Why we age

Aging is a process that we all feel for ourselves from birth to death. Today's science can already answer a large number of questions about aging, and it continues to strive to uncover more and more secrets of this fate of nature. The aging process is very difficult to explain at the cellular level, but in the macroscopic world, each of us can influence it with relatively simple actions. So what is it that we are aging? Why do some people age faster than others? Can we slow down, stop, or even reverse aging?

A constant process

We're all getting older. People and animals are aging, even the things around us are aging. Aging in this context is not just about gaining age, aging means physical wear and tear. According to the information theory of aging, this phenomenon can be caused by a physical property called entropy, which changes everything ordered into disordered ones. If we put a chilled drink on the table, it warms up to ambient temperature over time. If we invest our efforts in cleaning the apartment, over time we will find it in disarray again. A healthy and strong adult will become sick and weak in a few decades. To reverse the process of entropy, we must constantly supply energy from the outside to the system, which constantly keeps the system in the desired state. For example, we have to constantly clean to have a nice and clean apartment. Entropy plays an important role in our story.

The human body is constantly trying to fight the influence of entropy. In this context, entropy manifests itself as a accumulation of damage to our body, specifically the accumulation of cellular waste, genetic errors, and consequently inadequate responses in an attempt to repair such damage. In other words, the more the body is damaged, the less it manages to stay healthy.

The world of cells

Another important concept to keep in mind is that the human body is made up of tens of trillions of cells. These cells are grouped into functional units called organs. The system of organs then forms an independent person. Simply put, however, man is only a large cluster of different cells that communicate with each other. Each cell carries a common information stored in its nucleus in a very long molecule called DNA. Thus, each cell contains a prescription of the behavior of all other cells, but due to the so-called epigenetics, only some parts of DNA will be applied in a given cell, and another in another cell. Epigenetics reacts to the influence of the environment in which a cell is located.

For our story, let's briefly recall what a cell is and what it consists of. The cell is the basic structural and functional unit of the bodies of living multicellular organisms. It consists of a membrane and an interior formed by the cytoplasm. There are various organelles in the cytoplasm that have specific functions. Most genetic information is stored in the nucleus in the form of chromosomes. A chromosome consists of DNA and histones. DNA represents digital genetic information and histones represent analog epigenetic information. Digital information is almost unchanged over time, while analog information is given by the configuration of histones due to the environment. Histones have the ability to "turn off" or "turn on" certain sections of DNA and thereby activate or deactivate the synthesis of various proteins, i.e. proteostasis.

As another organelle, the cell also contains mitochondria, which are involved in cellular respiration by the production of ATP (adenosine triphosphate). ATP serves as a fuel for other reactions inside the cell.

Hallmarks of aging

The scientific community on aging has identified and has already extensively investigated nine hallmarks of aging. Because the human body is only a set of interacting cells, all of these hallmarks are processes at the cellular level. This article aims to explain the hallmarks of aging and conclude with easy-to-understand activities from the macroscopic world that affect or may affect these indicators. The hallmarks of aging are

• genomic instability
• telomere attrition
• epigenetic alterations
• loss of proteostasis
• deregulated nutrient sensing
• mitochondrial dysfunction
• cellular senescence
• stem cell exhaustion
• altered intercellular communication

Genomic instability

Genomic instability is characterized by a high number of genome mutations. Thus, it increases the probability of developing cancer or senescent cells and is behind some neurodegenerative and neuromuscular diseases. The genome becomes unstable for several reasons. The first important reason is the high frequency of external damage, so-called exogenous influences. These effects include, for example, exposure to ionizing radiation (background radiation, medical examinations, radon in buildings, flying, etc.) or exposure to free radicals (smoking, fried foods, polluted environment, obesity, etc.). Other causes are endogenous influences, such as the reduced ability to repair DNA due to damaged epigenetic information, which leads to the inability to express the genes responsible for DNA repair. Gene stability can also be disrupted by the natural process of DNA replication, when one of the elements of this complex process is disrupted. Last but not least, it can be the cause of inheriting a defect from parents.^[1]

Telomere attrition

The telomere is the area at the end of each arm of a chromosome that protects it from damage or merge with the surrounding chromosome. The telomere is made up of a high number of repetitive sequences of approximately 11,000 bases in the newborn and less than 4,000 bases in the elderly. This natural chromosome protection shortens with each cell division. When the maximum number of divisions, given by the Hayflick limit, is reached, the cell enters a state of replicative senescence.^[2] The length of the telomere is also one of the indicators called biological age of the organism and can predict its possible lifespan. By its very nature, DNA replication does not allow all genetic information to be copied. Telomeres therefore serve as a so-called reservoir, from which it is possible to constantly steal and thus leave the main genetic information intact.

