How we age
The inevitability of aging is a harsh reality of life. Aging cannot be confused with anything, given the fatigue, bone fragility and general deterioration of health that usually accompany it. Old age is a major risk factor for the development of many diseases, including Alzheimer's disease, cancer, cataracts and macular degeneration. While scientists have made significant progress in the study and treatment of each of these diseases separately, there are still huge gaps in our knowledge about the aging process.
The aging process can be traced not only to the level of cells that die as a result of it or enter the phase of physiological aging, but also to the level of the genome. There is a pronounced relationship between the symptoms of aging and the accumulation of mutations, as well as a decrease in the effectiveness of DNA damage repair mechanisms. Diseases leading to premature aging are usually caused by mutations of genes involved in maintaining DNA integrity. At the same time, a number of factors can contribute to aging at the cellular level, including: a decrease in the proliferative capacity of stem cells, mitochondrial dysfunction and a tendency to abnormal folding of protein molecules. According to Paul Robbins of the Scripps Research Institute, as researchers gain more and more information about each of these processes, the biggest question remains: which of the stages of all these mechanisms is the optimal target for intervention aimed at ensuring healthy aging?
Despite the fact that a number of approaches, ranging from a low-calorie diet to genetic manipulation, have demonstrated the possibility of increasing the lifespan of model organisms in laboratory conditions, these animals do not always enjoy extended periods of good health. The ultimate goal of such research should be not just the prolongation of life, but the development of methods to prevent age-related diseases and the extinction of physical functions of the body.
GENOMEDamage control
In the process of DNA replication, the mechanisms involved in it make mistakes, which leads to changes in the DNA sequence.
Mutagens such as reactive oxygen species (ROS) or ultraviolet radiation can also cause DNA damage. In most cases, special mechanisms repair these damages, but some errors avoid correction and accumulate as the body ages. The relationship between aging and a decrease in the effectiveness of DNA damage repair mechanisms was also revealed, which increases the frequency of irreversible errors in aging organisms.
With an excessive amount of DNA damage, the cell self-destructs or loses its ability to divide, that is, it enters the phase of physiological aging. Cell death can lead to tissue atrophy or disruption of its functions. At the same time, cells that have entered the phase of physiological aging, despite their passivity, can accelerate the aging process of the body by secreting pro-inflammatory cytokines, which are considered to be involved in the development of atherosclerosis and other age-related diseases. In addition, histones – proteins that act as a framework for DNA and ensure the stabilization of the genome – begin to show changes with age that contribute to disturbances in the process of cell division, their entry into the phase of physiological aging and other processes associated with aging.
According to Jan Vijg, a geneticist from the Albert Einstein College of Medicine, while the contribution of DNA damage to the aging process is not completely clear, the fact that these damages and mutations contribute to the development of cancer is absolutely unambiguous. As the body ages, the risk of developing cancer increases exponentially, so it is likely that the accumulation of damage to the genome in this case is really a decisive factor.
Human diseases characterized by premature aging also indicate the special role of damage repair mechanisms and DNA stabilization in the aging process. For example, people with Hutchinson-Guilford progeria have mutations in the gene encoding proteins that form the core framework – nuclear lamins, and already in childhood acquire an elderly appearance and suffer from hair loss, visual impairment and atherosclerosis. In Werner syndrome, or adult progeria, characterized by the appearance of symptoms of premature aging in adolescence, patients have mutations in a gene involved in the mechanisms of DNA damage repair.
However, how DNA damage leads to the aging of normal adults remains an open question. According to Vijja, we have at our disposal excellent sequencing methods of the latest generation and have the ability to sequence DNA extracted from tissues. However, this does not make much sense, since mutations occur randomly and their set varies from cell to cell. Currently, Viige is trying to figure out how the joint activity of this mosaic of cells leads to aging.
Epigenetic shiftsIn the early 1990s, Jean-Pierre Issa, then working at Johns Hopkins University and studying changes in DNA methylation in cells of malignant tumors of the colon, noticed that epigenetic profiles change over time, not only in cancer, but also, although to a lesser extent degrees, in normal cells of various types.
Indeed, mapping the DNA methylation profile in human cells has shown that with age certain regions of the genome become hypermethylated, while the level of methylation of other regions decreases significantly. It was also found that the nature of histone modification (another type of epigenetic labels) in a number of tissues also changes with age.
These changes are the result of errors that occur during replication and repair of DNA damage. During replication, DNA methylation and histone modifications are not always reproduced with high accuracy. When DNA is damaged, repair proteins often have to remove epigenetic tags to gain access to the damaged genetic material. Subsequently, these labels may be skipped or restored incorrectly.
We have to figure out whether these epigenetic changes affect aging, namely, whether they are a concomitant manifestation of aging or directly cause age–related symptoms and diseases, limiting life expectancy.
