Screening for Existing Drugs Capable of Enhancing the Mitochondrial Unfolded Protein Response
The growing interest in manipulating aspects of metabolism related to aging is still largely focused on the range of cell maintenance mechanisms that are triggered into greater operation by calorie restriction and other stresses. Efforts are underway to discover existing approved drugs that have a large enough effect on these mechanisms to be repurposed as therapies to slow aging. This type of initiative does has the potential to produce important discoveries, such as the first senolytic drugs capable of selectively destroying senescent cells. But where it focuses on upregulation of cell maintenance processes such as autophagy or the unfolded protein response, it seems unlikely to produce more than incrementally beneficial outcomes. We know what the practice of calorie restriction or exercise can achieve in humans via these stress response mechanisms, meaning a healthier old age but only a few additional years of life. Mimicking a fraction of these processes is not going to be capable of greatly changing the shape of a human life.
Researchers know that mitochondria play an important role in aging. Specifically, when mitochondria are harmed in some way and their function is impaired, a process called mitochondrial unfolded protein response (UPRmt) occurs that repairs mitochondria and benefits cell survival. Therefore, some scientists think it is possible to increase lifespan by identifying drugs that activate UPRmt. A team of scientists searched through a chemical library of existing drugs to find one that can activate this stress response in the worm Caenorhabditis elegans. They found that an anti-hypertension drug called metolazone prolongs C. elegans lifespan, marking the first step in developing anti-aging pharmaceuticals.
Past experiments with Caenorhabditis elegans - a worm commonly used in biological research as a model - have found several compounds that increase the worm's lifespan by triggering UPRmt. Against the backdrop of these previous studies, this team screened about 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. It is interesting to note that of these 3000 drugs, 1300 were off-patent drugs approved by regulatory agencies, and the remaining 1700 were unapproved bioactive ones.
Through this method, the team identified metolazone, a drug used to treat heart failure and high blood pressure. They then tested the drug on C. elegans and found that it increased wild-type worm lifespan. Additionally, they found that metolazone did not extend lifespans in worms in whom the genes atfs-1, ubl-5, and nkcc-1 were mutated and thus non-functional. The former two genes are known to be essential for UPRmt function, suggesting that metolazone is acting on the UPRmt pathway. The third gene, 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.