A unifying view of ageing and disease: the double-agent theory

The quest for therapies based on molecular genetics (pharmacogenomics, DNA microarrays, etc.) drives pharmaceutical research into individual diseases of old age, but has failed to deliver an unequivocal clinical breakthrough. Attempts to treat most age-related diseases using antioxidant supplements have been equally disappointing, despite the clear benefits of a healthy diet. The double-agent theory is a new, unifying synthesis that draws on flaws in three leading theories of ageing. It argues that there is a tradeoff between oxidative stress as a critical redox signal that marshals genetic defences against physiological stress (such as infection) and oxidative stress as a cause of ageing and age-related disease. The stress response and ageing are linked by redox-sensitive transcription factors, such as NFkappaB. Ageing is a function of rising intracellular oxidative stress, rather than chronological time, but this relationship is obscured because free-radical leakage from mitochondria also tends to rise with age. Mitochondrial leakage produces a genetic response which mirrors that following infection, but because mitochondrial leakage is continuous the shift in gene expression is persistent, leading to the chronic inflammation characteristic of old age. Age-related diseases are thus the price we pay for redox control of stress-gene expression. Because the selective pressure favouring the stress response in youth is stronger than that penalising degenerative diseases after reproductive decline, we may be homeostatically refractory to antioxidant supplements that 'swamp' the redox switch. Furthermore, because genetic selection takes place predominantly in the reductive homeostatic environment of youth, alleles associated with age-related diseases are not inherently damaging (they do not inevitably express a negative effect over time), but are simply less effective in the oxidising conditions of old age. Gene therapies for age-related diseases are unlikely to succeed unless oxidative stress can be controlled physiologically, thereby altering the activity and function of potentially hundreds of genes. (C) 2003 Elsevier Ltd. All rights reserved.