Researchers may have not discovered the fountain of youth but they have made impressive strides in understanding the role mitochondria plays in aging. When mitochondria are damaged, their function is impaired, leading to the UPRmt response that leads to repair. This insight provides an important clue to longevity as it is postulated that increased lifespan can be influenced by utilizing drugs that activate UPRmt.
Dr. Eriko Kage-Nakadai and her colleagues from Osaka City University in Japan are key investigators in the new study. As Dr. Kage-Nakadai explains, "Even though aging is not a disease, drugs may slow down aging and mitigate or prevent its negative effects on our health."
Their new study is published in Biogerontology and involved a screening of nearly 3,000 drugs in worms that are engineered to glow if drug treatment activates hsp-6, a gene that is highly expressed when UPRmt occurs.
The research team identified metolazone, used to treat heart failure and high blood pressure. They then tested the drug on C. elegans and discovered that it increased wild-type worm lifespan. Additionally, they determined that metolazone did not extend lifespans in worms in whom the genes atfs-1, ubl-5, and nkcc-1 were mutated (non-working). Atfs-1 and ubl-5 are known to be essential for UPRmt function, suggesting that metolazone is acting on the UPRmt pathway. Nkcc-1, "encodes" a protein that is part of a protein family targeted by metolazone in its usual function as an anti-hypertension drug. The fact that metolazone did not increase the lifespans of nkcc-1 mutated C. elegans suggests that the drug may need to block the nkcc-1 protein to activate the UPRmt pathway. Metolazone "induced" hsp-6 (Hspa9 in humans) expression in HeLa cells which could mean the drug's UPRmt-related effects could affect a variety of species.
Dr. Kage-Nakadai commented, "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. Worms always give us many hints."