A fasting mimetic that targets multiple longevity pathways, optimizes metabolic health, and increases autophagy.
Table of contents
In past articles, we delved deeply into the impact of cellular dysfunction on aging and the associated tissue degeneration. We focused on the role of senescent cells that accelerate age-related decline in tissue function. We have discussed in detail how the dysfunction of these damaged cells is characterized by toxic overactivity and growth, which compromises overall tissue function and accelerates aging. In this segment, we'll pivot to a detailed exploration of metabolic health, particularly the signaling pathways responsible for nurturing or inhibiting these dysfunctional cells. As we age, the cellular mechanisms that detect nutrient levels and gauge the energy status of cells start to falter. This article aims to shed light on the consequences of this metabolic decline and its interplay with aging.
By: Daniel Tawfik, Shriya Bakhshi
In our previous research review articles, we delved deeply into the impact of cellular dysfunction on aging and the associated tissue degeneration. We focused on the role of senescent cells that accelerate age-related decline in tissue function. We have discussed in detail how the dysfunction of these damaged cells is characterized by toxic overactivity and growth, which compromises overall tissue function and accelerates aging.
In this segment, we'll pivot to a detailed exploration of metabolic health, particularly the signaling pathways responsible for nurturing or inhibiting these dysfunctional cells. It's crucial to understand that as we age, the cellular mechanisms that detect nutrient levels and gauge the energy status of cells start to falter. This article aims to shed light on the consequences of this metabolic decline and its interplay with aging.
Our analysis draws upon a seminal 2017 paper from the Journal of Biogerontology authored by Lucia Beteddi and Lazaros Foukas, entitled 'Growth Factor, Energy, and Nutrient Sensing Signaling Pathways in Metabolic Ageing.' The paper explores the complexities of metabolic homeostasis and its deep-seated implications for aging and overall well-being. Beteddi and Foukas’s review stands as a foundational piece, highlighting the myriad cell signaling pathways that play into metabolic aging. Furthermore, it points to potential innovative therapeutic avenues that prioritize healthier aging and counteract age-related ailments.
Metabolic homeostasis is a fundamental aspect of biology, representing the body's precision-driven response to manage fluctuating nutrient levels. At its core, this system is like a sophisticated biological thermostat, adjusting internal processes to keep conditions optimal. Energy expenditure, which encompasses everything from basic cellular functions to physical activity, is finely tuned based on our nutritional intake and energy needs, ensuring an equilibrium that supports both immediate demands and long-term health.
A prime example of this precise regulation is how our body manages glucose levels, showcasing the importance of metabolic homeostasis.
Imagine you've gone a long time without eating - maybe you skipped breakfast and lunch. As a result, the amount of glucose (or sugar) in your bloodstream begins to drop. This drop signals to your body that energy stores are getting low. In response, your pancreas releases a hormone called glucagon. This hormone tells the liver to convert stored glycogen back into glucose, replenishing the blood glucose levels and providing you with the energy you need to function.
Now, imagine later that day, you have a big dinner, full of carbohydrates. This means there's a sudden influx of glucose into your bloodstream. To deal with this, your pancreas releases another hormone—insulin. Insulin signals to cells throughout the body to take in glucose, removing it from the bloodstream and either using it as energy or storing it for later.
This balancing act between insulin and glucagon is a perfect example of metabolic homeostasis. Just like a thermostat regulates temperature in a room, these hormones and metabolic processes regulate the levels of glucose in your blood, ensuring that it's neither too high nor too low, but just right for your body's needs. This intricate control mechanism is essential for the body to function optimally and avoid metabolic disorders such as diabetes. 
In our youth, our metabolic engine is efficient. Our bodies have natural mechanisms for maintaining metabolic homeostasis, including controlling growth factors, energy expenditure, and sensing nutrients. We process sugars well, burn energy efficiently, and our hormonal sensors work in harmony to keep everything balanced. But as we age, some of our metabolic processes might not work as smoothly. This decline can lead to metabolic dysfunctions, such as:
With age, cells may become less responsive to insulin. As we become more insulin resistant, we need more and more insulin to move glucose into a cell. This reduces the body’s ability to regulate blood glucose effectively and increases the risk for Type II diabetes.
