Two papers in last week’s Nature advance our knowledge of the genetics of calorie restriction (CR) in the worm C. elegans.

In the first paper, Bishop and Guarente show that dietary restriction activates expression of a transcription factor in two neurons. This protein, skn-1, is absolutely essential for the life extension effect of CR in the worm — the implication being that the neurons are integrating information about food availability (perhaps via olfaction?) and then sending a signal to the rest of the body:

Two neurons mediate diet-restriction-induced longevity in C. elegans

Dietary restriction extends lifespan and retards age-related disease in many species and profoundly alters endocrine function in mammals. However, no causal role of any hormonal signal in diet-restricted longevity has been demonstrated. Here we show that increased longevity of diet-restricted Caenorhabditis elegans requires the transcription factor gene skn-1 acting in the ASIs, a pair of neurons in the head. Dietary restriction activates skn-1 in these two neurons, which signals peripheral tissues to increase metabolic activity. These findings demonstrate that increased lifespan in a diet-restricted metazoan depends on cell non-autonomous signalling from central neuronal cells to non-neuronal body tissues, and suggest that the ASI neurons mediate diet-restriction-induced longevity by an endocrine mechanism.

In a series of straightforward experiments, the authors demonstrate that skn-1 activity specifically in the ASI neurons (as opposed to elsewhere in the body) is both necessary and sufficient to activate metabolic changes throughout the adult worm.

The “brain” (if you’ve ever looked at a C. elegans, you know why I put it in quotes) isn’t the only player in the CR drama. In the second paper, Panowski et al. (from the prolific lab of Andrew Dillin) show that the transcription factor pha-4 is also essential for CR-induced longevity.

PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans

Reduced food intake as a result of dietary restriction increases the lifespan of a wide variety of metazoans and delays the onset of multiple age-related pathologies. Dietary restriction elicits a genetically programmed response to nutrient availability that cannot be explained by a simple reduction in metabolism or slower growth of the organism. In the nematode worm Caenorhabditis elegans, the transcription factor PHA-4 has an essential role in the embryonic development of the foregut and is orthologous to genes encoding the mammalian family of Foxa transcription factors, Foxa1, Foxa2 and Foxa3. Foxa family members have important roles during development, but also act later in life to regulate glucagon production and glucose homeostasis, particularly in response to fasting. Here we describe a newly discovered, adult-specific function for PHA-4 in the regulation of diet-restriction-mediated longevity in C. elegans. The role of PHA-4 in lifespan determination is specific for dietary restriction, because it is not required for the increased longevity caused by other genetic pathways that regulate ageing.

The pha-4 gene is required for proper formation of the foregut (worm pharynx, whence the gene’s name) during larval development, but the role in CR-mediated lifespan extension appears to be specific to the adult. Hence this might be yet another example of a gene that is optimized for some early-life function but nonetheless highly significant in the genetic control of aging (though in this case the pleiotropy is not antagonistic: both the early-life and late-life functions of the gene are “good”).

An interesting open question arising from the juxtaposition of these two papers is whether they act in the same pathway: Is skn-1‘s neuron-derived signal upstream of pha-4, or does pha-4 action somewhere in the body (perhaps the gut, which is after all where food goes) trigger skn-1 expression in the brain? It’s also possible, of course, that the two genes act independently. Classical epistasis analysis using the dominant alleles already in hand could quickly answer this question.

Gee, I wonder what they’re doing in the Dillin and Guarente labs this week.

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