Abstract
One of the most popular damage accumulation theories of ageing is the mitochondrial free radical theory of ageing (mFRTA). The mFRTA proposes that ageing is due to the accumulation of unrepaired oxidative damage, in particular damage to mitochondrial DNA (mtDNA). Within the mFRTA, the “vicious cycle” theory further proposes that reactive oxygen species (ROS) promote mtDNA mutations, which then lead to a further increase in ROS production. Recently, data have been published on Caenorhabditis elegans mutants deficient in one or both forms of mitochondrial superoxide dismutase (SOD). Surprisingly, even double mutants, lacking both mitochondrial forms of SOD, show no reduction in lifespan. This has been interpreted as evidence against the mFRTA because it is assumed that these mutants suffer from significantly elevated oxidative damage to their mitochondria. Here, using a novel mtDNA damage assay in conjunction with related, well established damage and metabolic markers, we first investigate the age-dependent mitochondrial decline in a cohort of ageing wild-type nematodes, in particular testing the plausibility of the “vicious cycle” theory. We then apply the methods and insights gained from this investigation to a mutant strain for C. elegans that lacks both forms of mitochondrial SOD. While we show a clear age-dependent, linear increase in oxidative damage in WT nematodes, we find no evidence for autocatalytic damage amplification as proposed by the “vicious cycle” theory. Comparing the SOD mutants with wild-type animals, we further show that oxidative damage levels in the mtDNA of SOD mutants are not significantly different from those in wild-type animals, i.e. even the total loss of mitochondrial SOD did not significantly increase oxidative damage to mtDNA. Possible reasons for this unexpected result and some implications for the mFRTA are discussed.
Highlights
It is often suggested that ageing is a consequence of damage accumulation [1,2]
We developed three novel mitochondrial assays: one for single worm mitochondrial DNA (mtDNA) copy number determination, a second for sequence-specific mtDNA damage and a lipidomics method for the characterisation of mitochondrial cardiolipin species (CL)
While some of the parameters reported here have been assayed in ageing C. elegans previously, determining multiple closely related parameters in parallel and in the same cohort allows us to test the plausibility of various assumptions and predictions of the mitochondrial free radical theory of ageing (mFRTA) and of the ‘‘vicious cycle’’ theory
Summary
It is often suggested that ageing is a consequence of damage accumulation [1,2]. It is still unclear exactly how damage accumulation might lead to the time-dependent exponential increase in the risk of dying that is a defining characteristic of the ageing process [3]. While various types of damage do accumulate with age, what types of damage affecting which biomolecular targets, if any, determine the rate of ageing remains unclear. If damage accumulation were to explain exponential mortality dynamics, we might (but do not have to, see: [8]) expect damage to be autocatalytic, which would imply exponential damage accumulation, in turn explaining the observed exponential increase in the risk of dying. The ‘‘vicious cycle’’ variant of the mFRTA proposes that reactive oxygen species (ROS) cause mtDNA mutations which, by destabilising the mitochondrial electron transport chain (ETC), further increase ROS production [5,9,10]
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