Reduced Energy Expenditure:
Aging may be linked to reduced energy expenditure, meaning that the body burns fewer calories at rest.
Alterations in Hormone Levels:
Dysfunction in hormone levels can lead to decreased insulin sensitivity and changes in appetite-regulating hormones.
To better understand metabolic dysfunctions, imagine a 75-year-old woman. In her youth, she could eat a dessert, and her body would efficiently use the sugars with the help of insulin. Now at 75, she finds that after having the same dessert, her blood sugar levels remain higher for longer. This is because her cells are not as responsive to insulin as they used to be, which is a form of insulin resistance. Additionally, she might notice that even if she's not more active than she was a decade ago, she's gaining weight. This could be because her body isn't burning calories at rest as efficiently as it did when she was younger. Lastly, perhaps she's not feeling as hungry as she used to or feeling hungrier more often, indicating shifts in her appetite-regulating hormones.
The age-related deterioration in metabolic homeostasis is believed to be a significant contributing factor to the overall process of aging.  To fully understand the impact of this decline on aging, we need to comprehend how certain signaling pathways can either intensify or reduce cellular dysfunction. As these signaling pathways falter over time, they can lead to tissue dysfunction, further accelerating the aging process.
Cellular signaling pathways act as sophisticated communication networks that allow cells to convey and interpret information. By doing so, they help cells adapt to a myriad of internal and external signals, such as nutrient availability, hormones, growth factors, or shifts in the environment. These pathways adjust their functions based on the specific signals they detect.
Think of these pathways as a series of switches: they can either be 'turned on' or 'turned off'. When activated, usually by particular cues like hormones or environmental changes, a domino effect of molecular events triggers a specific cellular response.
On the other hand, suppression mechanisms are in place to restrain these pathways, ensuring they don't over-activate. Understanding how these pathways can be fine-tuned offers valuable insights into their association with the aging process.
One of the prime culprits in signaling dysregulation is compromised nutrient sensing. Think of it as a faulty sensor in a car's engine that either doesn't recognize there's enough fuel or perceives there's too little, leading the engine to overwork. Similarly, when nutrient sensing in cells is off-kilter, it can send exaggerated signals, causing unchecked cellular growth and hyperactivity.
In this analysis, we'll focus on pivotal signaling pathways essential for maintaining metabolic equilibrium, specifically highlighting the insulin/IGF-1, somatotropic axis, mTOR, AMPK, and Ras/ERK pathways. A key theme throughout our investigation will be understanding how hyperstimulation of these pathways, particularly when fueled by an overload of calories, can rapidly pave the way for the growth of dysfunctional cells.
Whenever you consume a meal rich in carbohydrates, blood glucose levels rise, triggering insulin secretion. This hormone then acts as a "key," allowing cells to "unlock" their membranes and uptake glucose, converting it into energy or storing it for later use.
Complementing insulin's role is IGF-1 or insulin-like growth factor-1. As the name suggests, IGF-1 shares structural similarities with insulin but wears a different hat functionally. Produced primarily in the liver under the influence of growth hormone (GH), IGF-1 is instrumental in cellular growth and the formation of new tissues. Its role becomes especially prominent during the developmental stages of life, ensuring proper anabolic growth and differentiation of cells.
Thus, after that carbohydrate-laden meal, the physiological ripple effect is twofold: not only does it trigger a rise in insulin, to transport that glucose into our cells to be used for energy, but it also can stimulate an uptick in IGF-1, which has its hand on the wheel of cellular growth and tissue genesis.
As we age, the insulin/IGF-1 pathway may become overactive—this overactivity is what we are referring to when we say that the pathway is dysregulated. This is at least in part driven by diet as we become insulin-resistant. Over time, frequently consuming high glycemic index foods can lead to insulin resistance, where cells no longer respond to insulin effectively—it requires more and more insulin to transport glucose into a cell. This overactivity of the insulin/IGF-1 pathway can have two main effects.
