Introduction to A NOVEL THEORY OF AGING –
AGING AS A CONSEQUENCE OF MISREPAIR
Jicun Wang1, Thomas M. Michelitsch2*, Arne Wunderlin3 and Ravi Mahadeva1
1Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom
2Institut Jean le Rond d’Alembert CNRS UMR 7190, Université Pierre et Marie Curie (Paris 6), 4 Place Jussieu, 75252 Paris cedex 05, France
31. Institut für Theoretische Physik, Pfaffenwaldring 57/4, D-70550 Stuttgart, Germany
*Send correspondence to: Dr. Thomas M. Michelitsch, Email: michel@lmm.jussieu.fr
2 April 2009
Abstract
It is now increasingly realized that the underlying mechanisms which govern aging is a complex interplay of genetic regulation and damage accumulation. Aging as a result of accumulation of ‘faults’ on cellular and molecular levels, has been proposed in the damage (fault)-accumulation theory by Kirkwood 2006. However, this theory fails to explain some aging phenotypes such as fibrosis and premature aging, since terms such as ‘damage’ and ‘fault’ are not specified. Therefore we introduce here a specification of the underlying mechanism of aging and arrive at a novel theory: aging of the body is a result of the accumulation of Misrepair of tissue. It emphasizes: a) it is Misrepair, not the original damage, that accumulates and leads to aging; and b) aging can occur at different levels, however aging of the body takes place at least on the tissue level, but not necessarily on cellular/molecular level. The novel concept of Misrepair introduced here unifies the understanding of the roles of environmental damage, repair, gene regulation, and multicellular structure in the aging process. The Misrepair-accumulation theory introduced in the present paper gives explanations for the aging phenotypes, premature aging, and the difference of longevity in different species, and is consistent with the point of view of physical theory of complex systems.
Introduction
Many theories have been proposed to answer the question of why and how we age. These theories fall into two main groups: genetic regulation and damage-accumulation. The gene-controlling theories emphasize the genetic regulation on aging. Many genes have been found to be related to aging, and some have shown lifespan-extending effects on animal models by gene knock-out (or -in), however their associations with aging are debated and far from confirmed. The Mutation-accumulation Theory assumes that the weak selection by nature in late age allows a wide range of gene mutations to accumulate, with deleterious effects (1,2): one interesting point which remains unanswered is why genes mutate to be deleterious. The Developmental Theory suggests that aging and development are coupled and regulated by the same mechanisms (3,4). It is theoretically interesting and reasonable; however this theory fails to explain how the development process influences the aging phenotypes. The Damage-accumulation theories imply that it is the extrinsic and intrinsic damage (or fault) accumulation on cellular or molecular level, that leads to aging: The causes can be free radicals, by-products, molecular cross-linking and so on (5,6). However, most of these theories actually mainly pointed out the phenotypes or causes but not the underlying common mechanism of aging.
It is now increasingly realized that genetic regulation and damage-accumulation actually interplay to account for aging, and it is predicted that: “aging is a result of accumulation of ‘faults’ at cellular and molecular level because of the limitation of maintenance and repair; the underlying driving force is damage. The genetic control of longevity comes through the regulation of the essential maintenance and repair processes that slow the build–up of faults”(7). However this recent damage (fault)-accumulation theory does not clarify the concepts of ‘damage’ and ‘fault’, and is weak in explaining some aging phenomena, such as fibrosis and premature aging. On the other hand, the slow process of aging in living beings must be complex, not simply explainable by the gradual accumulation of damage, as that in lifeless matter. Therefore we suggest here some crucial modifications of this theory and raise a novel theory of aging.
