Understanding mTOR: A Delicate Balance for Longevity

Understanding the functions of mTOR and its effects on overall health is paramount when considering targeting its pathway in your body.
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The latest contender in the quest for the elusive fountain of youth is mechanistic/mammalian target of rapamycin (mTOR). This powerful protein is critical for muscle growth, development, and metabolic health.
It is also implicated in a range of diseases, including cancer, Type 2 diabetes, insulin resistance, arthritis, and neurological disorders. However, it is important to note that this protein is neither good nor bad—it is just necessary.
When it comes to mTOR, it is all about balance. Too much mTOR activity can lead to health complications, as can too little. Modulating mTOR is key and can be achieved through lifestyle changes such as diet and exercise and therapeutic interventions such as rapamycin, a drug that has demonstrated the ability to extend lifespan in animal models.
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Understanding the functions of mTOR and its effects on overall health is paramount if you are considering targeting its pathway in your body. Interfering with our intricately balanced systems often has consequences. Do the risks associated with manipulating mTOR activity negate the potential benefits?

Discovering and Defining mTOR

While mTOR is a naturally occurring protein present in the body, rapamycin was discovered first. While it is probably best known as the name of the increasingly popular longevity drug, rapamycin is a substance created by a bacteria. In the 1970s, researchers isolated rapamycin from a soil sample collected on Easter Island about a decade earlier during a Canadian expedition. Easter Island’s indigenous name is Rapa Nui, the root of the word rapamycin.
Ultimately, the discovery of rapamycin led to the subsequent identification of its target in the body, mTOR. In the 1990s, mTOR was identified as the cellular target of rapamycin.
One of the initial established functions of rapamycin was its effect on TOR proteins, hence the moniker. TOR is a protein kinase that controls cell growth and metabolism in a wide range of organisms, including yeast, plants, flies, and mammals. A kinase is an enzyme, a protein that accelerates chemical reactions in the body.

Rapamycin was initially found to have antifungal properties. Eventually, researchers discovered that it also has immunosuppressive and anti-proliferative properties in the cells of mammals. This discovery ultimately led to investigating rapamycin’s potential use in cancer treatment. In 1999, the U.S. Food and Drug Administration approved rapamycin as a prescription immunosuppressant drug.

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The “m” in mTOR originally stood for “mammalian,” as the protein was first discovered in mammalian cells. With more research, it became apparent that mTOR also performs similar functions in other organisms, including yeast, flies, and plants. To reflect its broader role, the “m” was amended by many to stand for “mechanistic.” While “mechanistic” is now the preferred interpretation, “mammalian” is still historically accurate. Both terms are considered acceptable and interchangeable.

A Tiny Worker in Our Cells

The mTOR protein helps control how cells grow and thrive based on what they need and what is available. It reads the environment and gives the orders to grow, divide, and use energy effectively. The mTOR pathway, the larger network containing mTOR and other proteins, plays a crucial role in regulating lifespan due to its ability to sense and respond to nutrient levels.

Dr. Joseph Purita, who is board-certified in orthopedic surgery, pain management, and stem cell therapy and is a former president of the American Academy and Board of Regenerative Medicine, told The Epoch Times in an email that “mTOR functions as a master controller within our cells, operating much like a central command center that receives and processes signals from inside and outside the cellular environment.”

According to him, mTOR “makes strategic decisions about whether cells should grow and proliferate or conserve resources.”

Purita likened mTOR to a sophisticated switch that makes precise, moment-to-moment decisions to keep cells functioning optimally.

How mTOR Forms Complexes

The mTOR protein is found in different cells throughout the body, but it does not live on its own. It links up with other proteins and forms two distinct multi-protein groups: The mammalian target of rapamycin complex 1 (mTORC1) and the mammalian target of rapamycin complex 2 (mTORC2). The two complexes contain different proteins, but they all play a role in stabilizing mTOR, helping it bind to target receptors.
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Michael T. Nelson, researcher, exercise physiologist, and specialist in metabolic flexibility, told The Epoch Times in an email that mTORC1 plays a role in cell growth and proliferation and metabolism regulation. It senses the presence of amino acids, glucose, and growth factors and adjusts cellular metabolism and development accordingly.

When you are taking sufficient levels of nutrients, mTORC1 inhibits autophagy. Autophagy is how the body cleans out damaged cells. The mTORC1 complex is also found in the cell’s lysosome, which is akin to its recycling center. It is also sensitive to the drug rapamycin.
The mTORC2 is involved in influencing cell shape and movement. It is mainly found in the periphery of the cell. Nelson said that it contributes to the cell’s survival and is involved in regulating glucose and lipid metabolism. Nelson added that mTORC2 is primarily activated by growth factors, such as insulin and a growth hormone known as insulin-like growth factor.
Nelson said that “mTORC2 isn’t really as well understood as mTORC1.”

