A fasting mimetic that targets multiple longevity pathways, optimizes metabolic health, and increases autophagy.
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Although inflammation represents a hallmark of aging, to grasp the underlying mechanisms of aging, we must delve deeper into the cellular state of senescence and the evolutionary pathways that culminate in a dysfunctional state. Indeed, the story of aging is fraught with paradoxes - the same cellular programming that once safeguarded us is ultimately responsible for driving us toward a state of dysfunction.
By: Daniel Tawfik
Imagine you have two samples of separate muscle biopsies. You are told one muscle biopsy is that of an older person, and the other sample is that of a younger person. Your assignment is to identify which sample is the younger person's and which is the older person's muscle biopsy. How would you identify which is which?It turns out there is a really simple way to answer the question: look for inflammation. When you look at an older person's cell sample under a microscope, we would see much more inflammation—healthy cells interspersed with dysfunctional cells, bathing in a witch's brew of pro-inflammatory molecules. Inflammation is one of the most discernible hallmarks of aging. Scientists have even coined a term for this chronic low-grade inflammation that develops with advanced age: 'inflamm-aging'.As we grow older, we lose the phenotype of the young person's biopsy—smooth, less inflamed tissue—and enter into an inflammatory state. This shift is accompanied by a transition from functional to dysfunctional tissue, which, upon closer inspection, can be viewed as a hyper-functional state.Although inflammation represents a hallmark of aging, to grasp the underlying mechanisms of aging, we must delve deeper into the cellular state of senescence and the evolutionary pathways that culminate in a dysfunctional state. Indeed, the story of aging is fraught with paradoxes - the same cellular programming that once safeguarded us is ultimately responsible for driving us toward a state of dysfunction.
We are constantly incurring cell damage—whether from radiation from the sun or the oxidative stress we endure from converting food into energy—our cells are exposed to stressors that cause damage. The key to our survival is that when damage occurs, we need to make sure those cells do not replicate—damaged cells that replicate become tumors. To avoid a tumor state, we need to remove the damaged cells before they can replicate and wreak havoc on the system.We have amassed millions of years of built-in evolutionary programming to prevent damaged cells from replicating. A cell is armed with numerous biochemical sensors that can detect cellular damage. Once the damage is detected, the cell draws upon pre-programmed playbooks to prevent the damage from propagating. Understanding these cellular responses to damage is critical to understanding the drivers of aging.
Upon detecting damage, a cell has access to a "self-destruction" playbook known as apoptosis, which represents the cell's predetermined death plan. By recognizing biochemical signals of damage, the cell activates its apoptosis program, leading to self-destruction. While the concept of cell death may seem detrimental, apoptosis is a vital process that prevents uncontrolled cellular growth and replication, serving as the foundation of our survival.Imagine that after a day in too much sun, the UV radiation that you experience causes damage to your cellular DNA. UV radiation causes damage to the DNA and also generates a highly reactive chemical called a Reactive Oxygen Species (ROS) that can cause further cellular damage. It's imperative that these damaged cells do not replicate and undergo cancer formation in the skin.ROS activity and DNA damage are both signals that trigger apoptosis programming. In the case of damaged skin cells, apoptosis is triggered from within the inside the cell by the ROS activity and outside of the cell when molecules bind to special 'apoptosis receptors' on the cell membrane. Apoptosis programming can get triggered by internal cell signals and external extra-cellular molecules.Internally, one of the pathways it utilizes to self-detonate is by activating a tumor suppressor gene called p53. Additionally, its mitochondria will start to degrade and release a molecule called cytochrome C that stimulates the apoptosis machinery to destroy the cell.In executing apoptosis programming, the cell utilizes a cascade of signals and sensors, which can involve the degradation of its mitochondria and the release of cytochrome C to stimulate the apoptosis machinery. By initiating a self-destruct process, damaged cells are removed from the body, a critical process considering that the average adult human experiences the loss of roughly 50 to 70 billion cells each day due to apoptosis. Ultimately, apoptosis represents the cleanest way to deal with the potential hazards of a damaged cell and prevent the formation of tumors.
While apoptosis represents an effective means of removing damaged cells from the body, some cells fail to receive the biochemical signals that trigger apoptosis. However, just because a damaged cell does not undergo apoptosis does not mean it will develop into a tumor. Instead, the cell may enter into a cellular protection program known as senescence, which halts its cell replication cycle without destroying the cell.Senescent cells are often referred to as "zombie cells," as they remain dysfunctional but cannot form tumors due to their inability to replicate. As such, senescence serves as a protective mechanism to prevent tumor formation.We can observe the paradox of these evolutionary protective programs. Senescence, while ultimately leading to the formation of a dysfunctional cell, serves as a protective mechanism to prevent tumor formation. This paradox will be a fundamental driver of dysfunction associated with aging.
