Summary: A new study reveals minocycline, a popular antibiotic, can help extend lifespan and improve protein balance in aging worms. Researchers say the protective mechanism of the medication could be exploited to help prevent neurodegenerative diseases like Alzheimer’s or Parkinson’s in humans.
An antibiotic, minocycline, can increase the lifespan of roundworms by preventing the build-up of proteins during aging, a study in the open-access journal eLife reports.
Protein aggregation causes several progressive age-related brain diseases, including amyotrophic lateral sclerosis, Alzheimer’s, Parkinson’s and prion disease. This study shows that minocycline prevents this build-up even in older animals with age-impaired stress-response pathways.
The number of proteins in a cell is balanced by the rate of protein manufacture and disposal, called 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, US. “In this study, we investigated whether minocycline can reduce protein aggregation and extend lifespan in animals that already have impaired proteostasis.”
The team first tested 21 different molecules known to extend lifespan in young and old Caenorhabditis elegans (C. 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 two proteins called α-synuclein and amyloid-β, which are known to build up in Parkinson’s and Alzheimer’s disease, respectively. 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 protein-manufacturing machinery of the cell, known as 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.
“We have identified minocycline as a drug that can extend lifespan and improve protein balance in already-aging worms,” concludes Michael Petrascheck, PhD, senior author of the paper and Associate Professor at Scripps Research. “Our study reveals how minocycline prevents protein aggregation and lays the foundations for drug-development efforts aimed at optimising this already-approved drug for a range of neurodegenerative diseases.”
Funding: Funding provided by Lawrence Ellison Foundation, National Institutes of Health, National Science Foundation, Glenn Foundation for Medical Research.
Source: Emily Packer – eLife
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Open access research for “Translation attenuation by minocycline enhances longevity and proteostasis in old post-stress-responsive organisms” by Gregory M Solis, Rozina Kardakaris, Elizabeth R Valentine, Liron Bar-Peled, Alice L Chen, Megan M Blewett, Mark A McCormick, James R Williamson, Brian Kennedy, Benjamin F Cravatt, and Michael Petrascheck in eLife. Published November 27 2018.
Translation attenuation by minocycline enhances longevity and proteostasis in old post-stress-responsive organisms
Aging impairs the activation of stress signaling pathways (SSPs), preventing the induction of longevity mechanisms late in life. Here, we show that the antibiotic minocycline increases lifespan and reduces protein aggregation even in old, SSP-deficient Caenorhabditis elegans by targeting cytoplasmic ribosomes, preferentially attenuating translation of highly translated mRNAs. In contrast to most other longevity paradigms, minocycline inhibits rather than activates all major SSPs and extends lifespan in mutants deficient in the activation of SSPs, lysosomal or autophagic pathways. We propose that minocycline lowers the concentration of newly synthesized aggregation-prone proteins, resulting in a relative increase in protein-folding capacity without the necessity to induce protein-folding pathways. Our study suggests that in old individuals with incapacitated SSPs or autophagic pathways, pharmacological attenuation of cytoplasmic translation is a promising strategy to reduce protein aggregation. Altogether, it provides a geroprotecive mechanism for the many beneficial effects of tetracyclines in models of neurodegenerative disease.