First, we find issues linked directly to insulin's primary role in storing glucose. As we become insulin resistant, we see sustained high levels of glucose in the bloodstream. The cascade of health implications from such a condition is vast: the onset of diabetes, unanticipated weight gain, heightened blood pressure, elevated cholesterol levels, nerve damage (neuropathy), and an increased propensity for cardiovascular diseases.
Second, the increased presence of IGF-1 can lead to abnormal cell growth and proliferation. We all have senescent and cancer cells in our bodies. Persistent elevation and activation of IGF-1 signaling stimulates the growth of these cells, which then leads to the deterioration of the tissues they comprise. The overactivity of these anabolic hormones—whether it be IGF-1 or growth hormone (GH)—is like pouring kerosene onto a fire of dysfunctional cell growth.
In particular, IGF-1, as a growth factor, can increase the risk of various cancers, including breast, prostate, and colon cancers. This is because an environment with continuous cellular growth and division can lead to tumor development.
In the context of aging, dysregulation and overactivity of the insulin/IGF-1 pathway therefore have implications for both lifespan and metabolic health. We know from animal studies, that interventions that attempt to regulate the IGF-1 pathway, through genetic modifications, for example, change the trajectory of the lifespan and metabolic health.
In one pioneering study on IGF-1 and lifespan, researchers developed mice with a special modification: they knocked out the insulin receptor, specifically in fat tissues. While IGF-1 may be flowing through the bloodstream, there is no receptor for the IGF-1 to bind to.
These mice, dubbed FIRKO (Fat-specific Insulin Receptor KnockOut), presented a suite of positive health traits as they aged. Not only did they resist the usual signs of age-related obesity, but they also lived notably longer—an average lifespan extension of 18% for both males and females. Furthermore, these mice seemed more resilient against age-induced glucose intolerance and had reduced insulin levels .
The reduction in IGF-1 signaling tends to lead to improved metabolic health and extended lifespan. For humans, this research indicates that if we can reduce IGF-1 and insulin levels we can diminish some of the harmful effects of persistent overactivity.
As we review more of these anabolic growth signaling pathways, such as the somatotropic axis, we’ll see how attempts to reduce overactive signaling of these pathways, consistently provide positive healthspan-promoting benefits.
The somatotropic axis, also known as the growth hormone (GH) axis, is a hormonal system in the body that encompasses the pituitary gland, liver, and other tissues. It plays a pivotal role in regulating growth, guiding development, and maintaining metabolic balance from infancy through old age.
Studies using animal models have enhanced our knowledge of the growth hormone pathway and its link to lifespan. In particular, mutations that affect the somatotropic axis typically lead to lower growth hormone (GH) production. Animals with these reduced growth hormone levels tend to be smaller but live notably longer. This consistent observation has driven researchers to further investigate the reasons behind it.
Dr. Bruce Ames is a pioneer in the research into the role of growth hormone in aging. A key tool in this research has been the Ames dwarf mice. The Ames dwarf mice have been instrumental in studies related to growth hormone (GH) and its effects on lifespan. These mice carry a spontaneous mutation that results in a deficiency of growth hormone, thyroid-stimulating hormone, and prolactin. This unique genetic profile makes them an invaluable model for studying the effects of these hormonal deficiencies on lifespan and aging.
This deficiency results in a number of physiological changes, one of the most notable being an extended lifespan. The Ames dwarf mice live significantly longer than their normal littermates, and this difference has been a focal point for research into the molecular and genetic determinants of aging.
Ames dwarf mice provided some of the earliest evidence that reduced GH and insulin-like growth factor-1 (IGF-1) signaling can promote longevity in mammals. This finding opened the door for investigations into the molecular mechanisms by which reduced GH/IGF-1 signaling might extend lifespan.
The Ames dwarf mice also exhibit improved glucose tolerance and increased insulin sensitivity. These metabolic alterations are associated with longevity in a variety of organisms and suggest that pathways that regulate metabolism are important modulators of lifespan.
