The most powerful tool to stop the acceleration of aging caused by mTOR dysfunction and cellular senescence.
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The mTOR pathway has emerged as a focal point in the realm of longevity science. When mTORC1's signals are controlled, it potentially paves the way for a longer, healthier existence. Contrastingly, mTORC2 reveals a more complex tale, with its suppression leading to metabolic complications and decreased survival rates in mice. Rapamycin, a compound frequently highlighted in our previous research reviews, targets this pivotal pathway. The intrigue around rapamycin is rooted in its dual nature: it might extend lifespan and counteract age-related ailments, but it also walks a fine line between the benefits of inhibiting mTORC1 and the risks tied to inadvertently suppressing mTORC2. In this comprehensive analysis, we delve deep into the latest research on rapamycin to elucidate its potential and influence on the most critical markers of longevity and healthspan—highlighting the vital nuances of how dosing influences its potential benefits and side effect profile.
By: Shriya Bakhshi
Our previous research review articles have frequently focused on rapamycin, a compound with promising capabilities in extending lifespan and combating age-associated diseases. 
At its core, rapamycin targets a complex called mTOR, which affects how our cells grow and function. Think of mTOR as the mission control of a cell, orchestrating various processes that influence the pace of cellular aging. By intervening with this control center, rapamycin may help slow down the aging process. Recent research in humans and animal models has been focused on rapamycin's effects on various age-related diseases.
In a recent publication, the Journal of GeroScience released an exhaustive review of rapamycin, highlighting the results of recent clinical trials and research studies. Many experiments have shown that rapamycin can extend lifespan, improve memory, enhance muscle function, and even bolster the immune system. On the other hand, many trials have also been focused on meticulously gauging the safety, dosing specifics, and therapeutic promise of rapamycin. 
In this article, we will focus on what recently published research studies are saying about rapamycin: its upsides, drawbacks, and potential in combating age-related diseases.
To understand recent research developments on the safety, dosing, and therapeutic promise of rapamycin, it is essential to understand what rapamycin does in our bodies. Rapamycin is like a regulator switch for a crucial system in our body that oversees many processes, including how our cells grow, survive, and use energy. This system is called mTOR. Think of mTOR as a central control hub that receives signals from the environment and sends instructions to the cells.
As we age, various biological processes begin to deviate from their optimal states. One of the significant alterations is observed in the mTOR pathway. In our youth, mTOR plays an essential role in cell growth and protein synthesis. However, as we progress in age, mTOR often becomes hyperactive. This hyperactivity can lead to a cascade of undesired effects.
For instance, one of the repercussions of an overactive mTOR is the increase in senescent cells. Termed 'zombie' cells by some, these are cells that have stopped dividing but refuse to die. Rather than contributing positively to the body, these cells often release inflammatory substances that can promote tissue dysfunction and aging.
Furthermore, an overactive mTOR can also cause the body to go into an excessive growth mode, pushing cells to grow and divide even when it might be harmful. This might sound beneficial, but it's akin to a car engine revving non-stop – eventually, it leads to wear and tear. On a molecular level, this unchecked growth can promote age-related diseases
Another downside of this hyperactivity is the overproduction of potentially harmful inflammatory molecules, which can damage DNA, proteins, and other essential cellular components, further accelerating the aging process.
Rapamycin can regulate mTOR by inhibiting its activity. By inhibiting its hyperactivity, Rapamycin acts as a molecular "brake", ensuring that mTOR doesn't run amok. By doing so, Rapamycin might hold the key to counteracting several of the detrimental effects associated with aging.
The mTOR pathway is divided into two main complexes: mTORC1 and mTORC2.
mTORC1 is sensitive to rapamycin and plays a crucial role in protein synthesis, autophagy, and nutrient sensing. In simpler terms, imagine this as the department that checks for enough food (nutrients) for the cells, decides when to build more cell machinery, and when to clean up any waste inside the cells. Rapamycin, even in small doses, can strongly affect mTORC1. 
mTORC2 is generally considered to be rapamycin-insensitive under acute exposure, meaning that rapamycin does not impact this complex as strongly as mTORC1. mTORC2 is involved in regulating immune responses, cell survival, and lipid metabolism. In simpler terms, this department ensures that cells have the right shape and helps them survive harsh conditions. 
When it comes to longevity and anti-aging, the focus is on mTORC1 because of its prominent role in regulating cell growth, metabolism, and autophagy (cleaning out cellular waste). By adjusting how mTORC1 functions, scientists believe they can influence the aging process, potentially slowing it down or even reversing certain age-related conditions. 
