Is the Blood Pressure Drug Metolazone the Newest Longevity-Booster on the Block?

People have been searching for a magic pill or elixir to extend life for as long as humans have walked the planet, with scientists all over the globe concurrently striving to be the ones to discover it.

Researchers out of Osaka City University in Japan may have placed us one step closer to extending lifespan, using a medication that’s already safely and commonly used by many. Rather than discovering an entirely new compound, this research team chose to sift through thousands of available drugs and work with what we’ve already got. Published in Biogerontology in November 2020, this research adds another compound — metolazone — to the list of potential drugs that may combat aging and extend life.

Stayin’ alive: Survival instincts of the cell’s powerhouses

Mitochondria are essential components of every cell that create energy (ATP), earning their nickname as the “powerhouses” of the cell. Given the fundamental role of these energy-producing structures in cellular health and survival, impaired function or integrity of mitochondria is linked to accelerated aging and disease development.

One way mitochondria preserve themselves from damage and dysfunction is through the mitochondrial unfolded protein response (UPRmt). This protective process is activated by several forms of mitochondrial stress or dysfunction. The UPRmt regulates mitochondrial fusion and fission — the joining together and splitting apart of mitochondria — which play a critical role in maintaining cellular energy production and recycling damaged components. Additionally, this defense mechanism helps cell survival by recovering mitochondrial DNA replication; defects in this process are thought to speed up aging and contribute to disease. 

Through this repair and recovery process, UPRmt activation has been shown to extend lifespan across many species, including worms, flies, and mice. In this study, the Japanese researchers determined how to increase activation of UPRmt to promote longevity in Caenorhabditis elegans (C. elegans), a species of roundworm widely used in laboratory research. 

Glowing worms light the way

As several compounds and drugs that activate UPRmt have already been identified, the research team wondered if there were more that had yet to be discovered.  They screened 3,000 pharmaceutical drugs, including many that already have received FDA approval for use in the clinic. For this screening process, the researchers engineered the worms to glow if a drug activated a protein called HSP-6 (heat shock protein-6), as it is triggered during UPRmt activation. HSP-6 is a mitochondrial chaperone — molecules that heal the damage that occurs in mitochondria. Essentially, these chaperones help mitochondria survive fatal conditions. 

The team discovered that the medication metolazone, a diuretic (water pill that increases urine output) used to treat high blood pressure and heart failure, made the worms glow, indicative of HSP-6 activation. With the UPRmt enhancer identified, the next step was to test the effects of metolazone on the worms’ lifespan. 

The lifespan-extending effects of metolazone: from worms to human cells

First and most importantly, the team found that metolazone treatment did extend lifespan in C. elegans. The blood pressure drug exhibited life-extending effects that were comparable to olaparib, one of the known UPRmt-activators. 

Next, Ito and colleagues determined if metolazone extended lifespan specifically due to UPRmt activation or if some other mechanism was at play. The researchers believed that three genes were responsible for the longevity-promoting effects of metolazone, so they experimented on worms with inactive versions of those genes. 

As they predicted, worms without these three genes did not experience the same lifespan-extending benefits after treatment with metolazone. 

The first two genes, atfs-1 and ubl-5, are known to play a role in UPRmt activation and mitochondrial chaperone production. Worms without these genes that received metolazone treatment did not live longer lives. This indicates that metolazone does, in fact, act on the UPRmt pathway to promote longevity. 

The third gene, nkcc-1, encodes for a protein (NKCC-1) that is identical to the family of proteins that metolazone targets to treat high blood pressure. Because of this NKCC-1’s similarity, the researchers wondered if the drug extends lifespan primarily by blocking NKCC-1. They were right — worms with inactivated nkcc-1 genes failed to extend lifespan after metolazone treatment. 

In addition to testing their theories on worms, Ito and colleagues treated human cells with metolazone. These cells showed an increased production of HSP-6, indicating that metolazone may also be a mitochondrial chaperone activator — and potential longevity-booster — in humans. 

However, the researchers caution that this doesn’t necessarily mean metolazone will extend lifespan in humans — not yet, at least. Although the FDA has already approved this medication for blood pressure and heart failure treatment, it will still have to prove itself in new clinical trials for its effectiveness as an anti-aging drug in humans.

Key Takeaway: 

• Metolazone, a common diuretic drug used to treat high blood pressure and heart failure, shows promise as a longevity-booster. The medication increased the production and function of several genes and proteins related to lifespan and lengthened worms’ lives. 

• An internal survival mechanism of the cell’s powerhouses called the mitochondrial unfolded protein response (UPRmt) is essential for longevity, as it protects and repairs the cell’s mitochondria after damage or dysfunction. 

• Many researchers have looked to UPRmt activation as a means to extend lifespan. The authors of this study found that metolazone boosts UPRmt function with the help of three genes, leading to longer lives in C. elegans worms. 

• Although these results have not yet been verified in human studies, the researchers are hopeful that this already-approved and available medication may soon do more for human health and longevity than simply act as a water pill. 

References: 

Houtkooper RH, Mouchiroud L, Ryu D, et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature. 2013;497(7450):451-457. doi:10.1038/nature12188

Ito A, Zhao Q, Tanaka Y, et al. Metolazone upregulates mitochondrial chaperones and extends lifespan in Caenorhabditis elegans [published online ahead of print, 2020 Nov 20]. Biogerontology. 2020;10.1007/s10522-020-09907-6. doi:10.1007/s10522-020-09907-6

Owusu-Ansah E, Song W, Perrimon N. Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell. 2013;155(3):699-712. doi:10.1016/j.cell.2013.09.021

Shpilka T, Haynes CM. The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. Nat Rev Mol Cell Biol. 2018;19(2):109-120. doi:10.1038/nrm.2017.110