Mechanisms of aging

Authors

This area of investigations is developing by a number of scientists, among them are A. D. de Grey, J. Vijg, R. Holliday et al.

History:

The history of epigenetic researches is linked with studies of evolution and development. For a long time, many scientists did not acknowledged epigenetics at all or even intentionally passed it over in silence. 

That occurred mainly due to the fact that knowledge about the nature of epigenetic signals and ways of their realization in the organism was very indistinct. Actually, epigenetics in modern interpretation was developing and promoting by scientists of our country — I. v. Michurin, F. D. Lysenko and their followers, and by some foreign researches, e.g. D. L. Nanney an investigator of the ciliated protozoa. It should be noted that understanding of the molecular mechanisms providing epigenetic regulation of gene expressing has come only at the beginning of 2000s.

Example:

Enzygotic twins are known to be clones, i.e. exact genetic copies of each other. In the early childhood, their chromosomes have nearly the same patterns of DNA methylation in the same tissues. Nevertheless, when such twins grow old, they have sharply different patterns of DNA methylation in spite of the genetic identity and the same age.

Description:

Though chromosomes are regularly damaging and the effectiveness of the repair mechanisms declines with age, mutations occur quite rare and slowly accumulate with age.

 But the frequency of cancer and other age-related diseases indicates that gene activity changes much faster. It was found that the other type of chromosome changes appears substantially more often and makes more valuable contribution in aging. That is epimutations, i.e. changes in gene activity which are not accompanied with changes in DNA sequence. Epimutations influence gene activation and deactivation via changs in the pattern of methyl labels set in various areas of genome. If the methyl label present at nucleotides of definite gene, that gene becomes silent. On the contrary, taking methyl labels away activates the gene. The organism needs those manipulations with DNA methylation to be able to create cells and tissues with different sets of active genes and proteins synthesized on the basis of the same genotype. Proteins and functions necessary for brain neurons are vain for liver cells, and vice versa. 

When we age, global demethylation of genome takes place, and that activates genes that must normally be «silent». Demethylation is provoked by chromosome damages, age-related decline in the activity of enzymes putting methyl label through genome, redundancy of homocysteine amino acid, insufficient level of sex hormones. On the contrary, some important genes, e.g. genes of receptors of sex hormones, genes of telomerase and DNA repair ungergo selective hypermethylation in some tissues. That sort of epimutations switch the function of the gene off. All in all, as we age, epimutations accumulate in different tissues in a random way and change activity of a number of genes (1 to 10%). Now we know that epimutations can cause cancer, atherosclerosis, coronary heart disease, diabetes and Alzheimer’s disease.

Additions and Criticism:

Life style (including the type of diet) and environment influence substantially the probability of demethylation. For example, deficiency in uptake of vitamins (folic acid, B12) and microelements (zinc, selenium) in old age is one of the reasons of demethylation.

It is not clear as yet why age-related hypermethylation occurs. But there is no doubt that if we are able to control the process of methylation, we will possess one of the approaches allowing to control aging.

Publications:

• de Grey, Aubrey DNJ. «Protagonistic pleiotropy: why cancer may be the only pathogenic effect of accumulating nuclear mutations and epimutations in aging." Mechanisms of ageing and development 128.7 (2007): 456–459.
• Vijg, Jan. «The role of DNA damage and repair in aging: new approaches to an old problem." Mechanisms of ageing and development 129.7 (2008): 498–502.
• Gravina, Silvia, and Jan Vijg. «Epigenetic factors in aging and longevity." Pflügers Archiv-European Journal of Physiology 459.2 (2010): 247–258.
• Holliday, Robin. «Perspectives in aging and epigenetics." Epigenetics of Aging. Springer New York, 2010. 447–455.

Authors:

The understanding of this mechanism of aging is expanding owing to the works of such scientists as P. W. Landfield, A. K. Zalta, K. K. Wong, S. J. Lupien. et al.

