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ANNALS O F CLINICAL AND LABORATORY SCIEN CE, Vol. 25, No. 1 Copyright 1995, Institute for Clinical Science, Inc.
The Process and Theories of Aging*!
JOSEPH A. KNIGHT, M.D.
Pathology and Laboratory Medicine, Salt Lake VA Medical Center,
andD epartm ent o f Pathology,
University o f Utah School o f Medicine, Salt Lake C ity, UT 84132
A wide variety of theories to explain the aging process have been proposed including: (1 ) stochastic (somatic mutation, error catastrophe, protein glycosylation); (2) developm ental (immune and neuroendocrine); (3) programmed (genome-based); and (4) free radical. Although no single hypothesis fully explains all aging phenomena, the genome-based and free radical theories, in particular, are supported by significant observational and experimental evidence. In addition, these two proposals are related to each other in some respects, and possibly to other theories as well. Continued basic and clinical research in this highly complex and critically important area will add to our understanding and appreciation of the theoretical and practical implications of the aging process.
The aging process could be extended if it had to make its way through congress.
President George Bush.
Although philosophers and scientists have long been in terested in the aging process, general in terest in this important topic was minimal before about 1960. In recent decades, however, interest in the various aspects of aging has accelerated in great part owing to the realization that not only do the e lderly form an ever
* Send rep rin t requests to: Joseph A. Knight, M.D., D epartm ent of Pathology, University of Utah School of M edicine, Salt Lake City, UT 84132.
t The 1st Kendall Kane M emorial Lecture, presented at the m eeting o f the Association o f Clinical Scientists, Tampa, FL, Novem ber 17, 1994.
increasing percentage of the population, bu t they also utilize a disproportionately high percent of health care costs.
It is estim ated that 5,000 years ago the average life expectancy (birth to death) was about 20 years. From then to the turn of this century, the life expectancy in the United States increased to 47 years; in the subsequent 90 years, it increased an additional 28 years. That is, the National Center for H ealth Statistics reported that the average life expectancy in the U.S. in 1990 was 75.4 years, 78.6 years for women and 71.8 years for men.
It is tru e th a t as p e o p le age th ey become more susceptable to a variety of
0091-7370/95/0100-0001 $01.80 Institute for C linical Science, Inc. ' j
diseases. N evertheless, it is im portant that it is recognized that aging and disease are distinctly different. Although the term aging is understood in general terms, no single formal definition is universally accepted. As a result, there have been many attem pts to define it more p re c is e ly . In th is re g a rd , H a rm a n 1 defined aging as . . . the progressive accumulation of changes with time associated w ith or responsible for the ever increasing susceptibility to disease and death which accompany age. Rothstein2 stated that the changes from maturity through senescence constitutes the aging process, while Strehler and North3 suggested that the aging process was one that m ust be: (1 ) deleterious, (2 ) progressive, (3) intrinsic (i.e., not modifiable by environm ental agents), and (4) universal.
Regardless of how aging is defined, it is w idely accepted that its effects include the following:
(1 ) a progressive decrease in efficiency and vigor of essentially all physiologic functions;
(2 ) atrophy of most, if not all, organs and tissues;
(3) increased vu lnerab ility to traum a, infections, and various immune system
m alfunctions (autoimmune disorders, amyloidosis, lymphoid diseases);
(4) in c re a se d s u sc e p tib ili ty to m ost m alignant processes; and
(5) decreased V 0 2 max (the physiologic m easurem ent of the bodys capacity to extract oxygen from the air and transmit it to the circulatory system).
Life Expectancy versus Maximum Life Span
Do humans die of old age? The bio- sc ie n tif ic m ed ica l m odel o f d ise a se assumes that death always results from a single disease process or a combination of diseases. Although this model is commonly held to be true, it is occasionally difficult to defend. Nevertheless, all e ld erly who die and are autopsied have a variety of diseases; however, are they severe enough to cause death, either singly or in combination? In some cases it is difficult to be certain.
As noted previously, the average life expectancy has progressively increased over the past many centuries, bu t particularly so since 1900 (figure 1). The im pressive increase betw een 1900 and
F ig u r e 1. C om parison of individuals living at various ages and periods o f t im e w ith th e id e a l m ax im um life span: A (ideal); B (1980); C (1920); D (1900); and E (3000 BC).