One of the theories of aging posits that the accumulation of oxidative damage contributes to the aging process. Ames dwarf mice have demonstrated an increased resistance to oxidative stress, suggesting that reduced GH/IGF-1 signaling might promote longevity by increasing cellular defenses against oxidative damage.
Apart from living longer, Ames dwarf mice also show a delay in the onset of age-related diseases, including tumors. This suggests that the pathways affected by reduced GH/IGF-1 signaling can influence both healthspan (the disease-free portion of an organism's life) and lifespan.
Several theories attempt to explain this phenomenon. One theory suggests that reduced growth hormone levels may increase stress resistance in cells, enhancing their ability to counteract damaging agents.
Another theory focuses on the link between the somatotropic axis and the insulin/IGF-1 pathway. A consistent theme of this review is the interplay between different signaling pathways—this is the case between the somatotropic axis and the insulin/IGF-1 pathway. Studies in animal models have found that growth hormone deficiencies in animal models lead to decreased circulating IGF-1 levels . The combined decrease in both growth hormone and IGF-1 seems to decrease abnormal cellular growth, which would slow down the onset of age-related diseases and degeneration.
We know that reducing growth hormone levels has positive healthspan-promoting benefits, what happens when we supplement growth hormone?
Studies into the use of growth hormone replacement as an anti-aging intervention also provide additional insights into the connection between growth hormone and healthspan. While growth hormone replacement has been investigated as a possible anti-aging treatment, its efficacy is questionable. Research on mouse models, for instance, which were provided exogenous growth hormone as a replacement intervention, did not show an anti-aging effect. In fact, similar interventions had a negative impact on aging in humans. 
This isn't the only evidence suggesting caution in using GH as an anti-aging remedy. Human studies have revealed another intriguing observation: taller individuals tend to have shorter lifespans. This association implies that growth, which is influenced by GH and its downstream effector IGF-1 (Insulin-like Growth Factor-1), might not always be beneficial in the context of longevity. 
Research on Ecuadorian dwarfs, who naturally have GH receptor deficiencies, brought additional insights. These individuals displayed lower risks for some diseases like cancer and obesity. But, contrary to what one might expect, this protection didn't translate into longer lifespans. 
Taken together, the data suggests that while reducing somatotropic growth hormone signaling might enhance certain health outcomes, it does not always extend lifespan. However, by modulating these cellular pathways, we might discover ways to enhance metabolic health and perhaps even extend human lifespan.
The mammalian target of rapamycin (mTOR) is a critical player in metabolic regulation and aging. mTOR is a complex that exists in every cell type and across all species. It serves as a central hub that determines when a cell should grow, and when it should not. mTOR is highly responsive to various signals related to nutrient availability and energy status. When nutrients and energy are abundant, mTOR becomes activated in order to use energy for cellular growth.
As we age, mTOR can become chronically activated. Because mTOR is highly sensitive to the amount of available nutrients, when we overload a cell with energy through our diet, we are providing stimulus for this chronic activation.
Persistent activation of mTOR can lead to an overdrive in cellular growth, an increase in cellular senescence (the presence of damaged cells), imbalances in metabolic processes, and limited autophagy (a process by which the cell recycles damaged or unnecessary components). These cellular actions heighten the risk of diseases such as neurodegenerative disorders, heart disease, osteoporosis, cancer, and metabolic dysfunctions.
Neurodegenerative diseases offer a striking example of how mTOR 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. Chronic activation of mTOR in neurons leads to an increase in Tau protein production, exacerbating the pathological features of the disease. Conversely, when autophagy is induced by inhibiting mTOR, it promotes the clearance of Tau protein and other harmful cellular debris, ultimately reducing their toxicity and improving brain health.
Across nearly all age-related chronic diseases, the overactivity of mTOR leads to the deterioration of the tissue it comprises. We’ve written about this phenomenon in detail. To learn more about mTOR and aging, please review some of our research review articles:
Due to its critical role in cellular processes, the mTOR pathway has several implications for metabolic health and lifespan. Because mTOR activity becomes heightened and dysregulated as we age, mTOR inhibition is an important area of research for longevity scientists.
