MLKL Knockout Slows Some Aspects of Immune Aging
Researchers here report on the results of disabling the MLKL gene involved in necroptosis, a form of programmed cell death. This reduces age-related inflammation in female mice, and delays loss of lymphocyte production in male mice. The changes are not enough to produce differences in apparent signs of aging, such as mortality rate, however. The scientific challenge here lies in linking reduced necroptosis to the observed changes in immune aging, as is usually the case in any change that is broadly related cell survival or fundamental cell activities such as replication. This sort of activity can keep research teams busy for years, but it is unclear as to whether there is a practical outcome at the end of the tunnel given that the mice didn't fare any better for the change.
MLKL is one of the core signaling proteins of the inflammatory cell death pathway, necroptosis, which is a known mediator and modifier of human disease. Necroptosis has been implicated in the progression of disease in almost every physiological system and recent reports suggest a role for necroptosis in aging. Here, we present the first comprehensive analysis of age-related histopathological and immunological phenotypes in a cohort of Mlkl-/- mice on a congenic C57BL/6J genetic background.
Our extensive histopathological and immunophenotypic cohort analyses have identified several unique, sex-specific, differences between congenic C57BL/6J Mlkl-/- mice and their wild-type littermates that emerge with age. Several statistically significant findings were observed in hematological parameters across age in Mlkl-/- mice compared to wild-type littermate controls. Many of these parameters remained within normal range despite statistical significance, suggesting they are unlikely to assert biologically critical roles.
Of note, Mlkl-/- mice exhibit increased circulating lymphocyte numbers relative to wild-type littermates at 12-14 months of age. A comprehensive and unbiased blind scoring of inflammatory foci in more than 44 different sites revealed a 62% decrease in background, sterile inflammation of the skeletal muscle, bone, cartilage, adipose tissue, and connective tissue proper in 17-month-old female Mlkl-/- relative to age-matched wild-type littermates. It is important to consider, however, that these differences in age-related circulating lymphocyte numbers and tissue inflammation did not manifest in any overt differences in the general condition, mobility, or mortality of these mice up to 17 months of age.