Studying a strain of transgenic mice lacking the core circadian clock gene, Bmal1, Dr. Antoch and colleagues determined that BMAL1 also plays an important role in aging. Bmal1-deficient mice display a marked premature aging phenotype: By 4-7 months of age, the Bmal1 knockout mice experience weight loss, organ shrinkage, skin and hair weakening, cataracts, cornea inflammation and premature death.
The researchers went on to show that BMAL1's influence on the aging process is due to its previously established role in protecting the organism from the genotoxic stress. Some BMAL1-deficient tissues – like the kidney, heart and spleen – accumulate aberrantly high levels of free radicals. The scientists believe that oxidative stress may underlie premature aging in these animals.
Future research will be aimed at delineating BMAL1 target genes involved in the aging process, with the ultimate goal of elucidating molecular targets for the rational design of drugs aimed at alleviating specific, age-related pathologies. "The involvement of BMAL1, the key component of the molecular clock, in control of aging, provides a novel link between the circadian system, environment and disease and makes circadian proteins potential drug targets," explains Dr. Antoch.
Journal
Genes & Development