Just breathe: In yeast, aerobic metabolism required for longevity enhancement by calorie restriction

Calorie restriction (CR) extends lifespan in most organisms studied, including some of our more distant relatives — e.g. the baker’s brewer’s yeast Saccharomyces cerevisiae. The genetics underlying CR-mediated life extension are currently being worked out (for details, see our earlier piece, Biogerontology rising); despite lingering controversy, the story is starting to converge. Specifically, it’s becoming clear that TOR, Sch9 kinase and regulation of ribosome synthesis play an important role — and, in contrast to earlier models, it’s seeming less and less likely that sirtuins are involved.

A new twist in the plot comes from a comparative study of two budding yeasts, S. cerevisiae and its close relative Kluyveromyces lactis. Brewer’s yeast prefers to ferment (grow anaerobically) in glucose-rich environments (like an extract of malted barley), but when carbon is limiting, it starts to grow aerobically. According to Oliveira et al. this increase in respiratory capacity is essential to the lifespan extension mediated by CR in yeast:

Increased aerobic metabolism is essential for the beneficial effects of caloric restriction on yeast life span

Calorie restriction is a dietary regimen capable of extending life span in a variety of multicellular organisms. A yeast model of calorie restriction has been developed in which limiting the concentration of glucose in the growth media of Saccharomyces cerevisiae leads to enhanced replicative and chronological longevity. Since S. cerevisiae are Crabtree-positive cells that present repression of aerobic catabolism when grown in high glucose concentrations, we investigated if this phenomenon participates in life span regulation in yeast. S. cerevisiae only exhibited an increase in chronological life span when incubated in limited concentrations of glucose. Limitation of galactose, raffinose or glycerol plus ethanol as substrates did not enhance life span. Furthermore, in Kluyveromyces lactis, a Crabtree-negative yeast, glucose limitation did not promote an enhancement of respiratory capacity nor a decrease in reactive oxygen species formation, as is characteristic of conditions of caloric restriction in S. cerevisiae. In addition, K. lactis did not present an increase in longevity when incubated in lower glucose concentrations. Altogether, our results indicate that release from repression of aerobic catabolism is essential for the beneficial effects of glucose limitation in the yeast calorie restriction model. Potential parallels between these changes in yeast and hormonal regulation of respiratory rates in animals are discussed.

For those of you whose yeast metabolic biochemistry is a little bit rusty: The alternate carbon sources (carbohydrates other than glucose) are ones that S. cerevisiae must metabolize aerobically (to a greater or lesser extent: they can grow anaerobically, though poorly, on non-glucose sugars, but not at all on glycerol, which absolutely requires respiration).

To summarize: Only in S. cerevisiae and only in the context of growth on glucose metabolism (which happens anaerobically at high concentrations but aerobically at low concentrations) does CR results in lifespan extension. When limitation of a carbon source does not result in a net increase in respiration — in S. cerevisiae growing on alternate sugars, or in K. lactis, which prefers to grow aerobically even under glucose-rich conditions — CR does not extend longevity.

The title is too strongly worded for my taste. The data are ultimately correlative, and I would liketo see more genetic manipulation that tests the hypothesis: for example, using S. cerevisiae mutants that don’t undergo the shift to aerobic metabolism in response to limiting glucose, or “high respiratory” strains that respire constitutively or at least undergo the metabolic shift earlier in the glucose-limitation curve. (My K. lactis genetics is non-existent, so I don’t know whether the converse mutants — i.e., reluctant respirers or “ready fermenters” — exist in that species, but if they do, it would be nice to see whether they exhibit CR-mediated life extension.)

But given the huge contributions that yeast has made to biogerontology in general, and to CR in particular, it will be interesting to see whether CR in metazoans is also accompanied by an increase in aerobic metabolism. If so, is it required for the benefits of CR, and more importantly, what are the molecular mechanisms underlying the metabolic shift?