March 18, 2018Circadian Rhythms
Preclinical studies suggest that Cdk5 is a gene that is important for the normal wiring of the brain during early development and may be involved in some neurodegenerative disorders, including ALS, Parkinson's and Alzheimer's disease.
According to an article published online in Disease Models & Mechanisms (8 March 2018), a study of flies suggests neurodegenerative disorders may speed up aging process. To better understand the link between aging and neurodegenerative disorders such as Alzheimer's disease, the various genetic clocks that tick during the lives of normal and mutant flies were compared. Results showed that altering the activity of a gene called Cdk5 appeared to make the clocks run faster than normal, and that the affected flies presented older than their chronological age, including problems walking or flying later in life, showing signs of neurodegeneration, and shortened life expectancy.
On average, the normal flies in the study lived for 47 days. To create a genetic clock, the authors measured the levels of every gene encoded in messenger RNA molecules from cells from the heads and bodies of flies at 3, 10, 30, and 45 days after birth. This allowed the authors to use advanced analysis techniques to search for the genes that seemed to be sensitive to aging, and create a standard curve, or timeline, that described the way they changed. When the same experiments were performed on 10-day-old mutant flies and the results were compared with the standard curve, it was found that the flies were older than their chronological age. Altering Cdk5 activity made the brains of the flies appear genetically to be about 15 days old and their bodies to be about 20 days old. The study found that eliminating or increasing Cdk5 activity beyond normal levels shortened the lives of the flies to about 30 days. After 10 days of age, the manipulations reduced the distance flies could climb up tubes and the alterations caused older flies to have signs of neurodegeneration, including higher than normal levels of brain cell death and degradation. More analysis showed that altering Cdk5 activity changed the level of several groups of genes that were also affected by aging, including those that control immunity, energy, and antioxidant activity.
To explore this idea further, the authors tested the strength of the flies' antioxidant defenses against toxic versions of several chemicals found in cells called oxygen free radicals. Initial experiments showed that aging reduced these defenses in normal flies. Three-day-old healthy flies lived for about 100 hours after exposure to free radicals, and that time decreased with age. In contrast, the defenses of Cdk5 mutant flies were even weaker as they died sooner than the control flies at all ages.
According to the authors, the results suggest that aging may not just predispose an individual to degeneration, but that acceleration of aging may actually be part of the mechanism by which degenerative disease disrupts the structure and function of the brain.