25 Theories of Aging

Dr. Kanala Kodanda Reddy

Learning Objectives

To learn about “why do’ and “how do” we age
The differences between programmed and damage theories of aging
To learn about the role of free radicals in aging and disease

Introduction

While any number of people anguishes over their 30th birth day and try to hide their 40th birth day, it is with the 50th that most start to actually see themselves as beginning to be old. Every man desire to live long, but no man desires to be old. The passion that slower aging is feasible has been steadily increasing over the past 50 years due to gradual accumulation of the knowledge of the effects of age on biological systems and of reasonable hypothesis to account for such changes. The nature of aging process is dispute, because more than one mechanism is involved. It is unlikely that significant attempts to slow down the aging process will be made until clear understanding is reached on the cause of this basic biological process.

Aging is unequivocally universal and irreversible process and it varies considerably within and between cultures. Getting old is the result of the interplay of biological, social, psychological and ecological factors. Human longevity, experiences and quality of later life and vision over the old age enormously differ between religions, endogamous groups etc. Anthropologists try to understand not only the evolutionary patterns of population, but also aimed to know the variation within and between population groups in terms of health, well being and aging.

At the early part of this century infectious diseases accounted for most of the deaths in human beings. With the advent of antibiotics and other advances in medical sciences, these diseases have been more or less controlled, particularly in the developed nations and resulted in a large increase in the mean life span from 40 to 70 years and above. The control of infectious diseases, however, has not made man immune to aging and death. Rapid changes from all walks of life that have taken place in human life has resulted in the precipitation of several metabolic diseases (non-communicable diseases) and hence called old age diseases. Thus aging is a progressive accumulation of changes associated with disease and death. The role of genes and environment are the key dimensions that control specific condition vis-à-vis aging in the population. It is hypothesized that achieving the healthy blessed life years (100 years) is possible only if we control or delay the onset of the old age diseases. Several theories have been proposed to understand this phenomenon.

Description of aging

Scientists and philosophers of Greece and Rome described the process of aging in terms of biological and physiological way. Hippocrates, Aristotle, Galen, and Cicero were the few who dealt with the process of aging. Aristotle in his book “On youth and old age and life and death and on respiration”, presented that youth and old age as opposites. He characterized youth as time of excess and later life as time of conservativeness and small mindedness. Galen (130-200 A.D) a Greek philosopher was the first man to characterize aging as a process beginning with conception. Plato in his book “Republic” referred to two important features of the late life, the persistence or characteristics from earlier life and the relief of having outgrown some difficulties including frustrated ambition. Cicero’s (106-43 BC) “De senectute” has become a very favorite source for contemporary writers on aging.

A Belgium mathematician, Quetelet (1936) was considered to be the first gerontologist and he had contributed a book “On the nature of man and the development of his faculties”. An English statistician, Sir Francis Galton was perhaps the next prominent investigator in the field of aging. He was influenced by Quetelet work and his fundamental contribution to the study of aging was based on the data gathered by his Anthropometric laboratory at the International Health Exhibition in London in 1884. After Galton, a number of researchers showed interest on the study of aging from different angles. Miont (1908), Metohnikoff (1908), Child (1915) and Peerl (1922) were among the eminent biologists who explained the phenomenon of aging.

William Barton (1971) in his “Observations on the process of population and the probabilities of the duration of human life in United Sates of America” attempted to show that the people of America lived longer and were healthier than people of Europe. The first American work in Geriatrics “Account of the state of the body and mind in old age” was published in 1973 by the physician Benjamin Rush.

Definition of aging

Aging is variously defined by workers in the field of biological gerontology. Shock (1961; 1962) considered aging as the sum of total of changes during an individual life span, which are common to all members of his species or strain. Adelman (1971) suggests that age is dependent on modifications in the ability to synthesize certain enzymes in response to environmental alterations, which may be a general biochemical expression of aging. Harman (1985) feels that aging is the progressive accumulation of changes with time associated with or responsible for the ever increasing likelihood of disease and death which accompanies advancing age. Jhonson (1985) feels that aging is regarded as normal or physiological process distinct from abnormal or pathological process.

Aging is an intricate phenomenon characterized by progressive decline in physiological functions and increase in mortality that is often accompanied by many pathological diseases. Although aging is almost universally conserved among all organisms, the underlying molecular mechanisms of aging remain largely elusive. Many theories have been proposed to understand the aging phenomenon.

Theories of Aging

When we try understand the aging process, two important things will strike our mindset i.e., 1) why do we age? And 2) How do we age? While the former deal with adaptability and function, the latter deal with the mechanisms involved in that. Though aging or becoming old is universal in all living organisms including man, it is quiet interesting to note that some people seem to age faster than others. This variation can be understood upon understanding the various theories that explain the aging process. Current research undertakes to unlock further mysteries of the dynamics that control the natural lifespan of the human organism. Even though the above two hypothesis are the main drives to understand the aging phenomenon, no consensus has arrived on the two, as some are fallen out of pool while others have become widely accepted (American Federation of Aging Research, 2011).

