Looking at Immune Function in Long-Lived Clk1 Mutant Mice
Reducing expression of clk1 (known as Mclk1 in mice) is one of the few known single-gene alterations that can slow aging enough to extend life in mice by as much as 30%. First impressions were that it works by altering mitochondrial function - and regular readers will know by now that mitochondria and the the pace of their self-inflicted damage is very important in aging and longevity. There is some debate as to how exactly this works in the case of clk-1, however, as the way in which it changes metabolic processes isn't self-evidently beneficial given what is known today. A fair amount of wading through complexity to gain a better understanding of mammalian biochemistry still needs to happen.
Few single gene alterations change only one thing, and clk-1 reduction has all sorts of other knock-on effects in metabolism and biological systems. Researchers here are working their way through what it does to the immune system, and how that might be beneficial even though it doesn't at first look that way:
The immune response is essential for survival by destroying microorganisms and pre-cancerous cells. However, inflammation, one aspect of this response, can result in short- and long-term deleterious side-effects. Mclk1+/− mutant mice can be long-lived despite displaying a hair-trigger inflammatory response and chronically activated macrophages as a result of high mitochondrial [reactive oxygen species] generation. Here we ask whether this phenotype is beneficial or simply tolerated.We used models of infection [and] found that Mclk1+/− mutants mount a stronger immune response, control bacterial proliferation better, and are resistant to cell and tissue damage resulting from the response, including fibrosis and types of oxidative damage that are considered to be biomarkers of aging. Moreover, these same types of tissue damage were found to be low in untreated 23 months-old mutants. ... Mclk1+/− mutants thus display an association of an enhanced immune response with partial protection from age-dependent processes and from pathologies similar to those that are found with increased frequency during the aging process. This suggests that the immune phenotype of these mutants might contribute to their longevity. We discuss how these findings suggest a broader view of how the immune response might impact the aging process.