At long last

Drug could hold the key to a longer, healthier life

Ramiro Guerra, 90, does yard work whenever the weather’s good. Other times he is inside, often sleeping and sometimes agitated. The U.S. veteran began to forget things in 2006, the year his wife of 57 years, Elida, passed away.

“It seemed like my dad short-circuited,” said his son, Robert Guerra.

The elder Guerra served in Africa, Italy and France in World War II and helped liberate survivors of the Nazi concentration camp at Dachau. He was an Army platoon leader, performed reconnaissance missions and served in three infantry regiments.

In 1948, a year after the Air Force became its own military branch, Guerra enlisted again and served 28 more years, including duty in Korea and Vietnam.

“He did three wars,” Robert Guerra said, and for this Guerra earned Purple Heart and Bronze Star medals.

But it’s a time that his father sometimes struggles to remember.

Described as having a Type A personality, Ramiro Guerra can no longer “connect the dots” cognitively, his son said. “He can see his decline, and it bothers him.”

Ramiro Guerra, 90, is a triple-war veteran. He can still recall certain moments from his wartime youth, but more recent memories are fading away.

When asked to join a study of an experimental intervention in human aging involving rapamycin, Guerra “almost insisted he wanted to do it,” his son said.

Rapamycin is the first pharmaceutical intervention shown to extend the life span of middle-aged mice, a finding reported by researchers from the UT Health Science Center’s Barshop Institute for Longevity and Aging Studies and two collaborating institutions in Nature in 2009. Science, Nature and TIME magazine each extolled the finding as one of that year’s top discoveries.

Rapamycin was first proposed as an intervention for aging at the Health Science Center and has been extensively studied in cells and animals at the Health Science Center ever since.

A naturally occurring bacterial product first isolated from soil taken from Easter Island, the base drug rapamycin has long been federally approved to suppress organ rejection in transplant patients.

“We thought, goodness gracious, this is an approved drug. We should be able to do this [trial] fairly quickly,” said Dean L. Kellogg Jr., M.D., Ph.D., professor of medicine and the principal investigator of the rapamycin study.

“But how can researchers study life span in humans? A lot of times, the subjects will live longer than the researchers. So we are looking at proxies for life span.”

The first clinical trial was conducted in 2013 at the Audie L. Murphy Memorial VA Hospital by researchers from the Barshop Institute.

Ramiro Guerra and seven other male veterans, aged 80 to 95 years old and in relatively good health, were immunized for hepatitis B—chosen as a marker to determine an improvement in immune systems. Then the veterans were split into two groups. One group, including Guerra, received rapamycin; the second group received an inactive placebo. The trial lasted four months.

Researchers recorded any changes in the veterans’ physical functions, such as walking speed and hand-grip strength. They also documented changes in their cognitive functions such as decision making, learning and memory. They continue to study antibody responses to see if they were more robust during treatment with rapamycin.

“If we can demonstrate an effect on an age-related process, such as rejuvenating immune function or improving physical or cognitive function, then that will suggest rapamycin has a life-span function, as well,” Dr. Kellogg said.

Rapamycin was approved for use as an immunosuppressant in transplant patients in 1999. For years its value was debated—many scientists thought rapamycin might do as much harm in people as good.

“Rapamycin has been used in transplant patients who are very ill and receive many medications. I have found there is a clinical bias against it, that it causes diabetes or raises lipids [fats in blood]. This is based on studies from transplant patients,” Dr. Kellogg said.

“Very few studies have done work with rapamycin as a single agent in relatively healthy persons,” he said. “We’ve found it to be a well-tolerated drug, and there were no changes in the blood sugars and only a mild increase in triglyceride [lipid] levels, but this change was the same as in the placebo group.”

If clinical trials demonstrate rapamycin’s value as an intervention to improve health span, the drug would then need to gain Food and Drug Administration approval for use in healthy people. Health span refers to the years of good health a person enjoys across the life span.