While apoptosis and senescence represent two cellular protective programs against cancer formation, some damaged cells may evade their programmed death or senescence, continuing to replicate and propagate into a malignancy. This process is known as tumorigenesis, representing the worst possible fate for a damaged cell.To put it simply, apoptosis kills off damaged cells before they can give rise to a dysfunctional cell line, while senescence halts the replication cycle but allows the cell to remain in a dysfunctional state. However, if a damaged cell manages to evade both apoptosis and senescence, it will continue to replicate uncontrollably, ultimately transforming into a malignant tumor. Such a scenario underscores the critical importance of cellular protective mechanisms in preventing cancer formation, as tumorigenesis represents the absolute worst possible fate for a damaged cell.
Senescence plays a crucial biological role by serving as a protective mechanism against tumor formation in early life while also driving the aging process in later life. Senescent cells exhibit distinct hallmark features that lead to the dysfunction of tissues, which ultimately contributes to the aging process. Specifically, senescence induces a particular type of dysfunction characterized by excess growth, excessive production of disruptive molecules, and excess consumption. This excess ultimately leads to the deterioration of tissue function, which underlies the process of aging.The theory of cellular hyperfunction in aging is a phenomenon popularized by Dr. Mikhail Blagosklonny; it aims to explain much of the aging process and the success of drugs like rapamycin through the lens of cellular overactivity.Generally speaking, diseases of aging are characterized by cellular 'hyper-functions,' not the loss of cellular function or 'wear and tear' of tissues.Blagosklonny outlines three hyperfunctional features to describe the morphology and pathology of a dysfunctional senescent cell. These include hyperplasia, hypertrophy, and hyperfunctionality:
When a healthy cell is exposed to growth factor molecules, it can either grow in size or replicate. At a certain point in a cell's development, rather than continuing to grow in size, it will begin to replicate. In doing so, replication keeps the cell within the normal size range.What do we know about the key feature of a senescent cell? Senescent cells do not have the capacity to replicate. When a senescent cell is exposed to growth factor stimulus, it will simply continue to grow in size, exhibiting hypergrowth characteristics that fall into three categories:
Hypertrophy, the enlargement of the senescent cells and the release of growth factors that enlarge neighboring cells.
Hyperplasia, the release of mitogenic molecules that stimulate the replication of neighboring cells.
Hyper-funcitonality, the over expression of certain molecules in excess (like Tau proteins in neuronal cells) and inflammatory molecules.
The hypergrowth and hyperfunctionality that characterize a senescent state can have significant implications, ultimately driving individuals toward a diseased state. Indeed, when examining any age-related disease, the underlying cause is often cellular dysfunction characterized by excess growth, excessive production of disruptive molecules, and excess consumption, all of which are hallmark features of senescence.
Across all cell types, one of the defining characteristics of a senescent cell is its excessive release of inflammatory molecules. Senescent cells release a "witch's brew" of pro-inflammatory cytokines, chemokines, growth and mitogenic factors, pro-senescent proteins, and proteases that make up what we call the Senescent Associated Secretory Phenotype (SASP).The SASP signals that a cell is under duress, effectively acting as an SOS signal to recruit immune cells to eliminate the damaged cell. As senescence progresses, the SASP overexpresses more of these inflammatory molecules, leading to chronic inflammation that drives tissue damage and degeneration over time.The inflammatory response is not isolated to the damaged cell. The inflammatory response to the SASP actually causes the transformation of the adjacent healthy cells to become senescent. The SASP and inflammatory response activate the senescent programming of adjacent cells.This is why we call senescent cells 'zombie cells'—they don't merely release harmful chemicals; inflammatory signaling can actually cause adjacent healthy cells to become senescent, as the SASP and the resulting inflammation can activate senescent programming in these neighboring cells. A vicious cycle develops—senescence begets more senescence. This process contributes to the spread of cellular dysfunction and ultimately underscores the complexity of senescence and its role in aging and disease.When we are young, we have regularly scheduled clearances of senescent cells—as new senescent cells are introduced, they get cleared out at an equal rate. This is what keeps our tissues functional and healthy. The proportion of functional cells to dysfunctional cells remains balanced in favor of the functional cells due to this clearance mechanism.However, as we age, the rate at which we accumulate senescent cells outpaces the rate at which we eliminate them. The accumulation of these hyper-functional cells ultimately drives aging later in life. As we accumulate more and more senescent cells, the proportion of dysfunctional cells to functional cells begins to shift, contributing to the gradual decline in tissue function that characterizes the aging process.
