Innate Immune Regulation in Life Extension via Calorie Restriction

The primary challenge in understanding how calorie restriction slows aging and extends life is that it changes near everything in the operation of cellular metabolism. Finding the important differences is a matter of searching for the needle in the haystack. The most compelling evidence to date points to increased autophagy as the important determinant, greater effort made by cells to repair damage, maintain function, and recycle components. It remains likely that other mechanisms are also important, however. Here, researchers focus on regulation of the innate immune system in response to a reduced calorie intake; they are working with nematodes, but many of the noteworthy aspects of calorie restriction are much the same across all species.

Dietary restriction (DR) is a practically effective and reproducible nutritional intervention that extends lifespan in many organisms. Many studies have shown that DR improves immune function, and immune signaling components are required for DR-induced lifespan extension. These results support the idea that the immune system acts as an important mechanism for DR-induced longevity. Recently, analysis of genes that regulate aging or immune response in animal models, including C. elegans, Drosophila, mice, and even humans, has revealed that aging and immunity are controlled by the same signaling pathways, such as TOR/S6K signaling pathway, pleiotropically. DR-induced longevity is also associated with the modulation of the TOR/S6K signaling pathway. Thus, these results suggest that the immune function may be closely associated with aging regulation through DR.

In this study, we found that the F-box gene fbxc-58 is a downstream effector of the S6K signaling pathway, and that it regulates both pathogen resistance and aging in C. elegans. Furthermore, fbxc-58 is necessary for the effects of DR on lifespan extension. F-box protein acts as a modular E3 ubiquitin ligase adaptor protein, and the ubiquitin-dependent mechanisms have been shown to determine lifespan in response to DR or modulate the innate immune response. Therefore, we suggest that gaining insights into the detailed mechanistic aspects of fbxc-58 signaling pathway could elucidate the conserved signaling mechanism that links innate immunity and DR-induced healthy aging in animals.

Further, DR prevents or reduces the burden of age-related diseases or disabilities. Especially, in an aging and sedentary society, sarcopenia, an age-associated muscle disease, is beginning to be recognized as an acute disease condition. Although an effective sarcopenia treatment regime has not yet been identified, nutritional intervention is considered an effective method of preventing sarcopenia. In this study, we found that DR prevents muscle aging via fbxc-58 in C. elegans. fbxc-58 is essential for DR-mediated alleviation of the age-associated decline in muscle activity and protection of mitochondrial network in body wall muscle. Thus, we propose that investigating the molecular mechanism of action of F-box proteins, including fbxc-58, in DR will shed light on means to prevent sarcopenia and offer a potentially practical means of encouraging healthy aging via DR.


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