Dietary restriction extends lifespan in many species, but how it does so is unknown. Now, Bishop and Guarente have revealed a molecular process by which diet restriction, through activation of the transcription factor SKN-1 in two sensory neurons, can influence mitochondrial activity in peripheral tissues and thereby possibly delay the ageing process in Caenorhabditis elegans.
The authors provided C. elegans with a diet containing different concentrations of bacteria (their usual food) and confirmed that the worms' lifespan increased as the concentration of bacteria decreased. Searching for the underlying molecular mechanism, they focused on the transcription factor SKN-1. SKN-1 has a role in embryogenesis, but is also implicated in the regulation of oxidative stress, a process that has been linked to ageing.
The authors tested whether the effect of diet restriction on longevity was impaired in worms with a loss-of-function mutation in the skn-1 gene. Two mutations, skn-1(zu135) and skn-1(zu169), prevented the extended lifespan in diet-restricted worms but had no effect in control worms, indicating that they did not alter lifespan per se. The insertion of a transgene expressing SKN-1 restored the effect of diet restriction on longevity, confirming that SKN-1 mediates this effect. Another known mediator of longevity in worms, DAF-16, which has a role in the insulin signalling pathway, was not required for diet-induced longevity.
The skn-1 gene codes for three protein isoforms, SKN-1A, SKN-1B and SKN-1C. The authors focused on SKN-1B and SKN-1C, which they showed are exclusively expressed in C. elegans' two sensory ASI neurons and intestine, respectively. They set out to determine which of these two isoforms is crucially involved in the effect of dietary restriction on lifespan. Re-expression of skn-1b in the ASI neurons of skn-1(zu135) mutant worms re-established the effect of dietary restriction on longevity in these worms, whereas re-expression of skn-1c in the intestine of mutant worms had no effect. Moreover, the researchers showed that dietary restriction upregulated skn-1 expression in the ASI neurons but not in the intestine.
To confirm the crucial role of the ASI neurons, the researchers ablated them with laser microbeams. This abolished the effect of diet on longevity, but also extended the basal lifespan of non-diet restricted worms. This basal lifespan extension was dependent on DAF-16, as it did not occur when ASI neurons were ablated in daf-16 mutant worms. Importantly, ablation of the ASI neurons in daf-16 mutants did abolish their response to dietary restriction. These findings indicate that ASI neurons influence longevity through two different pathways, one affecting basal lifespan through DAF-16 and the other regulating the effect of diet restriction on lifespan through SKN-1B.
How does SKN-1B, localized to ASI neurons, delay ageing in peripheral tissues under conditions of caloric restriction? The authors found that diet-restricted worms showed an increase in whole-body oxygen consumption, which is a measure of mitochondrial activity. This effect was reduced in skn-1(zu135) mutant worms, but could be partially rescued by the re-expression of SKN-1 in the ASI neurons (but not in the intestine), indicating that SKN-1B expression mediates the effect of dietary restriction on increased mitochondrial activity. As reduced mitochondrial function has been associated with the ageing process, this finding provides a mechanism by which ASI neurons can influence ageing in body cells.
This study has begun to identify the molecular processes that, triggered by dietary restriction, increase lifespan, and has found that SKN-1, a transcription factor that is involved in embryogenesis, also plays a crucial part in the link between diet restriction and ageing. Importantly, the findings suggest that brain neurons may be vital for sensing dietary restriction and signalling peripheral tissues to increase metabolism, thus extending the lifespan of the animal.