Biogerontology

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The hand of an older adult Altenpflege 02.jpg
The hand of an older adult
Life expectancy in various countries of the world in 2019 Healthy life expectancy bar chart -world.png
Life expectancy in various countries of the world in 2019

Biogerontology is the sub-field of gerontology concerned with the biological aging process, its evolutionary origins, and potential means to intervene in the process. The term "biogerontology" was coined by S. Rattan, and came in regular use with the start of the journal BIOGERONTOLOGY in 2000. It involves interdisciplinary research on the causes, effects, and mechanisms of biological aging. Biogerontologist Leonard Hayflick has said that the natural average lifespan for a human is around 92 years and, if humans do not invent new approaches to treat aging, they will be stuck with this lifespan. [1] James Vaupel has predicted that life expectancy in industrialized countries will reach 100 for children born after the year 2000. [2] Many surveyed biogerontologists have predicted life expectancies of more than three centuries for people born after the year 2100. [3] Other scientists, more controversially, suggest the possibility of unlimited lifespans for those currently living. For example, Aubrey de Grey offers the "tentative timeframe" that with adequate funding of research to develop interventions in aging such as strategies for engineered negligible senescence, "we have a 50/50 chance of developing technology within about 25 to 30 years from now that will, under reasonable assumptions about the rate of subsequent improvements in that technology, allow us to stop people from dying of aging at any age". [4] The idea of this approach is to use presently available technology to extend lifespans of currently living humans long enough for future technological progress to resolve any remaining aging-related issues. This concept has been referred to as longevity escape velocity.

Contents

Biomedical gerontology, also known as experimental gerontology and life extension, is a sub-discipline of biogerontology endeavoring to slow, prevent, and even reverse aging in both humans and animals.

Approaches to aging

Wrinkled skin on the face is a characteristic feature of old people. Altenpflege 07.jpg
Wrinkled skin on the face is a characteristic feature of old people.

Biogerontologists vary in the degree to which they focus on the study of the aging process as a means of mitigating the diseases of aging, or as a method for extending lifespan. A relatively new interdisciplinary field called geroscience focuses on preventing diseases of aging and prolonging the 'healthspan' over which an individual lives without serious illness. [5] [6] [7] The approach of biogerontologists is that aging is disease per se and should be treated directly, with the ultimate goal of having the probability of individual dying be independent of their age (if external factors are held constant). [8] [9] [10] This is in contrast to the opinion that maximum life span can not, or should not, be altered.

Biogerontology should not be confused with geriatrics, which is a field of medicine that studying the treatment of existing disease in aging people, rather than the treatment of aging itself.

There are numerous theories of aging, and no one theory has been entirely accepted. At their extremes, the wide spectrum of aging theories can be categorized into programmed theories – which imply that aging follows a biological timetable, and error theories – which suggest aging occurs due to cumulative damage experienced by organisms. [11]

Stochastic theories

Stochastic theories of aging are theories suggesting that aging is caused by small changes in the body over time and the body's failure to restore the system and mend the damages to the body. Cells and tissues are injured due to the accumulation of damage over time resulting in the diminished functioning of organs. The notion of accumulated damage was first introduced in 1882 by biologist Dr. August Weismann as the "wear and tear" theory. [12] [13]

Wear and tear theories

Wear and tear theories of aging began to be introduced yet in 19th century. [13] They suggest that as an individual ages, body parts such as cells and organs wear out from continued use. Wearing of the body can be attributable to internal or external causes that eventually lead to an accumulation of insults which surpasses the capacity for repair. Due to these internal and external insults, cells lose their ability to regenerate, which ultimately leads to mechanical and chemical exhaustion. Some insults include chemicals in the air, food, or smoke. Other insults may be things such as viruses, trauma, free radicals, cross-linking, and high body temperature. [14]

Accumulation

Accumulation theories of aging suggest that aging is bodily decline that results from an accumulation of elements, whether introduced to the body from the environment or resulting from cell metabolism. [14]

Mutation accumulation theory

Mutation accumulation theory was first proposed by Peter Medawar in 1952 [12] as an evolutionary explanation for biological ageing and the associated decline in fitness that accompanies it. [15] The theory explains that, in the case where harmful mutations are only expressed later in life, when reproduction has ceased and future survival is increasingly unlikely, then these mutations are likely to be unknowingly passed on to future generations. [16] In this situation the force of natural selection will be weak, and so insufficient to consistently eliminate these mutations. Medawar posited that over time these mutations would accumulate due to genetic drift and lead to the evolution of what is now referred to as ageing.