Pharmacological inhibition of mTOR signaling, through the use of rapamycin, can prevent chronic activation of mTOR and has been shown to extend lifespan in animal models. This extension is often associated with improved metabolic health.
Additionally, mTOR and the insulin/IGF-1 signaling pathways are closely interconnected. They jointly regulate energy metabolism and glucose balance. We know, for example, that IGF-1 activates mTOR. When we stimulate IGF-1 and mTOR through persistent nutritional excess, we are stimulating excessive anabolic pathways that cause cellular dysfunction, which then leads to tissue decline—as we saw in the example of neurodegenerative disorders. Conversely, when we use intermittent deprivation of calories, we can inhibit mTOR and thereby increase autophagy (we will discuss this in more detail in our section on AMPK signaling).
As we will discuss later in this review, targeting the mTOR pathway as a lever of aging may protect against a myriad of age-related chronic diseases. 
The AMP-activated protein kinase (AMPK) pathway plays a crucial role in metabolic health by ensuring that cells respond appropriately to changes in energy availability. AMPK is activated when cellular energy levels are low, signifying a state of energy depletion or metabolic stress.
When a cell's energy, stored as the molecule ATP (adenosine triphosphate), is in high supply, everything runs smoothly. However, during times of stress or increased demand, these ATP levels can drop. As they decrease, the levels of AMP (adenosine monophosphate), a marker of low energy, rise. It's this shift in the ATP-to-AMP ratio that AMPK detects.
Upon recognizing increased AMP levels—a sign of energy depletion—AMPK becomes active. Once activated, AMPK initiates a series of events designed to restore the cell's energy balance. It does this by pausing processes that consume energy and promoting pathways that generate ATP. This ensures that essential cellular activities can continue, even if conditions are challenging.
The AMPK pathway includes a family of proteins called sirtuins which are involved in metabolic health. SIRT1, one of the primary sirtuins involved in metabolic regulation, can be activated through the AMPK energy-sensing pathway. 
When activated, the AMPK pathway and the proteins in its complex promote five key actions.
Increase Glycolysis. One of its primary actions is to increase glycolysis, which is the process where glucose is broken down to produce energy. By doing this, AMPK helps to stabilize the amount of glucose in the blood. At the same time, this action supports cells in taking in more glucose, ensuring they have the necessary fuel for their functions.
Increase Glucose Uptake. In skeletal muscle, AMPK has a crucial function related to energy regulation. When activated, AMPK promotes the uptake of glucose, but not through the usual insulin-dependent method most of us are familiar with. Instead, AMPK increases the number of glucose entry points, or channels, on the surface of the cell. This action ensures that even if there's an issue with the insulin pathway, or during times when the muscle is under energy stress, the cell can still take in the glucose it needs to function. This is especially important for maintaining energy levels in situations where insulin might not be as effective or available.
Fat Oxidation. When activated, AMPK encourages the process of fatty acid oxidation. This means that the body is prompted to break down its stored fats to produce energy. This action becomes particularly beneficial when energy levels are low, as it provides an alternative energy source by tapping into the body's fat reserves.
Sirtuins and Adipose Tissue Transformation in the AMPK Pathway. Within the AMPK pathway, there are proteins called sirtuins that play a significant role in how the body manages fat. These sirtuins are linked to a process known as adipose tissue browning. Here's what this means:
Typically, our body has white adipose tissue, which is primarily for storing fat. Think of it as the body's savings account for energy. On the other hand, there's brown adipose tissue, which is more metabolically active and can be "burned" to produce heat and energy. Sirtuins help convert the white, storage-focused fat into this brown, energy-releasing fat. This conversion is beneficial because it allows the body to use stored energy more efficiently, especially during times of increased energy demand or when the body is trying to generate heat.
Inhibit mTOR. When a cell has low energy, it's crucial to prioritize how that limited energy is used. One of the most energy-consuming processes a cell can undertake is to grow, which is why it's essential to control when growth occurs.
