A Darwinian-evolutionary concept of age-related diseases
Introduction
Aging is an intrinsic process that affects all cells, tissues, organs and organisms, the basic mechanisms of which are not yet understood. In humans, the discrepancy between chronological and biological age is particularly evident; while intrinsic aging seems to be primarily under genetic control, age-dependent diseases develop on this background as a consequence of external, modulatory factors. Therefore, the pace of aging of different organs and whole organisms differs markedly in accordance with individual experiences over a lifetime. Thus, an age-dependent decrease in mental capacity may occur in an elderly person with a still perfectly functioning cardiovascular system, while in other instances, locomotor system insufficiency may be present together with full intellectual capacity. Furthermore, there are principal differences in the pattern of the aging process in different species that are, among other hallmarks, reflected by different capacities for regeneration. Thus, elephants can re-grow their teeth many times, while humans obviously are only able to replace them once. On the other hand, in humans, keratinocytes and leucocytes are replaced every few weeks, but neuronal cells are not. Why can liver cells regenerate, but not cardiomyocytes?
In their seminal book, ‘Evolution and Healing. The New Science of Darwinian Medicine’, Nesse and Williams stated that apparently there are inherent advantages in these biological facts in the younger reproductive years, such as being able to escape or preserve one's genes for reproduction or fight for one's offspring, that have to be ‘paid’ for by the deteriorations in later years (Nesse and Williams, 1995).
From a gerontologic viewpoint, it seems attractive to adopt the idea that all organisms, including humans, seen from an ‘engineering’ viewpoint, represent optimal compromises aimed at securing the safe propagation of their genes. One may ask why human evolution did not lead to qualities matching those of other mammals, such as the sense of smell of dogs, the vision of eagles, the sonographic orientation system of bats, etc. We may also ask why the construction of certain parts of our bodies seems so odd, i.e. the awkward position of the prostate surrounding the male urethra, inevitably leading to the compression of the latter with the increasing size of the former during aging. Would it not also be much better if our elbow and knee joints could be bent in all directions while being fixed with stronger and more durable ligaments, and moved by muscles with much higher strength than those we are naturally equipped with?
Obviously, all of these conceivable ‘improvements’ of the building plan of the human organism would have to be at the expense of other characteristics, such as increased gestation time, significantly increased energy expenditure with the attendant problems of ingestion of food, transport of oxygen, requirement for a larger brain to cope with, for example, the much larger amount of data collected via more potent sensory organs, etc.
Olshansky et al. (2001) compared the human body with a race-car designed for a certain purpose, in their example a 500 mile racing distance or, in the human body, survival up to the age of reproduction. For the engineer building the car, the only fact that counts is to make sure that it runs continuously, with optimal speed and without the necessity to undergo repair until it crosses the 500 mile finish line. To achieve this goal, a certain reserve capacity has to be built into this car that will allow it to run for a considerably longer distance, perhaps even 1.000 mile or more, but not forever. Thus, the engineer has to build a car that represents an optimal compromise with respect to weight, power, streamlining, gasoline and oil consumption, resistance to high and low temperatures, etc.
Extrapolating this example to the human situation, we have to admit that survival time beyond the age of reproduction, adding a few years as a ‘safety cushion’, represents a luxury that had not been foreseen by evolution. As a matter of fact, old members of most animal species cannot be observed in the wilderness, but are only encountered in their domesticated brethren or in zoological parks. Notable exceptions to this rule are animals that have few natural enemies or that are especially protected when they grow older, such as elephants and turtles.
Clearly aging is a process that is not yet fully understood in molecular and cellular terms, and that cannot yet be influenced by medical interventions (Olshansky et al., 2002) This applies to products and procedures that are falsely propagated as ‘anti-aging medicines’ (Wick, 2002). Age-related diseases may, therefore, be the price we have to pay to enjoy the vigour of youth. The concept of antagonistic pleiotropy (Nesse and Williams, 1998) postulates that genetic traits, that are beneficial in the years up to the age of reproduction may exert detrimental effects later in life. Thus, a gene necessary for calcification of bones that has been selected and modified by evolution to provide sufficient strength for fight and flight may lead to severe problems later in life when the individual has survived beyond the ‘warranty period’, resulting in the calcification of arteries.
In contrast to what is often inferred by basic gerontologists, we and many other groups believe that studying age-related diseases is not only important for devising better methods for their prevention, early diagnosis and treatment, but is also crucial for understanding the general aging processes through which these diseases develop. In our opinion, and as members of an Institute for Biomedical Aging Research, true advances in understanding the basic principles of the aging process will mainly be made by combining basic gerontology with the study of age-related diseases. In our opinion, the Darwinian-evolutionary concept for the development of these diseases has proven to be a very valuable hypothesis, leading to a better understanding of these fundamental and essential issues from an individual, medical and socio-economic viewpoint.
In the following sections, examples of this conceptual approach taken from our own fields of research will be briefly discussed.
Section snippets
Inflammation and Alzheimer's disease
Alzheimer's disease (AD) is the most common dementia of old age. In the last decade, it has become increasingly clear that the degeneration of neurons is connected with a dysregulation in the metabolism of beta-amyloid precursor protein (βAPP), with a consequent deposition of amyloid beta (Aβ) in the brain. Aβ occurs as a 40 and 42 amino acid peptide (Aβ 40, Aβ 42) that is cleaved from APP by the sequential actions of two proteases referred to as β- and γ-secretase (Li et al., 2000). An early
Conclusion
A Darwinian-evolutionary concept is deemed an original and plausible explanation for the development of age-related diseases. It postulates that genetic traits that are of benefit in the years up to the age of reproduction may have deleterious effects later in life as manifested by the examples of diseases presented in this paper. We do, however, concede that this principle may not underlie all age-related diseases and hope that our ideas presented herein will arouse critical discussions.
Acknowledgements
This work was supported by grants of the Austrian Science Fund (G. Wick: P-14741-PAT; P. Berger: P-13652-GEN; P. Jansen-Dürr: P-13217-GEN), by the Austrian Federal Ministry of Education, Science and Culture (B. Grubeck-Loebenstein: GZ 70.060/2) and by the Merkur Insurance Company (G. Wick). We would like to thank all our collaborators cited in the text who have contributed in generating the data that were presented. We also thank Ms. Anita Hohenegger for expert secretarial help.
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