Kondratov et al. show that the life span of mice deficient in brain and muscle ARNT-like protein (BMAL1), a component of the circadian clock, is decreased and the mice show early onset of multiple aging-related pathologies. The 40-week-old BMAL1-knockout mice show decreased body weight primarily due to decreased adipose and muscle mass, decreased organ weight (with the exception of liver), and male infertility compared with their wild-type counterparts. Additional changes that are associated with mammalian aging were also observed in the 40-week-old BMAL1-deficient mice and included alterations in white blood cell composition, reduced subcutaneous fat, reduced hair growth, decreased bone mass, and cataracts and eye pathologies. Reactive oxygen species (ROS) displayed temporal variation in wild-type mice, and in kidney, heart, and spleen, but not liver, the BMAL1-deficient mice had higher concentrations of ROS than were observed in the same tissues from time- and age-matched wild-type mice. To verify that BMAL1 contributes to ROS regulation, small interfering RNA (siRNA) was used in L929 cells to decrease BMAL1 abundance, and ROS levels were higher in these cells. This effect of BMAL1 in aging appears to be unique in that mice deficient in other circadian clock components do not show the same phenotype.
R. V. Kondratov, A. A. Kondratova, V. Y. Gorbacheva, O. V. Vykhovanets, M. P. Antoch, Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock. Genes Dev. 20, 1868-1873 (2006). [Abstract] [Full Text]