History:

Our current use of the term stress originated only a little more than 50 years ago. This term was borrowed from the field of physics by one of the fathers of stress research H. Selye. H. Selye began using the term stress in the 1920’s. H. Selye pioneered the field of stress research and provided convincing arguments that stress impacted health. From the late 1960s, a large amount of research was undertaken to examine links between stress and disease of all kinds. By the late 1970s, stress had become the medical area of greatest concern. There was also a great amount of laboratory researches into the neuroendocrine, molecular, and immunological bases of stress. By the 1990s, «stress» had become an integral part of modern scientific understanding in all areas of physiology and human functioning, and one of the great metaphors of Western life.

Example:

Old people have increased level of the stress hormone cortisol. Under stress, that essential hormone increases sugars (glucose), amino acids and lipids in the bloodstream, suppresses inflammatory processes. 

At the same time, if the concentration of cortisol is heightened for a long period of time, that can disturb nourishment of tissues, cause arterial hypertension and suppress functions of hippocampus (that is brain region responsible for the memory). As the result, old people often have weak memory, reduced learning capability, increased irritability and increased susceptibility to depression.

Description:

Stress is a nonspecific organism’s response to a stressor (any action that causes imbalance in the stability of internal conditions). Factors favouring emergence of stress in an organism are quite numerous. They can be external (exogenous): increased or decreased environment temperature, fluctuations of oxygen concentrations in the air, injuries, hypodynamia, infections, excess or lack of nutrients, toxins, chemical mutagens, ionizing radiation and untraviolet. They can also be internal (endogenous): the psychological, neurohormonal, oxidative stress, mitochondrial stress and the stress of the endoplasmic reticulum.

By rights aging may truly be called the chronic stress. During aging more and more physiological constants of our body go beyond acceptable limits. Failure of constancy is clearly seen in the deviation of blood indeces from norma — it concerns blood pH, levels of glucose and other nutrients, amount of lipoproteins of various classes, concentrations of vitamins, macro- and microelements. The deviation of the parameters mentioned above causes activation of compensatory processes, and the latter frequently cause more damages than deviation on its own.

Additions and Criticism:

Recent researches made at the Harvard Medical School have revealed the physiological mechanism binding chronic stress and acute dysfunction of cardiovascular system. It was found that prolonged stress trigger the cascade of reactions which result in excess production of leukocytes — cells of immune system which accumulate in arteries and cause formation of complicated, rupture-prone atherosclerotic plaques. Finally, that provokes stroke.

Publications:

• Kerr, D. Steven, et al. «Chronic stress-induced acceleration of electrophysiologic and morphometric biomarkers of hippocampal aging." The Journal of neuroscience 11.5 (1991): 1316–1324.
• Simon, Naomi M., et al. «Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging." Biological psychiatry 60.5 (2006): 432–435.
• Juster, Robert-Paul, Bruce S. McEwen, and Sonia J. Lupien. «Allostatic load biomarkers of chronic stress and impact on health and cognition." Neuroscience & Biobehavioral Reviews 35.1 (2010): 2–16.
• Kiecolt-Glaser, Janice K., et al. «Chronic stress and age-related increases in the proinflammatory cytokine IL-6." Proceedings of the national Academy of Sciences 100.15 (2003): 9090–9095.

Authors:

This mechanism of aging is investigated by v. Pouthas, M. J. Allman, O. v. Reeth et al.

History:

The earliest known account of a circadian process dates from the 4th century BC, when Androsthenes, a ship captain serving under Alexander the Great, described diurnal leaf movements of the tamarind tree. The observation of a circadian or diurnal process in humans is mentioned in Chinese medical texts dated to around the 13th century. The first recorded observation of an endogenous circadian oscillation was by the French scientist J.-J. d’Ortous de Mairan in 1729 when he studied the movement of the leaves of the plant Mimosa pudica. In 1918, J. S. Szymanski showed that animals are capable of maintaining 24-hour activity patterns in the absence of external cues such as light and changes in temperature. R. Konopka and S. Benzer isolated the first clock mutant in Drosophila in the early 1970s and mapped the «period» gene, the first discovered genetic component of a circadian clock. Joseph Takahashi discovered the first mammalian «clock gene» using mice in 1994. The term «circadian» was coined by F. Halberg in the late 1950s.

