Living longer and staying stronger

Future

Written by Jessica Binkley Lain

Breakthroughs in research on aging at the Sam and Ann Barshop Institute for Longevity and Aging Studies are pushing the field of geroscience forward. Here, investigators are gaining an understanding of why getting older is the biggest risk factor for so many chronic diseases.

Why do our bodies become frail as we age?

For Elena Volpi, MD, PhD, FGSA, this question drives her career. As the recently appointed director of the Barshop Institute at UT Health Science Center San Antonio, she aims to uncover the fundamental mechanisms behind aging that cause the wide range of age-related diseases that can lead to disablement and death. Her goal is to keep older patients independent and active.

“The Barshop Institute is at the forefront of geroscience,” Volpi said. “We study the basic mechanisms of aging, starting from cell systems, through animal models and, finally, translating them to humans.”

Volpi has focused her research largely on sarcopenia, or the involuntary loss of muscle that occurs in older adults, and on finding novel methods to prevent it by targeting its underlying mechanisms.

“As we age, skeletal muscle becomes resistant to the normal anabolic action of nutrients, insulin and resistance exercise. This condition is called anabolic resistance,” Volpi said. “Inactivity, such as bed rest, worsens anabolic resistance and sarcopenia.”

Anabolic resistance leads to a reduced capacity of the blood vessels in our muscles to vasodilate, or widen to increase blood flow, in response to eating and insulin. With blood vessels unable to properly vasodilate, muscle tissue is not sufficiently exposed to the dietary nutrients that enter the bloodstream from the gut during a meal, a malfunction known as endothelial dysfunction. It also limits the availability of insulin to the muscle, further reducing the overall anabolic efficacy of the two crucial stimuli required for muscle growth after food intake, Volpi explained.

Anabolic resistance also causes reduced strengthening of muscle by dietary amino acids and resistance exercise. This loss of muscle strength comes from reduced signaling through the mTORC1 pathway within the muscle cells. Volpi’s research found that improving endothelial function using vasodilatory drugs (antihypertensives) or aerobic exercise could restore normal mTORC1 signaling and anabolic effect of nutrients and insulin on the muscle of older adults.

“We also found that by increasing the amount of dietary amino acids or protein contained in a meal, we could improve the overall muscle protein anabolism that occurs after the meal. These studies have led us to testing amino acid/protein supplementation, aerobic exercise, intensive physical therapy or a combination of these treatments in clinical trials in healthy older adults and in geriatric patients recovering from an acute illness.”

Maintaining muscle maintains independence

So far, Volpi’s research suggests that taking adequate preventive measures, like regular aerobic and resistance exercise and eating the optimal amount of protein, can go a long way toward maintaining muscle, physical function and independence as people age.

“Based on our studies, balancing protein across all three meals and aiming for an intake of 25–30 grams of protein per meal could help stave off sarcopenia,” she said.

Exercise is also fundamental in preventing anabolic resistance. A recommended exercise routine includes at least three days of moderate exercise such as walking, jogging, swimming or cycling, and resistance exercise such as weightlifting twice a week.

“When appropriate, use of drugs such as anabolic hormones [e.g., testosterone] to recover from illnesses or injuries can also help,” Volpi added. While these hormones should only be used under supervision of a physician, they can help an elderly patient recover from chronic illness more rapidly.

“In the future, I would like to focus research on treatments that can specifically improve muscle growth and strength by targeting at the same time endothelial function and the basic cellular mechanisms of muscle growth using gerotherapeutics along with exercise and nutritional interventions.”

New treatments from an enduring intervention

In addition to finding interventions for sarcopenia and maintaining muscle, investigators at the Barshop Institute are at the forefront of discovering the mechanisms behind longevity and investigating treatments that could extend healthy lifespan, or what is known as health span.

Some new treatments on the horizon include existing drugs that are being repurposed to target the hallmarks of aging. For instance, canagliflozin is a glucose-lowering drug that targets many cellular processes linked to aging, and rapamycin is an immunosuppressant that at low doses has been shown to extend lifespan in animals, Volpi said.