Free radical theory

Free radicals are reactive molecules produced by cellular and environmental processes, and can damage the elements of the cell such as the cell membrane and DNA and cause irreversible damage. The free-radical theory of aging proposes that this damage cumulatively degrades the biological function of cells and impacts the process of aging. [17] The idea that free radicals are toxic agents was first proposed by Rebeca Gerschman and colleagues in 1945, [18] but came to prominence in 1956, when Denham Harman proposed the free-radical theory of aging and even demonstrated that free radical reactions contribute to the degradation of biological systems. [19] Oxidative damage of many types accumulate with age, such as oxidative stress that oxygen-free radicals, [20] because the free radical theory of aging argues that aging results from the damage generated by reactive oxygen species (ROS). [21] ROS are small, highly reactive, oxygen-containing molecules that can damage a complex of cellular components such as fat, proteins, or from DNA; they are naturally generated in small amounts during the body's metabolic reactions. These conditions become more common as humans grow older and include diseases related to aging, such as dementia, cancer and heart disease. Amount of free radicals in the cell can be reduced with help of antioxidants. But there's a problem that some free radicals are used by organism as signal molecules, and too active general reduction of free radicals causes to organism more harm than good. Some time ago[ when? ] idea of slowing aging using antioxidants were very popular but now high doses of antioxidants are considered harmful. At present[ when? ] some scientists try to invent approaches of local suppression of free radicals only in certain places of cells. [22] [23] Efficiency of such approach remains to be unclear, research is ongoing.

DNA damage theories

DNA damage has been one of the major causes in diseases related to aging. The stability of the genome is defined by the cells machinery of repair, damage tolerance, and checkpoint pathways that counteracts DNA damage. One hypothesis proposed by physicist Gioacchino Failla in 1958 is that damage accumulation to the DNA causes aging. [24] The hypothesis was developed soon by physicist Leó Szilárd. [25] This theory has changed over the years as new research has discovered new types of DNA damage and mutations, and several theories of aging argue that DNA damage with or without mutations causes aging. [26] [27]

DNA damage is distinctly different from mutation, although both are types of error in DNA. DNA damage is an abnormal chemical structure in DNA, while a mutation is a change in the sequence of standard base pairs. The theory that DNA damage is the primary cause of aging is based, in part, on evidence in human and mouse that inherited deficiencies in DNA repair genes often cause accelerated aging. [28] [29] [26] There is also substantial evidence that DNA damage accumulates with age in mammalian tissues, such as those of the brain, muscle, liver and kidney (see DNA damage theory of aging and DNA damage (naturally occurring)). One expectation of the theory (that DNA damage is the primary cause of aging) is that among species with differing maximum life spans, the capacity to repair DNA damage should correlate with lifespan. The first experimental test of this idea was by Hart and Setlow [30] who measured the capacity of cells from seven different mammalian species to carry out DNA repair. They found that nucleotide excision repair capability increased systematically with species longevity. This correlation was striking and stimulated a series of 11 additional experiments in different laboratories over succeeding years on the relationship of nucleotide excision repair and life span in mammalian species (reviewed by Bernstein and Bernstein [31] ). In general, the findings of these studies indicated a good correlation between nucleotide excision repair capacity and life span. Further support for the theory that DNA damage is the primary cause of aging comes from study of Poly ADP ribose polymerases (PARPs). PARPs are enzymes that are activated by DNA strand breaks and play a role in DNA base excision repair. Burkle et al. reviewed evidence that PARPs, and especially PARP-1, are involved in maintaining mammalian longevity. [32] The life span of 13 mammalian species correlated with poly(ADP ribosyl)ation capability measured in mononuclear cells. Furthermore, lymphoblastoid cell lines from peripheral blood lymphocytes of humans over age 100 had a significantly higher poly(ADP-ribosyl)ation capability than control cell lines from younger individuals.

