Immune Function as an Important Mediator of the Benefits of Calorie Restriction

Calorie restriction is the practice of adopting up to a 40% reduction in calorie intake versus an ad libitum diet, while still obtaining optimal micronutrient levels. It is perhaps the most studied of all interventions known to slow aging and extend healthy life span in short-lived species, but equally there is still much that we do not know about how it actually works. The challenge is that calorie restriction changes near everything in the operation of metabolism, so it is hard to determine which of those changes are contributing to an extended life span, and to what degree. The best evidence to date suggests that upregulation of the cell maintenance processes of autophagy is the dominant mechanism, but equally there are any number of other changes for which compelling arguments can be mounted. Loss of visceral fat tissue, for example, or as noted here, improved immune function.

Dietary restriction (DR) is the most reproducible and effective nutritional intervention tested to date for delaying the aging process and prolonging the health span in animal models. Preventive effects of DR on age-related diseases have also been reported in human. In addition, highly conserved signaling pathways from small animal models to humans mediate the effects of DR. Recent studies have reported that DR-induced longevity is regulated by innate immune signaling components.

In C. elegans, the transcription factor ZIP-2 is an innate immune signaling component molecule that is upregulated in response to infection by Pseudomonas aeruginosa (PA14), and is necessary for survival against PA14 infection. It has been reported that ZIP-2 is a key mediator of the effects of DR on healthy aging in C. elegans. ZIP-2 activity increased in response to DR, and zip-2 was necessary for DR-induced longevity and physical activity improvement in worms subjected to DR. ZIP-2 activity was increased by inhibition of the TOR signaling pathway and rapamycin treatment. It was concluded that zip-2 extends longevity through TOR/S6K inhibition by DR.

Consistent with the results in C. elegans, acute DR boosts innate immunity in Drosophila. DR via yeast restriction enhanced Drosophila survival against PA14 infection, and reduced TOR signaling protected flies from pathogenic bacterial infection. In addition, researchers confirmed the beneficial effects of yeast restriction on Drosophila immunity following rapamycin treatment.

The p38-MAPK signaling pathway is an important innate immune pathway that is highly conserved from C. elegans to human. It was reported that the p38-MAPK signaling pathway is related to longevity extension by DR in C. elegans. They found that DR maintained the level of the p38-ATF-7 (ATF-7 is a transcription factor downstream of p38) innate immune response at the basal activation level, and that maintaining p38-ATF-7 activity at the basal level is an important factor for longevity in C. elegans. Thus, these results imply that the regulation of immune signals by DR is an important mechanism for extending longevity.

Link: http://doi.org/10.5483/BMBRep.2023-0095