Cindy Holmes and Robert Guerra have seen their 90-year-old father, Ramiro Guerra, slowly lose his memories as he ages. Their father recognized his own cognitive decline, so when he was offered the chance to join a research study of an intervention in human aging, he jumped at the chance.

Cindy Holmes and Robert Guerra have seen their 90-year-old father, Ramiro Guerra, slowly lose his memories as he ages. Their father recognized his own cognitive decline, so when he was offered the chance to join a research study of an intervention in human aging, he jumped at the chance.

For Guerra’s family, the rapamycin did make a difference, although it was small.

During the trial, he could again follow plots of TV shows and was more interactive, according to family members. Sadly, the family noticed after the study that the effects went away, although it is not known why, said Dr. Kellogg. That is one of the mysteries Dr. Kellogg hopes to solve as clinical trials continue. He and his team are applying for additional funding to continue the human research.

“It wasn’t a magic pill, but we did see some improvement in his cognitive abilities,” Robert Guerra said. He offered an analogy to describe his father’s daily life:

“When we get up in the morning and start our day, and we begin creating all these memories, we are writing a run-on sentence on a chalkboard all day long, and we can refer back to things,” he said. “In the case of my father, he is writing that sentence with his right hand, but with his left hand he is erasing it as he goes. If he tries to refer back to what he did 10 minutes ago, it’s gone.

“We believe rapamycin might have slowed down his eraser.”

Photos by Lester Rosebrock, Creative Media Services

 

How we got here

To prove that aging interventions, such as rapamycin, actually work in humans, researchers must first move the science of healthy aging from the idea stage to preclinical and animal studies.

Human clinical trials are at the end of a multi-year, sometimes arduous process.

The Barshop Institute for Longevity and Aging Studies, which opened in 2005 after many years of aging research had been conducted at the UT Health Science Center, is one of the few places in the country that can both investigate the aging process and move the findings into the clinic. As a recipient of the Claude D. Pepper Older American Independence Center grant from the National Institute of Aging (NIA), the Barshop Institute is now comprehensive, said Barshop Institute Director Nicolas Musi, M.D., a physician-scientist in the areas of aging and metabolic disease.

The Pepper Center designation, expected to bring as much as $3.5 million over five years, enables translation of research into practical applications in the lives of older Americans. It joins another NIA award, also totaling $3.5 million over five years. The Health Science Center received a perfect score on its renewal application for the Nathan Shock Center of Excellence in the Biology of Aging. This will provide core services and support for aging research and education.

These new grants ensure that the research geared toward improving how people age will continue and expand over the next several years, Dr. Musi said.

“We will be unique in the country in our capacity to investigate the aging process and move our findings into the clinic,” he said.

The Barshop Institute became one of a handful of centers in the country to have a Shock Center in 1995, and has maintained the designation ever since, receiving more than $18 million in funding.

“A very small number of these centers are able to secure the NIA Shock Center funding,” Dr. Musi said. “It is the equivalent of a National Cancer Institute designated cancer center in terms of stature in the world of aging research.”

The Barshop Institute is also one of only three centers in the NIA Interventions Testing Program and last year received funding of $7.5 million through 2019. With the renewal of the Geriatric Research, Education and Clinical Center designation within the South Texas Veterans Health Care System, also received last year, the Barshop Institute has all four sought-after designations.

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Living livelier

For a picture of productive, healthy aging, U.S. Air Force veteran Allie Burton’s progeny need look no further than their family patriarch. The Barshop Institute for Longevity and Aging Studies at the UT Health Science Center is even looking at the fitness of this rural Texan.

At 91 years old, Burton is running 15 head of cattle at his 500-acre ranch near Junction, Texas. In the late fall, he’ll take his cattle to market about 60 miles east in Fredericksburg.

“I raise exotic game and cattle and at times take goats out there,” he said. “It keeps me busy; there’s always something to do. It keeps me physically active.”

