L-Carnosine causes an increase in the lifespan of human fibroblasts 
and E. coli
. Our experiments to determine the effect of L-carnosine on yeast revealed a profound effect on the viability of glucose-grown cells (; ), consistent with earlier findings by Holliday and McFarland, who showed that L-carnosine inhibits the growth of cancer cells 
. More recently, in an attempt to understand the mechanisms responsible for L-carnosine-induced inhibition of cancer cell growth, two studies have shown that L-carnosine addition to tumor cells results in a reduction in cellular ATP production 
from glycolysis 
When S. cerevisiae
is grown on a fermentable carbon source, the Crabtree effect 
leads to a decrease in oxidative phosphorylation. Addition of L-carnosine promotes cell death under these conditions (), as also seen for cancer cells 
. The fermentable carbon sources, mannose, galactose and fructose, also repress oxidative phosphorylation, but to a lesser degree than glucose 
, consistent with the smaller L-carnosine-induced reduction in the viability of yeast cultures grown on these carbon sources ().
To explore whether a shift of metabolic flux to fermentation could provide mechanistic insight into how L-carnosine influences viability in yeast cells, the consequence of L-carnosine addition to yeast cultures grown on the non-fermentable carbon sources, glycerol, xylose, ribose and sorbitol was explored (, ); non-fermentable carbon sources require the presence of oxygen to be metabolized via oxidative phosphorylation. shows that L-carnosine addition does not reduce the viability of these yeast cultures. An increased dependence on respiration, similar to the effect on non-fermentable carbon sources, may underlie these results, as seen for the respiratory yeast species, P. pastoris, which is also minimally affected by L-carnosine addition. We therefore propose that L-carnosine has a detrimental effect on cells when their energy generation is dependent on glycolysis.
Closer examination of our yeast optical density (, ) and microcalorimetry rate data () shows that L-carnosine may have a tendency to promote cell growth on glycerol, possibly by acting as an amino acid source. The slightly improved viability of yeast grown on a non-fermentable carbon source following L-carnosine addition could also reflect the anti-senescence properties seen in human fibroblasts when grown in the presence of L-carnosine, i.e. decreased glycolysis and increased mitochondrial activity 
The mechanisms by which L-carnosine exerts its inhibitory effects on growth and viability remain uncertain, one proposal being the ATP-lowering effect mentioned above 
. Early work demonstrated that L-carnosine stimulated the activity of the gluconeogenic enzyme fructose-1-6-biphosphatase 
which converts fructose-1-6-bisphosphate to fructose-6-phosphate. Should L-carnosine stimulate fructose-1-6-bisphosphatase in yeast, an ATP-consuming futile cycle might be created in glucose-grown cells, but not in cells growing on glycerol. By limiting the availability of fructose-1-6-bisphosphate for conversion by aldolase to triose-phosphates, both ATP generation and the supply of precursors for macromolecule synthesis would be reduced. Our data for deletion mutants in nutrient sensing pathways (), which have an increased dependence on a respiratory metabolism 
and hence exhibit a decreased response to L-carnosine addition, would fit with this hypothesis.
Overall, our data for yeast cells grown on glucose are consistent with observations previously published for cancer cells 
. Furthermore studies with yeast cells have an additional advantage in that the action of L-carnosine can be examined under aerobic growth on glycerol; in this study we show that L-carnosine adversely affects fermentative growth on glucose, while aerobic growth on glycerol is not inhibited. In contrast, D-carnosine does not affect growth on glucose, but significantly stimulates growth on glycerol, suggesting these metabolism-dependent effects are mediated by different mechanisms. Yeast cells therefore provide an amenable system whereby the metabolism-dependent effects of L-carnosine are tractable for further study.