Previous studies have linked regular, long-term use of proton pump inhibitors (PPIs) to an increased risk of dementia, cardiovascular disease and renal failure, but until now, scientists haven’t known exactly why. Results published Tuesday in the journal Circulation Research signal a plausible answer, researchers say: Vascular cells chronically exposed in vitro to PPIs led to a buildup of cellular garbage in cellular linings, thus accelerating blood vessel aging.

“I’m perplexed that the pharmaceutical industry didn’t run across this first,” senior study author John P. Cooke, chair of cardiovascular disease research at the Houston Methodist Research Institute, told FoxNews.com. “This is something that should have been apparent a long time ago and should have been investigated.”

An estimated one in 14 Americans uses an over-the-counter PPI like omeprazole, sold as Prilosec, to treat gastroesophageal reflux disease (GERD), also called heartburn or acid reflux. Considered the most effective treatment for GERD, PPIs are approved by the Food and Drug Administration (FDA) for use four weeks at a time, but research suggests up to 70 percent of PPI use may be inappropriate.

Cooke helped author research in 2013 that suggested PPIs decrease nitric oxide in endothelial cells, which line blood cells in the body— an effect that can have an adverse impact on cardiovascular health. He also worked on a 2015 study that linked regular, long-term PPI use to a 20 percent increased risk of heart attack among a database of 3 million patients.

“We now have a plausible mechanism that unifies how PPIs are associated with heart attack, vascular dementia and renal failure,” said Cooke, who is also director of the Center for Cardiovascular Regeneration at the Houston Methodist Research Institute.

For his latest study, Cooke and his colleagues exposed endothelial cells over weeks— roughly equal to months or years in a clinical model— to the PPI esomeprazole, or Nexium, as well as another PPI that isn’t commercially available, and to an H2 blocker, another type of medication for GERD.
The vascular cells chronically exposed to PPIs had a “fried egg” look, Cooke said.

“That was not expected, and then we thought, ‘What could be causing them to age faster if that’s the case?’” he said.

Cooke and his team proved that was the case by using a stain called beta-gal to expose markers for aging. Next, it occurred to them that vascular cells have tiny organelles inside called lysosomes, which act like garbage disposals, or stomachs. It’s well known that if lysosomes are impaired, garbage accumulates and aging accelerates.

Researchers found that while the H2 blockers had no effect on vascular aging, chronic use of the PPIs indeed impaired the lysosomes, preventing them from generating acid.

“We also saw the telomeres shortening— they’re on the tips of chromosomes and like our biological clock,” Cooke added. “Those vascular cells couldn’t proliferate or divide as well, and that’s necessary for repairing a wound in the vessel.”

Previous research has associated free radical generation and telomere shortening with expedited cell aging. Free radical accumulation in particular can trigger oxidative damage, an effect linked with age-related chronic conditions such as neurodegenerative disorders, like Alzheimer’s disease, as well as cardiovascular disease and cancer.

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Nick Leeper, associate professor and chief of vascular
medicine at Stanford University, was not involved in the current study but called the new findings “provocative.”Medicine at Stanford University

“I think that this is yet another piece of data which all points to a potential risk that should be studied in a prospective, randomized fashion,” Leeper, who worked with Cooke on the 2015 study linking PPIs to an increased heart attack risk, told FoxNews.com. “I think it’s important to note, as the authors point out, that these medicines are frequently used for much longer than the approved indication and are also available over the counter. And so I think that, given this pattern of potential harm that’s been seen in this series of studies described here, that regulators should consider whether additional prospective studies are necessary.”

Cooke said a prospective, randomized trial is the next step for researchers, as the main limitation of his team’s new study is that, although its model is clinically relevant, it was conducted in vitro.

However, he thinks his team’s findings warrant action among regulators and doctors.

“I’m not saying these drugs should be pulled off the market— they’re safe and effective as approved by the FDA,” Cooke said, “but I do think it’s time to reconsider their use over the counter and re-educate ourselves.”