Database research on anti-aging

Author:

T. Boland.

History:

3D printing for producing a cellular construct was first introduced in 2003, when Thomas Boland of Clemson University patented the use of inkjet printing for cells. This process utilized a modified spotting system for the deposition of cells into organized 3D matrices placed on a substrate.
Organs that have been successfully printed and implemented in a clinical setting are either flat, such as skin, vascular, such as blood vessels, or hollow, such as the bladder. When artificial organs are prepared for transplantation, they are often produced with the recipient’s own cells.
More complex organs are undergoing research; these organs include the heart, pancreas, and kidneys. Estimates for when such organs can be introduced as a viable medical treatment vary.

In 2013, the company Organovo produced a human liver using 3D bioprinting, though it is not suitable for transplantation, and has primarily been used as a medium for drug testing.

Example:

Organs that have been successfully printed and implemented in a clinical setting are skin, blood vessels and the bladder.

Description:

3D bioprinting is the process of generating spatially-controlled cell patterns using 3D printing technologies, where cell function and viability are preserved within the printed construct. 3D printing allows for the layer-by-layer construction of a particular organ structure to form a cell scaffold. This can be followed by the process of cell seeding, in which cells of interest are pipetted directly onto the scaffold structure. Additionally, the process of integrating cells into the printable material itself, instead of performing seeding afterwards, has been explored.

3D bioprinting is being applied to regenerative medicine to address the need for tissues and organs suitable for transplantation. 3D bioprinting has already been used for the generation and transplantation of several tissues, including multilayered skin, bone, vascular grafts, tracheal splints, heart tissue and cartilaginous structures. Other applications include developing high-throughput 3D-bioprinted tissue models for research, drug discovery and toxicology.

Additions and Criticism:

Compared with non-biological printing, 3D bioprinting involves additional complexities, such as the choice of materials, cell types, growth and differentiation factors, and technical challenges related to the sensitivities of living cells and the construction of tissues. Addressing these complexities requires the integration of technologies from the fields of engineering, biomaterials science, cell biology, physics and medicine.

Publications:

• Mironov, Vladimir, Nuno Reis, and Brian Derby. «Review: bioprinting: a beginning." Tissue engineering 12.4 (2006): 631–634.
• Derby, Brian. «Bioprinting: inkjet printing proteins and hybrid cell-containing materials and structures." J. Mater. Chem. 18.47 (2008): 5717–5721.
• Murphy, Sean v. , and Anthony Atala. «3D bioprinting of tissues and organs." Nature biotechnology 32.8 (2014): 773–785.
• Cui, Xiaofeng, et al. «Direct human cartilage repair using three-dimensional bioprinting technology." Tissue Engineering Part A 18.11–12 (2012): 1304–1312.

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

Author

Mitochondrial free radical theory of aging — J. Miquel, A. W. Linnane.
Mitochondrial non free radical theory of aging — A. N. Lobachev.

History

The mitochondrial theory of aging has got two variant: mitochondrial free radical theory and mitochondrial non free radical theory of aging. The first one is properly a version of free radical theory of aging. It was formulated by J. Miquel in 1980 and then was developed by A. W. Linnane (1989). The second one was proposed by A. N. Lobachev in 1978. 

Example

As we age, mitochondrial functions declines in various tissues while a number of mutations in mithochondrial DNA increases.

Description of the Theory

Mitochondrial theory of aging proposes that changes in mitochondria functioning during our lipe play the main role in human aging.

Both variants of mitochondrial theory postulate that as we age, mitochondrial DNA accumulate damages (mutations and structure abnormalities). As the result, mitochondia provide less energy to cells and the cells age. Moreover, damages of mtDNA can provoke apoptosis. The main difference between the two variants of mitochondrial theory is how each of them explains the reason of age-related changes in mtDNA. 

According to the mitochondrial free radical theory of aging, the main source of age-related changes in mtDNA are free radicals. And mitochondria are not only the target for free radicals, but also the main source of free radicals found in cells (free radicals are generated in mitochondria during the process of respiration).

The mitochondrial non free radical theory of aging suggests that the main reason 

of accumulation of damages in mt DNA is the fact that at certain moment of cell life, the development of mitochondria begin to conflict with the development of nucleus. The fact is that mitochondria are quite autonomous cell organelles and they are programmed to devide infinitely. At the same time, mature somatic cells divide negligibly. And in some moment mitochondria receive less nuclear proteins than they need. As the result, mitochondria start up the process of programmed degradation. This process manifests itself mainly in occurring deletions (cutting out of pieces) in mtDNA. As the result, mtDNA becomes storter. To conclude, according to the mitochondrial non free radical theory of aging, mitochondria appears to be the «biologic clock» of the cell and programm the duration of its life. 

