A Darwinian-evolutionary concept of age-related diseases

https://doi.org/10.1016/S0531-5565(02)00161-4Get rights and content

Abstract

Humans and animals are structurally designed as a compromise to guarantee optimal survival until the time of reproduction based on natural selection that is effective until that age. Modern conditions of life including improvement of hygiene, preventive and curative medicine as well as socio-economic and political developments have led to an increase of the mean life expectancy that allows ever larger proportions of the population to reach an age that is far beyond that of the reproductive phase. The concept of a Darwinian-evolutionary basis for the development of age-related diseases in principle postulates that genetic traits that are beneficial in younger years to allow for successful reproduction may become deleterious in the elderly, i.e. when selective pressure does not seem to be effective anymore. Examples for this mechanism of pleiotropic antagonism taken from the work of the Institute for Biomedical Aging Research in Innsbruck, Austria, include atherosclerosis, benign and malignant prostate hypertrophy, Alzheimer's disease and the reciprocal relationship between cellular senescence and cancer.

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.

References (101)

  • M. Hermann et al.

    Aging of the male reproductive system

    Exp. Gerontol.

    (2000)
  • F. Hoppichler et al.

    Changes of serum antibodies to heat-shock protein 65 in coronary heart disease and acute myocardial infarction

    Atherosclerosis

    (1996)
  • G.H. Jeohn et al.

    Synergistic neurotoxic effects of combined treatments with cytokines in murine primary mixed neuron/glia cultures

    J. Neuroimmunol.

    (1998)
  • D.B. Jones et al.

    Sequence homologies between hsp60 and autoantigens

    Immunol. Today

    (1993)
  • J.A. Maier et al.

    Senescence stimulates U937-endothelial cell interactions

    Exp. Cell Res.

    (1993)
  • F. Marx et al.

    The possible role of the immune system in Alzheimer's disease

    Exp. Gerontol.

    (1998)
  • P.L. McGeer et al.

    The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases

    Brain Res. Brain Res. Rev.

    (1995)
  • A.J. Millis et al.

    Differential expression of metalloproteinase and tissue inhibitor of metalloproteinase genes in aged human fibroblasts

    Exp. Cell Res.

    (1992)
  • D.M. Peehl et al.

    Induction of smooth muscle cell phenotype in cultured human prostatic stromal cells

    Exp. Cell Res.

    (1997)
  • M.S. Rao et al.

    Stem cells and aging: expanding the possibilities

    Mech. Ageing Dev.

    (2001)
  • H. Rumpold et al.

    The development of benign prostatic hyperplasia by trans-differentiation of prostatic stromal cells

    Exp. Gerontol.

    (2002)
  • D.L. Sachs et al.

    Skin cancer in the elderly

    Clin. Geriatr. Med.

    (2001)
  • N.A. Saunders et al.

    Regulation of proliferation-specific and differentiation-specific genes during senescence of human epidermal keratinocyte and mammary epithelial cells

    Biochem. Biophys. Res. Commun.

    (1993)
  • L.J. Schedlich et al.

    Insulin-like growth factor-binding protein (IGFBP)-3 and IGFBP-5 share a common nuclear transport pathway in T47D human breast carcinoma cells

    J. Biol. Chem.

    (1998)
  • T.L. Schmitt et al.

    Interactions of the Alzheimer beta amyloid fragment (25–35) with peripheral blood dendritic cells

    Mech. Aging Dev.

    (1997)
  • B.J. Soltys et al.

    Cell surface localization of the 60 kDa heat shock chaperonin protein (hsp60) in mammalian cells

    Cell Biol. Int.

    (1997)
  • M. Tamatani et al.

    Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFkappaB activation in primary hippocampal neurons

    J. Biol. Chem.

    (1999)
  • K. Trieb et al.

    APP peptides stimulate lymphocyte proliferation in normals, but not in patients with Alzheimer's disease

    Neurobiol. Aging

    (1996)
  • G. Untergasser et al.

    Proliferative disorders of the aging human prostate: involvement of protein hormones and their receptors

    Exp. Gerontol.

    (1999)
  • J.C. Vickers et al.

    The cause of neuronal degeneration in Alzheimer's disease

    Prog. Neurobiol.

    (2000)
  • M. Wagner et al.

    Replicative senescence of human endothelial cells in vitro involves G1 arrest, polyploidization and senescence-associated apoptosis

    Exp. Gerontol.

    (2001)
  • G. Wick et al.

    Is atherosclerosis an autoimmune disease?

    Trends Food Sci. Technol.

    (1992)
  • G. Wick et al.

    Is atherosclerosis an immunologically mediated disease?

    Immunol. Today

    (1995)
  • G. Wick et al.

    Diseases of aging

    Vaccine

    (2000)
  • G. Wick et al.

