Protein aggregation causes a number of age-related disorders including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and prion diseases. Scientists at the Scripps Research Institute have now found that an FDA-approved antibiotic, minocycline, can prevent the buildup of proteins in aging roundworms and extend the animals’ lifespan.

Crawling C. elegans hermaphrodite worm
Credit: Bob Goldstein

Although its not known whether the antibiotic could have similar protective effects in humans, the researchers, headed by Michael Petrascheck, Ph.D., an associate professor at the Scripps Institute, suggest the findings in the roundworm model Caenorhabditis elegans could lead to the development of optimized minocycline-based treatments for neurodegenerative disorders in people.

“We have identified minocycline as a drug that can extend lifespan and improve protein balance in already-aging worms,” commented Dr. Petrascheck, who is senior author of the team’s paper in eLife. “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,” added lead author Gregory Solis. “Our study reveals how minocycline prevents protein aggregation and lays the foundations for drug-development efforts aimed at optimizing this already-approved drug for a range of neurodegenerative diseases.”

The team’s report is titled, “Translational attenuation by minocycline enhances longevity and proteostasis in old post-stress-responsive organisms.”

Cells balance the rate of production and degradation of proteins through a process known as proteostasis, but as we age proteostasis mechanisms can become less effective, which may contribute to the development of neurodegenerative disorders such as Alzheimer’s disease, the authors suggested. “… there is compelling genetic evidence for an age-associated collapse of proteostasis that contributes to protein aggregation and degradation phenotypes.”  Studies in roundworms have also shown that longevity is dependent on the ability to activate both proteostatic mechanisms and stress signaling pathways (SSPs), and that the response to stress also declines dramatically with age. “As a consequence, longevity pathways whose mechanisms depend on the activation of SSPs can be predicted to become nonresponsive with aging.”

To look more closely at whether proteostasis and longevity can be influenced during aging, the Scripps Institute researchers first determined that C. elegans roundworms develop age-related nonresponsiveness to stress from day 8 after reaching adulthood—their post-stress-responsive age. Then, to investigate whether lifespan in aging animals could be increased pharmacologically, the team treated aging, adult roundworms (at adult day 8) using 21 different molecules that had previously been shown to extend lifespan when administered at early adulthood. Of these 21 compounds, only the tetracycline antibiotic minocycline extended lifespan when administered to adult worms on day 8. “Minocycline still extended lifespan when treatment was initiated on day 8, albeit by 22% instead of the 48% observed when treatment commenced on day 1,” the team writes.

Minocycline is a regulatory agency-approved antibiotic used to treat acne, but the compound has also long been known to reduce tumor growth, inflammation, and protein aggregation in mammals, albeit by an unknown mechanism of action (MOA). To find out why minocycline increased lifespan in aging C. elegans worms the team looked at the effects of the antibiotic on the aggregation of α-synuclein and amyloid-β—the proteins that accumulate in the brains of patients with Parkinson’s disease and Alzheimer’s disease, respectively—in both young and old roundworms. They found that minocycline prevented protein aggregation with age, and extended C. elegans lifespan even in mutants that were defective of SSP.

Subsequent studies in the roundworms and in mouse cells and human cells demonstrated that minocycline directly affects ribosomes, which are key organelles in cells’ protein producing machinery. The study findings indicated that the drug selectively reduces translation. Additional tests confirmed that the drug also reduces mRNA translation in human cells. And whereas in mutant worms with already depleted protein-production capacity less minocycline was needed to further reduce protein levels and extend lifespan, in worms with increased protein manufacturing, the opposite was found.

“While it is not known whether minocycline extends lifespan in mammals, its geroprotective effects reduce age-associated protein aggregation and inflammation as evidenced by numerous preclinical and clinical studies,” the authors commented. They also suggested that the drug’s suggested mechanism of action offers “a unifying explanation for the many seemingly unrelated effects of minocycline observed in preclinical and clinical studies, including its ability to reduce tumor growth, inflammation, and improve symptoms of fragile X … Translation attenuation by reducing ribosomal load as an MOA provides a simple and compelling explanation for these seemingly unrelated beneficial effects.”

“Our study reveals how minocycline prevents protein aggregation and lays the foundations for drug-development efforts aimed at optimizing this already-approved drug for a range of neurodegenerative diseases,” concluded Dr. Petrascheck. And as the authors summarized, “Repurposing FDA-approved drugs such as minocycline using phenotypic screens reveals promising effects outside the primary indication (antibiotic) of minocycline and inevitably leads to promising new drug target(s) and MOAs … our studies on minocycline shed light on the plasticity of longevity mechanisms upon aging and reveal an MOA for minocycline that explains its geroprotective effects.”

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