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Biol. Chem., Vol. 389, pp. 267–272, March 2008 • Copyright by Walter de Gruyter • Berlin • New York. DOI 10.1515/BC.2008.030

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Increased molecular damage and heterogeneity as the basis of aging

Suresh I.S. Rattan
Laboratory of Cellular Ageing, Department of Molecular Biology, University of Aarhus, DK-8000 Aarhus C, Denmark
e-mail:rattan@mb.au.dk

Abstract
Aging at the molecular level is characterized by the progressive accumulation of molecular damage. The sources of damage act randomly through environmental and metabolically generated free radicals, through spontaneous errors in biochemical reactions, and through nutritional components. However, damage to a macromolecule may depend on its structure, localization andinteractions with other macromolecules. Damage to the maintenance and repair pathways comprising homeodynamic machinery leads to age-related failure of homeodynamics, increased molecular heterogeneity, altered cellular functioning, reduced stress tolerance, diseases and ultimate death. Novel approaches for testing and developing effective means of intervention, prevention and modulation of aging involvemeans to minimize the occurrence and accumulation of molecular damage. Mild stress-induced hormesis by physical, biological and nutritional methods, including hormetins, represents a promising strategy for achieving healthy aging and for preventing age-related diseases. Keywords: biogerontology; gerontogenes; homeodynamics; homeostasis; reactive oxygen species; stress.

there is progressiveaccumulation of molecular damage, which is the universal characteristic of aging. All small and large molecules are prone to damage, but the source and biological consequences of various types of molecular damage vary widely. Furthermore, whereas the action of a damaging agent is essentially stochastic, the vulnerability of a macromolecule to the damaging agent and the final occurrence of damage aredetermined by the chemical sequence, structure and accessibility of the macromolecule in the presence of several other interactive macromolecules. Therefore, some macromolecules may be preferentially damaged, whereas others may not be easily damaged. What is more important is to realize that it is not a straightforward and simple matter to relate any particular type of damage and its level in cells toa specific biological consequence. However, it is generally agreed that increased molecular damage and heterogeneity are the fundamental basis of aging and age-associated pathologies (Holliday, 2006, 2007; Rattan, 2006; Hipkiss, 2007). This article reviews the causes and mechanisms of molecular damage during aging, the consequences of progressive accumulation of molecular damage during aging, andanti-aging strategies for intervention in and prevention of age-related diseases.

Molecular damage during aging
There are three major sources of damage within a cell: (i) reactive oxygen species (ROS) and other free radicals (FRs) formed by the action of external inducers of damage (e.g., UV rays) and as a consequence of intrinsic cellular metabolism involving oxygen, metals and othermetabolites; (ii) nutritional glucose and its metabolites, and their biochemical interactions with ROS and FRs; and (iii) spontaneous errors in biochemical processes, such as DNA duplication, transcription, post-transcriptional processing, translation, and post-translational modifications. The occurrence of molecular damage has led to the formulation of at least two mechanistic theories of biologicalaging, which have been the basis of most of the experimental aging research during the last 50 years (Rattan, 2006). The first is the so-called free radical theory of aging (FRTA), originally proposed in 1954 but first published in 1956, which arose from consideration of the aging phenomenon from the premise that a single common biochemical process may be responsible for the aging and death of all...