The antibiotic minocycline has been shown to increase the lifespan of Caenorhabditis elegans and prevent the build-up of proteins, according to a paper published yesterday in eLife. Protein aggregation causes several progressive age-related brain diseases, including amyotrophic lateral sclerosis, Alzheimer's, Parkinson's and prion disease.
The number of proteins in a cell is balanced by proteostasis. As we age, proteostasis becomes impaired. "It would be great if there were a way to enhance proteostasis and extend lifespan and health, by treating older people at the first sign of neurodegenerative symptoms or disease markers such as protein build-up," says lead author Gregory Solis, a graduate student at Scripps Research.
The team first tested 21 different molecules known to extend lifespan in young and old Caenorhabditis elegans worms. They found that all of these molecules prolonged the lives of young worms; however, the only drug that worked on the older worms was minocycline. To find out why, they looked at whether minocycline had any effect on protein aggregation in the worms. They treated young and old worms with either water or minocycline and then measured α-synuclein and amyloid-β. Regardless of the worms' age, those treated with minocycline had reduced aggregation of both proteins as they grew older without even without the activation of stress responses.
The team next turned their attention to the mechanism behind this discovery. First, they looked at whether minocycline switches on stress-signalling proteins that are impaired in older worms, but they found the drug actually reduces their activity. Next, they studied whether it turns off the cell's protein-disposal processes, but this was not its mode of action either.
When they used a chemical probe to see how minocycline affects the major protein-regulating molecules in the cell, it revealed that minocycline directly affects the ribosome. This was true in worms, as well as mouse and human cells.
Finally, the team used worms with increased or decreased protein-manufacturing activity and studied how this altered the effect of minocycline on protein levels and lifespan. As predicted, in mutant worms where protein manufacturing was already decreased, they found that a lower dose of minocycline was needed to further reduce protein levels and extend lifespan. In worms where protein manufacturing was increased, the opposite was seen. This suggested that minocycline extends lifespan by controlling the rate of protein manufacturing at the ribosome.