Example:

Disorders of the internal clock predispose our organism to system inflammation, cancer, cardiovascular diseases, metabolic syndrome and diabetes, neurodegenerative, cognitive and sleep disorders.

Some acute pathologies like hypertensic crisis, myocardial infarction, attacks of asthma and allergy are sometimes linked to the definite day hours.

Description:

Internal body clock, or circadian rhythms are the cyclic oscillation of the intensity of various biological processes which is linked to alternation of day and night. Although circadian rhythms are connected with external stimuli, they have endogenous origin. The central (in the brain) and peripheral (in liver, lungs, heart, kidneys, skin) internal body clocks play important role in the regulation of the metabolism, sleep/wake cycles, rhythmicity of the hormones secretion, physical activity, intestinal peristalsis, body temperature, arterial pressure and levels of various metabolites in the blood.

Circadian rhythms disorders cause oxidative stress, disorders in synthesis of regulatory and other proteins, lead to inflammatory processes, insensibility to insulin, hormonal disbalance. Mistiming between the internal clock and environmental signals leads to the onset of the symptoms of tiredness, disorientation, sleeplessness, as well as to deterioration in the general level of health.

Additions and Criticism:

Tests on laboratory animals have shown that the activity of key genes controlling circadian rhythms comes down as an individual grows older. Thus, mice with mutations reducing activity of the key genes mentioned above live substantially less than normal animals. At the same time, artificial activation of some of those genes in the muscle tissue of mice leads to lifespan extension. Similar results were obtained in researches on fruit flies.

Finally, we can resume that circadian rhythms disorders conform with three characteristics of the criterion acceptable for aging detection: their appearance may be observed at the early stage of aging; such disorders promote aging; but if we prevent them, aging may be delayed.

Publications:

• Baudouin, Alexia, et al. «Differential involvement of internal clock and working memory in the production and reproduction of duration: A study on older adults." Acta Psychologica 121.3 (2006): 285–296.
• Allman, Melissa J., et al. «Properties of the internal clock: first-and second-order principles of subjective time." Annual review of psychology 65 (2014): 743–771.
• Perbal, Séverine, et al. «Effects of internal clock and memory disorders on duration reproductions and duration productions in patients with Parkinson’s disease." Brain and cognition 58.1 (2005): 35–48.
• Turek, Fred W., et al. «Effects of age on the circadian system." Neuroscience & Biobehavioral Reviews 19.1 (1995): 53–58.

Authors:

Researches on this mechanism of aging are carrying out intensively by A. Bartke, D. A. Sinclair, J. E. Brown et al.

History:

The history of researches on the metabolism covers several centuries. At present, metabolic diseases associated with aging are actively investigated. The purpose of those investigations is improvement of the life quality and development of methods allowing to increase human life span. 

Example:

Alterations of cell metabolism during aging, especially energy generation pathways often result in disease or acceleration of the aging process, namely diabetes, fatty liver disease, cardiovascular diseases, infertility and cancer.

Description:

Metabolism is a term that is used to describe all chemical reactions involved in maintaining the living state of the cells and the organism.

The aging process is characterized by progressive metabolic decline over time, namely by insulin resistance, and physiological declines in growth hormone (GH), insulin-like growth factor-1 (IGF-1), and sex steroids.

Aging is arguably the most universal contributor to the etiologies of metabolic decline and related diseases, including type 2 diabetes mellitus, cardiovascular disease, and stroke. Insulin resistance represents a major component of metabolic syndrome and is commonly observed in older adults. Major impairments include unrestrained hepatic gluconeogenesis, adipose lipogenesis, and defective glycogen synthesis and glucose uptake in skeletal muscle. Abdominal obesity, which is commonly observed with aging, is a major contributor metabolic syndrome.

Aging is also associated with an increase in proinflammatory cytokines, which are known to interfere with insulin action. These cytokines are derived from both the age-associated accrual of visceral fat and secretion of proinflammatory cytokines by increasing numbers of senescent cells. Collectively, these age-related alterations in metabolism and body fat distribution can accelerate the aging process and the onset of disease.

