Zinc, an inexpensive dietary supplement that cures everything from diarrhea and anorexia to the common cold, could also be a treatment for a far more serious condition: idiopathic pulmonary fibrosis (IPF).
In a recent experiment, researchers genetically engineered mice to develop fibrosis. When these mice consumed zinc along with NAD+ and sirtuin 1 activators—all 3 of which are sold as over-the-counter supplements—their fibrosis improved, and even disappeared.
This unexpected finding is the culmination of 3 decades of work by Paul W. Noble, MD, director of the Women’s Guild Lung Institute at Cedars-Sinai Medical Center in Los Angeles, California.
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Simply put, Dr. Noble’s team discovered that stem cells lining the air sacs in the lungs of people with IPF lose their ability to process zinc, a common mineral, because they’re missing a protein known as ZIP8. This lack of zinc prevents type 2 alveolar epithelial cells (AEC2s) from regenerating. Restoring this ability could potentially stop and even reverse IPF-related lung damage, he said.
Shelly Mathis, executive director of the patient advocacy organization PF Warriors, has praised Dr. Noble’s “extensive and amazing” background in the field, calling him “the Indiana Jones” of pulmonary fibrosis research during a webinar sponsored by the charity.
In fact, Dr. Noble said his interest in medicine came from his father, who always wanted to be a surgeon but ended up in surgical sales because he never got the chance to go to medical school.
“It was embedded in my brain,” the pulmonologist recently told Rare Disease Advisor, speaking from his Los Angeles clinic. “I had originally wanted to play professional baseball but wasn’t good enough, so this was my backup plan. I feel very fortunate to be able to do what I do.”
Dr. Noble first encountered pulmonary fibrosis while doing his residency in internal medicine at the University of California in San Francisco. There, he treated a number of bone marrow transplant patients who developed a rapid form of the disease. He started wondering why patients’ lungs would form scar tissue.
“I became completely smitten with this idea of fibrosis, and particularly IPF,” he explained. “Many of my patients that I took care of succumbed to the disease. I’ve spent the last 30 years taking care of patients who have fibrotic lung diseases and trying to better understand the disease with the goal of curing it.”
Treating the Root Cause
Dr. Noble, who’s just marked his 10th year at Cedars-Sinai, did his pulmonary and critical care fellowship at the University of Colorado and the National Jewish Center in Denver—one of the nation’s leading programs in interstitial lung disease. He’s also launched similar programs at Johns Hopkins University in Baltimore, Maryland, at Yale University School of Medicine in New Haven, Connecticut, and at Duke University in Durham, North Carolina.
“It was during that time that I had some extraordinary research collaborators that helped develop the ability to isolate cells from patients with IPF who had undergone lung transplants,” Dr. Noble said. “That has formed the basis for our work over the last decade to try to understand why patients are so sick with this disease, and to try to identify potential targets for treatment.”
IPF affects more than 100,000 people in the United States. Its incidence rises dramatically with age—particularly among patients older than 70—and men are more likely than women to get it.
Despite the approval of pirfenidone (Esbriet®) and nintedanib (Ofev®) in 2014 by the US Food and Drug Administration (FDA) to treat the disease, IPF is still the leading reason for lung transplants in the United States. Neither of them treat the underlying cause of IPF.
Notably, even with available therapeutics, the prognosis for IPF patients is worse than for those with most cancers, including lung cancer, said Dr. Noble, who was involved in the original development of both FDA-approved drugs. Dr. Noble compared the prognosis in IPF to that of cystic fibrosis (CF), another rare disease that currently affects some 40,000 Americans, according to the Cystic Fibrosis Foundation.
Since the mid-1950s, the life expectancy for a person born with CF has jumped from 5 years to around 53 years, thanks to the development of drugs that attack the root cause of the disease: mutations in the CF transmembrane conductance regulator (CFTR) gene.
Similarly, he said, “I’m excited because we think we’ve identified a pathway that could potentially improve the regenerative capacity of stem cells that help oxygen get from the environment into our blood. Our dream would be to have an impact similar to cystic fibrosis.”
But since not everyone with IPF is a candidate for a lung transplant, he added, “our hope is that we can not only stop this disease in its tracks, but if we can get it early enough, we can actually make it go away.”
That’s where zinc comes in.
Taking the Next Steps
In June 2022, the Journal of Clinical Investigation published a study coauthored by Dr. Noble, “The ZIP8/SIRT1 Axis Regulates Alveolar Progenitor Cell Renewal in Aging and Idiopathic Pulmonary Fibrosis.”
Investigators found that zinc works along with a metabolite known as NAD+ and a molecule called sirtuin 1 activator that slows the aging process. Zinc is the critical link that makes this protein translation pathway possible.
Attempting to prove his theory in another way, Dr. Noble said, “we genetically engineered a mouse so that this critical stem cell is missing the zinc transporter. This mouse spontaneously develops fibrosis as it ages. This is, again, further evidence to suggest that this zinc‑NAD‑sirtuin pathway is perhaps the fundamental defect in IPF.”
Gísli Jenkins, MD, PhD, a British respiratory therapist at Imperial College London’s National Heart & Lung Institute, said Dr. Noble’s experiments “hold tremendous promise” for people with IPF.
“The studies by Dr. Noble’s group describing an impairment of zinc metabolism represent an important advance, because zinc is a readily available mineral that may restore the regenerative capacity to lung epithelial cells,” he said in an email. “However, further studies are required to determine whether zinc supplementation will be sufficient to overcome the described molecular defect to provide any clinical benefit.”
Dr. Noble is now working with colleagues to determine how many participants would be needed for a clinical trial to test his theory. Some “grateful patients” have offered to help him philanthropically, he said, and talks have also begun with supplement companies to possibly supply the drug at no charge, he said.
Officials of the National Institutes of Health (NIH) have already spoken with Cedars-Sinai about organizing a trial to restore NAD+ levels, but any such trial will take at least a year.
“I’ve been involved in industry‑sponsored clinical trials, and we have an investigator‑initiated clinical trial about to start based on another aspect of our scientific work that a pharmaceutical company is funding,” he said. “I’m optimistic that we can move this forward.”