Cross-linking theory

The cross-linking theory proposes that advanced glycation end-products (stable bonds formed by the binding of glucose to proteins) and other aberrant cross-links accumulating in aging tissues is the cause of aging. The crosslinking of proteins disables their biological functions. The hardening of the connective tissue, kidney diseases, and enlargement of the heart are connected to the cross-linking of proteins. Crosslinking of DNA can induce replication errors, and this leads to deformed cells and increases the risk of cancer. [12]

Stem cell theory of aging

Genetic

Genetic theories of aging propose that aging is programmed within each individual's genes. According to this theory, genes dictate cellular longevity. Programmed cell death, or apoptosis, is determined by a "biological clock" via genetic information in the nucleus of the cell. Genes responsible for apoptosis provide an explanation for cell death, but are less applicable to death of an entire organism. An increase in cellular apoptosis may correlate to aging, but is not a 'cause of death'. Environmental factors and genetic mutations can influence gene expression and accelerate aging.

More recently epigenetics have been explored as a contributing factor. The epigenetic clock, which relatively objectively measures the biological age of cells, are useful tool for testing different anti-aging approaches. [33] The most famous epigenetic clock is Horvath's clock, but now already more accurate analogues have appeared.

General imbalance

General imbalance theories of aging suggest that body systems, such as the endocrine, nervous, and immune systems, gradually decline and ultimately fail to function. The rate of failure varies system by system. [14]

Immunological theory

The immunological theory of aging suggests that the immune system weakens as an organism ages. This makes the organism unable to fight infections and less able to destroy old and neoplastic cells. This leads to aging and will eventually lead to death. This theory of aging was developed by Roy Walford in 1969. According to Walford, incorrect immunological procedures are the cause of the process of aging. [17] Walford, who stated that his optimized health regime would allow him to live to 120, died of Amytrophic lateral sclerosis at age 79.

See also

Related Research Articles

Senescence or biological aging is the gradual deterioration of functional characteristics in living organisms. The word senescence can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence involves an increase in death rates and/or a decrease in fecundity with increasing age, at least in the later part of an organism's life cycle. However, the resulting effects of senescence can be delayed. The 1934 discovery that calorie restriction can extend lifespans by 50% in rats, the existence of species having negligible senescence, and the existence of potentially immortal organisms such as members of the genus Hydra have motivated research into delaying senescence and thus age-related diseases. Rare human mutations can cause accelerated aging diseases.

Life extension is the concept of extending the human lifespan, either modestly through improvements in medicine or dramatically by increasing the maximum lifespan beyond its generally-settled limit of 125 years. Several researchers in the area, along with "life extensionists", "immortalists", or "longevists", postulate that future breakthroughs in tissue rejuvenation, stem cells, regenerative medicine, molecular repair, gene therapy, pharmaceuticals, and organ replacement will eventually enable humans to have indefinite lifespans through complete rejuvenation to a healthy youthful condition (agerasia). The ethical ramifications, if life extension becomes a possibility, are debated by bioethicists.

Maximum life span is a measure of the maximum amount of time one or more members of a population have been observed to survive between birth and death. The term can also denote an estimate of the maximum amount of time that a member of a given species could survive between birth and death, provided circumstances that are optimal to that member's longevity.

The free radical theory of aging states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, most biologically relevant free radicals are highly reactive. For most biological structures, free radical damage is closely associated with oxidative damage. Antioxidants are reducing agents, and limit oxidative damage to biological structures by passivating them from free radicals.

<span class="mw-page-title-main">Reactive oxygen species</span> Highly reactive molecules formed from diatomic oxygen (O₂)

In chemistry and biology, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (O2), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (O2H), superoxide (O2-), hydroxyl radical (OH.), and singlet oxygen. ROS are pervasive because they are readily produced from O2, which is abundant. ROS are important in many ways, both beneficial and otherwise. ROS function as signals, that turn on and off biological functions. They are intermediates in the redox behavior of O2, which is central to fuel cells. ROS are central to the photodegradation of organic pollutants in the atmosphere. Most often however, ROS are discussed in a biological context, ranging from their effects on aging and their role in causing dangerous genetic mutations.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encodes its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

<span class="mw-page-title-main">Molecular lesion</span> Damage to the structure of a biological molecule

A molecular lesion or point lesion is damage to the structure of a biological molecule such as DNA, RNA, or protein. This damage may result in the reduction or absence of normal function, and in rare cases the gain of a new function. Lesions in DNA may consist of breaks or other changes in chemical structure of the helix, ultimately preventing transcription. Meanwhile, lesions in proteins consist of both broken bonds and improper folding of the amino acid chain. While many nucleic acid lesions are general across DNA and RNA, some are specific to one, such as thymine dimers being found exclusively in DNA. Several cellular repair mechanisms exist, ranging from global to specific, in order to prevent lasting damage resulting from lesions.