Additions and Criticism:

Results of researches made on experimental animals and human demonstrated that the process of aging is accompanied by changes in the ability of an organism to regulate water and electrolyte (mainly, sodium) balance. 

Generally, dehydratation of tissues, hypo- or hypernatremia take place, and mineral balance becomes negative. Moreover, elderly people are much more sensitive to the changes of that balance than young ones.

Imbalance of minerals (e.g. calcium and magnesium) observed as we age promotes osteoporosis. That imbalance is associated with age-related disorders of intestinal uptake of minerals and vitamin D, and changes in renal functioning. Magnesium deficiency can cause additional decrease in melatonin production making sleep quality worse.

Publications:

• Barzilai, Nir, et al. «The critical role of metabolic pathways in aging." Diabetes 61.6 (2012): 1315–1322.
• Rana, Karan S., et al. «The interaction between metabolic disease and ageing." Global journal of obesity, diabetes and metabolic syndrome 1.1 (2014).
• Wu, Lindsay E., Ana P. Gomes, and David A. Sinclair. «Geroncogenesis: metabolic changes during aging as a driver of tumorigenesis." Cancer cell 25.1 (2014): 12–19.

Authors:

Investigations of this mechanism of aging were conducted by A. Moskalev, F. Wu, S. Imai and other scientists.

History:

Connection between disorders of system regulation and aging was revealed in the neuroendocrine theory of aging. Modern investigations confirm the presence of that correlation.

Example:

Numerous investigations made by Russian and American researches have shown that activation and suppression of certain genes in hypothalamus (a central neuroendocrine t regulator of the metabolism at the base of the brain) can slow down aging in the whole body.

Description:

Regulation of metabolism and homeostasis, as well as realization of system functions (respiration, excretion, digestion, blood circulation, immunity) is very essential. Its disturbance causes varied diseases and increases the probability of death. Simultaneously, all the regulatory processes mentioned above are exposed to age-dependent changes, and most of them are unfavorable. For example, the ability to maintain concentration of sugars, lipids and electrolyte in blood, concentration of hormones, blood pH, arterial pressure at a stable level is often lost while we age. Thus disorders of system regulations are key to aging understanding. Those disorders become apparent at early stages of aging, exacerbation of them hasten aging but counteraction to them decelerates aging.

Physiological regulation of all functions of our organism is under control of the nervous and endocrinous systems, and both of them change substantially during aging. Functioning of some brain regions (e.g. hypothalamus, hypophysis, epiphysis) become worse as an organism ages, and this has negative influence at the functions of peripheral endocrine glands (thyroid body, pancreatic gland, adrenal gland, gonads) and diffuse endocrine system. As the result, the level of many essential hormones goes beyond normal and beyond daily rhythmics, and that increases the risk of tens of diseases.

At a cell level, aging is also caused by disorders of regulation. A good half of all the proteins acting in the development of age-dependent pathologies and in longevity supporting is regulatory proteins. They be needed for signals perception and transferring among cells and from without. Hormonal shifts, disorders of intercellular communication and genetic instability cause changes in regulations of the activity of hundreds and thousands of genes. First of all, those are genes necessary for cell growth and divisions as well as for providing stress resistance.

Additions and Criticism:

Different endocrine glands have different rate of age-related changes. Some glands, e.g. thymus, reach maximum level of development early, and by puberty, their functions decline sharply. Most other endocrine glands reduce their intensity of functioning during aging only, and that reduction is usually gradual. At the same time, activity of vasopressin (neurohypophysial hormone) and gonadotropins (hormones of the anterior pituitary) increases as we mature and reduces in very advanced age only.

Publications:

• Satoh, Akiko, and Shin-ichiro Imai. «Systemic regulation of mammalian ageing and longevity by brain sirtuins." Nature communications 5 (2014).
• Matsumoto, A. M., et al. «Aging and the neuroendocrine regulation of reproduction and body weight." Experimental gerontology 35.9 (2000): 1251–1265.
• Imai, Shin-ichiro, and Jun Yoshino. «The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing." Diabetes, Obesity and Metabolism 15.s3 (2013): 26–33.
• Wu, Frederick CW, et al. «Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study." The Journal of Clinical Endocrinology & Metabolism 93.7 (2008): 2737–2745.