Burton was among the first eight veterans to participate in a clinical research study of the drug rapamycin. The study, conducted by the Barshop Institute and the South Texas Veterans Health Care System, is testing the drug as a possible intervention for aging. Dean Kellogg, M.D., Ph.D., and other faculty in the School of Medicine are studying test results from Burton and the other veterans to assess whether rapamycin improved their physical ability, immune system function, and learning and memory.

“I happened to go down to the San Antonio VA to a prisoner-of-war clinic,” Burton said. “While I was there, Dr. Kellogg came up and told me something about the study and asked if I would be interested. I said yes, if it would make me livelier.”

Burton served 23 years in active duty in the Air Force and five in the Air Force Reserves. He went through pilot training during World War II and was disappointed to be assigned to the training command as an instructor.

“I wanted to be in the sky, like Snoopy chasing the Red Baron,” he said.

During the Korean War, he got his wish. But while flying an F-84 fighter-bomber, he was shot down by anti-aircraft fire. The loneliest and coldest winter of his life ensued.

Burton was a POW from 1952 to 1953.

“I was a guest of the Chinese Communists for 10 months,” he said. “It was way up north, just across the Yalu River from China. It is very cold up there—I always thought that’s where Admiral Byrd [Richard Byrd, 1888-1957] went to train for his cold-weather operations at the South Pole.”

After his release in 1953, he returned to his hometown of Kerrville, Texas. The 29-year-old war hero was welcomed with a parade, where, incidentally, he would meet his future wife, Betty, for the first time.

“I’ve known him since I was 9,” said Betty Burton. “My father said, ‘We’re going to see this local man who came home.’ I remember that day.”

After his active duty, Allie Burton retired in Kerrville and became a real estate broker. He realized his lifelong dream when he was able to buy the ranch, in addition to a house in Ingram where he stays when not at the ranch.

He and Betty were married in 1997—44 years after they met. He has two children and she has three. Together they have nine grandchildren and six great-grandchildren.

“We have ’em every day. Someone is always here,” he said.

Allie Burton is a dancer who always walks fast, his wife said. They enjoy country dancing in area dance halls, from Bandera to Fredericksburg to Hunt.

But last year, there was a change in her husband, Betty Burton said. He was lying down two to three times during the day because he was tired.

“After taking rapamycin for a length of time, he quit lying down so often,” she said.

It’s impossible to base a therapy for aging on anecdotal stories. Dr. Kellogg pointed out that only a few volunteers have received the drug, and more study is needed. He and other School of Medicine researchers are seeking additional funding to expand the study.

The Burtons agree that whatever is learned about rapamycin will prove to be important.

“I would like to think that I can help humanity in some way, if that’s what it comes to, and that my grandkids and great-grandkids could benefit from that,” Allie Burton said.

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Barshop Institute

Through the years

1970s, 80s and 90s – Research in basic science departments of the Health Science Center includes a strong focus on dietary calorie restriction and its effects on aging in mice, conducted by pioneers such as Edward J. Masoro, Ph.D.

1992 – The Aging Research and Education Center (AREC), the forerunner of today’s Barshop Institute, is established. Arlan G. Richardson, Ph.D., was the founding director.

1995 – The AREC is one of the first centers in the country to be named a Nathan Shock Center of Excellence in the Biology of Aging, a designation the Barshop Institute retains today. Shock Centers are funded by the National Institute on Aging (NIA) of the National Institutes of Health. They provide leadership in the pursuit of basic research into the biology of aging.

2001 – The University of Texas System Board of Regents approves the honorific name: The Sam and Ann Barshop Institute for Longevity and Aging Studies. Mr. Barshop served on the Board of Regents previously, and he and Mrs. Barshop were generous donors to aging research at the Health Science Center. Other donors to the institute included The Brown Foundation Inc. and the UT System.

2004 – The NIA selects three U.S. centers, including the Barshop Institute, to participate in the NIA Interventions Testing Program (ITP). The centers investigate treatments that have the potential to extend life span and delay disease and dysfunction in mice. Randy Strong, Ph.D., is principal investigator of the ITP at the Barshop Institute.