However, scientists also need to observe rapamycin's effect on mTORC2 because prolonged exposure to rapamycin—as is the case with transplant patients who are dosed daily—can indeed influence its activity. Disruption or alteration of mTORC2 can impact vital cellular processes and affect overall health and the balance of cellular functions. Understanding the complete picture of how rapamycin interacts with mTORC1 and mTORC2 ensures that therapies can be developed safely, minimizing potential side effects and maximizing therapeutic benefits. 
Using specialized genetic models, scientists have made fascinating discoveries regarding these two complexes in relation to their role in longevity. When mTORC1 signaling is suppressed, both the lifespan (how long one lives) and healthspan (how long one lives healthily without age-related diseases) are enhanced . This suggests that keeping mTORC1 in check could be key to a longer, healthier life.
However, the story with mTORC2 is quite different. When mTORC2's activity is decreased throughout the body or in specific tissues using genetic techniques, it leads to adverse outcomes. Specifically, the metabolic health of the organism deteriorates, it becomes more frail, and overall survival rates drop in mice .
The emerging model from these studies proposes that while drugs like rapamycin that inhibit mTORC1 might be beneficial in promoting longevity (termed "geroprotective"), any unintended suppression of mTORC2 by these drugs could lead to their associated adverse effects. In essence, while mTORC1 suppression appears promising for anti-aging strategies, mTORC2 remains a complex factor, underscoring the nuanced balance of the mTOR pathway in aging and health.
In the proceeding sections, we will delve into current research on rapamycin's effects on metabolic health, cognition, physical function, and immunity. As we navigate through recent research studies, we will continue to clarify the differences between mTORC1 and mTORC2 to demonstrate how these specific complexes impact the effects of rapamycin.
Metabolic health refers to the efficiency with which our body converts food into energy. Our metabolism can falter as we age, leading to health issues like insulin resistance and diabetes. These health issues can intensify the possibility of more severe conditions like heart disease. Several recent studies have looked at rapamycin's role in metabolic health.
Insulin resistance is a significant concern in the field of medical research due to its strong association with conditions like type 2 diabetes. In this state, cells don't properly respond to insulin, a hormone essential for regulating blood sugar. This malfunction causes elevated glucose levels in the bloodstream, setting the stage for various health issues.
The role of mTOR, specifically its component mTORC1, has been in the spotlight in the context of insulin resistance. At the Friedrich Miescher Institute for Biomedical Research, a study was undertaken to explore this connection more deeply. Earlier theories and studies indicated that if mTORC1 is chronically active, it might contribute to the onset of insulin resistance.
To validate this hypothesis, the researchers used advanced genetic modification tools to remove S6K1, a molecule that mTOR interacts with. Remarkably, removing S6K1 curtailed mTOR's usual activity.
This intervention showed significant results: mice exhibited a strong resistance, more than double the usual rate, against insulin resistance caused by factors like aging or dietary habits.  This finding underscores the potential importance of the mTOR pathway in understanding and perhaps treating insulin-related conditions in the future. 
A second study, conducted at the Medical University of Vienna, aimed to study rapamycin's impact on mTOR inhibition and insulin sensitivity in humans. This study administered a one-time dose of 6mg of rapamycin to young, healthy males. The results showed reduced mTORC1 activity and an increased insulin sensitivity by almost 20%. In essence, the human subjects were better able to respond to the hormone insulin, indicating that their bodies may be better equipped to lower blood sugar levels. 
A third study, conducted at The Whitehead Institute for Biomedical Research, examined the impact of high doses of rapamycin in mice. This study found that high doses over an extended period led to insulin resistance, meaning that the mice could not effectively use insulin to regulate their blood sugar levels, potentially increasing the risk of diabetes and other metabolic disorders. The researchers have hypothesized that high doses of rapamycin disrupted the mTOR2 complex, leading to insulin resistance. 
These three studies shed light on how the impact of rapamycin on metabolic health is strongly influenced by dosage. Low doses predominantly target the mTORC1 complex, leading to improvements in metabolic health. Conversely, high doses extend their inhibitory effects to the mTORC2 complex, which appears detrimental to metabolic health. This nuanced understanding underscores the importance of precision in dosage when considering rapamycin's potential therapeutic applications in the realm of metabolic health.
Research has shown that cognitive function is another frontier that rapamycin may influence. Cognitive function describes a range of abilities, including thinking, learning, memory, and problem-solving.
Many of us might experience forgetfulness or a decline in sharp thinking as we age. One theory behind this decline in cognitive function is that it is driven by decreased cerebral blood flow (CBF), meaning that the brain may receive less oxygen and nutrients essential for optimal function.