For centuries, scientists and philosophers have been perplexed by the aging process and the ultimate question of why we are mortal. Traditionally, we have believed that aging results from wear and tear and the gradual loss of cellular function. This understanding has been rooted in the idea that living organisms have a limited ability to repair themselves, leading to the accumulation of damage over time.However, recent research has proposed an entirely different perspective, challenging the notion that aging results from the loss of cellular function.According to this counterintuitive theory, known as cellular hyperfunctionality, age-related diseases are caused by excessive cellular activity, not by a loss of function or damage to tissues. This shift in understanding has significant implications for how we approach the aging process and has captured the attention of longevity scientists.In fact, the loss of function observed in age-related diseases is often preceded by hyperfunction of damaging factors. These age-related changes can include the accumulation of fat, increased blood pressure, glucose and lipoproteins, excessive platelet function, cellular hyperplasia (excessive replication), and hypertrophy (excessive growth), highlighting the role of cellular hyperfunctionality in the aging process.Cellular excesses, or hyperfunctionality, are the foundation of the most visible signs of aging. For example, overexpression of the insulin-like growth factor II gene (IGF-2) in keratinocytes can cause skin overgrowth, as seen in wrinkling.In men, age-related changes such as male pattern baldness and an enlarged prostate are caused by excessive androgen stimulation. Osteoporosis, which leads to broken bones, results from the excessive activity of osteoclasts during bone reabsorption. In fact, excessive growth and activity can be seen in a range of diseases, from cancer to hypertension.Heart disease serves as an example of the cascading implications of hypergrowth and overexpression of molecules by senescent cells. Myocardial infarction, or the damage and death of cardiomyocytes, results from a combination of atherosclerosis and arterial spasm, thrombosis, hypertension, and myocardial hypertrophy. Atherosclerosis is caused by the proliferation and hypertrophy of arterial smooth muscle cells, while hypertension results from the high contractile functions, hyperplasia, and hypertrophy of these cells. Thrombosis is a result of increased platelet aggregation and adhesion. Thus, hypertrophy, hyperplasia, and hyper-functions can cause ischemia, myocardial infarctions, and strokes.In neurodegenerative disorders such as Alzheimer's and Parkinson's, the overexpression of certain molecules, such as toxic Tau proteins, triggers an immune response that ultimately impairs neuronal cells.All of these disease states are the end-states of cellular overexpression, growth, and resistance to apoptosis, which are defining features of senescent cells.
When exposed to growth factors, senescent cells do not divide like healthy cells. Instead, they grow in size, resulting in an enlarged morphology and the overproduction of certain molecules that can become toxic in excessive amounts. The dysfunction of senescent cells extends beyond the loss of their original function, as they also amplify their activity in a way that causes harm to the tissue as a whole.Thus, when we say senescent cells are dysfunctional, we refer to their hyperactivity and overexpression of certain molecules that can damage tissue and contribute to aging.Limiting cellular growth has been found to have positive outcomes for lifespan and healthspan. From worms to mammals, mutations that inactivate certain cell growth signaling pathways, such as the insulin/IGF-1 signaling pathway, have been shown to slow senescence and increase lifespan by up to sevenfold.When we examine senescence, we find that the growth pathway at the core of its hypergrowth is the overactivation of the TOR (Target of Rapamycin) pathway. Therefore, targeting the TOR pathway may provide a promising approach to slow down or even reverse the effects of cellular senescence and age-related diseases.TOR is a complex that exists in every cell type and across all species. It serves as the air traffic control for determining when a cell should grow and divide, and when it should not. TOR turns on the cellular machinery to promote growth when nutrients, particularly amino acids (specifically leucine), are available, and it shuts down cellular growth when nutrients are scarce.However, in senescent cells, TOR amplifies its hypergrowth and functionality, resulting in excessive growth and overproduction of molecules. Additionally, it amplifies its resistance to apoptosis, making it difficult for these cells to undergo programmed cell death. This hyperactivation of TOR is a major contributor to the dysfunction of senescent cells and the aging process.From an evolutionary perspective, this makes a lot of sense—we would want to grow when there are ample nutrients to sustain growth, and when nutrients are low, TOR stops cell growth and replication because of the lack of energy to do so.When TOR is