Unlocking the secrets to aging well

What if instead of 80-year-old lungs, you could have 40-year-old lungs? Or younger versions of your own cells? Or age without frailty or dementia?

What if, rather than seeking a mythical fountain of youth, scientists could unlock the body’s secrets to aging with fewer illnesses and less inflammation? In other words, what if they could find viable ways to not live longer, but healthier?

“We are not trying to prolong life,” says Texas Biomed Professor Jordi B. Torrelles, PhD. “But for the years we are going to live, at least we are as healthy as possible. This is the mission.”

At Texas Biomed, aging research goes hand-in-hand with studying infectious diseases. Growing older makes people more vulnerable to infections. COVID-19 is a vivid example. Elderly populations were hit hard by the novel virus, while the majority of children and young adults were either asymptomatic or had relatively mild symptoms.

Improving healthspan – the number of years one can live relatively free from disease – is becoming increasingly important as more people around the world live into old age. According to the World Health Organization, the global population of people aged 60 years and older is approximately 1 billion and is projected to double by 2050. In the same timeframe, the number of people 80 years and older is expected to triple to reach 426 million.

“How do we keep people out of nursing homes? How do we prevent Alzheimer’s and Parkinson’s and frailty – these long diseases that ravage the person and their families and cost a ton of money?” says Corinna Ross, PhD, Director of the Southwest National Primate Research Center (SNPRC).

Across Texas Biomed and SNPRC, researchers are striving to address these and other aging questions. The combination of expertise and resources located on one campus is profoundly unique. Texas Biomed is led by experts in lung immunology, genetics, respiratory illnesses and aging, and hosts SNPRC, one of seven federally-supported primate research centers. It’s home to the nation’s largest marmoset colony, including the largest geriatric marmoset population, and the pioneers who established marmosets as a prime research model for human aging.

“Aging is a really challenging topic to work on because there is so much variability,” says Texas Biomed Executive Vice President for Research Joanne Turner, PhD. “But it is so important to study. Everyone gets it. No one is immune.”

Angelica M. Olmo Fontanez is completing her PhD in Dr. Torrelles’ Lab. She studies how age affects *M.tb’s* ability to replicate and spread.

If you could turn back time

One of the key research areas for Texas Biomed is the lungs. Teams are seeking to understand the specifics of how older lungs, when compared to younger lungs, respond to illnesses such as flu, tuberculosis (TB) and COVID-19. These insights can be used to develop therapies to turn back the clock and keep lungs looking and behaving younger and healthier.

For example, Dr. Torrelles and his lab have found that with aging, pollution byproducts build up in the lungs. Specifically, they observe an increase in molecules called oxidants, which block proteins from doing their jobs correctly and cause tissue damage. This makes it harder to mount a functional immune response and fight disease.

The Torrelles lab is collaborating with Southwest Research Institute on an exciting innovation involving nanoparticles designed to deliver antioxidants to the lungs to protect against harmful pollution byproducts.

“The concept is to create a spray that you take once a month to help keep your lungs healthy as you age, so you are not as susceptible to respiratory illnesses like the flu,” Dr. Torrelles says. “It won’t prevent infection, but your lungs will be functional and control infections better.”

Mitochondria mysteries

Dr. Turner is looking at ways to reinvigorate the aging lung environment by focusing on the powerhouse of the cell, mitochondria. She and a postdoctoral researcher put mitochondria from younger mice into older mice, specifically into a type of immune cell called T cells. Their studies showed that the elderly mice were able to fend off TB and flu just as well as younger mice, and far better than elderly mice with elderly mitochondria.

Likewise, Dr. Torrelles received a Texas Biomedical Forum pilot grant to study young versus old mitochondria in the lungs and explore ways to replace one’s own mitochondria with younger versions of themselves. He suspects that mitochondria are responsible for a lot of the pollution buildup observed in the lungs as people age.

“Within our cells, there are a lot of oxidative byproducts from making energy, which younger mitochondria clean up well,” he says. “We suspect that older cells are not as good about taking out the trash, and so then things start to get dirty and become dysfunctional. We’d like to find a way to help prevent this.”

What’s inflammation got to do with it?

When the immune system reacts to an illness, there is a fine line between mounting enough of a response to clear the illness and going into such overdrive that it causes damage throughout the body. Texas Biomed President/CEO Larry Schlesinger, MD, is especially interested in the interplay between the immune system, inflammation and aging.

“Aging is not just everything in our body slowing down and dying, but in fact, it creates a unique baseline of inflammation that influences our ability to properly respond to infection, cancer and other insults,” Dr. Schlesinger says.

He and his lab study a particular immune cell called alveolar macrophages, which are present in the lining of the lung’s air sacs where air exchange occurs. They gobble up any particles that get past the nose and throat and into the deep lung, keeping the lungs healthy. Typically, macrophages are programmed to not be overzealous so they don’t cause excessive inflammation.

But he and his colleagues found that in aging mice and monkeys, as well as in healthy elderly humans, alveolar macrophages had much higher markers for inflammation, meaning they were poised to launch a scorched earth offensive at any sign of infection, such as TB.

“With inflammation turned way up, you would think these macrophages would fight off TB bacteria faster because they are primed and ready to respond,” Dr. Schlesinger says. “But it turned out to be the opposite. They were more susceptible to infection. It was bizarre. These are very different cells.”

