Drug used to treat heart failure, high blood pressure may help defy aging by activating mitochondrial stress response

In a recent research study, a group of researchers at the Osaka City University, Japan have found that a blood pressure drug called metolazone may be effective in improving lifespan by activating mitochondrial stress response in Caenorhabditis elegans (a model organism).

The findings of the study are published in the journal Biogerontology.

“Even though aging is not a disease, drugs may slow down ageing and mitigate or prevent its negative effects on our health. Current research shows promising signs.

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 UPR^mt” said Dr Kage-Nakadai, one of the researchers of the study, in a news release by the Osaka City University.

Mitochondria and stress response

Mitochondria is a cellular organelle (structure inside body cells) that performs various important functions in the body. It generates energy for everyday functions, helps maintain calcium homeostasis and fuels the oxidation of fatty acids. Mitochondria also helps respond to various stressors the body is exposed to.

Mitochondrial function changes every time it detects an external or internal threat. However, with ageing, mitochondrial function starts to decline. This happens because of the accumulation of harmful mutations in the mitochondrial genome and reactive oxygen species. Unlike some other organelles, mitochondria has its own genetic material too (in addition to the genetic material of the cell). However, a lot of to and fro happens between the mitochondrial genome and the nuclear genome to keep up the cellular processes.

In case the mitochondrial function is impaired, body cells activate something called unfolded protein response (UPR^mt) to keep itself alive and give the mitochondria some time to recover.

Experts suggest that stress and ageing share some common mechanisms. Better stress response is suggested to help increase longevity.

Metolazone and its effects UPR^mt

Metolazone is a type of diuretic drug (causes the body to lose more water and salts) that is given for the treatment of swelling associated with kidney diseases and heart failure. It is also used for the treatment of hypertension.

For the study, the researchers screened about 3,000 drugs in C elegans, which was designed to glow in case the drug activates a gene called hsp-6 that is associated with UPR^mt. About 1,300 of these drugs were pre-approved for other health conditions and the rest were unapproved still.

Here is what they found on testing the drug metolazone:

• The drug increased longevity in wild type worms.
• Metolazone did not work in worms which had mutated versions of atfs-1, ubl-5 and nkcc-1 genes. The last one is code for a protein that is targeted by metolazone for reducing hypertension, while the former two are involved in the functioning of the unfolded protein response.

Explaining some of the findings, the authors of the study suggested in the news release that metolazone may need to target nkcc-1 to activate UPR^mt.

When tested on the human cell line, metolazone induced hsp-6 and hence UPR^mt, showing that it may have some sort of effect on humans too.

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