Adam Salmon, PhD, professor of molecular medicine and associate director of the Barshop Institute, studies the life-extending effects of rapamycin by examining its effects on mTOR, or the mechanistic target of rapamycin, which is the same pathway Volpi examined in her studies of anabolic resistance.

“The mTOR-signaling pathway has been shown to have a central regulatory role in aging and age-related disease,” Salmon said. “It regulates growth signals to tell the cell when it’s OK to divide and grow. Or, when nutrients are low, it reduces growth signals to tell the cell to go into survival mode.”

In 2009, health science center researchers administered rapamycin to genetically heterogeneous mice and found that inhibiting mTOR extended median and maximal lifespan. Today, Salmon and his team continue to study the lifespan-extending effects of rapamycin in marmosets, a non-human primate used for preclinical translation studies.

Rapamycin, as well as other lifespan-extending drugs studied at the Barshop Institute, may work on the same mechanistic principles as a long-standing, well-established intervention to increase longevity: caloric restriction.

“This intervention has been known scientifically for around 100 years,” Salmon said, though a proven explanation as to why it works remains unknown.

“We know this intervention affects many different pathways and many different physiologies. The mechanisms for aging aren’t a single pathway, so the reason why caloric restriction extends lifespan is likewise probably working through its effects on multiple pathways.”

After seeing the lifespan-increasing effect of inhibiting mTOR, Salmon conjectures that calorie restriction might reduce signals through mTOR because there are fewer nutrients available.

In any case, researchers have established that rapamycin increases longevity in mice. But does it work in humans?

“We’ve been using non-human primates to bridge the gap. Mice are the workhorses of much of research, but primates have more similar physiology and genetics to humans, they live much longer than mice and they develop many of the same things that people develop with age like cardiovascular disease,” Salmon explained.

While marmosets are not a perfect human model, this animal study, which is currently in its seventh year, will provide a much better understanding of rapamycin’s potential for increasing lifespan and healthy aging in humans, Salmon said.

Finding the off-and-on switch for obesity

Other investigators at the Barshop Institute are focusing on metabolic homeostasis and how aging disrupts the intricate balance of metabolism of fat.

“As individuals age, the body tends to accumulate excess energy, attributed to decreased energy expenditure from inactivity and increased energy storage resulting from overeating,” said Masahiro Morita, PhD, assistant professor of molecular medicine and investigator in the Barshop Institute.

“This metabolic shift leads to an elevated risk of metabolic syndromes, such as obesity and diabetes, which, in turn, heightens susceptibility to cancer and neurological diseases.”

Research in Morita’s lab has made significant strides in unraveling the pivotal role of the mRNA-degrading enzyme complex called CCR4-NOT, which functions as a switch for secretory protein expression. By degrading the mRNA’s encoding secretory proteins, the CCR4-NOT complex effectively turns off their production once an external stimulus like feeding or exercise subsides.

“Notably, we have observed an elevated function of the CCR4-NOT complex in the obese state, leading to the excessive degradation of target mRNAs and subsequent downregulation of secretory protein expression. Our findings demonstrate that suppressing the function of the CCR4-NOT complex can alleviate metabolic syndromes caused by overeating,” said Morita.

In a study published in April 2022 in Cell Metabolism, Morita’s lab demonstrated the effects of suppressing the CCR4-NOT complex in the liver. The study identified a novel compound named iD1, or inhibitor of deadenylase 1, that when administered to mice, stimulated the secretion of proteins GDF15 and FGF21, effectively suppressing appetite and boosting energy expenditure.

“These exciting results provide compelling evidence for the therapeutic potential of CCR4-NOT inhibition in combating metabolic imbalances associated with aging,” Morita said. “We believe that iD1 holds tremendous potential in ameliorating age-related metabolic syndrome, offering a promising avenue for combating health issues associated with aging.”

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