Additions and Сriticism

Nowadays scientific papers present lots of circumstantial evidence supporting the mitochondrial theory of aging. There is a progbem though in studying mtDNA and mitochondria in general. Actually, scientists have only a few ways that allow working with mitochondrial mutations. There is no methods of genetic engineering suitable for mitochondria and nowadays, it is impossible to create mutation or gene, insert it into mithochondria and then study the cell line obtained. The only possible way is to study mutations given by the nature.

Publications:

• Gruber, Jan, Sebastian Schaffer, and Barry Halliwell. «The mitochondrial free radical theory of ageing — where do we stand?» Frontiers in bioscience: a journal and virtual library 13 (2007): 6554–6579.
• Jang, Youngmok C., and Holly Van Remmen. «The mitochondrial theory of aging: insight from transgenic and knockout mouse models." Experimental gerontology 44.4 (2009): 256–260.
• Rasmussen, Ulla F., et al. «Experimental evidence against the mitochondrial theory of aging A study of isolated human skeletal muscle mitochondria." Experimental gerontology 38.8 (2003): 877–886.
• Gadaleta, Maria Nicola, et al. «Aging and mitochondria." Biochimie 80.10 (1998): 863–870.
• Jacobs, Howard T. «The mitochondrial theory of aging: dead or alive?» Aging cell 2.1 (2003): 11–17.
• Mandavilli, Bhaskar S., Janine H. Santos, and Bennett Van Houten. «Mitochondrial DNA repair and aging." Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 509.1 (2002): 127–151.

Author

v. M. Dilman

Histiory

This theory was proposed in 1968. Аt first, it was named the elevation hypothesis.

Example

As an individual age, there is a decline in the work of neuroendocrine system. First of all, that leads to the decline in the production of many hormones that are necessary for normal functioning of an organism. Secondly, that affect hormones interractions. Althogether a lot of bodily changes connected with aging arise, e.g. menopause, decrease in muscle mass and increased chance of degenerative disease emergence and severity. 

Description of the Theory

This theory supposes that aging is a result of age-related changed in nervous and endocrine systems coordinating interraction between all the systems of human body and responding to the changs of the internal environment or to the external medium stimuli. Age-related changes mentioned above have an impact at neuronal and hormonal paths that regulate such significant functions as reproduction, growth, development and survival.

What is the mechanism of these age-related changes? v. M. Dilman has apparently found the answer on this question. According to his elevation hypothesis (1968), aging is a result of age-dependent increasing of the threshold of sensitivity of nervous system to the regulatory homeostatic signals.
v. M. Dilman affirmed that the key condition of homoestasis maintenance is «coordinated activity of the two main regulatory sistems — endocrine and nervous».

Endocrine glands permanently oversee the internal environmet of an organism and register any abnormalities. If such abnormalities are found, endocrine glands secrete certain hormones into blood, and the state of health comes to normal. «The main gland» of an organism is the pituitary gland. It produce a lot of hormones which control how other endocrine glands produce hormones. Hypothalamus and pituitary body control many essential functions of an organism, including internal temperature, blood pressure, thirst, hunger, sexual appetites, chemical and water balances, menstrual cycles.

v. M. Dilman believed that aging is a disorder of internal homeostasis connected with increased activity of hypothalamus. The effect of this disorder is increased level of hormones in blood which leads to the development of number of pathologies, including age-related diseases and disorders (obesity, diabetes, atherosclerosis, hypertension, cancer, autoimmune disorders, metabolic immunodepression, hyperadaptosis, depression and climax). These post-maturational diseases and disorders cause aging and death.

Additions and Сriticism

Nowadays there are no doubts that hormones play very important role in aging process.

Publications

• The neuroendocrine theory of aging and degenerative disease / Vladimir Dilman, Ward Dean. — Pensacola, Fla. : Center for Bio-Gerontology, 1992. — 138 p.
• Zjacic-Rotkvic, Vanja, Lovro Kavur, and Maja Cigrovski-Berkovic. «Hormones and aging." Acta Clinica Croatica 49.4 (2010): 549–554.
• Mikhaĭlovich, v. A., et al. «[Central hemodynamics and hormonal homeostasis during surgical stress in young patients with different levels of physical preparation]." Anesteziologiia i reanimatologiia 6 (1990): 22–26.

Author:

I. I. Mechnikov, v. N. Gladyshev

History:

Initial postulates of the intoxication theory of aging were proposed by I. I. Mechnikov in 1903. In up-to-date condition, the theory was well described in 2012–2013 in v. N. Gladyshev’s papers.