    Atherosclerosis as an autoimmune disease: an update

    Trends Immunol.

    (2001)
  • G. Wick

    'Anti-aging' medicine: does it exist? A critical discussion of 'anti-aging health products'

    Exp Gerontol.

    (2002)
  • C.J. Wraight et al.

    Intranuclear localization of insulin-like growth factor binding protein-3 (IGFBP-3) during cell division in human keratinocytes

    J. Invest. Dermatol.

    (1998)
  • Q. Xu et al.

    Immunology of atherosclerosis: cellular composition and major histocompatibility complex class II antigen expression in aortic intima, fatty streaks and atherosclerotic plaques in young and aged human specimens

    Clin. Immunol. Immunopathol.

    (1990)
  • Q. Xu et al.

    Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis (+Editorial)

    Lancet

    (1993)
  • T. von Zglinicki et al.

    Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence?

    Exp. Cell Res.

    (1995)
  • A. Amberger et al.

    Co-expression of ICAM-1, VCAM-1, ELAM-1 and Hsp60 in human arterial and venous endothelial cells in response to cytokines and oxidized low-density lipoproteins

    Cell Stress Chaperones

    (1997)
  • S.W. Barger et al.

    Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation

    Proc. Natl Acad. Sci. USA

    (1995)
  • R.C. Baxter

    Signalling pathways involved in antiproliferative effects of IGFBP-3: a review

    Mol. Pathol.

    (2001)
  • M.R. Bennett et al.

    Cooperative interactions between RB and p53 regulate cell proliferation, cell senescence, and apoptosis in human vascular smooth muscle cells from atherosclerotic plaques

    Circ. Res.

    (1998)
  • D.H. Birnie et al.

    Association between antibodies to heat shock protein 65 and coronary atherosclerosis. Possible mechanism of action of Helicobacter pylori and other bacterial infections in increasing cardiovascular risk

    Eur. Heart J.

    (1998)
  • I. Blasko et al.

    TNFalpha plus IFNgamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs

    FASEB J.

    (1999)
  • H. Bonkhoff et al.

    Morphogenetic concepts of normal and abnormal growth in the human prostate

    Virchows Arch.

    (1998)
  • G.M. Castillo et al.

    Novel purification and detailed characterization of perlecan isolated from the Engelbreth–Holm–Swarm tumor for use in an animal model of fibrillar A beta amyloid persistence in brain

    J. Biochem. (Tokyo)

    (1996)
  • Q.M. Chen et al.

    Molecular analysis of H2O2-induced senescent-like growth arrest in normal human fibroblasts: p53 and Rb control G1 arrest but not cell replication

    Biochem. J.

    (1998)
  • Y. Du et al.

    Reduced levels of amyloid beta-peptide antibody in Alzheimer disease

    Neurology

    (2001)
  • Cited by (63)

    • Associations of solid fuel use and ambient air pollution with estimated 10-year atherosclerotic cardiovascular disease risk

      2021, Environment International
      Citation Excerpt :

      A study conducted in rural India explored the link between long-term exposure to solid fuel smoke and genotoxicity (Mondal et al. 2010), which demonstrated that smoke from the use of solid fuels can induce increased ROS production and decreased levels of superoxide dismutase and total antioxidant status. Long-term exposure to solid fuel smoke may induce persistent oxidative stress, furthermore, increased DNA oxidative damage and ultimately cause age-related diseases such as atherosclerosis (Wick et al. 2003). Studies on the combined effect of HAP from solid fuel use on the association between AAP and cardiovascular events are very limited.

    • ‘Evolutionary medicine’ perspectives on Alzheimer's Disease: Review and new directions

      2018, Ageing Research Reviews
      Citation Excerpt :

      Wick et al. refer to possible pleiotropic effects of the immune system in AD etiology. Activation of innate immune response initially protects neurons against Aβ toxicity, but, chronic activation has destructive effects (Wick et al., 2003). Not only are the relevant cytokines toxic when produced chronically and at high concentrations (Jeohn et al., 1998), but also they stimulate the production of amyloid precursor-protein (APP) (Goldgaber et al., 1989) and, in certain combinations, Aβ (Blasko et al., 1999).

    • Hypertension and aging

      2016, Ageing Research Reviews
      Citation Excerpt :

      The most widely held belief regarding the cause of immune-senescence is that chronic antigen burden over the course of a lifetime exhausts a finite capacity of the immune system (Buford and Willoughby, 2008; De Martinis et al., 2007). As a result, we trade the long-term risk of chronic inflammation and disease for life-long protection against infection and injury (Wick et al., 2003). Inflammation is the most consistently documented biological feature of aging, though it remains unknown whether inflammatory mediators directly cause adverse health outcomes.

    View all citing articles on Scopus
    View full text