A study on fruit flies has revealed that boosting a cellular cleanup-mechanism known as autophagy prevents the age-dependent accumulation of cellular damage in neurons, and promotes longevity.
While scientists are well aware the suppressing autophagy can accelerate the accumulation of protein aggregates that leads to neural degeneration, researchers at the Salk Institute for Biological Studies claim that their study is the first study to show that the opposite is true as well.
Advertisement"We discovered that levels of several key pathway members are reduced in Drosophila neural tissue as a normal part of aging, which suggests there is an age-dependent suppression of autophagy that may be a contributing factor for human neurodegenerative disorders like Alzheimer's disease," says senior author Dr. Kim Finley, a scientist in the Cellular Neurobiology Laboratory.
Most experts in the geriatrics field consider the age-related accumulation of proteins and lipids damaged by chemically aggressive forms of oxygen to be a normal part of the ageing process. In most age-associated diseases like Alzheimer's, damaged proteins accumulate in excessive amounts, which leads to progressive cell death in the brain.
All cells undergo autophagy, which requires the assembly of specialized vesicles called autophagosomes. The vesicles surround or engulf damaged cellular proteins or structures, and then traffic the "bagged garbage" to a second group of vesicles, which disposes of the trash with the help of digestive enzymes.
The researchers say that this process can be enhanced when animals are placed on a calorie-restricted diet, a regime known to extend lifespan.
"The activation of autophagy facilitates the removal of damaged molecules that accumulate during cellular aging. This may be particularly important in the nervous system since neurons produce damaged molecules at a much higher rate than most cell types," says Finley.
The Salk researchers experimented with the fruit fly Drosophila, a powerful model organism whose genetics can easily be manipulated. Initial experiments conducted by them indicated that several autophagy genes decreased over the normal lifespan of fruit flies.
The researchers then turned their focus particularly on a gene called Atg8a, which is an essential component needed for the formation of new autophagosomes.
It was found that levels of Atg8a were significantly reduced by four weeks of age, a time when the flies are considered middle aged. At the same time, protein aggregates were not efficiently cleared by the cellular clean-up crew and started to accumulate.
In the absence of Atg8a, things went from bad to worse. Damaged proteins tagged for degradation started to pile up early and life expectancy plummeted.
"The abnormal accumulation of protein aggregates had striking similarities to those seen in the most common human neurodegenerative diseases," says first author Dr. Anne Simonsen, a visiting scientist from the University of Oslo, Norway.
The study, reported in the journal Autophagy, further showed that the flies were spared the ravages of time when the researchers kept the neuronal levels of Atg8a high.
According to them, promoting the pathway not only prevented the accumulation of protein aggregates, but also significantly extended the average lifespan.
"Our experiments show for the first time genetically that autophagy can sequester and eliminate misfolded and damaged proteins, which accumulate in neurons as normal part of the aging process, but most importantly they demonstrate that enhancing the clearance of damaged proteins and protein aggregates increases longevity," says Simonsen.
Given that Insulin signalling and caloric restriction are two major determinants of longevity and that they impact the activity level of autophagy, the researchers believe that regulating autophagy may be the key factor in controlling the aging process.
"By maintaining the expression of a rate-limiting autophagy gene in the aging nervous system there is a dramatic extension of lifespan and resistance to age-associated oxidative stress," says Finley.
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