Example:

There are a lot of cells in mature organism which do not divide or divide very slowly but continue taking part in the metabolism. Among these cells are brain and heart cells. Systematically, these cells accumulate side products of the metabolism and these products begin to impede cells' normal functioning.

Description of the Theory:

The theory postulates that aging is connected with the accumulation of different chemical agents in the cells and the organism can not use or throw this agents away.

It is supposed that in the course of the metabolism, there are side reactions in the cells due to fundamental imperfection of chemical and, specifically, enzymatic transformations. The more complex and intensive metabolism, the more types of side products arise in chemical reactions. Some of these products leave cells easy, but some ones are utilizing by special enzymes. One or even more enzymes have to work for each side product utilization. Different organisms have different sets of enzymes destroying side products of metabolism. Usually, these enzymes are not numerous and they operate only with the most common and the most toxic of the side products.

Remaining side products simply accumulate in the cells. The only and universal way to fight these substances is to dilute them in the process of cell division. This method successfully works, but it works for dividing cells only. Multicellular organisms, such as human being, have problems with side products because a lot of cells stop dividing but continue to take part in the metabolism. Such cells, e.g. essential brain and heart cells, accumulate side products of the metabolism, and these products begin to impede cells' normal functioning.

The main intracellular side product is lipofuscin, also known as «wear-and-tear» pigments. Lipofuscin is a complex mixture of substances which appear to be terminal products of the oxidation of intracellular lipids and proteins. As we age, lipofuscin accumulates in lysosomes of nondividing cells. Lysosomes are membrane-bound cell organelles breaking down nutrients which are entering into the cell, as well as cellular debris. Lysosomes contain hydrolytic enzymes belonging to acid hydrolases. All of the lysosomal enzymes are acid hydrolases, which are active at the acidic pH (about 5) that is maintained within lysosomes but not at the neutral pH (about 7.2) characteristic of the rest of the cytoplasm. Accumulation of lipofuscin in lysosomes leads to the dilution of enzymes and impede lysosomal content acidulation. Gradually, this reduce efficiency of the work of acid hydrolases.

Nowadays, such scientists as B. Davidson and S. L. Hofmann develop methods of lipofuscin decomposition as well as investigate ways allowing to reduce lipofuscin accumulation in the cells.

The second type of toxic products are amiloids that accumulate in the nervous tissue mainly. The most well-known amiloid is β-amiloid causing Alzheimer’s disease.

Furthermore, side products of metabolism somehow include glycated proteins that are proteins which have covalent bonds with a sugar molecule. Thereby, the intoxication theory includes someway the cross-linking theory of aging.

Additions and Сriticism:

Nowadays, this theory develops actively. Its postulates find wide application in the creation of practical methods for preventing of aging.

Publications:

• Сергиев, П. В., О. А. Донцова, and Г. В. Березкин. «Теории старения. Неустаревающая тема." Acta Naturae (русскоязычная версия) 7.1 (24) (2015).
• Gladyshev, Vadim N. «On the cause of aging and control of lifespan." Bioessays 34.11 (2012): 925–929.
• Gladyshev, Vadim N. «The origin of aging: imperfectness-driven non-random damage defines the aging process and control of lifespan." Trends in Genetics 29.9 (2013): 506–512.

Author:

F. M. Burnet, R. Walford.

History:

In 1950-60s F. M. Burnet proposed the first postulates of the immunological theory. Then this theory was developed by R. Walford and other scientists.

Example:

As we age, immune function declines. As the result, in elderly age the risk of autoimmune pathologies (in this case, the immune system does not recognise structures of the own organism) increases.

Description of the Theory:

According to the immunological theory, the immune system is programmed to decline its functions over time, and this fact is the main cause of aging.

The immune system has several important functions. It detects and destroys a wide variety of alien agents, and distinguish them from the organism’s own healthy cells and tissues, which are preserved from destruction. The efficiency of the immune system reaches the peak in the puberty, and then it gradually decreases. Thymic involution (shrinking of the thymus with age) is believed to be the main age-related change in the immune system, and this alteration begins after puberty.

In most elderly people, immunosenescence is characterized by decreased resistance to infectious diseases and decreased protection against cancer. As the result, the risk of death becomes significantly higher in elderly age. Nowadays, death caused by such infections as pneumonia, influenza, nephritis and sepsis are on the first place among the main causes of death of people over 65 years old.

Last years, lots of intense scientific researches are held which can enhance immune function in elderly people, and as the result, slow down the process of aging. One of the directions of such researches — creation of the immune system cells using methods of genetic engineering — is developed by G. Pawelec, J. Macleod, A. Thomson. Another direction is the development of methods that allow delaying thymic involution. This direction is developed by G. Sempowski, A. N. Devallejo, v. Dixit.

