OP30 - More damage, longer life in C. elegans?

Abstract

Since its inception almost 60 years ago, the free radical theory of ageing (FRTA) has become the foremost damage accumulation theory of ageing. The FRTA posits that ageing is caused, at least in part, by mitochondrial reactive oxygen species (ROS) and the resulting oxidative damage. However, antioxidant intervention studies have often failed to extend lifespan in model organisms such as C. elegans and have also generally failed to show consistent beneficial effects in mammals and humans. In addition to the often questionable in vivo antioxidant efficacy of such compounds, one explanation for these largely disappointing results of antioxidants in modulating lifespan and healthspan may be a complex role of homeodynamic systems during perturbations. Both ROS production and ROS detoxification are part of a complex regulatory network affecting the expression of damage-repair and stress-response genes, but also directly impacting energy production, metabolism and life-history traits. Such complexity often leads to surprising (even counter intuitive) outcomes. This complexity also provides an exciting new area of development for interventions against age-dependent functional decline. Hormesis refers to the phenomenon whereby a stimulus or challenge that is detrimental or lethal at high dose exhibits beneficial effects at low dose. Hormetic interventions are one way of leveraging endogenous homeodynamic systems and responses instead of trying to control or overwrite them. Hormesis can even result in lifespan and healthspan benefits following exposure to low levels of stressors. However, this poses new questions. For example, does the success of hormetic interventions challenge damage accumulation theories or does, as often suggested, activation of endogenous stress response and damage repair pathways following hormetic insult result in a net decrease in damage? I will attempt to illuminate some of these questions based on data from our C. elegans mtDNA damage assay.