Authors:

Researches on this mechanism of aging are carrying out by M. B. Kastan, R. A. Beckman, K. Neveling etc.

History:

The role of this mechanism in aging process was evaluated due to investigations that were started in the majority in 1990s. Correlation between aging and genetic instability was analyzed on various biological systems.

Example:

The fact that genetic instability is the mark of aging is supported by the accelerated aging syndrome. It is caused by congenital mutations in genes controlling DNA repair. As the result of those mutations, young people or even children have signs of aging and even look like elderly people. Mutations induced in genes of DNA repair of mice under experimental conditions also result in accelerated aging.

Description:

The main functions of our body are under control of genes situated in nuclear chromosomes. Every cell has only two copies of each chromosome, and these copies are not identical — they can have different variants of the same gene (alleles). That is why damages of DNA molecules could badly affect cell functions. The surge of mutations that is observed during aging was called genetic instability. An example of genetic instability is telomere shortening. Telomeres are special areas at chromosome ends. They protect chromosomes so cells with defective telomeres cannot divide and even survive, but sometimes such cells begin to divide in an uncontrolled manner and become tumor ones. When we age chromosomes accumulate damage not only in telomere regions but also along the full length. The main reason of that phenomenon is that mechanisms of DNA repair cease to work effectively. Any damage of nucleotides that form genes or breaks in DNA strands cause mutations in aging cell with repair deficiency. The more mutations cell accumulates, the less viable it becomes and the high risk of its transformation into cancer one arises.

Another reason of genetic instability observed under aging is the activation of mobile genetic elements, also known as «jumping genes» or retrotransposons. Those are virus-like DNA fragments hiding in our chromosomes.

Normally, they are inactivated by addition of the methyl groups. When DNA breaks occur in a chromosome, such chromosome becomes less accessible for the methylation enzymes. This activates retrotransposones that start copy and jump to other places of chromosome. While jumping, they can take along fragments of some important genes, as well as switch some genes of and switch other genes on. That results in genome destabilization and cell aging.

Additions and Criticism:

For preventing telomeres shortening in germ and embryonal stem cells the special enzyme — telomerase — is activated in those cells. Telomerase elongates telomeres after every cell division. In the cells of most human tissues and organs, a gene responding for one of the telomerase components is switched off or works poorly. Accessory effect of that switching-off is so-called replicative aging — fading of the ability to divide. The nature took that step to protect an developing organism from a deadly disease — cancer. Ordinary cells can not divide more than certain number of times and that impede tumor formation.

Similar to retrotransposones, silent virus infections are activated in aging cells. That results in triggering of inflammatory response.

Publications:

• Kastan, Michael B., ed. Genetic instability and tumorigenesis. Vol. 221. Springer Science & Business Media, 2012.
• Strehler, Bernard L. «Genetic instability as the primary cause of human aging." Experimental gerontology 21.4 (1986): 283–319.
• Slagboom, P. Eline, and Jan Vijg. «Genetic instability and aging: theories, facts, and future perspectives." Genome 31.1 (1989): 373–385.
• Beckman, Robert A., and Lawrence A. Loeb. «Genetic instability in cancer: theory and experiment." Seminars in cancer biology. Vol. 15. No. 6. Academic Press, 2005.

Authors:

A number of scientists researches this mechanism of aging, among them are T. A. Rando, C. J. Hutchison, R. O. Oreffo et al.

History:

Owing to investigations made by L. Hayflick and P. S. Moorhead in 1961, correlation between tissues' regeneration capasity and cell aging was found. Numerous researches conducted since then and up to date allowed to establish that processes of cell aging underlie neurodegenerative diseases, osteoporosis, retinal degeneration, hearing loss, cardiovascular diseases, sarcopenia, decrepitude, diabetes mellitus type II, metabolic syndrome, pulmonary and renal insufficiency as well as carcinogenesis.

