A team of scientists from the National Institutes of Health (NIH) has shed light on the link between aging and neurodegenerative diseases like Alzheimer’s disease, after comparing the genetic “clocks” of normal and mutant flies.
The researchers found that the gene Cdk5 appears to make flies biologically older than their chronological age, causing them to have problems walking or flying, show signs of neurodegeneration, and experience earlier death.
“We tried to untangle the large role aging appears to play in some of the most devastating neurological disorders,” Edward Giniger, PhD, a senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke and the senior author of the study published in Disease Models & Mechanisms, said in a statement. “Our results suggest that neurodegenerative disorders may accelerate the aging process.”
To create a genetic clock, the team measured the levels of every gene encoded in messenger RNA molecules in cells from the heads and bodies of flies at three, 10, 30 and 45 days after birth. They then used advanced analysis techniques to search for the genes that seemed to be sensitive to aging.
This also allowed them to create a standard curve or timeline that described the way the flies changed over time.
When they performed the same experiments on 10-day old Cdk5 mutant flies and compared the results with the standard curve, they saw that the flies were “older” than their chronological age. However, after altering Cdk5 activity, the brains of the flies appeared to be about 15 days genetically old and their bodies to be about 20 days old.
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.
The researchers found that eliminating or increasing Cdk5 activity beyond normal levels shortened the lives of the flies to about 30 days, compared to the standard lifespan of an average of 47 days. After 10 days of age, the manipulations reduced the distances the flies could climb up tubes.
The alterations also caused older flies to have signs of neurodegeneration, including higher than normal levels of brain cell death and degradation.
Further analysis showed that altering the gene activity changed the level of several groups of genes that were also affected by aging, including those that control immunity, energy and antioxidant activity.
Next, the team tested the strength of the flies’ antioxidant defenses against toxic versions of several chemicals found in cells called oxygen free radicals. The researchers initially found that aging reduced the defenses in normal flies, where three-day-old healthy flies lived for about 100 hours after exposure to free radicals. The lifespan also decreased in older, healthy flies who were exposed to free radicals.
The defenses of Cdk5 mutant flies were even weaker as they died sooner than the control flies at all ages.
“Our results suggest that aging may not just predispose an individual to degeneration, as we thought,” Ginger said. “Acceleration of aging may actually be part of the mechanism by which degenerative disease disrupts the structure and function of the brain. We hope that our approach will help researchers untangle the mysteries behind several neurodegenerative disorders.”
The study was published in Disease Models & Mechanisms
