Of Tiny Mice and Giant Discoveries: Past Guides Future of Aging Research

Z. Dave Sharp (left), PhD, professor emeritus of molecular medicine, came up with the idea to test rapamycin on mouse longevity and proposed it to the National Institute on Aging Interventions Testing Program (ITP). Randy Strong, PhD, director of the Nathan Shock Center of Excellence in the Biology of Aging, directs the San Antonio ITP and led the local study. The pioneering studies showed that rapamycin, an antibiotic used in transplant patients, extended the life span of mice.

By Michael Seringer

When Francisco Cigarroa, MD, first became president of UT Health San Antonio in 2000, a community and business leader called him with a new idea.

“Sam Barshop [founder of La Quinta Inns, Inc. and former Regent of UT System] calls me up and says, ‘I have this great idea. You need to invest in aging research.’

“ ‘Why?’ I said. ‘Look around you, Dr. Cigarroa, we are all aging,’ he said. ‘All the baby boomers like you are aging. I am good at business, and I’m telling you we gotta invest in aging research.’ ”

Bess Frost, PhD, Bartell Zachry Distinguished Professor for Research in Neurodegenerative Disorders, and her research team use fruit fly models to study the cause of Alzheimer’s disease—a buildup of tau proteins inside of cells and amyloid plaques outside of it—in The Zachry Family Laboratory at the Sam and Ann Barshop Institute for Longevity and Aging Studies at UT Health San Antonio.

Sam Barshop was right, and his vision led to the basic research-to-clinic pipeline that exists today at the Sam and Ann Barshop Institute for Longevity and Aging Studies.

There is much more to aging than its inevitability. UT Health San Antonio is finding answers to aging hidden among many abnormalities, such as deficient genes and tangled tau proteins. The Barshop Institute is not only making key laboratory discoveries, its researchers are working hard to translate discoveries all the way to the clinic—and it all started with tiny mice.

The Nature of Discovery

One of the reasons Randy Strong, PhD, came to UT Health San Antonio was the mice already in the labs.

“One of the big things that attracted me was they were already using genetically altered mice to answer questions about aging,” said Dr. Strong, who is director of the Nathan Shock Center of Excellence in the Biology of Aging at the Barshop Institute. “I liked the new technology and benefited from being able to build a program around it.”

Soon after his arrival at UT Health San Antonio, Dr. Strong’s lab became one of three Aging Interventions Testing Program (ITP) sites in the country funded by the National Institute on Aging (NIA). Around the same time, Z. Dave Sharp, PhD, now professor emeritus at the Joe R. and Teresa Lozano Long School of Medicine at UT Health, couldn’t stop thinking about dwarf mice who were deficient in the gene responsible for producing prolactin and growth hormone. He and Dr. Strong soon struck up a spectacularly successful collaboration, based on novel approaches to the problem of aging.

“It turned out that a mouse that is deficient in this gene lives a really long time. They never really grow up,” said Dr. Sharp, who recently retired as a researcher at the Barshop Institute. “The only other thing that leads to a small mouse is calorie restriction. When I read a paper about yeast being given rapamycin having the same phenotype as the yeast that were given less nutrients—the bell went off.” Could rapamycin inhibit aging the same as caloric restriction, well known for decreasing aging?

Dr. Sharp proposed testing rapamycin in mice to determine its effects on lifespan. After a few rejections, Dr. Strong recommended he write a proposal to test chronic rapamycin in the new ITP. They teamed up to determine the effects of rapamycin on aging due to its ability to inhibit the mTOR (mammalian target of rapamycin) protein.

Dr. Strong, associate director for translational research at the Barshop Institute and professor of pharmacology, recalls how he and Dr. Sharp immediately encountered problems when rapamycin was added to the mouse food during the initial test.

“Our first problem was when we put the rapamycin in the mouse chow, it didn’t last long,” said Dr. Strong. “Rapamycin is very volatile, and only about 20 percent of it was left once it was processed into the food. The second problem was rapamycin is destroyed by stomach acids.”

Luckily, Dr. Strong remembered an article he’d read about microencapsulation, and as it turned out, the Southwest Research Institute in San Antonio was starting to look into this technology as well. Dr. Sharp and Dr. Strong developed a rapamycin formulation and a plan for effectively delivering it to the mice. Southwest Research Institute helped encapsulate the rapamycin formulation at the sub-micron level into a specialized polymer that protects the drug in the stomach until it is released in the lower gastrointestinal tract, Dr. Strong said.

