is a pattern characteristic of a particular age. And changes in the activity of these genes can be used to modify the rate of aging, that is, to track how we return to normal senile disturbances in the activity of genes, this chaos that occurs in the level of activity of certain genes.
In this regard, the research of centenarians is very interesting. It has long been known that people who live more than 90-100 years, 20-30 years later get sick with various age-dependent diseases, and some of them do not get diabetes, osteoporosis, or senile dementia at all. It turned out that the study of their blood metabolites, the level of activity of certain genes, and methyl tags in DNA allows us to find those differences from the average person that characterize these long-lived people. And this is a separate aspect of the problem of biomarkers of aging, that is, then we are trying to bring the indicators of a particular person not to a younger age, but to a state close, for example, to the state observed in centenarians, in the hope that this will allow us to achieve healthy longevity, that is, we are trying to bring him not to a young state, but in the state of a long-lived person who lives for more than 100 years.
Now there are about six hundred different indicators that can serve as biomarkers of human aging. They concern both cognitive functions and the functioning of various organ systems. In the metabolism and transcription of the activity level of certain genes, we find biomarkers, and, in addition, these may be proteomic biomarkers, that is, for example, the level of certain enzymes in the circulating blood. These may be markers associated with the non-enzymatic interaction between proteins and sugars, the so-called end product of glycation. These can be markers of DNA damage – for example, 8-oxyguanine is a marker of oxidative, oxidative damage to DNA molecules, and its level really increases with age. The number of mitochondria in cells decreases with age (mitochondria are the energy stations of cells responsible for the synthesis of ATP, which is necessary for all metabolic processes as an energy source). Conversely, extracellular DNA, including mitochondrial DNA, accumulates more and more in the blood with age, and this leads to inflammatory processes, because mitochondria and their oxidized ring DNA resemble bacterial and the body reacts as an infection, although this is a process that causes inflammation, but for internal reasons of our body. And the most important thing to understand is that biomarkers of aging do not work alone, that is, it is impossible to judge the rate of human aging by any one biomarker, for example, by the length of telomeres. It is necessary to take biomarkers from different organ systems, because different organ systems can age at different rates, and combine them to assess the so–called biological age, when we are already talking about the aging rate of the whole organism - not a separate indicator of some biological system, but the organism as a whole.
The determination of biological age has been carried out for a long time, but initially it was quite simple indicators: the rate of return of the heart rate to normal after physical exertion, the vital capacity of the lungs. The results of assessing the rate of aging of the body by such simple indicators are very inaccurate and hardly reproducible even for the same person at different time intervals.
But with the advent of more modern approaches, the length of telomeres has already allowed us to speak with an accuracy of plus or minus ten years about the age of a person, the level of markers of inflammation, N-glycans in the blood - plus or minus eight years, and epigenetic markers of DNA methylation are by far the most accurate – it's three years. Thus, all these indicators can already be measured in the clinic, but so far there are no such clinics where this is actively used. This gap needs to be filled, and then we will see, perhaps, hundreds of geroprotectors among existing drugs, that is, drugs that slow down aging in humans, because without biomarkers of aging, we will not be able to bring geroprotectors to the clinic.
About the author:
Alexey Moskalev is a Doctor of Biological Sciences, Head of the Laboratory of Molecular Radiobiology and Gerontology of the Institute of Biology of the Komi National Research Center of the Ural Branch of the Russian Academy of Sciences, Head of the Department of Ecology of Syktyvkar State University, Head of the Laboratory of Genetics of Life Expectancy and Aging at MIPT.
Portal "Eternal youth" http://vechnayamolodost.ru
31.03.2016