PROCESS AND TH EO R IES O F AGING 3
1960 was prim arily due to declining neonatal, in fan t, and m aterna l m ortality rates, along with the control of various infectious diseases. More recently, there has also been a significant reduction in coronary artery d isease and stroke, as well as im proved m anagem ent and treatm ent o f a w ide variety of diseases, such as cancer, diabetes, hormone disorders, etc. Nevertheless, there is no evidence that the maximum theoretical life span has increased over the past many centuries. In this regard, it was reported in 1993 that the oldest docum ented person in the world, living in France, was doing surprisingly w ell at 118 years of age .4 Furtherm ore, over the past decade, the oldest living person in the world, invariably a woman, has been in the 1 1 2 to 116 year age range.
The Aging Theories
Although the specific biologic basis of aging remains obscure, there is general agreem ent that its elucidation will be at the m o lecu la r level. F u rthe rm ore , it should be consistent, not only with the life span differences betw een species, bu t also w ith the fact that non-cycling cells such as neu rons and m yocytes undergo a relatively uniform functional decline w ith age.
There have been numerous theories to explain the aging process. However, curren t th o ugh t g enera lly p roposes tha t senescence results from various extrinsic events tha t progressively lead to cell damage and death or characteristic intrinsic events such as the genom e-based theory. These general groups have been presented in a variety of ways. Table 1 o u t l in e s th e c la s s if ic a t io n sc h em e referred to in this discussion. It should be em phasized , how ever, th a t no single theory is entirely satisfactory. Rather, it is probable that aging is due to a combination of several theories, in which some are more im portant than others. Further-
Theories of Aging
A. Stochastic (random event; wear and tear)1. Somatic mutation/DNA damage2. Error catastrophe3. Protein glycosylation
B. Developmental1. Immune2. Neuroendocrine
C. Programmed (genome-based)D. Free radical
more, it may be difficult in some cases to determ ine which processes are primary and which are secondary to other causes.
A. S t o c h a s t i c T h e o r i e s
1. Som atic m uta tion /D N A damage: This theory is based, in part, on the idea that background radiation and/or various endogenous m utagens produce random chrom osom e dam age. O ver tim e, the genetic loci become sufficiently altered such that various critical functions fail, and the cells die. Certainly, the fact that irradiation of laboratory animals leads to early death lends some credence to this hypothesis. However, since irradiation also produces free radicals, it could be considered as part of that theory.
The ability of a cell to repair itself follow ing deoxyribonucle ic acid (DNA) damage is also an integral part of this theory. Indeed, each mammalian cell has an e la b o ra te system of DNA re p a ir enzym es w hich becom e less efficien t with time. Thus, failure to repair damaged DNA or to m isrepair it could lead to gene inactivation or possibly excision of key genes. Since there is some correlation betw een the efficiency of DNA repair and life span , 5 failure to repair completely the damaged DNA is of considerable importance for certain types of damage that could further accelerate the aging process .6
A major problem with this theory is that it implies that senescence is based on random events. Aging is, however, clearly a non-random phenomenon.
2. E rror C a tastrophe: T h is theo ry holds that through random errors in translation or transcription, erroneous copies of proteins associated w ith chromosomes lead to genetic abnorm alities .7 These, in turn, result in persistently abnormal protein synthesis, and an eventual error catastrophe destroys the cell. Therefore, the ability of a cell to produce its normal c o m p le m e n t o f fu n c tio n a l p ro te in s depends not only on the correct genetic specification of the various amino acid sequences, bu t also on the competence and fidelity of the protein-synthesizing apparatus. That is, the information m ust be translated correctly.
A lthough it is tru e th a t in c re ase d amounts of abnormal proteins are present in the elderly, most of them are a result of post-translational changes. An example would be the various isoforms of creatine kinase (CK). Here, the major isoenzyme, CK-MM (also designated CK-33), is norm ally synthesized . H ow ever, after its release into the circulation, the serum
enzyme carboxypeptidase hydrolyzes off a te