Short-Term Calorie Restriction Boosts Innate Immunity in Flies

Calorie restriction slows aging, with the current consensus being that this is largely mediated through increased autophagy, the housekeeping processes that clear out and recycle broken components within the cell. Calorie restriction does, however, change more or less everything there is to be measured in cellular metabolism, so it is certainly possible that other mechanisms are relevant. In this context, researchers here present evidence to show that, at least in flies, the defense against infection mounted by the innate immune system is enhanced by short term calorie restriction. It is also worth considering that this sort of effect may explain some of the degree to which calorie restriction reduces the burden of cellular senescence and cancer risk over the long term, by incrementally improving the ability of the immune system to remove harmful and potentially harmful cells.

Studies of dietary restriction, a reduction in nutrient intake without malnutrition, in a diverse array of organisms have revealed it to be an effective way to extend lifespan and promote broad-spectrum improvement in health during aging. Early work focused on total caloric intake as the driving force behind these beneficial effects, but studies that have comprehensively examined the effects of individual macronutrients on lifespan underscore the importance of protein-to-carbohydrate ratio. In the fruit fly, Drosophila melanogaster, yeast restriction has been used as an alternative to wholesale dilution of the diet to effectively extend female fly lifespan. These effects have also been observed in mammals, where protein restriction increased rodent lifespan. Together, these studies establish that the life-extending benefits associated with dietary restriction can be achieved without reducing total caloric intake when the relative consumption of protein to carbohydrates is low.

A striking feature of the effects of dietary restriction is its acute nature, yielding beneficial outcomes with short-term application. In Drosophila, a switch to a restricted diet reduced short-term mortality risk within 48 hr, and in mice, 1 week of protein starvation decreased tissue damage caused by temporary blockage of blood flow during surgical operation, greatly improving survival following renal ischemic injury. Even ad libitum feeding of low-protein, high-carbohydrate diets for 8 weeks resulted in metabolic improvement in mice compared to those fed high-protein, low-carbohydrate diets.

A significant threat to global health is infectious diseases. Acute preventative strategies that strengthen immunity prior to such procedures are therefore of strong interest. To answer the questions of whether, similar to general health and aging, innate immune function is acutely modulated by individual nutrients, we executed a comprehensive analysis of the effects of dietary composition on survival following pathogenic infection in Drosophila. Although lacking adaptive immunity, insects are equipped with innate immunity, which is an ancient first-line defense mechanism that recognizes the pattern of invading microorganisms as well as their virulence factors. Drosophila innate immunity has humoral and cellular components, and this innate immune response is highly conserved between Drosophila and mammals.

Here, we present evidence that yeast restriction, but not carbohydrate restriction, substantially improves fly survival following bacterial infection through several components of innate immunity. We find that yeast-restriction-mediated enhancement of innate immunity is orchestrated by components of the target of rapamycin (TOR) signaling network, in which reduced TOR signaling results in a stabilization of the transcription factor Myc through its suppressor protein phosphatase 2A. Myc in turn mediates a sustained induction of genes that encode antimicrobial peptides, which are effective bacterial killers. These results implicate a function for protein phosphatase 2A (PP2A) and Myc as signaling molecules that serve to potentiate the immune response in yeast-restricted animals following pathogenic infection.



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