Mutations in the CLK-1 gene, which is involved in the synthesis of coenzyme Q (ubiquinone), slow down aging in both worms and mice. The gene’s mechanism of action has been murky: Deficiency in the gene leads to a dietary dependence on ubiquinone and accumulation of a precursor molecule, DMQ, but neither the high levels of DMQ nor a shortage of Q is responsible for the physiological changes observed in CLK-1-/- mutants — therefore, it’s possible that the lifespan function of CLK-1 protein is unrelated to its role in co-Q biosynthesis.
Wang et al. have characterized the wide-spectrum anti-neurodegeneration drug cliquinol, and discovered that it downregulates the activity of the CLK-1 enzyme. The data suggests that heavy metal cations are important for the protein’s longevity-regulation function:
The development of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease is strongly age-dependent. Discovering drugs that act on the high rate of aging in older individuals could be a means of combating these diseases. Reduction of the activity of the mitochondrial enzyme CLK-1 (also known as COQ7) slows down aging in C. elegans and in mice. Clioquinol is a metal chelator that has beneficial effects in several cellular and animal models of neurodegenerative diseases as well as on Alzheimer’s disease patients. Here we show that clioquinol inhibits the activity of mammalian CLK-1 in cultured cells, an inhibition that can be blocked by iron or cobalt cations, suggesting that chelation is involved in the mechanism of action of clioquinol on CLK-1. We also show that treatment of nematodes and mice with CQ mimics a variety of phenotypes produced by mutational reduction of CLK-1 activity in these organisms. These results suggest that the surprising action of clioquinol on several age-dependent neurodegenerative diseases with distinct etiologies might result from a slowing down of the aging process through action of the drug on CLK-1. Our findings support the hypothesis that pharmacologically targeting aging-associated proteins could help relieve age-dependent diseases.
Note the underlined section (emphasis mine) — this reminds me of a speculation I offered up a couple of years ago: Could coenzyme Q supplementation, which has a variety of health benefits in mammals, act by end-product inhibition of the ubiquinone synthesis pathway? In other words, high levels of the pathway’s ultimate product could be shutting down the both the enzymatic and lifespan-regulatory function of CLK-1, resulting in a phenocopy of the CLK-1 loss-of-function mutation. Here, the authors argue that direct enzymatic inhibition of the pathway might be preventing neurodegeneration primarily by slowing down the aging process.
Of course, it’s also possible that the effect on CLK-1 is an epiphenomenon and that heavy metal cations cause neurodegeneration directly, so that chelating them is a generally good thing totally unrelated to the drug’s effect on ubiquinone synthesis. (If that were true, then we would predict that clioquinone would further prevent the delayed neurodegeneration that eventually occurs in CLK-1 mutants as well.)