Other risk factors, including poor metabolic health, can further aggravate the decline in CBF. Deficits in CBF that come with age have been directly linked to memory problems and neurological disorders like Alzheimer's Disease.
Given these findings, there's a growing interest in therapeutic interventions that target the biological aspects of aging and lessen the risk of dementia as people age. Two recent studies have examined rapamycin as one potential treatment. 
Researchers at the University of Texas Health Science Center examined mice's cognitive function after receiving oral rapamycin in their diet throughout their lifespan. The study found that dietary rapamycin enhanced cognitive function in mice by more than 25%. The same study also found that rapamycin intervention successfully halted age-associated mental deterioration in older mice. 
Another study by the Barshop Institute for Longevity and Aging examined rats' spatial learning and memory capabilities after receiving a 15-month rapamycin regimen. The study found that after more than one year of rapamycin treatment, the subjects had a 50% improvement in both spatial learning and memory. 
These research findings demonstrate that inhibiting mTOR through low-dose rapamycin can in fact improve cognitive function. mTOR inhibition is intrinsically tied to restoring cerebrovascular blood flow (CBF), meaning treatments such as rapamycin can support the brain in properly absorbing oxygen and nutrients, ultimately leading to improved cognition. 
Another aspect of health and wellness that researchers are examining with regards to rapamycin's potential is physical function. Physical function describes capabilities such as skeletal muscle health and cardiorespiratory fitness (CRF), or in other words, physical strength and stamina. Physical wellness is paramount in ensuring mobility, healthy metabolism, and longevity. With age, the decline in skeletal muscle mass and CRF heightens the risk of disability, loss of autonomy, and the potential for developing age-related diseases. 
It is well established as we age, we become ‘anabolic resistant’. However, the precise molecular mechanism in which this occurs is relatively unclear.
“Anabolic resistance refers to a reduced ability of the body to build new muscle protein, despite the presence of anabolic stimuli such as resistance exercise or protein intake.”
One theory is the chronic elevation in mTOR in aging, as we have the inability to respond to protein and/or exercise because the machinery controlling the cellular size is already at maximal capacity. Therefore, targeting mTOR through pharmacological treatment may solve physical health deterioration due to age. Three experimental studies have examined rapamycin's role in promoting physical fitness. 
One study, conducted by The Novartis Institute for Biomedical Research, utilized low-dose rapamycin treatment in rats and examined muscle mass throughout each rat's lifetime. The study found that the rats treated with rapamycin either partially or wholly staved off age-related muscle wasting. The researchers concluded that rapamycin could be a therapeutic intervention to maintain muscle strength and prevent deterioration in aging populations. 
Recent evidence from the Laboratory of Prof. David Glass observed a linear increase in the basal (fasted) activity of RPS6, a downstream target of mTOR, across the lifespan . Notably, the same study administered rapamycin for 6 weeks, resulting in a restoration of mTOR signaling intermediates and reversal of sarcopenia .
Therefore, if mTOR is chronically activated in a basal, rested state, then mTOR cannot be further activated in response to protein and/or exercise – Therefore, mTOR activity may need to be restored to ‘youthful’ levels with pharmacological therapies.
The second study, conducted at the University of Washington, implemented a three-month regimen of low-dose rapamycin in older mice. The study found that the mice treated with rapamycin exhibited enhanced physical abilities, illustrated by increased grip strength and stamina, compared to untreated mice. More interestingly, the study also found that the mice maintained their improved physical abilities three months after the rapamycin treatment had stopped. 
A third study, conducted at the University of Texas, examined the impact of rapamycin in human adults. This study differed from the previous two described, as it utilized a higher dose of rapamycin (12 - 16 mg). In the experiment, researchers had young men take a single rapamycin dose and undergo resistance training. They found that the single, high rapamycin dose hindered muscle protein synthesis, indicating that the medication interfered with the muscle growth process. 
The results of these studies present a paradox: while rapamycin at low doses might mitigate the effects of aging on muscles, at high doses, its interaction with exercise, a known muscle enhancer, may lead to counterproductive effects on muscle health and function. The two mTOR complexes can explain this ambiguity. While low doses of rapamycin inhibited mTORC1, leading to benefits in physical function, high doses of rapamycin provided inhibition to mTORC2 as well, leading to adverse effects in muscle growth. So, while rapamycin holds potential on this front, proper medication dosing is critical for optimizing physical function. 