It is known that epigenetic changes contribute to the development of cancer. There are also very interesting data obtained in experiments on animal models, according to which changes in histone modifications really have an impact on the aging process. For example, inhibition of the histone deacetylase enzyme increases the lifespan of roundworms Caenorhabditis elegans, while modifications of proteins involved in histone methylation lead to the appearance of long-lived fruit flies and C.elegans. Similarly, a change in the nature of acetylation can affect the lifespan of yeast. Issa is currently searching for drugs that can modulate DNA methylation in malignant cells, and hopes that over time such drugs will slow down the aging process.
However, he notes that age-related changes in DNA methylation are not uniform. Its level increases in some regions of the genome and decreases in others, therefore, eliminating or increasing the expression of methyltransferase enzymes carrying out this modification is not enough to return the methylation profile characteristic of a young age.
The telomere problemA particularly important form of DNA damage occurs on telomeres – repetitive sequences of nucleotides at the ends of chromosomes that shorten as the body ages.
While germ and stem cells express the enzyme telomerase, which provides telomere repair, in most cells telomeres are shortened after each division, since the enzyme DNA polymerase is not able to fully replicate the ends of chromosomes. With excessive shortening or damage of telomeres in cells, the process of apoptosis (programmed cell death) is triggered or they enter the phase of physiological aging.
Telomere damage definitely has an effect on aging. Mice with short telomeres are characterized by a short lifespan, as well as reduced functionality of stem cells and organs, whereas mice with increased telomerase activity age more slowly than ordinary animals. Telomere mutations in humans are associated with diseases accompanied by organ dysfunction and an increased risk of cancer.
In recent years, researchers have also established that telomeres are the target of stress-induced DNA damage. According to Joao Passos from the Institute of Aging at Newcastle University, for reasons unknown to date, telomeres are more sensitive to external stress than the rest of the genome.
Repairing telomere damage is a very difficult task. Telomeres protect chromosomes from merging with each other by involving protein complexes – shelterins, thanks to which proteins that restore DNA damage do not mistakenly mistake the ends of chromosomes for fragments of double-stranded breaks. However, this can prevent the restoration of real DNA damage, leading to cell death or its entry into the phase of physiological aging.
Pasush suggests that the strong susceptibility of telomeres to DNA damage may be aimed at protecting the body from the development of cancer. Considering the damage to telomeres inadequate to the strength of the stressors causing them, as well as the fact that their damage often leads to the entry of cells into the phase of physiological aging, telomeres can act as indicators warning cells about the presence of a carcinogen. That is, telomeres can actually be a kind of DNA damage sensors that suppress cell proliferation during periods of stress. This mechanism is a double-edged sword, since the physiological aging of cells not only reduces the risk of cancer, but also leads to the appearance of aging symptoms.
CELLULAR LEVELIn the folds of protein molecules
The viability of an organism depends on the normal functioning of proteins, which, in turn, is impossible without proper folding (folding) of protein molecules.
Improperly formed proteins are useless in most cases and often form intracellular aggregates with other abnormal proteins. To date, it is unclear whether a violation of the formation of protein molecules leads to aging, however, apparently, these two phenomena are components of one whole. To top it all off, old age is accompanied by the extinction of the functions of molecular chaperones – proteins that contribute to the folding of protein molecules – and protective mechanisms that, under normal conditions, contribute to the removal of abnormal proteins from the cell.
According to neuroscientist Claudio Soto from the University of Texas, there is a hypothesis that the systemic accumulation of aggregates of abnormally folded protein molecules in all cells of the body leads to progressive disruption of their functions and aging.
Experiments on C.elegans model organisms have brought very interesting data that can facilitate the search for an answer to the question from the "chicken or egg" series concerning abnormal folding of protein molecules and aging. Molecular biologist Richard Morimoto from Northwestern University and his colleagues have demonstrated that the functionality of mechanisms for maintaining proteostasis (stability of protein molecules) in the body of roundworms, such as molecular chaperones, transcription factors involved in the stress reaction and enzymes that break down proteins, begins to fade already at the early stages of the three-week life cycle these organisms. In fact, these changes begin to manifest themselves during the first days after maturity.
Soto believes that problems with the folding of protein molecules may be the main factor among the many molecular disorders characteristic of an aging organism. After all, the normal folding of protein molecules is necessary for gene expression, the functioning of proteins and a huge number of other vital mechanisms.
If the abnormal folding of protein molecules really is a kind of "trigger" for aging, normalization of this process will delay the development of many age-related diseases, and possibly aging itself.
MitochondriaAccording to the free radical theory of aging developed in the 1950s, reactive oxygen species (ROS) cause aging through global cell damage.
It is believed that, as the main sources of ROS, mitochondria and, in particular, ROS-induced damage to these organelles and their DNA, have a special role in the aging process. According to Gerald Shadel, who studies mitochondria at Yale University, this theory is one of the most viable theories of aging. However, despite the existence of many facts confirming it, recently there has been a lot of data refuting this theory.
