Scientists from Osaka City University have found metolazone, an anti-hypertension drug that has been around for almost 50 years, can kickstart a lifespan-extending cellular repair process in roundworms. The research suggests this mechanism could be translatable to humans, offering new research pathways in the search for an anti-aging drug.
Mitochondria are tiny structures that act like cellular power plants. As we age mitochondria become increasingly dysfunctional and, in the search for lifespan-extending medicines, some scientists are looking at ways to repair these fundamental structures.
When mitochondria are damaged a process called mitochondrial unfolded protein response (UPRmt) is sometimes triggered. This mechanism involves the repair of mitochondria, and some anti-aging researchers suspect we could live longer if this process could be activated by taking a drug.
“Even though aging is not a disease, drugs may slow down aging and mitigate or prevent its negative effects on our health,” says Eriko Kage-Nakadai, one of the scientists working on the new research.
Kage-Nakadai led a team of scientists from Osaka City University to set out to discover whether there are any pre-existing drugs that can trigger UPRmt. The first step involved screening around 3,000 known drugs in worms that had been genetically engineered to glow when a gene called hsp-6 is activated. This gene is known to be highly expressed during the process of UPRmt.
One drug called metolazone quickly stood out as significant in its effect on the hsp-6 gene. Metolazone is a common drug used to treat high blood pressure and it has been in clinical use for nearly 50 years.
The lifespan-extending effect of metolazone was then tested on C. elegans worms, an organism frequently used in early preclinical anti-aging research. Metolazone was confirmed to indeed significantly extend the lifespan of the roundworms.
The lifespan-extending effect of metolazone was not seen when the researchers blocked the activity of several genes known to play a role in UPRmt. This affirmed that the anti-aging effects potentiated by metolazone were most likely a result of activating that specific mitochondrial repair process.
Finally, the researchers looked at the effect of metolazone on the hsp-6 gene (known as Hspa9 in humans) in human cell lines. The common blood pressure drug did heighten expression of the gene, adding weight to the hypothesis this drug-related UPRmt activation could translate into mammals.
It is still early days for this research, so don’t expect metolazone to suddenly be touted as an anti-aging miracle drug. But this new study offers valuable building blocks for the science of lifespan extension, particularly in its confirmation of a link between longevity and the activation of this mitochondrial repair process. Kage-Nakadai also points out the value in studying pre-existing and pre-approved drugs, especially ones that are off-patent, easily accessible, and known to be safe.
“What is particularly exciting is that we tested already available approved drugs here, and we have revealed the potential of repurposing existing drugs for aging control,” says Kage-Nakadai. “Worms always give us many hints.”
The new study was published in the journal Biogerontology.
Source: Osaka City University
