Metolazone Shown to Slow Aging, Extend Lifespan in C. elegans

Metolazone Shown to Slow Aging, Extend Lifespan in C. elegans

Posted by Valerie Walters on Jan 7, 2021 5:14 am

What’s the key to living longer? Better heart health? Keeping the brain active? A new study finds the answer may be in the energy our cells produce. Scientists in Japan have demonstrated how a drug that is currently used to treat high blood pressure, activates a mitochondrial stress response to prolong lifespan in the roundworm, Caenorhabditis elegans (C. elegans).

While modern medicine does not strive to find the fountain of youth, keen interest in promoting longevity has prompted research into the mechanisms of aging and the possibility of anti-aging drugs. Dr. Eriko Kage-Nakadai and her colleagues from Osaka City University in Japan are one of the many research teams fascinated by aging research. Against the backdrop of previous studies, his team, in their new study published in Biogerontology, 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 the USFDA, EMA, and other agencies, and the remaining 1700 were unapproved bioactive ones.

The team’s screen highlighted metolazone, a diuretic drug that is used to treat heart failure and high blood pressure. The study discovered that metolazone could trigger this mitochondrial response and also extended the lifespan of the worms in the study. While successful in increasing wild-type worm lifespans, researchers note the drug did not help worms with certain mutations in three specific genes. Two of these genes, atfs-1 and ubl-5, are essential to proper UPRmt function. The Japanese team says they believe this proves metolazone is acting as a UPRmt pathway. The third gene, nkcc-1, codes proteins which the drug targets while treating high blood pressure. Researchers say this may mean metolazone needs to block nkcc-1 proteins in order to start the UPRmt process.

The researchers’ experiments also showed that metolazone induced hsp-6 (Hspa9 in humans) expression in human HeLa cells, suggesting that its UPRmt-related effects could possibly span multiple species. “In human cells, supplementation with metolazone induced the expression of mtHSP70 and HSP60, which encode mitochondrial chaperones: however, ER chaperone HSP70 was not induced,” they further commented. “Taken together, we conclude that metolazone is a potent and specific mitochondrial chaperone activator across species.”

When asked about the broader significance of her work, Dr. Kage-Nakadai comments, "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." The researchers acknowledged that their reported work is still in the early stage, but it does open up a potential new route for developing future anti-aging drugs.

Metolazone and related compounds for non-human research use:

Compound More information
Metolazone https://www.vulcanchem.com/product/inhibitors/VC1070575
Bendroflumethiazide https://www.vulcanchem.com/product/inhibitors/VC1041499
Benzthiazide https://www.vulcanchem.com/product/inhibitors/VC1041869
Chlorothiazide https://www.vulcanchem.com/product/inhibitors/VC1047075
Hydrochlorothiazide https://www.vulcanchem.com/product/inhibitors/VC1060281
Trichlormethiazide https://www.vulcanchem.com/product/inhibitors/VC1091615
Polythiazide https://www.vulcanchem.com/product/inhibitors/VC1079989
Quinethazone https://www.vulcanchem.com/product/inhibitors/VC1081709
Indapamide https://www.vulcanchem.com/product/inhibitors/VC1061203

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