As we’ve discussed, the cell has a growth "switch" known as mTOR. When this switch is on, the cell undergoes growth. However, growth requires energy, and if the cell is already running low, it can't afford to use more on growth.
When energy levels in a cell are dwindling, AMPK levels rise. High AMPK levels act as a signal to "turn off" the mTOR switch, preventing the cell from engaging in its growth activities. This ensures that when energy is scarce, the cell doesn't embark on an energy-intensive growth process.
Not only does it prevent further energy expenditure on growth, but it also activates a clean-up system called autophagy. Through autophagy, the cell can break down and recycle old or damaged components, turning this cellular "debris" into a source of energy. This cellular cleaning improves cellular health. In essence, when faced with low energy, AMPK ensures the cell conserves what it has and finds innovative ways to generate more, all while avoiding any unnecessary energy-draining processes.
When activated briefly, or in "pulses," AMPK sets off signals that contribute to improved health and longevity. These signals initiate pathways that help cells function better, which can improve one’s overall healthspan.
We don’t want persistent elevations of AMPK, which put us in a perpetual catabolic state. Continuous high levels of AMPK would mean the body is constantly in a breakdown mode. Staying in this state for extended periods isn't beneficial for longevity. It would potentially make us feeble, which compromises our longevity.
From a healthspan perspective, we can see how these pulses of AMPK activation initiate numerous signaling pathways that promote improved healthspan. Getting these intermittent pulses of AMPK activation, whether it be through caloric restriction, fasting, or exercise, can initiate these healthspan-promoting signaling pathways.
Age-related decline in AMPK activity has been observed in multiple tissues, including skeletal muscle and the liver. reduction in AMPK's functionality means our body may not manage energy as efficiently as it once did, which has a ripple effect on various metabolic activities. As AMPK activity decreases, processes like insulin response, fat regulation, and cellular cleanup (known as autophagy) can become less efficient. This can lead to conditions such as insulin resistance, a precursor to diabetes, and other age-related health challenges.
Interestingly, studies indicate that we might have a way to counteract this decline. By activating the AMPK pathway – either through specific dietary choices or with the help of certain medications – we can address some of the metabolic shortcomings associated with aging. These interventions can reduce the chances of the body producing too much glucose or storing excessive fat, two issues that often become more prevalent as we get older.
Given AMPK's integral role in maintaining metabolic balance and ensuring that cells respond well to insulin, it's an important lever for us to consider when thinking about interventions to improve our healthspan. Researchers see it as a promising avenue for treating metabolic disturbances and ensuring that, even as we age, our metabolic health remains robust .
The Ras/ERK pathway plays dual roles: it helps regulate cell growth and division (mitogenesis) and modulates lifespan, potentially impacting metabolic health. In simpler terms, this pathway ensures cells grow and split efficiently when they have enough nutrients.
However, as we age, the Ras/ERK pathway might not function properly. Instead of its usual regulation, it can become overactive. This hyperactivity can distort cell signals, leading to cells that age prematurely (senescence). This miscommunication in cells can contribute to problems often associated with aging, including organ malfunctions and increased cancer risks.
It's noteworthy that the Ras/ERK pathway interacts with other pathways crucial to age-related processes, notably the insulin/IGF-1 pathway, which governs how our bodies handle glucose. When the Ras/ERK pathway doesn't work as it should, it can throw off other important metabolic processes.
To target dysfunction in the Ras/ERK pathway, researchers have used genetic modifications in animal models to inhibit its activity. This inhibition has been shown to extend lifespan and improve metabolic function. Therefore modulation of this pathway may be explored as a potential strategy for managing metabolic conditions such as obesity and diabetes, and increasing lifespan .
A common misconception when looking at cellular signaling pathways is viewing them as independent paths. In reality, these pathways are interconnected through a complex network of signaling interactions.