inhibited by the lack of sufficient nutrients, the cell will enter into a cleanup mode and use cellular debris within the cell to use as a fuel source. Any misfolded proteins or other toxic molecules will be consumed by the cell for energy. This cellular deep cleaning process, in which a cell consumes its debris, is called autophagy.Autophagy is an essential process for maintaining cellular health and preventing the accumulation of damaged or dysfunctional components. In addition to degrading and recycling cellular debris, autophagy can also provide nutrients to support cellular metabolism and maintain cellular energy levels.We saw earlier how senescent cells emit a lot of toxic proteins that cause harm to the tissue as a whole. When TOR is activated in a senescent cell, it amplifies the production of the toxic proteins that are part of the Senescence-Associated Secretory Phenotype (SASP), leading to tissue damage and dysfunction. On the other hand, when autophagy is induced in senescent cells, the cell begins to degrade and recycle these toxic proteins, leading to a reduction in their production and less harm to the surrounding tissue.This highlights the importance of autophagy in regulating cellular function and maintaining tissue health. By promoting the degradation and recycling of damaged or dysfunctional cellular components, autophagy helps to prevent the accumulation of toxic molecules and minimize the harmful effects of cellular hyperfunctionality, including the SASP.Neurodegenerative diseases offer a striking example of how TOR contributes to age-related illnesses. In Alzheimer's disease, the accumulation of Tau proteins in the brain leads to the formation of neurofibrillary tangles and brain cell death. These excess Tau proteins also elicit an immune response, leading to inflammation and further damage to neuronal cells. Activation of TOR in neurons leads to an increase in Tau protein production, exacerbating the pathological features of the disease. Conversely, when autophagy is induced by inhibiting TOR, it promotes the clearance of Tau protein and other harmful cellular debris, ultimately reducing their toxicity and improving brain health.Through these examples, we see how important intermittent inhibition TOR is to suppressing senescence. When we inhibit TOR, we mute its capacity to stimulate unhealthy cellular growth. To do so, we can take advantage of the fact that TOR is a nutrient-sensing complex. By manipulating TOR to intermittently activate autophagy, we have a lever to reduce the accumulation of dysfunctional senescent cells.
If TOR delegates when a cell is growing and replicating, and when it is not, what interventions do we have to control TOR activity? To understand how to enhance autophagy, we first need to understand how TOR works as a nutrient-sensing compound.
To convert nutrients into energy, those nutrients have to be processed by the cell's mitochondria. The cell's mitochondria is responsible for taking a nutrient in the form of glucose, fatty acids, and amino acids and converting those nutrients into a unit of cellular energy in the form of ATP.When there is an abundance of nutrients, there should be an abundance of ATP. When the cell is deprived of nutrients, there will be a higher ratio of lower energy molecules ADP (diphosphate) and AMP (monophosphate). These molecules differ in the number of phosphate groups they contain, with ATP having three phosphate groups, while AMP and ADP have one and two phosphate groups, respectively. The phosphate group is where all the energy is stored. When the ratio of ATP/AMP and ADP decreases, there is less available energy for cellular work.While TOR is responsible for regulating cellular growth and division in response to nutrient availability, it does not directly detect the cell's energy status. Instead, AMP-activated protein kinase (AMPK) acts as the energy sensor in cells. AMPK is a central regulator of cellular metabolism and serves as a "metabolic master switch" that adjusts ATP levels to match cellular energy needs. When the ratio of ATP to AMP and ADP decreases, indicating low energy availability, AMP and ADP bind to AMPK and activate it, triggering a series of downstream responses that promote energy production and conservation.AMPK is a key regulator of autophagy and plays a critical role in inhibiting TOR. When AMPK is activated, it signals the cell to shut down energy-consuming processes that synthesize new proteins and fatty acids. Simultaneously AMPK will stimulate glucose uptake by increasing the number of GLUT transport channels to transport glucose into the cell.By inhibiting TOR, AMPK conserves energy and propels the cell into a state of autophagy, where cellular debris is cleared up and used for energy. This process is crucial for maintaining cellular health and preventing the accumulation of dysfunctional senescent cells.This gives us great insights into how we can manipulate these nutrient states to inhibit TOR. Now that we understand how nutrient sensing and TOR activity are interconnected, we can explore how lifestyle interventions can modulate TOR to promote autophagy and inhibit senescence.
