The CLK-1 gene is a longevity regulator that has been conserved across evolution: loss of function in both C. elegans (where the gene was first described) and hemizygosity in mouse (where the gene is called mCLK1) results inincreased lifespan (though at a cost to evolutionary fitness). Consistent with this, at least one anti-neurodegeneration drug inhibits mCLK1, raising the possibility that the drug acts by delaying aging and thereby postponing age-related neurological disease. Genetic crosses and other evidence suggest that the longevity extension is independent of the action of the insulin-like growth factor (IGF)/DAF-2 pathway, another conserved regulator of longevity.
The CLK-1 protein catalyzes a late step in the biosynthesis of ubiquinone (aka coenzyme Q or coQ), an essential cofactor in mitochondrial electron transport, but it’s not completely clear whether this enzymatic function has to do with the life-extension phenotype. In worm, even among clk-1 mutants that completely lack detectable coQ and accumulate the same levels of the metabolic precursor DMQ, null mutants (which make no CLK-1 protein) exhibit more severe phenotypes than missense mutants (which express normal levels of a defective protein). Furthermore, tRNA suppressor mutations appear to differentially affect the lifespan, developmental and ubiquinone synthesis phenotypes. Finally, dietary supplementation with coQ fails to rescue the developmental and lifespan phenotypes (though this is confounded by the fact that these worms never accumulate cellular levels of coQ that are comparable to wildtype). (For a more detailed treatment of CLK-1 biology in both worm and mouse, see this excellent review by Stepanyan et al.).
How, then, do clk-1 mutants extend longevity? To address this question, Cristina et al. compared the the gene expression profiles of wildtype and clk-1 worms:
A regulated response to impaired respiration slows behavioral rates and increases lifespan in Caenorhabditis elegans
When mitochondrial respiration or ubiquinone production is inhibited in Caenorhabditis elegans, behavioral rates are slowed and lifespan is extended. Here, we show that these perturbations increase the expression of cell-protective and metabolic genes and the abundance of mitochondrial DNA. This response is similar to the response triggered by inhibiting respiration in yeast and mammalian cells, termed the “retrograde response”. As in yeast, genes switched on in C. elegans mitochondrial mutants extend lifespan, suggesting an underlying evolutionary conservation of mechanism. Inhibition of fstr-1, a potential signaling gene that is up-regulated in clk-1 (ubiquinone-defective) mutants, and its close homolog fstr-2 prevents the expression of many retrograde-response genes and accelerates clk-1 behavioral and aging rates. Thus, clk-1 mutants live in “slow motion” because of a fstr-1/2-dependent pathway that responds to ubiquinone. Loss of fstr-1/2 does not suppress the phenotypes of all long-lived mitochondrial mutants. Thus, although different mitochondrial perturbations activate similar transcriptional and physiological responses, they do so in different ways.
The transcriptional phenotype of clk-1 mutant animals is similar to the phenotype observed when mitochondrial respiration is inhibited; this is the “retrograde response” mentioned in the abstract (so called because the signal travels from the mitochondria to the nucleus rather than in the other direction). Importantly, blocking the retrograde response by knocking down two effector molecules (FSTR-1 and -2) both prevents many of these transcriptional changes and rescues the lifespan phenotype — strongly implying that the retrograde response is inducing genes that contribute to the enhanced longevity of the mutants.
Taken together, I think these findings make a strong argument that coQ synthesis and lifespan phenotypes are closely related. The observation that clk-1 mutants phenocopy inhibition of respiration is not surprising when one recalls that coQ is a key mitochondrial cofactor. If knocking down respiration causes life-extending transcriptional changes, and reduction in coQ levels knocks down respiration, then it follows that the reduction in coQ levels is the ultimate cause of lifespan extension in clk-1 mutants.
There is a danger that we’re seeing the forest but missing a specific tree: The transcriptional responses to clk-1 mutation and inhibited respiration are not identical. It remains a formal possibility that wildtype CLK-1 mediates lifespan effects via one of the genes that is regulated (in a FSTR-1/2-dependent manner) in clk-1 but not during the retrograde response, and that the similarity to the retrograde response is a red herring. This is a tough sell, however, since one must still account for the growing body of evidence (cited by Cristina et al.) that inhibition of respiration by other means can also increase longevity.
Cristina, D., Cary, M., Lunceford, A., Clarke, C., & Kenyon, C. (2009). A Regulated Response to Impaired Respiration Slows Behavioral Rates and Increases Lifespan in Caenorhabditis elegans PLoS Genetics, 5 (4) DOI: 10.1371/journal.pgen.1000450