Programmed theory

Genetic theories are in place which proposes that aging is a programmed one by our alleles covering 30 percent of stake in our lifespan. Programmed theories function on the hypothesis that aging and death are the inevitable consequence of the workings of an internal biological system, involuntary from conception that decides when cells can no longer operate and reproduce at a rate sufficient to maintain health.

These theories works with the hypothesis that aging is an essential and innate part of the biology of the people under the control of three main systems like hormonal, immune and genetics. These systems may change in course of individual life span by precipitating with aging or old age symptoms. This theory basically argues that aging and death is fixed or programmed one. The best example that can be cited for the above hypothesis is a great deal of variation in life span with in species. Elephant die around 70 yrs, monkey around 25 yrs and tortoise around 200 yrs. Though environmental modifications (nutrition and medical care) to certain extent show variation in life expectancy of an individual, fairly the life span within species is constant.

Many genes have been found to be related to aging and some have proven to life extending methods, even though their effects are quiet controversy. For example several genes involved in the metabolism of high density lipoprotein (HDL) have proved to be involved in longevity (Yasumichi and Nobuyoshi, 2004).

Structural Damage Theories

Damage theories highlight the damage caused by external agents which produce irreversible reactions in our molecules. These changes are concerned with the molecular damage that accumulates inside cells over time. Damage theories of aging are based on the view that the molecular components of cells, over time, begin to malfunction and break down:

Wear and Tear Theory: August Weismann, a German biologist (1881), hypothesize that the daily break up of life, in particular abuse or overuse, literally wears the body out, leading to disease states. Body organs like heart, liver, kidney, pancreas etc are subjected to damage by toxic products out of our diet and exposure to the environment. Some of the examples are increased consumption of energy dense foods, smoking, alcohol consumption, less physically demanding work besides economic and psychological stress etc. Even under the conditions if managed by healthy diets and life styles (no smoking, alcohol optimum physical activity), advancement of age feels the effect of destroy. In the early part of life body repair system continue to compensate the effects of normal and excessive wear and tear, but as age advances, body loses the ability to repair the damage caused by external agents. Thus elderly could die of diseases that perhaps they could have effectively encountered at their young age. The degeneration of cartilage and eventual crushing of bone on bone is an example of the aging process on body joints, as wear and tear exceed the body’s ability to repair (Kirkwood and Cremer, 1982).

Waste Accumulation Theory: Accumulation of waste products due to normal metabolic processes in the cells is the main feature of this theory. Once cell accumulates with waste products, the normal function of the cell will be impaired and the process itself will become toxic to the body. Accumulation of lipofuscin pigment is an example of this waste material. The accumulation of lipofuscin within postmitotic cells is a recognized hallmark of aging occurring with a rate inversely related to longevity. Lipofuscin is an intralysosomal, polymeric substance, primarily composed of cross-linked protein residues, formed due to iron-catalyzed oxidative processes. Because it is undegradable and cannot be removed via exocytosis, lipofuscin accumulation in post mitotic cells is inevitable, whereas proliferative cells efficiently dilute it during division. Lipofusc in accumulation may also diminish autophagocytotic capacity by acting as a sink for newly produced lysosomal enzymes and, therefore, interfere with recycling of cellular components. Lipofuscin, thus, may be much more directly related to cellular degeneration at old age than was hitherto believed (Brunk and Terman, 2002).

Faulty Reconstruction Theory: Body continues to exercise the repair and rebuilding of some of the molecules in the body. This theory works with the hypothesis that with advancement of age the repair process itself produces imperfect reconstruction leading to the weakening of the cell.

Errors and Repair Theory: According to Leslie Orgel (1963) “the machinery for making protein in cells is so essential, an error in that machinery could be tragic”. The production of proteins and the reproduction of DNA sometimes are not carried out with accuracy. The body’s DNA is so vital that natural repair processes kick in when an error is made. But the system is incapable of making perfect repairs on these molecules every time, therefore the accumulation of these faulty molecules can cause diseases and other age changes to occur.

Mitochondrial Damage Theory: This theory guess the cumulative damage to mitochondria and mitochondrial DNA (mtDNA) caused by reactive oxygen species (ROS). Oxidative damage affects replication and transcription of mtDNA and results in a decline in mitochondrial function which in turn leads to enhanced ROS production and further damage to mtDNA (Hang Cui et al., 2012). Once mitochondria are lost to the cell, they cannot be replaced, leading to a gradual but unavoidable loss of energy and function in cells over time. Damage based theories assumes that damage to tissue and the organs of the body eventually lead to development of degenerative diseases such as: heart disease, cancer, diabetes, arthritis, senile dementia, alzheimer’s disease and other life ending processes.

The most widely accepted structural damage theory – and the one theory that covers all of the previous theories – is the Free Radical Theory of aging.