However, the cell is able to fight telomere shortening with an enzyme called telomerase that functions as reverse transcriptase. As the name suggests, this enzyme is able to elongate telomeres. Under normal circumstances, however, it is active only in germ cells, some stem cells and white blood cells. The reason is their ability to divide quickly. The exception are most of the carcinogenic cells, which are almost immortal. However, there are substances that have the ability to indirectly suppress telomerase expression.^[3] One of these substances is, for example, turmeric, which, but also for other reasons, is used to prevent cancer.^[4] To increase the absorption of curcumin, it is good to consume it with black pepper, for example in the form of curry.^[5]

We can influence telomere shortening by our own behavior, including smoking, mental stress, obesity, but also shift work that suppresses natural circadian rhythms.^[6] Physical activity and a healthy diet, composed mainly of vegetables, whole grains and omega-3 fatty acids, on the other hand, slows down telomere shortening by blocking some of the negative effects.^[7]

Epigenetic alterations

As mentioned in the introduction, the epigenome is affected by the environment in which the cell is located. As a result, all possible cells of the human body are created from the same DNA sequence. Which sections of DNA are to be switched off and which are switched on is determined by the epigenome. Proteins called histones are used for this purpose, around which individual sections of DNA are wrapped. Binding of the acetyl group to certain histones will allow the DNA segment to be opened and allow the synthesis of the protein that the region encodes. Conversely, the removal of the acetyl group from histone causes it to tighten and transcription cannot take place.

Over time, the epigenetic information of the cell is altered. Acetyl groups bind to the wrong histones or to the right histones at the wrong time and vice versa. The cell slowly ceases to perform the functions it was originally intended to perform, and errors arise. We perceive the manifestation of these errors on a large range of cells as aging. However, changes in the epigenome can potentially return to their original state, thereby delaying the manifestations of an aging.

Loss of proteostasis

Proteostasis is the regulation of the balance of functionality of all proteins in the body. Our body is full of proteins fulfilling various specific and unmistakable functions. Proteins are chains of amino acids and the prescription for their structure is stored in the individual DNA genes, by the expression of which proteins are formed. Gradual disruption of proteostasis also manifests as aging. Proteostasis can be disrupted both by environmental influences through oxidative stress^[8] and by DNA mutations or other errors in the process of genesis of new proteins.

The autophagic-lysosomal and ubiquitin-proteasome systems are also responsible for the correct regulation of proteostasis, and their activity decreases over time.^[9]

Deregulated nutrient sensing

Reduced calorie intake without malnutrition prolongs human life. This phenomenon is also the basis of calorie restriction diets^[10] or so-called intermittent fasting.^[11] However, the same or similar effect can be achieved without starvation by targeting the metabolic pathways behind longevity. The most important of these pathways are GH/IGF-1/insulin, mTOR, FOXO3 and sirtuins. Their positive effect on survival is mainly that if the cell feels reduced food intake, it enters a stress mode, which results in a more efficient metabolism (activation of autophages by ingesting unnecessary proteins and organelles) and slowing down the division process (prolonging cell life by preventing the negative effects of division).

IGF-1 is an acronym for insulin-like growth factor 1, which aims, among other things, to inform the cell of the presence of glucose. Aging is manifested by both glucose intolerance and increased insulin resistance. Experiments in mice have shown that suppression of the IGF-1 pathway significantly prolongs their survival. A positive effect has been observed with respect to cancer, dementia, cardiovascular and metabolic diseases. In contrast, stimulation of the IGF-1 pathway has been shown to shorten life. It has also been found that certain gene mutations affecting IGF-1 expression prolong the survival of the test animals. On the other hand, IGF-1 plays an important role in fetal development, child growth, and tissue regeneration in adulthood. The combination of suppression of the IGF-1 pathway with caloric restriction leads to an even longer lifespan. In conclusion, however, it should be mentioned that the timing of suppression of the IGF-1 pathway, in terms of the life cycle of the individual, as well as influencing specific parts of this pathway play a major role in survival.^[12]

mTOR (mammalian target of rapamycin) is a mammalian protein complex capable of responding to the presence of amino acids, insulin and the growth factors IGF-1 and IGF-2, and is involved in the regulation of cell growth, metabolism and nutrient response and others. Its name is derived from an immunosuppressive substance called rapamycin, which affects its activity and is used as an immunosuppressant in organ transplants because it is able to block the transition from the G1 phase to the S phase of T-lymphocytes. Deregulation of the mTOR pathway prolongs life due to its positive effect on autophages, which eat unused proteins and cellular organelles. On the other hand, mTOR (specifically the mTORC1 complex) plays an important role in muscle growth after physical activity and intake of certain essential amino acids.^[13]