Example:

In adult skeletal muscle, where the resident dedicated stem cells («satellite cells») are capable of rapid and highly effective regeneration in response to injury, there is a loss of regenerative potential with age.

Description:

Tissues are maintained through a balance of cellular aging and regeneration. Aging refers to the gradual loss of cellular function. And regeneration is the repair of damaged tissue that allows preserving tissue function in an organism. Tissue regeneration is generally mediated by tissue-specific stem cells, as they maintain the ability to divide and self-renew throughout adulthood, giving birth to a variety of specialized cell types that can replace damaged cells.

With age, there is a gradual decline in the regenerative properties of most tissues. This decline is linked to a decreased number of stem cells, their dysfunction in self-renewal and lineage potential, and/or the inhibitory activity of the local and systemic factors in the aged stem cell niches.

It should be noted that defective regulation of regenerative processes may account for the age-related increase in the incidence of cancer.

Additions and Criticism:

Cell aging is a universal phenomenon. Scientists observed age-related accumulation of the cells unable to divide in the skin, retina, liver, spleen, aorta, kidneys and lings of a human and various aminals (primates, rodents, fish).

Publications:

• Conboy, Irina M., and Thomas A. Rando. «Aging, stem cells and tissue regeneration: lessons from muscle." Cell cycle 4.3 (2005): 407–410.
• Pekovic, Vanja, and Christopher J. Hutchison. «Adult stem cell maintenance and tissue regeneration in the ageing context: the role for A‐type lamins as intrinsic modulators of ageing in adult stem cells and their niches." Journal of anatomy 213.1 (2008): 5–25.
• Smith, James Oliver, et al. «Skeletal tissue regeneration: current approaches, challenges, and novel reconstructive strategies for an aging population." Tissue Engineering Part B: Reviews 17.5 (2011): 307–320.
• Elmore, Lynne W., et al. «Upregulation of telomerase function during tissue regeneration." Experimental biology and medicine 233.8 (2008): 958–967.

Authors:

A number of scientists make researches in this area, among them are J. Campisi, H. Y. Chung, C. E. Finch, N. S. Jenny et al.

History:

Investigation of inflammatory process have been conducting for thousands of years. Last years, inflammatory process is actively investigated at the molecular level.

Example:

Atherosclerosis provides an example of a chronic disease that involves inflammatory mechanisms. Recruitment of blood leukocytes characterizes the initiation of this disease. Its progression involves many inflammatory mediators, modulated by cells of both innate and adaptive immunity.

Description:

Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants.

The purpose of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and to initiate tissue repair.

Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli. Chronic inflammation is a prolonged inflammation.

Human aging is characterized by a chronic, low-grade inflammation, and this phenomenon has been termed as «inflammaging." Inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly people, as most if not all age-related diseases share an inflammatory pathogenesis. Among these diseases are atherosclerosis, Alzheimer disease, and cancer.

Additions and critiсism:

An inflammatory process begins as the result of a set of changes. Regulation of immune function declines during aging. Particularly, malfunctioning of niches of hemopoietic cells takes place. As the result, the amount of monocytes and macrophages, which can cause the inflammatory process in the walls of blood vessels or even in brain tissues, increase drastically. Accumulation of DNA damages and disfunctional mitochondria cause excess activation of innate immunity mechanisms. That leads to the formation of aging-dependent secretory phenotype accompanied with emission of inflammatory signal substances. Secretion of inflammatory cytokines is also associated with the increase in the amount of adipose cells that are not only a store of lipids in the organism but also play role of the distributed endocrine system.

Publications:

• Franceschi, Claudio, and Judith Campisi. «Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases." The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 69.Suppl 1 (2014): S4-S9.
• Chung, H. Y., et al. «Molecular inflammation as an underlying mechanism of the aging process and age-related diseases." Journal of dental research 90.7 (2011): 830–840.
• Finch, C. E. «Inflammation in aging processes: an integrative and ecological perspective." Handbook of the Biology of Aging (2010): 275–96.
• Jenny, Nancy S. «Inflammation in aging: cause, effect, or both?» Discovery medicine 13.73 (2012): 451–460