A Balancing Act

The mTOR protein plays a nuanced role in the body, and it is not as simple as stating that more or less of its activity is better. Modulating mTOR is about finding balance, not turning it off.
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“We probably don’t want mTOR running amok all the time, but we don’t really want to shut it down entirely,” Nelson said.

“Modulating mTOR activity is like adjusting the thermostat in your body’s cellular processes,” Purita said.

He said that hyperactive mTOR signaling is strongly associated with various forms of cancer. It is also linked to Parkinson’s and Alzheimer’s disease, as well as disruptions in brain growth and development. Increased mTORC1 activity can also contribute to metabolic dysfunction and heart failure and may accelerate age-related decline and increased inflammation in the body.

Conversely, he noted that insufficient mTOR signaling can lead to a cascade of adverse effects. Cells can experience decreased protein synthesis, disrupted cell cycle progression, and altered metabolic functions.

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“Particularly noteworthy is mTOR’s impact on mitochondria, the powerhouses of cells,” Purita said. “Inhibiting mTOR can reduce mitochondrial membrane potential, oxygen consumption, and cellular energy (ATP) production, potentially compromising overall cellular health and energy generation. Most diseases ultimately involve the mitochondria.”

Factors That Influence mTOR Activity

Several lifestyle factors contribute to fluctuations in mTOR activity:

Nutrition

Protein. Amino acids, the building blocks of protein, are known to promote mTORC1 activation. Leucine, a key amino acid found especially in animal proteins, directly activates mTORC1. Consuming protein, notably leucine-rich sources, stimulates mTORC1 activity. Purita said excessive animal protein, including red meat, chicken, tuna, beans, cheese, milk, and eggs, can lead to mTOR overactivation.
Carbohydrate Intake. Carbohydrates, particularly those that cause rapid increases in blood sugar, can indirectly activate mTOR. Nelson said that too many carbohydrates can cause an increase in mTOR activity through their stimulation of insulin, which has a more direct effect on mTORC2.
A study published in the International Journal of Molecular Sciences in 2019 found that​​ glucose and fructose intake activates mTORC1 in mice.

However, this response to carbohydrates does not seem to have a blanket effect on all.

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“The impact of carbohydrates on mTOR depends on an individual’s insulin sensitivity,” Nelson said. “People with obesity, higher body fat, or Type 2 diabetes—who have impaired insulin sensitivity—may experience greater metabolic disruptions.”

Research shows that the ketogenic diet can reduce mTOR signaling activity. A high-fat, low-carbohydrate diet that produced elevated ketone levels in mouse models weakened the mTOR pathway.
Caloric Restriction. Intermittent and prolonged fasting can reduce mTOR activity due to decreased nutrient availability. Caloric restriction has been shown to reduce mTOR activity and extend lifespan in various organisms, from yeast to primates. Purita pointed out that a bout of time-restricted eating can temporarily suppress mTOR, while a high calorie intake beyond the body’s needs can increase mTOR activity.
Ultimately, interventions that promote weight loss, such as fasting and caloric restriction, reduce mTOR activity due to less nutrient availability. Conversely, conditions that likely cause weight gain through excessive calorie consumption tend to increase mTOR activity.

Obesity

Nelson said obesity can cause more circulating free fatty acids and that this can possibly stimulate mTORC1 via lipid signaling pathways, although not much is known about this relationship.
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“Obesity also downregulates AMPK, a counter-regulatory pathway that inhibits mTOR,” he said. “This creates a cycle of metabolic dysfunction, increasing the risk of chronic diseases.”

Exercise

Resistance training, such as weightlifting, strongly activates mTOR in skeletal muscle, leading to muscle growth and strength gains. While endurance exercises can also influence mTOR, their effects are generally less pronounced than those of resistance training.

“This doesn’t mean mTOR stays perpetually activated, but it does turn on when needed to support muscle growth and repair,” Nelson said.

He said mTOR is critical for maintaining muscle mass as we age. Additionally, a systematic review published in Contemporary Issues in Cancer Rehabilitation in 2017 confirmed that exercise improves clinical, functional, and survival outcomes across various cancer types.
“The potential cancer risk from mTOR activation via exercise pales compared to the benefits of regular physical activity,” Nelson said.

Sleep Deprivation

A lack of sleep is known to decrease glucose tolerance and insulin sensitivity. Consequently, an insufficient night’s sleep might indirectly affect mTOR signaling by hindering insulin’s ability to activate the pathway.

Chronic Stress

Though more research is needed, there is a link between stress and mTOR. Prolonged stress can lead to elevated cortisol levels, affecting mTOR activity by causing the protein levels to either rise or fall.
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A study published in Frontiers in Pharmacology in 2021 found that chronic stress led to a reduction in mTORC1 signaling in the hippocampus of mice. This highlights that stress does not universally activate mTOR, and its effects seem context-dependent and require more research.