The lab is working on understanding what’s at play here – such as what influences the cells to become more inflammatory and less effective. As part of this work, Dr. Schlesinger and his team have developed an innovative method to generate alveolar macrophages in a petri dish using cells from a simple blood draw. This new tool, now available to researchers around the world, is helping accelerate discoveries and screen potential therapies that target the lung.

Magic cocktail generates critical immune cell

Dr. Schlesinger and postdoctoral researcher Susanta Pahari, PhD, developed a new way to generate the lung’s most important immune cell, the alveolar macrophage, in the lab. Human alveolar macrophages are challenging to study because they must be extracted from lung fluid samples, which are invasive, time consuming and expensive to collect.

It took years of trial and error to determine the most effective combination for the cocktail. The patented model makes it much easier and less expensive to study respiratory diseases and screen potential therapies, including for COVID-19, TB, asthma, cystic fibrosis and chronic obstructive pulmonary disease.

This new model starts with a simple blood draw. White blood cells are isolated and placed in Teflon jars with a “magic cocktail” containing four ingredients usually present inside our lungs. Within six days, the cells transform into alveolar macrophage-like cells (pictured) that are 94% genetically similar to alveolar macrophages collected from humans.

Marmoset Pioneers

Along with the lungs, researchers are also studying how aging affects the brain and the gut, how those changes affect the ability to fight infection and how changes in one part of the body affect the other. To do that requires animal research.

Mice are the workhorse of aging studies because within 18 months to two years, they are the equivalent of 60- to 65-year-old humans. They provide critical insights that can then be verified in nonhuman primates, which are the gold standard for understanding how an entire complex system works. Or, in the case of aging, begins to stop working.

In the mid 2000s, the research community was looking for a primate with a relatively short lifespan that could help reveal the mechanisms of aging and potential interventions. At the time, 12-year- old marmosets were considered ancient; macaques, by comparison, typically live well into their mid-20s. While marmosets had been excellent for studying reproduction and genetics, it was unclear if they would also make a good model for human aging.

“There was a possibility that they didn’t die from the same things, that they didn’t have the same kind of deterioration with age, so we had to classify all of that,” says Dr. Ross.

Dr. Ross and her mentor, Professor Emeritus Suzette Tardif, PhD, documented how marmosets age. They found the small monkeys develop many, though not all, of the same conditions and disease as humans with age. It is notable that between Dr. Tardif, Dr. Ross and colony manager Donna Layne-Colon, Texas Biomed and SNPRC has had three of the world’s foremost experts in marmosets under one roof. (Read more about Donna, who has been with the colony since its inception 30 years ago.)

Marshmallows & Microbiomes

Cognitive decline is one of the aging metrics SNPRC scientists study. While some researchers test this using touch screens, Dr. Ross prefers a more “I Love Lucy” approach – think of Lucy at the chocolate factory, sneaking truffles off the conveyor belt as they pass. Similarly, as food comes down a conveyor belt, marmosets have to use more control, or executive brain function, to let an unsavory turnip pass by and wait for a tastier treat; apples are good, marshmallows are best.

The scientists have documented that older animals with greater cognitive decline have a much harder time waiting for their preferred treat than their younger counterparts. This test helps the researchers measure the degree of cognitive decline, assess what factors may be contributing and test potential interventions.

Dr. Ross is particularly interested in studying how the gut microbiome affects aging, and if giving an older animal a younger microbiome makes a difference for a wide range of health metrics, from body condition and obesity, to cognition. To do this requires fecal transplants, which in marmosets is relatively easy to achieve.

“Thankfully, marmosets, they like poop,” Dr. Ross says. Through careful control of environment and diets, supplemented with shakes blended with feces from younger marmosets – savor that thought for a moment – the team is successfully transforming the gut microbiomes of elderly marmosets. Dr. Ross and researchers at UT Austin, Northwestern University, University of Idaho and Smithsonian Institution are collaborating on these studies to determine how altering gut microbiomes affect health outcomes.

The external partnerships complement ongoing internal collaborations between Drs. Schlesinger, Torrelles, Turner and Ross, which leverage immunology and biochemistry methods to tease apart observations in animals on the cellular and molecular level.

“Interdisciplinary, team science like this brings diverse skillsets and perspectives together, and is critical to drive research forward and make impactful discoveries,” Dr. Schlesinger says.

Living longer

It turns out captive marmosets are living longer, especially when they go to the “nursing home” and get extra “TLC” and medical interventions, much like humans. SNPRC’s oldest marmoset reached 19, while Japan has reported a marmoset living to 22. While these added years may not seem ideal for research, it actually shows the model is robust.

“It’s that same kind of medical revolution that we went through with humans,” Dr. Ross says. “With the

invention of antibiotics and vaccines, that means you’re living past these early life diseases, and you have a more stable life course until you’re older. Now, we’ve done that with the marmosets.”

While the studies to unlock secrets to aging well continue, researchers are often asked, what can we do to live healthier as we age? Dr. Turner notes there is no magic pill.

“Sorry… there’s no shortcut to this,” she says. “You have to be really mindful about taking care of yourself, eating well and exercising to reduce your inflammatory footprint. The less inflammation you have in your body, the more likely you will live longer and healthier.”

You have to be really mindful about taking care of yourself, eating well and exercising to reduce your inflammatory footprint. The less inflammation you have in your body, the more likely you will live longer and healthier.
Dr. Joanne Turner