These interactions serve a critical purpose: they help cells adjust to changes in their environment. When a cell encounters different factors – like varying nutrient amounts, shifts in energy, or specific hormonal signals – these pathways will either activate or suppress certain cellular responses. Their combined effects ensure cells can adapt appropriately, balancing growth and energy use. A synchronized coordination between pathways is essential to keep metabolism stable and is also tied to how we age and our overall health.
To illustrate this interconnectedness, consider the body's response to a meal high in carbohydrates. As glucose levels rise, several growth-related signaling pathways are activated. Concurrently, the pathway that conserves energy and resources, known as AMPK, is suppressed. In this scenario, the body releases more insulin, which in turn stimulates the RAS pathways. Moreover, the anterior pituitary gland releases growth hormone, one of whose primary jobs is to prompt the liver to produce IGF-1. This contributes to increased protein synthesis and cell growth. Insulin and IGF-1 can activate mTOR to trigger its anabolic programming, reinforcing the promotion of protein synthesis and cell growth.
In simpler terms, a high carbohydrate meal sets off a cascade of events in the body, pushing it towards growth and energy storage, rather than conservation and maintenance. This has important implications for fueling the growth of unhealthy tissue and the acceleration of aging.
In the field of longevity medicine, calorie restriction has been considered a potential intervention for not only extending lifespan but also improving metabolic health. Calorie restriction involves reducing daily caloric intake without malnutrition or deprivation of essential nutrients.
The idea of calorie restriction is nothing new, and, in fact, dates back to the 1930s when the mechanisms were first pioneered by Professor Clive McKay, where he observed a life extension effect in male & female rats following a calorie-restricted diet compared to a standard ad libitum diet .
Several health benefits have been linked to calorie restriction, including enhanced stress resistance, reduced inflammation, leaner body composition, increased insulin sensitivity, and improved glucose tolerance. The molecular mechanisms responsible for these benefits have been extensively studied. The cellular signaling pathways discussed earlier are all implicated in the effects of calorie restriction .
Calorie restriction serves as a signal for the body’s metabolic pathways. When an individual restricts their calorie intake, the body interprets this as a period of limited food availability and adapts its metabolism accordingly. As cells begin to sense a nutrient-deficient state, they initiate a series of responses aimed at conserving energy and promoting cellular survival.
Research in animal models has looked to see the impact of calorie restriction on various metabolic pathways. In these animal studies, researchers have found that calorie restriction suppresses the IGF-1/Insulin Pathway, the Somatotropic Axis, and the mTOR pathway while activating the AMPK pathway.
Calorie Restriction and IGF-1/Insulin Pathway
When calorie intake is reduced, there is a consequent reduction in the levels of circulating insulin. This is because there's less glucose entering the bloodstream from digested food, limiting how much insulin the pancreas releases. This reduction in insulin impacts the IGF-1/Insulin Pathway. Lower insulin levels shift the body's focus towards utilizing stored energy reserves and maintaining cellular integrity rather than fueling growth. This promotes the burning of fat, reduces the storage of excess energy as fat, and limits excessive cell growth that may be linked to cancer or other age-related diseases.
Calorie Restriction and the Somatotropic Pathway
When calorie intake is reduced without malnutrition, the somatotropic axis is suppressed. This suppression means that less growth hormone (GH) is released from the pituitary gland in the brain. GH normally stimulates the production of insulin-like growth factor-1 (IGF-1), which promotes cell growth and proliferation. By reducing GH and, ultimately, IGF-1 levels, calorie restriction limits the energy-consuming processes associated with growth. This can limit the risk of age-related diseases such as cancer, metabolic disease, and cardiovascular disease, while also allowing saved energy to be diverted towards maintenance and repair processes at the cellular level.
Calorie Restriction and the mTOR Pathway
Calorie restriction inhibits the mTOR pathway, which is responsive to nutrient availability. By inhibiting mTOR, calorie restriction limits the negative effects that occur when mTOR is hyperactivated with age. Calorie restriction allows for the conservation of energy and cellular resources, enhanced autophagy, reduced cellular stress, reduced harm and growth of senescent cells, and protection against age-related diseases.