AMPK is a key regulator of cellular energy balance and a central nutrient-sensing molecule in the cell. Its role is to monitor cellular energy status and respond accordingly by promoting energy conservation and fuel uptake. For instance, when the cell requires new fuel to power its functions, AMPK increases the number of GLUT channels on the cell membrane that transport glucose into the cell. At the same time, AMPK inhibits TOR and its downstream growth machinery from using existing fuel sources for energy-consuming protein synthesis. As a result, the cell conserves energy and undergoes autophagy to recycle cellular debris into fuel.It's easy to understand how elements of the nutrient deprivation driven-autophagy pathway extend to exercise. From a biochemical perspective, we need ample glucose to be converted into ATP in order to fuel muscle contraction. Exercise can be characterized by a large (>100 fold) increase in muscle energy turnover. When we exercise, ATP gets reduced to AMP.This, in turn, leads to large increases in AMP concentration dependent on the intensity and duration of the exercise. Simultaneously, glycogen concentrations become depleted. The high concentrations of AMP and the depletion of glycogen lead to the activation of AMPK.The activated AMPK mediates the uptake of glucose into the cell to further fuel the muscle contraction—one of the primary adaptations to exercise is the translocation of glucose channels to the cell surface to mediate the shuttling of glucose into the cell so that it can be converted into ATP.While AMPK serves the immediate need to shuttle glucose into the cell, a secondary adaptation is the inhibition of TOR, ultimately leading to the upregulation of autophagy. Exercise ultimately upregulates autophagy through multiple signaling pathways. Still, this example of AMPK signaling illustrates how the stressor of exercise causes the cell to respond in ways to deal with the immediate need to attain ATP, which has many downstream therapeutic benefits.This is just one example of how exercise can stimulate multiple signaling pathways to promote cellular health and longevity. Other pathways that can be activated by exercise include the insulin/IGF-1 signaling pathway, which has been shown to play a role in aging and age-related diseases. Exercise can also stimulate the production of certain hormones and growth factors, such as growth hormone and brain-derived neurotrophic factor (BDNF), which have been linked to improved cognitive function and neuroprotection.
If a state of nutrient deprivation induces autophagy, fasting is the most obvious way to trigger it. Fasting results in the depletion of nutrients like glucose, fatty acids, and amino acids. When the body is in a fasted state, the ratio of lower energy molecules like ADP and AMP rises relative to ATP, leading to the activation of AMPK. As a result, TOR is inhibited and the cell's autophagy machinery is activated. This is how fasting triggers autophagy through nutrient deprivation.When we look at observational studies of individuals who have sustained calorie restriction over long periods, those individuals exhibit longer lifespans. However, to be in a nutrient deficit for sustained periods, you don't get the benefits of cellular growth.Cellular growth and breakdown are neither inherently good nor bad; rather, it is the persistent state of being in any one state that can lead to dysfunction. Sustained cellular growth leads to the dysfunctions of excess that we have covered—we grow dysfunctional tissues that create malignancies and age-related diseases. However, tissue growth is healthy within normal parameters.Intermittent fasting is a method of cycling between periods of nutrient deprivation and feeding. By intermittently inducing autophagy through this approach, we have the ability to cycle through healthy growth and catabolic breakdown states. This allows for a balance between growth periods and deep cellular cleaning. With intermittent fasting, we can pulse our doses of autophagy and growth phases to promote optimal cellular function and overall health. Additionally, studies have shown that intermittent fasting can lead to numerous health benefits, such as improved insulin sensitivity, weight loss, and reduced inflammation.While it is true that fasting and exercise can activate AMPK and lead to autophagy, the exact levels of activation and their effects on TOR activity still need to be better understood. Additionally, measuring the biomarkers of autophagy can be challenging, making it difficult to determine the optimal duration and type of caloric reduction needed to induce autophagy. However, studies have shown that intermittent fasting and caloric restriction can lead to improvements in various health outcomes, including reducing the risk of age-related diseases and increasing lifespan. More research is needed to fully understand the mechanisms behind these benefits and how to optimize fasting protocols for maximum effect.
