Hair loss and wrinkled skin are typical signs of a long life, but for children born with Hutchinson-Gilford progeria syndrome, these old age features appear when they are just one year old. A swap of a single cytosine to a thymine in the lamin A gene — an important component of the structure that surrounds the cell nucleus — causes this rare, accelerated aging disease.
Children with progeria grow much slower than their healthy peers and are also shorter and lighter. They suffer from complications that are much more common in older adults such as cardiovascular disease and strokes. So far, progeria has no cure, and these children typically only live to about age 14.
“This has been extended recently because of all the clinical trials, but they do live a very short life,” said Kan Cao, a cell biologist and aging researcher at the University of Maryland. Cao has studied progeria’s molecular mechanisms for 17 years, almost as long as people have even known the cause of the disease.
Cao also uses progeria as a launching pad to study how humans age and to identify ways to slow or prevent aging’s detrimental health effects. In doing so, she discovered the surprising rejuvenative effects of the diagnostic and medicinal dye methylene blue, from which she spun off the company Mblue Labs, and developed an anti-aging cream. She and her team have contributed to numerous progeria treatment clinical trials, including one that looks like it may cure progeria once and for all.
How did you get interested in studying progeria?
It was actually an accident! I was a graduate student in cell biology and cancer at Johns Hopkins University, and I applied for a postdoctoral fellowship in Francis Collins’s laboratory at the National Institutes of Health. He had an advertisement out for a postdoctoral position in type two diabetes, but when he saw my cell biology background on my CV, he said, “Kan, I think I have a better match for you, and that's progeria.”
Had you heard of progeria before?
I hadn’t, actually. I applied for the position in 2004, and Collins and others had just discovered the mutation in the lamin A gene that causes progeria in 2003 (1). At the time when I applied for the position, there were probably less than 100 researchers worldwide studying progeria. It was a very small field. But now, over the last two decades, the number of researchers has grown dramatically.
What kinds of progeria treatments have researchers developed?
People have studied the function of the lamin A gene for years, which positioned progeria research in a nice spot for a clinical trial. The first clinical trial started in 2007, which was only four years after researchers discovered the causative mutation. That kind of speed is unheard of. In that trial, the scientists tested an approved cancer drug called farnesol transferase inhibitors (FTIs). We and others showed that the drug was beneficial for progeria in cells and in animal models, and the trial was very successful. The treatment can extend patient lives and reduce the risk of the very dangerous cardiovascular malfunctions that lead to most patient deaths. It was really an honor to contribute data to that trial. I saw how research can make an impact. Since that first trial, there have been a few more, including one based on my own research.
What treatment is that trial investigating?
The idea behind that trial is to see whether we can ask the cell to remove the mutant lamin A protein by activating autophagy using the drug rapamycin. Clinicians have also used this drug for many other conditions such as cancer and to prevent organ transplantation rejection. During my postdoctoral research, we showed that rapamycin worked effectively in progeria cells. Now, the clinical trial coordinators just finished assessing the last patient, and I think the data will be publicly available later this year.
You coauthored a recent paper demonstrating that in vivo base editing could correct the lamin A mutation in progeria patients. How does that treatment strategy work?
In traditional CRISPR gene editing, the nuclease Cas9 comes in and, like scissors, it cleaves the double stranded DNA and then repairs it. By making a double strand break, there is a high chance of introducing mutations because we do not have much control over how to repair this break. With base editing, we only cut one strand, and an enzyme precisely changes one nucleotide to another. Basically, we can rewrite the DNA without breaking it, so it reduces the nonspecific mutations caused by the traditional Cas9-based gene editing methods.
Progeria researchers wanted to see whether this method could correct the lamin A mutation in progeria cells. My team mostly contributed to the first step of the project by using this approach to correct patient cells in a dish. Once we showed we could do that, other researchers tested this approach in progeria animal models. The result was better than we ever expected (2). We got almost 100% rescue of the progeria animals’ phenotype. They started to live as long as the normal animals. This has brought a lot of hope for the future of progeria treatment. There are a few hurdles to overcome such as delivery into humans, toxicity, and efficacy. I just hope things will work, and we can help progeria patients as soon as possible.
Along with your progeria research, you also run a company called Mblue Labs that produces an anti-aging cream. How did Mblue Labs come about?
That’s a good story! Around 2014, the progeria research field was at a stage where researchers had discovered many different phenotypes inside of the progeria cell nucleus. The nuclear morphology is different, the gene expression is different, and the nuclear organization is different. But people were not paying much attention to anything outside of the nucleus. Mitochondrial health is connected to human aging, and mitochondrial mutations associate with many age-related diseases.
At that time, one of my postdoctoral researchers was looking into mitochondrial defects in progeria, and she discovered so many different mitochondrial defects in progeria cells: mitochondria that do not produce enough ATP, that do not move around. All of the things that could possibly be wrong are wrong in progeria mitochondria. We then wondered if we could rescue the mitochondrial defects in progeria cells, and if we did that, how much could we improve the overall progeria cell’s health. Could we extend its lifespan? That's how I started screening through the traditional mitochondrial drugs that people use and landed on methylene blue, an antioxidant that stimulates mitochondrial function.
Because progeria patients are very fragile, we can only get skin cells from one skin biopsy, so those are the cells we test. As controls, we always use young normal and old normal skins cells to make sure we control for the progeria cells well. When I added methylene blue to all of those samples, all of the skin cells just became happy — the young normal, old normal, progeria — everybody was happy! They looked much healthier. They produced more collagen, elastin, and ATP. The cells were more hydrated and had fewer reactive oxygen species. You name it, they had all of the benefits we want human skin cells to have. I filed a patent, and then I founded a startup company using methylene blue as a key ingredient in a skincare line. People can buy them on our website, Amazon, or even at Macy’s.
What was it like to take a discovery from the bench to a product available in stores?
It was quite a journey. I enjoyed every single minute. I wish I had 48 hours in a day. I'm an active researcher with graduate students, undergraduate students, postdoctoral researchers, and technicians in my lab, and I teach. I'm also a mother of two kids, so life is busy. The fun part of the company is that it excites another location in my brain, so when I work on my company, my neurons on science get a respite.
What do you plan to work on next?
There are some diseases that are very similar to progeria that have other mutations in lamin A and other lamin genes but lead to a different phenotype. There are very few patients with these laminopathies because the mutations are rare, so these diseases do not attract as much attention as progeria at the moment. We are interested in studying these progeria-like diseases, and we have also started studying age-related neurological diseases with a focus on Alzheimer's disease. I have been in the aging field for long enough to see the similarities in different diseases, so hopefully I can bring a different angle to the field.
What do you find most rewarding about your progeria and aging research?
Seeing the patients every few years at the International Progeria Workshop really gives me a lot of strength. These children and young adults are the people we serve as researchers. I can see progeria as a disease that can be cured in the not-too-distant future. I feel very optimistic about that.
This interview has been condensed and edited for clarity.
- Eriksson, M. et al. Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 423, 293-298 (2003).
- Koblan, L.W. et al. In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice. Nature 589, 608-614 (2021).