The results of feeding the micro-encapsulated rapamycin-rich mouse chow were groundbreaking. In both male and female mice, lifespan increased significantly. It was the first time in human history that a drug was shown to extend lifespan in mammals, and it even worked in senior mice. The discovery made the pages of Nature in 2009.

“I was running around hollering, ‘It’s working, it’s working. I can’t believe it,’ ” Dr. Sharp said. “That whole year was sort of like a dream.”

Sara E. Espinoza, MD, MSc, co-director of the Claude D. Pepper Older Americans Independence Center, is collaborating with colleagues at the Barshop Institute on a clinical trial on the effects of an antiretroviral drug in patients with Alzheimer’s disease.

Dr. Sharp and Dr. Strong’s discovery unleashed a torrent of research into the effects of rapamycin on aging, and their microencapsulated formulation was awarded a United States patent. Before the technology was sold to a commercial enterprise, UT Health San Antonio provided close to 10 metric tons of mouse chow, at cost, to investigators around the world, Dr. Strong said.

The discovery and resulting Nature article, which became one of the most cited research papers of the decade, quickly elevated the profile of aging research at UT Health San Antonio.

“Getting our paper published in Nature was great, but the reason our paper was so strong is because it was replicated at three different sites by investigators who had no stake in the outcome,” Dr Sharp said. “It’s really strong science; I think that’s the reason the paper was cited so much.”

From TOR to Tau

After Dr. Sharp and Dr. Strong’s rapamycin discovery, the Barshop Institute deployed a new focus on existing compounds and a comprehensive translational approach designed to move therapies from the lab to the clinic. Current research by Bess Frost, PhD, Bartell Zachry Distinguished Professor for Research in Neurodegenerative Disorders at the Long School of Medicine at UT Health, focuses on how the toxic forms of tau proteins in the brain kill cells, contributing to Alzheimer’s and other diseases.

Dr. Frost, associate professor of cell systems and anatomy and an investigator at the Barshop Institute, is investigating ancient remnants of viral DNA or “transposable elements” that have been trapped in human DNA.

“Almost all organisms have a large fraction of their genome composed of this trapped viral DNA,” Dr. Frost said. “The genome has learned to control these transposable elements. We are finding in cancer, Alzheimer’s, and in normal aging that our genomes lose their control over the viral DNA.”

The innovative collaboration modeled by Dr. Sharp and Dr. Strong had a lasting impact on the Barshop Institute. The Barshop started viewing disease through the spectrum of aging before it became a popular concept. This perspective defines the institute, changes outlooks and fosters collaboration among researchers.

“When I came here, I was exposed to all these people who are doing real aging research, and I ended up taking what we have learned from the aging field and applying it to a disease,” Dr. Frost said. “It made me think about Alzheimer’s in the context of aging. Thinking about all of these diseases as aging changed my scientific worldview.”

Dr. Frost is working with colleagues, including Sara E. Espinoza, MD, MSc, associate professor of medicine, on a clinical trial on the effects of an antiretroviral drug in patients with Alzheimer’s disease. The trial’s goal is to determine if this existing therapy keeps tau proteins from exerting their toxic effects on the brain that drives neurodegeneration in Alzheimer’s disease.

“You can really advance the science through collaboration,” said Dr. Espinoza, co-director of the Claude D. Pepper Older Americans Independence Center at the Barshop Institute. “We’re doing these trials now that translate discoveries to the clinic, and it’s really exciting.”

Another existing drug being studied at UT Health San Antonio is metformin, one of the most widely prescribed diabetes therapies in the world. Insulin resistance and inflammation are major predictors of frailty in aging. Metformin is widely used to treat diabetes, and through improving insulin resistance and chronic inflammation in older adults with pre-diabetes, metformin may also prevent frailty, Dr. Espinoza said. A clinical trial led by Dr. Espinoza may add metformin to the list of existing drugs that can improve not only lifespan but also healthspan—the period of life free of disease.

“The end of life is going to be bad, but our goal should be reducing the amount of time a person is sick,” Dr. Sharp said.
The spirit of collaboration at the Barshop Institute enabled advances in the understanding of aging, with implications for the quality of life people can experience even at an advanced age. The life-extending effects of rapamycin in mice, for example, could prove to be a game changer for humans.

“Mice really like this drug,” Dr. Sharp said with a chuckle. “It remains to be seen if humans like it too, but I think they will.”

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