A simple web search of the word 'rapamycin' will reveal its immunosuppressive properties, meaning that the medication suppresses the immune system. So, how can a drug that supposedly suppresses the immune system, enhance immune function? The answer to this question lies in the difference between mTORC1 and mTORC2.
At higher doses, rapamycin's impact is more significantly seen on mTORC2, which ultimately can suppress the immune system. But at low doses, rapamycin's effect is most seen considerably on mTORC1, the complex implicated in anti-aging benefits. 
In aging populations, immune function declines, reducing vaccine effectiveness and heightened infection susceptibility. This diminished immune response has played a role in the increased mortality rates in older individuals from illnesses like influenza and COVID-19. Interestingly, recent studies have examined rapamycin's potential in counteracting this decline with particular emphasis on the impact of dosing. 
One study at the University of Michigan administered a 6-week regimen of low-dose rapamycin in older mice. After completing this regimen, researchers administered the influenza vaccine (flu shot). The study found that mice that received rapamycin had an enhanced immune response to the influence vaccine, meaning that their cells built up a stronger immunity against the disease than mice who did not receive rapamycin .
Researchers at the Novartis Institute for Biomedical Research administered a 6-week regimen of everolimus, a medication similar to rapamycin. This study utilized a similar approach to the study completed at the University of Michigan but used adult volunteers. After rapamycin dosing, the researchers administered the influenza vaccine. They found that participants experienced a rejuvenation in certain immune functions. Their response to the influenza vaccine improved by over 1.25-fold, and they experienced no metabolic side effects. 
The same researchers also examined whether higher doses of everolimus, a medication similar to rapamycin, would lead to similar results in immunity. The researchers administered a heftier weekly dose (20 mg/week) and found that not only did this high dose not boost the vaccine's response, but it caused two times as many adverse effects. 
The data released in these studies suggests that mTOR inhibitors can positively influence adults' immune functions when administered at low doses. These low-dose inhibitors, like rapamycin, can directly target mTORC1 and enhance immune function and vaccine efficiency. However, scientists, physicians, and patients should be wary of administering and taking high doses of rapamycin, as its impact on mTORC2 can lead to potential side effects. 
Recently published research highlights that rapamycin has shown promising results in extending lifespan, enhancing memory, improving muscle function, and bolstering immune systems. The biggest concern lies within dosage. Low doses of rapamycin primarily target mTORC1, leading to improved metabolic health, cognitive function, physical fitness, and immunity. However, high doses of rapamycin can impact mTORC2, leading to possible detrimental effects like insulin resistance, reduced muscle growth, and immune system suppression.
So what is the ideal dosage?
Several clinical trials are still underway to determine the optimized dosing for rapamycin. But there is a lot that we know. The research that currently exists emphasizes the importance of maintaining a low-dose of the medication and cycling this dose. This means that rapamycin is not administered as a daily, consistent, medication, but rather as a weekly or biweekly dose. This dosing strategy allows for brief inhibition of mTORC1, leading to health and aging benefits, while limiting interactions with mTORC2.
The careful inhibition of mTORC1 through a cycled rapamycin dose can allow for improved metabolic health, cognitive function, physical fitness, and even immunity.
Recently published research on rapamycin has not only shed light on the medication’s potential, but also on the nuances of dosing. This information can help guide physicians and patients in making informed decisions about their rapamycin protocols.
The future of rapamycin holds promise. With advanced drug delivery systems and personalized medicine, there is potential to target mTORC1 and use optimized dosing. Additionally, several human clinical trials are underway to further ascertain the drug's efficacy, safety profile, and optimal dosage. In our following research review, we will provide an in-depth description of clinical trials currently underway and what their future results could mean for rapamycin's potential in enhancing human health and longevity.
TAKE HOME POINTS
mTOR is a central regulator of cellular growth, survival, and energy. mTOR is composed of two distinct complexes, mTORC1 (regulates protein synthesis, autophagy) and mTORC2 (controls immune responses, cell survival).
Recently published research studies have shown that low doses of rapamycin inhibit the mTORC1 complex and can positively impact metabolic health, cognitive function, immune health, and physical function.
Researchers have also found that higher doses of rapamycin can inhibit both mTORC1 and mTORC2. Inhibition of mTORC2 is linked to metabolic dysfunction and reduced physical functionality.
Current research recommends low-dose and cycled administration of rapamycin, rather than daily consistent doses. Cycled dosing targets mTORC1 for health and aging benefits while minimizing interference with mTORC2.
Ongoing clinical trials are continuing to determine the optimal dosing for rapamycin as well as potential benefits and risks.
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