Since the 1990s, researchers engaged in the study of model organisms have begun to describe phenomena that contradict the free radical theory. For example, enzymes blocking ROS production did not increase the lifespan of mice. And the effect of free radicals on the mitochondria of roundworms at a certain stage of development even increased their life expectancy. In 2011, Shadel's group also demonstrated that enhancing the production of mitochondrial ROS prolonged the life of yeast. Shadel suggests that, in fact, ROS-mediated signaling mechanisms play an important role in the normal physiology of the body.
Such data help to form a new vision of the role of oxidative damage to mitochondria. According to Toren Finkel from the US National Institute of Heart, Lung and Blood Diseases, if the damage is not too serious, a certain protective reaction develops in response to them. And, as you know, what doesn't kill us makes us stronger.
However, there is a limit to the amount of damage that the organelle can cope with, and mitochondrial dysfunction may well contribute to the aging process. Recently, data have been obtained demonstrating the existence of a relationship between mitochondrial DNA mutations and short life expectancy.
Shadel believes that the role of mitochondria in the aging process is likely not limited to the synthesis of ROS and even DNA damage. Given the multifaceted involvement of mitochondria in metabolism, inflammation and epigenetic regulation of nuclear DNA, these organelles may well be an integrating link for many mechanisms involved in aging.
Stem cellsIn the body of a healthy adult, approximately 200 billion new red blood cells are formed daily, replacing the same number of cells removed from the circulation every 24 hours.
However, the activity of hematopoiesis decreases with age. For this and a number of other reasons, approximately 10% of people aged 65 and older suffer from anemia. Currently, researchers are approaching the solution of the causes of age-related extinction of regenerative abilities of hematopoietic stem cells (HSCs) and other stem cell populations.
Despite the fact that HSCs can be dormant for long periods of time, they remain susceptible to DNA damage. At the same time, according to data recently obtained by Derrick Rossi from Harvard University and his colleagues, resting mouse HSCs are characterized by a weakening of the mechanisms of response to DNA damage and repair of these damages. Such a decline in the ability to repair DNA damage can contribute to the preservation of dangerous mutations.
The researchers also demonstrated the existence of a relationship between epigenetic changes, such as locus-specific changes in DNA methylation, and an age-related decrease in the regenerative capacity of stem cells. Also, age-related changes in the microenvironment, or the niche in which they divide and differentiate, can contribute to the aging of stem cells. For example, in 2012, Hartmut Geiger from the University of Ulm (Germany) and his colleagues demonstrated that age-related changes in the cells of the supporting microenvironment affect populations of hematological progenitor cells. They found that more homogeneous cell populations are formed in the young microenvironment compared to the microenvironment of an aging organism.
AT THE LEVEL OF THE BODYIntercellular interactions
Stem cells and other cells susceptible to damage and age-related loss of function do not age in isolation.
Researchers are getting more and more new data, according to which some aging processes affect the release of regulatory molecules circulating in the bloodstream.
One of these regulators is growth and differentiation factor-11 (growth differentiation factor 11, GDF11), which controls the gene expression profiles that provide anterior-posterior orientation of mammalian embryos and significantly weaken with age. Recently, researchers at Harvard University surgically connected the blood streams of young and old mice (this classic approach is called parabiosis) to study the contribution of factors contained in the blood to aging. As a result, Amy Wagers, Richard Lee and their colleagues found that young blood can restore a number of fading functions of the heart, brain and skeletal muscles of aging mice and that these effects can be reproduced by administering GDF11 to aging animals.
Currently, researchers are searching for sources of circulating GDF11, as well as trying to understand the mechanisms by which it rebuilds aging tissues. Another important issue is the confirmation of the universality of this mechanism among mammals, since in this case the results obtained in mice can extend to humans.
To study changes in GDF11 levels with age, scientists collect blood samples from mammals of different ages, ranging from cats to cows and other farm animals. They also hope to develop a more sensitive quantitative method for determining this protein in human blood to study associations between GDF11 levels in the blood and age-related diseases.
Other groups of researchers have devoted their work to studying the role of the nuclear transcription factor kappa-bi (NF-kB), which is the main activator of inflammation, in the aging process. Excessive activation of this factor can trigger the release of signaling molecules (cytokines) by cells in the phase of physiological aging that stimulate inflammation and aggravate the degradation of the body at the systemic level. According to Paul Robbins of the Scripps Research Institute, reducing the level of almost any of the NF-kB activating factors improves the symptoms associated with aging. Robbins and his colleagues demonstrated that inhibition of NF-kB can prevent the entry into the phase of physiological aging of mouse cells whose premature aging is caused by defects in DNA repair mechanisms. In fact, they want to describe the contribution made to the aging process by events occurring inside the cell, in comparison with the contribution of factors secreted by this cell and influencing cells removed from it.
For links to publications in scientific journals, see the original article.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of The Scientist: How We Age.
10.04.2015