FOXO3, which belongs to the group of FOX proteins, is a tumor suppressor that is widely present in most centenarians, regardless of their ethnicity. The expression of the FOXO3 gene is affected by food through beta-hydroxybutyric acid, which is formed in the liver from fatty acids during starvation or the so-called keto diet.^[14]

Sirtuins are groups of proteins that regulate a variety of cellular processes related to cellular energy and homeostasis. They are also active during colorectal restriction and help the cell to overcome the stress period caused by lack of food. This condition, if it lasts for a suitable time, could be very positive for the human body and stand for longevity. But it is necessary to wait a while to confirm this theory. On the other hand, a positive effect was shown on obese mice, which lived longer than obese mice in the control group due to the sirtuin activator, resveratrol.^[15]

Mitochondrial dysfunction

Mitochondria provide the cell with energy to produce ATP. As we age, the number of dysfunctional mitochondria increases, giving rise to reactive oxygen species. The accumulation of these substances in the cell at high concentrations causes oxidative stress, which disrupts other processes in the cell by damaging the structure of lipids, proteins and DNA itself. This process is still debated as a possible cause of aging of the organism, but its role is probably smaller than the role of other processes mentioned in the article.^[16][17]

Cellular senescence

Cellular aging, or cellular senescence, is one of the last stages of cell development. The senescent cell no longer divides, but remains metabolically active. If it does not trigger controlled cell death, it has a negative effect on surrounding cells due to the secretion of a number of mediator molecules. These molecules can have an inflammatory effect and promote the growth of tumors around the senescent cell. We perceive the accumulation of senescent cells as aging. The cell may enter a state of senescence by all the hallmarks of aging described above, i.e. reaching the Hayflick limit through telomere shortening, expression of oncogenes that are incorrectly opened due to epigenetic noise, or accumulating DNA damage.^[9] A reduction in the rate of accumulation of senescent cells can be achieved by calorie restriction or caloric restriction mimic. Similar effects can be achieved with regular aerobic exercise such as brisk walking, running, cycling and more.

Stem cell exhaustion

Stem cells are undifferentiated cells that have the ability to proliferate (divide) and differentiate (transform). The function of stem cells is to repair damaged parts of the body. Differentiation takes place due to the influence of the environment, i.e. by altering epigenetic information. Stem cell exhaustion can occur for several reasons. Inflammatory processes, for example due to the accumulation of senescent cells, suppress the activity of stem cells. Furthermore, the stem cell may suffer from telomere shortening, despite the effect of telomerase reverse transcriptase, which aims to prolong telomeres. The stem cell may also suffer from DNA damage and genetic mutations. All processes that negatively affect other cells can also affect stem cells. The accumulation of these damages again appears as aging.^[18]

Altered intercellular communication

Pathological intercellular communication plays a role especially in inflammation, which occurs to a large extent in the elderly. Senescent cells play a major role in this, secreting cytokines into the extracellular matrix, which are involved in the immune response of surrounding cells. Surrounding cells then respond to these signals, which negatively affects their functionality. Long-term exposure to these substances causes chronic inflammation.^[9]

Conclusion

Aging is the process of an individual that is melancholy and gradually coming to an end. However, with the right lifestyle and physical activity, it is possible to slow down aging and even get into a state of so-called successful aging, which is characterized by the fact that an aging person does not suffer from any unpleasant diseases and death comes suddenly at a very old age. Soon, however, even successful aging will not be completely disease-free. The World Health Organization has included aging in the new official ICD-11 disease code, which will be published on 1 January 2022^[19]. All Member States adopt this code. Perhaps time is finally coming to recognize aging as a disease and thus the willingness to cure aging as a disease. The rapid discoveries in the field of aging science have revealed fascinating facts to us over the last 30 years, and all indications are that we have something to look forward to in the coming years or decades.