2004 – A Health Science Center researcher, Z. Dave Sharp, Ph.D., proposes rapamycin, a medication used in transplant and other patients, to be studied in the ITP. Dr. Sharp later wins the Mprize Lifespan Achievement Award from the Methuselah Foundation for his foundational ideas about rapamycin’s potential effects in aging.

2005 – The Barshop Institute building is dedicated. Mr. and Mrs. Barshop are joined by keynote speaker Sen. Kay Bailey Hutchison and many faculty and dignitaries for the celebration.

2005 – Drs. Strong and Sharp run into a problem studying rapamycin: It is not stable enough in food to register in the blood level of mice. This causes a delay in the mouse studies. Dr. Strong works with Southwest Research Institute to microencapsulate rapamycin, making it feasible to do animal studies. Because of the delay, rapamycin is studied in mice that are 20 months old – the equivalent of 60 years of age in humans.

2009 – Results of the ITP study of rapamycin in mice of both sexes are published in the prestigious journal Nature. The rapamycin formulation developed by Dr. Strong extends the maximum life span of the middle-aged mice by 28 percent to 38 percent. This is the first pharmaceutical intervention shown to extend longevity in mice; previously only dietary calorie restriction and genetic manipulation had been successful.

2010 – Veronica Galvan, Ph.D., of the Health Science Center, publishes results showing that administration of rapamycin improves learning and memory in a strain of mice engineered to develop Alzheimer’s-like deficits.

2013 – Rapamycin enters human clinical trials, with four military veterans receiving the drug and another four receiving a placebo. Nicolas Musi, M.D., is named director of the Barshop Institute.

2014 – The Barshop Institute receives renewals of the NIA Interventions Testing Program and the Geriatric Research, Education and Clinical Center. The GRECC is within the South Texas Veterans Health Care System.

2015 – Dr. Musi announces the Barshop Institute’s first NIA Claude Pepper Center designation and a perfect score on the application for competitive renewal of the NIA Nathan Shock Center. Dr. Strong is the Shock Center director and Peter Hornsby, Ph.D., is co-director.

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7 comments

  • Mary June 29, 2015  

    Fabulous issue!

  • Mary Ann Alfaro July 1, 2015  

    Very interesting article on aging.

  • nancy July 1, 2015  

    I personally know Mr. Guerra’s son and daughter. Having my father, also a WWII and Korea veteran, go thru the same process of forgetfulness, I think he also would have jumped at the chance to be in this trial. Sadly, my father has passed, but if this drug could help Mr. Guerra in these waning days, then I wish they would either put him back into the study or press for the use of this drug for all aging people. Robert, Cindy and Mary deserve to be able to enjoy this time with their father, because when the time comes for him to leave them, having him be fully cognitive would be such a blessing.

  • Rosanne July 1, 2015  

    I love the article about aging! And the photos are gorgeous! Nice job!

  • joy July 15, 2015  

    If Mr. Guerra stopped taking the Rapamycin when the study ended, It seems that the drug must have been the reason for his improvement. Would it would be possible to continue him on the drug?

  • Mary Katherine Fields September 2, 2015  

    What an inspiring article!!!

  • Lety Laurel September 21, 2015  

    Dr. Dean Kellogg of our faculty told us the following: Because this research was a pilot study of eight participants conducted over an approved, defined four-month period, and rapamycin has not been studied in the context of a larger clinical research study for the purpose of determining its effectiveness and safety profile in this age group, it was not possible for us to continue the participants on the drug. We hope to conduct a larger study in the future as more funding becomes available. It is possible for Mr. Guerra’s personal physician to prescribe rapamycin to him on an ‘off-label’ basis, but as mentioned, since no effectiveness and safety profile for rapamycin exists in this age group, such a decision would between the patient and physician and based on little scientific or safety data.

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