One of the most intriguing medical compounds in extending healthspan is the diabetes medication metformin. Researchers started focusing on metformin as a healthspan-expanding therapeutic, trying to understand the paradoxical health outcomes in diabetes patients.Metformin is a drug that has been used for decades to treat type 2 diabetes, but in recent years, researchers have also become interested in its potential to extend healthspan and lifespan. Observational studies have shown that metformin has protective effects against several age-related diseases, including cancer and cardiovascular disease. For example, a large study of over 78,000 people treated with metformin found better survival rates than non-diabetic and diabetic patients treated with other drugs.This suggests that metformin may confer a prophylactic benefit against many age-related chronic diseases through its ability to reduce glucose and insulin/IGF-1 levels in peripheral blood circulation.Metformin is believed to work by reducing the activity of the insulin/IGF-1 axis, which is involved in promoting cell growth, division, and preventing cell death, all of which contribute to the development and progression of cancer. By decreasing the levels of insulin and insulin-like growth factors in the bloodstream, metformin may lead to a reduction in cancer risk.Several observational studies have found that patients with type-2 diabetes who are treated with metformin alone have lower rates of cancer-associated mortality compared to those treated with other diabetes drugs like sulfonylurea and insulin. These studies suggest that metformin may have an anti-tumor effect, possibly due to its ability to decrease insulin levels and reduce the activity of the insulin/IGF-1 axis.Metformin is often referred to as a "fasting mimetic" because it induces some of the same cellular responses that occur during fasting, such as activating AMPK and inhibiting TOR. As we've discussed, AMPK is the central nutrient-sensing molecule in the cell and plays a crucial role in regulating autophagy. When activated, AMPK shuts down processes that are energy-consuming, such as synthesizing new proteins and fatty acids, and instead signals for the cell to enter a state of autophagy to break down and recycle cellular debris for energy.Overall, metformin's ability to activate AMPK and inhibit TOR makes it a promising candidate for interventions to promote healthy aging and prevent age-related diseases.
Chronic overactivation of TOR is at the foundation of many age-related diseases. As we get older, TOR may stay active all the time—opening the door to out-of-control cell growth that can lead to cancer and closing the door on cell repair. It is a driver of cell hypertrophy, hyper-function, and hyperplasia, leading to the decline of healthy tissue. In total, the overactivity of the TOR pathway is involved in cell senescence, organism aging, and diseases of aging.Lowering TOR activity represents a broadly applicable treatment to reduce cellular hyper-functions and the following decline of tissue function.Rapamycin is a potent inhibitor of the TOR signaling pathway, which is involved in many cellular processes such as protein synthesis, cell growth, and autophagy. It is one of the most promising tools to combat senescence and toxic cellular hyper-functions.Unlike metformin, which inhibits TOR through AMPK, rapamycin inhibits TOR directly. One of the benefits of rapamycin is that it provides cyclical TOR inhibition, not sustained mTOR inhibition. This means that a patient can cycle the usage of rapamycin to get the cyclical benefit or TOR inhibition, but also get the anabolic benefits of protein synthesis when TOR is not inhibited.By targeting and suppressing the TOR pathway, rapamycin effectively mitigates the release of detrimental molecules from senescent cells. This not only safeguards neighboring tissues from potential harm, but also encourages the elimination of these aging cells through the natural process of autophagy. Consequently, rapamycin plays a crucial role in decelerating the accumulation of cellular damage and reducing the overall population of senescent cells, thereby mitigating their harmful effects on our bodies.In the National Institute of Aging's Intervention Testing Program, rapamycin treatment on a mouse model increased their lifespan by up to 23%. This effect was observed even when rapamycin was administered later in life, suggesting that it can reverse some age-related changes. In nearly every animal model, rapamycin-induced TOR inhibition has been shown to have healthspan-promoting benefits. In addition to extending lifespan, rapamycin treatment also improved a variety of age-related health outcomes, such as better metabolic health and reduced cancer incidence.
We can see how the regulation of TOR, AMPK, and mTOR is a critical aspect of maintaining cellular health and preventing age-related diseases. The cellular response to changes in nutrient availability and energy status is a complex interplay between different signaling pathways, including those activated by exercise, fasting, and the use of pharmaceutical interventions like metformin and rapamycin.Intermittent fasting and caloric restriction are effective ways to activate autophagy and inhibit TOR, leading to many downstream therapeutic benefits. Exercise can also stimulate multiple signaling pathways to promote cellular health and longevity.Metformin and rapamycin are promising candidates for interventions to promote healthy aging and prevent age-related diseases. Metformin's ability to activate AMPK and inhibit TOR makes it a potent fasting mimetic, while rapamycin provides cyclical mTOR inhibition, reducing cellular hyper-functions and accumulating cellular damage.
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