Alcohol Consumption

Further research is needed to fully understand the diverse effects of alcohol on mTOR, but a study published in Biomolecules in 2022 found that acute and chronic alcohol use can alter mTORC1 signaling.

Drinking alcohol might lessen the positive effect of exercise on the mTORC1 pathway.

When it comes to these factors affecting mTOR activity, particularly diet and exercise, once again, it comes down to finding balance.

Nelson shared his take on the bottom line with balancing mTOR: “Higher protein intakes, regular exercise, and balanced nutrition promote better health, longevity, and physical performance. While theoretical concerns about mTOR exist, the benefits of maintaining muscle mass and metabolic health far outweigh the risks.”

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Purita said, “It’s worth noting that while both diet and exercise can activate mTOR, their effects are context-dependent, and the optimal balance of mTOR activation for health and longevity may involve periods of activation through exercise followed by periods of lower activity through dietary modulation.”

What About Taking Rapamycin?

The association of excessive mTOR activity with cancer and other diseases has fueled a boom in the mTOR inhibitors market, which is projected to reach several billion dollars within the next few years. Rapamycin seems to be leading the charge as the key player in suppressing mTOR activity and boosting longevity.
A systematic review spanning five databases published in 2024 in The Lancet found that rapamycin improved aging-related issues in the immune system, heart, blood vessels, and skin in both healthy individuals and those with age-related diseases. The researchers said they believed it improved immunity largely through changes in the adaptive immune system.

Purita said that low-dose rapamycin is undergoing research for its potential anti-aging effects.

“Rapamycin’s effects appear robust across different mouse strains and dosing regimens, with consequential benefits observed in female mice,” he said. “However, translating these findings to humans requires careful consideration.”

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Taking the drug can come with serious side effects, including an increased risk of infections, metabolic disturbances, and potential diabetes-like symptoms, Purita said. He added that long-term effects and optimal dosing strategies remain unclear.

“Long-term use of mTOR inhibitors may lead to unwanted effects on muscle growth, wound healing, and immune function,” he said. “It’s crucial to note that mTOR signaling plays complex roles in the body, and both excessive activation and inhibition can have negative consequences.”

As with any powerful intervention, he said, the use of rapamycin for longevity should be approached with caution and under the proper medical supervision of a physician.

Considering an Evolutionary Mismatch

Given what we know about mTOR activity and the importance of balance, we should consider how our present-day lifestyle has thrown its delicate harmony askew. It is easy to point fingers at protein, carbohydrates, stress, exercise, and other factors that may lend a hand in increasing mTOR activity.

However, J Gulinello, a clinical nutritionist, told The Epoch Times via email that we should not overlook how much our food environment has changed from an evolutionary perspective.

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Gulinello said that since amino acids are known to activate mTOR activity, the rationale for eating a low-protein diet for longevity may seem solid.

“If a disease like cancer is out-of-control cell proliferation, let’s suppress the permission slip for cancer to proliferate,” he said.

But he also said that a point seldom articulated is that insulin also stimulates mTOR, and for a longer period of time.

“When you combine that with today’s food environment where carbohydrates, specifically the refined versions, make up the base of the government food pyramid, you have consistently and chronically stimulated mTOR, which is likely not a good thing,” he said. “All the protein restriction in the world won’t solve this problem.”

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Alas, it is an evolutionary mismatch.

In previous eras, periods of feasting were offset by periods of famine. This cycle was the norm, and mTOR activity is designed to function in such a cycle. A feast would flip the on-switch for the mTOR pathway, but the subsequent period of famine prevented a chronically activated switch.

The current Standard American Diet, however, consists of a surplus of nutrients with little downtime between feasts. Gulinello said this is a recipe for disaster that could lead to accelerated aging and out-of-control cell proliferation.

“We need mTOR for survival,” he told The Epoch Times. “What we don’t need or want is mTOR locked in the ‘on’ position.”

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Instead of blaming a necessary internal mechanism and healthy habits such as exercise and diet, it is likely more accurate to blame our modern lifestyle and food choices, Gulinello said.

“That’s like blaming firefighters for the fires they continually respond to,” he said.

He said mTOR is not something to be feared but is something to be concerned with in the pro-inflammatory food environment we find ourselves in today.

Until more research is available and more is known about interfering with mTOR activity for longevity, it may be wise to support your body’s natural checks and balances by incorporating a diet of moderation, bouts of intermittent fasting, appropriate exercise, and healthy lifestyle habits.
Jennifer Sweenie
Jennifer Sweenie
Author
Jennifer Sweenie is a New York-based health reporter. She is a nutritional therapy practitioner and trained health-supportive chef focused on functional nutrition and the power of natural, whole foods. Jennifer serves on the board of directors for Slow Food NYC and is a former board member of the Farm-to-Consumer Foundation.