What causes organ failure during aging? Is it stochastic, with individual organ systems deteriorating and failing more or less independently — or is it more like a chain of dominoes, with a primary organ failure in one tissue putting pressure on other tissues and accelerating their decline?

Piazza et al. explored this question in flies lacking the Sod2 gene (encoding the mitochondrial superoxide dismutase, a key antioxidant enzyme), which age more rapidly than wildtype flies — almost definitely due to increased oxidation of cellular components. They found that functional failures happened in random order, implying that there is no key organ system serving as the primary victim of oxidative damage:

Multiple measures of functionality exhibit progressive decline in a parallel, stochastic fashion in Drosophila Sod2 null mutants

Oxidative damage has been proposed as an important factor in the progression of pathological and non-pathological age-related functional declines. Here, we examine functional deterioration in short-lived flies mutant for the mitochondrial antioxidant Manganese Superoxide Dismutase (Sod2). We find that the decline of several functional measures of aging occurs, in an accelerated fashion, in Sod2 mutants. Olfactory behavior, locomotor ability and cardiac performance were all seen to decline rapidly in Sod2 mutants. On average, functional declines in Sod2 mutants occur in a pattern similar to that seen in late-life Drosophila with a normal complement of Sod2. In longitudinal experiments, however, we find that functional failures occur in every possible sequence in Sod2 mutants. Significantly, failure of these functional measures is not irreversible, as spontaneous functional recovery was sometimes observed. These findings support a model where ROS-related damage strikes at multiple organ systems in parallel, rather than a “chain of dominos” model, in which primary organ failure contributes to the deterioration of further organ systems.

I still think it’s possible that failure of one organ system could cause accelerated decline in other systems — this wouldn’t show up as a change in the order of failures but rather in the contingent frequency of functional decline, e.g., is the trachea more likely to fail after the liver is already gone? But the data do seem to conclusively demonstrate that (in the fly at least) there’s no “key organ” whose failure is required in order for other age-related deterioration to take place.