Free Radical Theory of Aging: The Free Radical Theory of Aging was proposed by Dr. Denham Harman in 1954. Like most bold scientific theories, Harman’s ideas were largely ignored- even disregarded – until several investigations in the late 1960’s overwhelmingly validated his brilliant insight. According to Harman, aging occurs when cells become permanently damaged from the life-long and unrelenting attack of charged molecular fragments, known as free radicals. The cellular damage inflicted by this uncontrolled oxidative stress inevitably spreads outward to the level of tissues and organs, where it eventually manifests itself as some form of degenerative disease.

According to Harman, such diseases are not really separate entities, but rather different forms of expression of the aging process, influenced by genetic endowment and environmental factors. An estimated 80 to 90 percent of all degenerative diseases are now believed to involve free radical activity. Which disease wounds you mortally depends much on the roll of the genetic risk, cast upon your conception, as well your individual lifestyle and life-long dietary choices. The human lifespan simply reflects the level of free radical damage that accumulates in cells. When enough damage accumulates, cells can’t survive properly anymore and they just simply give up (Earl Stadtman, 1998).

Free radicals in aging

The aging process may be produced due to the deleterious irreversible changes by free radical reactions (Harman, 1982). The rate of aging process would then be the sum of the adverse alterations produced in an organism per unit time. Deleterious changes attributed to free radicals include:

1) Accumulation of oxidative alterations in the long lived molecules like collagen, elastin and chromosomes

2) Breakdown of mucopolysaccharides through oxidative degradation

3) Accumulation of metabolically inert material such as ceroid and age pigment through oxidative polymerization reactions of lipids particularly polyunsaturated fatty acids and proteins

4) Changes in membranes of organelles like mitochondria and lysosomes because of lipid peroxidation and

5) Arteriocapillary fibrosis secondary to vessel injury resulting from peroxidation of serum and vessel-wall components

The hypothesis that free radicals are generated in excessive amounts from cellular reactions or from environmental factors may cause damage to cellular membranes and other components. In a logical extension of this hypothesis, Harman (1960) have argued that such damage could accumulate metabolic problems during aging and bring about death of the organism before its natural life span is attained.

Free radical reactions are implicated in a growing number of disorders including the two major diseases cancer and atherosclerosis (Harman, 1981). Free radical mediated lipid peroxidation has been proposed to be critically involved in several disease states including cancer, rheumatoid arthritis, drug associated toxicity and post ischaemic reoxygenation injury as well as in the degenerative processes that are associated with aging (Frei et al.,1988). Evidence has accumulated suggesting that circulating lipid hydroperoxides play a pivotal role in atherogenesis and thus coronary artery disease risk (Reddy et al., 1993), the single most frequent cause of death in the United States and the western world. Lipid peroxidation initiates a series of events in vitro that eventually leads to enhanced uptake of LDL by macrophages and formation of lipid laden foam cells, one of the earliest atherosclerotic lesion in the arterial intima.

Antioxidants

One of the biological changes associated with aging is an increase in free radical formation with subsequent damage to cellular processes. Several studies have investigated the free radical theory of aging and the role of antioxidants, including vitamin E (vit.E) in the life expectancy (Blumberg and Meydani, 1986). It has been suggested by Harman (1982) that Vit.E and other antioxidants may increase longevity by reducing age related diseases.

The free radical reactions would be expected to produce progressive adverse changes throughout the body and these changes more or less common to all persons to produce the normal aging pattern (Harman, 1982). The probability of developing any one of the “free radical generated diseases” should be lowered by decreasing the free radical reactions by means of food restriction, antioxidants, increase in glutathione peroxidase (GPx) and superoxide dismutase (SOD) and in case of specific disease, by decreasing the contributing environmental pollutants.

Summary

Aging is a progressive accumulation of changes associated with disease and death.
Aging is unequivocally universal and irreversible process and it varies considerably within and between cultures.
Anthropologists try to understand not only the evolutionary patterns of population, but also aimed to know the variation within and between population groups in terms of health, well being and aging.
Though aging or becoming old is universal in all living organisms including man, it is quite interesting to note that some people seem to age faster than others. This variation can be understood upon understanding the various theories that explain the aging process.
Important theories which tried to explain the aging phenomenon are programmed theories and damage theories.
Programmed theories function on the hypothesis that aging and death are the inevitable consequence of the workings of an internal biological system, involuntary from conception that decides when cells can no longer operate and reproduce at a rate sufficient to maintain health.
Damage theories highlight the damage caused by external agents which produce irreversible reactions in our molecules.
The most widely accepted structural damage theory is free radical theory of aging.
The cellular damage inflicted by uncontrolled oxidative stress inevitably spreads outward to the level of tissues and organs, where it eventually manifests itself as some form of degenerative disease.
The probability of developing any one of the “free radical generated diseases” should be lowered by decreasing the free radical reactions by means of food restriction, increased intake of antioxidants and reduce the exposure to environmental toxicants.

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References

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