A network theory of ageing: the interactions of defective mitochondria, aberrant proteins, free radicals and scavengers in the ageing process.

Evolution theory indicates that ageing is caused by progressive accumulation of defects, since the evolutionary optimal level of maintenance is always below the minimum required for indefinite survival. Evolutionary theories also suggest that multiple processes are operating in parallel, but unfortunately they make no predictions about specific mechanisms. To understand and evaluate the many different mechanistic theories of ageing which have been proposed, it is therefore important to understand and study the network of maintenance processes which control cellular homeostasis. In this paper we describe a Network Theory of Ageing which integrates the contributions of defective mitochondria, aberrant proteins, and free radicals to the ageing process, and which includes the protective effects of antioxidant enzymes and proteolytic scavengers. The model simulations not only confirm and explain many experimental, age related findings like an increase in the fraction of inactive proteins, a significant rise in protein half-life, an increase in the amount of damaged mitochondria, and a drop in the energy generation per mitochondrion, but they also show interactions between the different theories which could not have been observed without the network approach. In some simulations, for example, the mechanism of the final breakdown seems to be a consequence of the cooperation of mitochondrial and cytoplasmic reactions, the mitochondria being responsible for a long term, gradual change which eventually triggers a short lived cytoplasmic error loop.

[1]  T. Kirkwood Evolution of ageing , 1977, Nature.

[2]  J. Carlson,et al.  Changes in superoxide radical and lipid peroxide formation in the brain, heart and liver during the lifetime of the rat , 1987, Mechanisms of Ageing and Development.

[3]  A Ciechanover,et al.  How are substrates recognized by the ubiquitin-mediated proteolytic system? , 1989, Trends in biochemical sciences.

[4]  J. Carlson,et al.  Biochemical changes associated with the mechanism controlling superoxide radical formation in the aging rotifer , 1990, Journal of cellular biochemistry.

[5]  A. Sentenac,et al.  Role of DNA‐RNA hybrids in eukaryots 1. Purification of yeast RNA polymerase B , 1972, FEBS letters.

[6]  T. Kirkwood,et al.  Mitochondrial mutations, cellular instability and ageing: modelling the population dynamics of mitochondria. , 1993, Mutation research.

[7]  J. Dice Altered degradation of proteins microinjected into senescent human fibroblasts. , 1982, The Journal of biological chemistry.

[8]  R. Huemer,et al.  Mitochondrial studies in senescent mice. II. Specific activity, buoyant density, and turnover of mitochondrial DNA. , 1971, Experimental gerontology.

[9]  D. Shibata,et al.  A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[10]  W. Neupert,et al.  Requirement of a membrane potential for the posttranslational transfer of proteins into mitochondria. , 1982, European journal of biochemistry.

[11]  J. Dice Altered intracellular protein degradation in aging: A possible cause of proliferative arrest , 1989, Experimental Gerontology.

[12]  R. Lane,et al.  The effect of age on enolase turnover in the free-living nematode, Turbatrix aceti. , 1979, Archives of biochemistry and biophysics.

[13]  A. Reznick,et al.  Decreased protein and puromycinyl-peptide degradation in livers of senescent mice. , 1982, The Biochemical journal.

[14]  T B Kirkwood,et al.  Towards a network theory of ageing: a model combining the free radical theory and the protein error theory. , 1994, Journal of theoretical biology.

[15]  Peter Calow,et al.  Physiological Ecology: An Evolutionary Approach to Resource Use , 1983 .

[16]  W. Neupert,et al.  Transport of cytoplasmically synthesized proteins into the mitochondria in a cell free system from Neurospora crassa. , 1977, European journal of biochemistry.

[17]  A. Richardson,et al.  Current concepts: I. The relationship between age-related changes in gene expression, protein turnover, and the responsiveness of an organism to stimuli. , 1982, Life sciences.

[18]  B Chance,et al.  Hydroperoxide metabolism in mammalian organs. , 1979, Physiological reviews.

[19]  T. Kirkwood,et al.  Accuracy of tRNA charging and codon: anticodon recognition; relative importance for cellular stability. , 1993, Journal of theoretical biology.

[20]  E. Geremia,et al.  Superoxide dismutase activities in aging rat brain. , 1982, Gerontology.

[21]  T. Kirkwood,et al.  The evolution of ageing and longevity , 1979, Proceedings of the Royal Society of London. Series B. Biological Sciences.

[22]  Alexander Varshavsky,et al.  The tails of ubiquitin precursors are ribosomal proteins whose fusion to ubiquitin facilitates ribosome biogenesis , 1989, Nature.

[23]  M R Rose,et al.  Evolution of senescence: late survival sacrificed for reproduction. , 1991, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[24]  C. Franceschi,et al.  Is Aging As Complex As It Would Appear? , 1992, Annals of the New York Academy of Sciences.

[25]  R. Menzies,et al.  The turnover of mitochondria in a variety of tissues of young adult and aged rats. , 1971, The Journal of biological chemistry.

[26]  D. Harman Aging: a theory based on free radical and radiation chemistry. , 1956, Journal of gerontology.

[27]  L. Orgel,et al.  The maintenance of the accuracy of protein synthesis and its relevance to ageing. , 1963, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Sangkot Marzuki,et al.  MITOCHONDRIAL DNA MUTATIONS AS AN IMPORTANT CONTRIBUTOR TO AGEING AND DEGENERATIVE DISEASES , 1989, The Lancet.

[29]  D. Harman,et al.  The aging process. , 1981, Basic life sciences.

[30]  M. Rechsteiner Natural substrates of the Ubiquitin proteolytic pathway , 1991, Cell.

[31]  J. Johnson,et al.  Mitochondrial role in cell aging , 1980, Experimental Gerontology.

[32]  H. Riezman,et al.  Transcription and translation initiation frequencies of the Escherichia coli lac operon. , 1977, Journal of molecular biology.

[33]  D. Gershon,et al.  Rat-liver superoxide dismutase. Purification and age-related modifications. , 1976, European journal of biochemistry.

[34]  L. Szilard ON THE NATURE OF THE AGING PROCESS. , 1959, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Z. Medvedev AN ATTEMPT AT A RATIONAL CLASSIFICATION OF THEORIES OF AGEING , 1990, Biological reviews of the Cambridge Philosophical Society.

[36]  G. Rotilio,et al.  A pulse radiolysis study of superoxide dismutase. , 1972, Biochimica et biophysica acta.

[37]  A. Fersht,et al.  Transition-state stabilization in the mechanism of tyrosyl-tRNA synthetase revealed by protein engineering. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Sir Macfarlane Burnet Intrinsic mutagenesis: a genetic approach to ageing , 1974 .

[39]  A. Ciechanover Regulation of the ubiquitin‐mediated proteolytic pathway: Role of the substrate α‐NH2 group and of transfer RNA , 1987, Journal of cellular biochemistry.

[40]  R. G. Allen,et al.  Effect of physical activity on superoxide dismutase, catalase, inorganic peroxides and glutathione in the adult male housefly, Musca domestica , 1984, Mechanisms of Ageing and Development.

[41]  C. Richter Do mitochondrial DNA fragments promote cancer and aging? , 1988, FEBS letters.

[42]  N. Kjeldgaard,et al.  Regulation of Biosynthesis of Ribosomes , 1974 .

[43]  R. S. Sohal,et al.  Relationship between superoxide anion radical generation and aging in the housefly, Musca domestica. , 1989, Free radical biology & medicine.

[44]  A. Davison,et al.  Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging? , 1990, Free radical biology & medicine.