Additions and Сriticism:

Up to date, the immunological theory has a lot of open questions. Particularly, there is no consensus about the supreme cause of the immune system senescence. Moreover, although the role of the immune system in aging processes is established, purely immune mechanism of aging is doubtful. The immunological theory is merging with neuroendocrine and free radical theories of aging.

Publications:

• Fulop, Tamas, et al. «On the immunological theory of aging." (2014): 163–176.
• Franceschi, Claudio, et al. «The immunology of exceptional individuals: the lesson of centenarians." Immunology today 16.1 (1995): 12–16.
• George, Andrew JT, and Mary A. Ritter. «Thymic involution with ageing: obsolescence or good housekeeping?» Immunology today 17.6 (1996): 267–272.
• Daynes, R. A., and B. A. Araneo. «Prevention and reversal of some age-associated changes in immunologic responses by supplemental dehydroepiandrosterone sulfate therapy." Aging, immunology and infectious disease 3.3 (1992): 135–154.

Author:

P. Medawar

History:

This theory was proposed in 1952. Medawar’s theory was written in response to, and as an alternative for, A. Weismann’s earlier programmed death theory.

Example:

A strong, active, good-looking individual who has genes associated with Alzheimer’s disease or cancer, has a chance to die earlier in an old age, but to leave more numerous descendants.

Description of the Theory:

The sense of the theory is following: genes with harmful mutations exhibiting in old age does not meet any significant resistance of the natural selection, thereby mutations in such genes accumulate and cause aging. According to the mutation accumulation theory, genes useful in early life of an individual (e.g. genes involving in reproduction) are supporting by the natural selection in contrast to genes useful in old age (e.g. genes reducing the risk of oncological or neurodegenerative diseases).

Thus just the young generation, not the old one makes the main contribution in the creation of new generations. The author of the mutation accumulation theory relied on the fact that any population experiences hunger, drought, predator pressure, diseases and accidents, therefore, frequently, the cause of death is random injuries. Hence P. Medawar concluded that old individuals are too scanty in nature that they cannot impact on the genepool of the population neither in favour of aging not against it. The mutation accumulation theory demonstrates non-adaptive nature of aging as well as absence of special genes which cause «programmed aging». P. Medawar showed that changes an organism undergoes after reproductive age have no value for evolu

tion. While harmful mutations showing its effects in youth meet tough resistance of the natural selection due to negative effect on reproductive fitness, the similar mutations showing its effects in old age are comparatively neutral as their carriers have already given their own genes to descendants. 

Additions and Сriticism:

Restricted field of use. The mutation accumulation theory implies that an individual lives in very aggressive and unstable environment when even a small difference in qualities important for survival (e.g. speed and strength) may be useful.
If there is enough resources, no predator and if the environment is quite stable, elderly individuals will be able to leave descendants. Thus the natural selection will advantage the genes associated with longevity.
These critical notes result in the emergence of the antagonistic pleiotropy theory.

Existence of organisms with «acute» programmed death. There is a number of diverse organisms (e.g. salmon, octopus, marsupial mouse, and bamboo) which display instances of death closely following an act of sexual reproduction. Death in these species appears to be controlled by the reproductive function or controlled by whatever triggers reproduction as opposed to calendar age.

Mutations influence mainly the active genes. Therefore, accumulation of mutations in active genes only will affect the process of aging. That means these genes’ activity is associated with aging and beyond the reproductive period. The evolution assists in keeping these genes' activity in old age, and if the mutagenesis in such genes is weak, these genes will probably be able to play a positive role in the health maintenance in a senescent organism.

Resume:

It is necessary to supplement the mutation accumulation theory with other theories of aging such as the antagonistic pleiotropy theory.

Publications:

• Medawar PB: An Unsolved Problem of Biology. London, HK Lewis, 1952.
• Charlesworth B: Fisher, Medawar, Hamilton and the evolution of aging. Genetics 2000; 156:927–931.
• Charlesworth B: Evolution in Age-Structured Populations. Cambridge, Cambridge University Press, 4. Gavrilova NS, Gavrilov LA, Evdokushkina GN, Semyonova VG, Gavrilova AL, Evdokushkina NN, Kushnareva YE, Kroutko VN, Andreyev AY: Evolution, mutation, and human longevity: European royal and noble families. Hum Biol 1998;70:799–804.
• Strehler BL: Origin and comparison of the effects of time and high energy radiations on living systems. Quart Rev Biol 1959;34:117- 142.