RecQ helicase is a family of helicase enzymes initially found in Escherichia coli that has been shown to be important in genome maintenance. They function through catalyzing the reaction ATP + H2O → ADP + P and thus driving the unwinding of paired DNA and translocating in the 3' to 5' direction. These enzymes can also drive the reaction NTP + H2O → NDP + P to drive the unwinding of either DNA or RNA.

<span class="mw-page-title-main">Xeroderma pigmentosum</span> Medical condition

Xeroderma pigmentosum (XP) is a genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light. Symptoms may include a severe sunburn after only a few minutes in the sun, freckling in sun-exposed areas, dry skin and changes in skin pigmentation. Nervous system problems, such as hearing loss, poor coordination, loss of intellectual function and seizures, may also occur. Complications include a high risk of skin cancer, with about half having skin cancer by age 10 without preventative efforts, and cataracts. There may be a higher risk of other cancers such as brain cancers.

Strategies for engineered negligible senescence (SENS) is a range of proposed regenerative medical therapies, either planned or currently in development, for the periodic repair of all age-related damage to human tissue. These therapies have the ultimate aim of maintaining a state of negligible senescence in patients and postponing age-associated disease. SENS was first defined by British biogerontologist Aubrey de Grey. Many mainstream scientists believe that it is a fringe theory. De Grey later highlighted similarities and differences of SENS to subsequent categorization systems of the biology of aging, such as the highly influential Hallmarks of Aging published in 2013.

<span class="mw-page-title-main">Poly (ADP-ribose) polymerase</span> Family of proteins

Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death.

A DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair.

Enquiry into the evolution of ageing, or aging, aims to explain why a detrimental process such as ageing would evolve, and why there is so much variability in the lifespans of organisms. The classical theories of evolution suggest that environmental factors, such as predation, accidents, disease, and/or starvation, ensure that most organisms living in natural settings will not live until old age, and so there will be very little pressure to conserve genetic changes that increase longevity. Natural selection will instead strongly favor genes which ensure early maturation and rapid reproduction, and the selection for genetic traits which promote molecular and cellular self-maintenance will decline with age for most organisms.

Following is a list of topics related to life extension:

The following outline is provided as an overview of and topical guide to life extension:

<span class="mw-page-title-main">PARP1</span> Mammalian protein found in Homo sapiens

Poly [ADP-ribose] polymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an enzyme that in humans is encoded by the PARP1 gene. It is the most abundant of the PARP family of enzymes, accounting for 90% of the NAD+ used by the family. PARP1 is mostly present in cell nucleus, but cytosolic fraction of this protein was also reported.

Ageing is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In a broader sense, ageing can refer to single cells within an organism which have ceased dividing, or to the population of a species.

The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear DNA is the main subject of this analysis. Nuclear DNA damage can contribute to aging either indirectly or directly.

The disposable soma theory of aging states that organisms age due to an evolutionary trade-off between growth, reproduction, and DNA repair maintenance. Formulated by Thomas Kirkwood, the disposable soma theory explains that an organism only has a limited amount of resources that it can allocate to its various cellular processes. Therefore, a greater investment in growth and reproduction would result in reduced investment in DNA repair maintenance, leading to increased cellular damage, shortened telomeres, accumulation of mutations, compromised stem cells, and ultimately, senescence. Although many models, both animal and human, have appeared to support this theory, parts of it are still controversial. Specifically, while the evolutionary trade-off between growth and aging has been well established, the relationship between reproduction and aging is still without scientific consensus, and the cellular mechanisms largely undiscovered.

<span class="mw-page-title-main">Mitochondrial theory of ageing</span> Theory of ageing

The mitochondrial theory of ageing has two varieties: free radical and non-free radical. The first is one of the variants of the free radical theory of ageing. It was formulated by J. Miquel and colleagues in 1980 and was developed in the works of Linnane and coworkers (1989). The second was proposed by A. N. Lobachev in 1978.

References

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