Calorie Restriction and the AMPK Pathway
Unlike the other three metabolic pathways discussed, calorie restriction has an activation impact on the AMPK pathway. When you reduce your caloric intake, the body's immediate energy supply (glucose) becomes limited. This shift activates AMPK. The activation of this pathway signals the need for increased energy production and resource conservation. This can help maintain stable blood sugar levels, improve insulin sensitivity, enhance autophagy, and promote the efficient breakdown of fats for energy, which can contribute to weight loss. The increase in levels of AMPK also contributes to the inhibition of mTOR, and in doing so, increases the level of autophagy.
Calorie restriction is not a simplistic dietary intervention that only affects one aspect of metabolism. Instead, it influences a myriad of metabolic pathways. Through its impact on multiple metabolic pathways, calorie restriction allows the body to optimize its energy utilization and distribute energy efficiently throughout the body. In essence, calorie restriction results in metabolic homeostasis, allowing cellular pathways to work together to promote cellular health and longevity. 
Constant caloric restriction, while challenging to maintain, can also have negative implications. By continuously suppressing metabolic pathways due to reduced nutrient intake, we miss out on the advantages offered by the periodic activation of these signaling pathways for healthy anabolic processes. For instance, processes like muscle growth, tissue repair, and anabolic activities are essential for longevity and healthy aging.
Ideally, we aim to harness the advantages of caloric restriction in one phase and tap into the anabolic benefits of activating these pathways in a separate phase. A more sustainable and promising approach to get the benefits of the dampening of these pathways, but also getting the benefits of their activation, is to intermittently restrict caloric intake via intermittent fasting or a fasting-mimicking diet. We have discussed this in more detail in our review of intermittent fasting.
Knowing that calorie restriction is an effective intervention for improving metabolic health opens the doors for other therapeutic treatments that may offer similar benefits. In the field of longevity medicine, there have been several research studies focused on developing pharmacological agents that target cellular pathways linked to growth factors, nutrient sensing, and energy. The use of pharmacological agents to target these cellular pathways may have the potential to mimic the positive effects of calorie restriction.
Two commonly researched pharmacological interventions are rapamycin and metformin.
Rapamycin is a potent inhibitor of the mTOR pathway. As we’ve discussed, as we age, mTOR 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. Studies in mice have shown that low doses of rapamycin may have the ability to extend lifespan by reducing cellular senescence, improving autophagy, and reducing cellular hyperactivity. In older adults, low doses of rapamycin seem to set mTOR activity back to its youthful state: on when you need it, off when you don’t.
Additionally, rapamycin’s impact on the mTOR pathway can also influence metabolic health. By inhibiting the mTOR pathway, rapamycin can also impact the Insulin/IGF-1 pathway, leading to more balanced glucose levels, enhanced insulin sensitivity, and protection against metabolic disorders. 
Metformin is considered to be a fasting mimetic and is an indirect activator of the AMPK pathway. When activated, this pathway signals that the body is in a state of energy depletion. The activation of AMPK encourages the body to tap into its stored fats as an alternative energy source. By doing so, fats are broken down and utilized, which can lead to weight loss and improved lipid profiles.
Additionally, metformin's impact on the AMPK pathway can enhance cellular uptake of glucose, subsequently improving insulin sensitivity. This means that cells respond better to the presence of insulin, reducing the body's need to produce excessive amounts. Such an effect can significantly help in the management and prevention of insulin resistance, a precursor to type 2 diabetes. 
Additionally, through its activation of AMPK, metformin also indirectly inhibits mTOR to recalibrate its activity to more youthful ranges.
In addition to these existing pharmacological interventions, research is continuing on other pharmacological agents that target the various cellular pathways involved in metabolic homeostasis. Ongoing clinical trials on rapamycin, metformin, and other agents will allow the longevity community to further understand how we can modulate cell signaling pathways to promote healthier aging and combat age-related diseases.
In conclusion, cellular signaling pathways are intricate networks that help maintain cellular and organismal homeostasis by responding to both internal and external cues. One of the critical aspects of this homeostasis is the regulation of metabolism, which in complex organisms, requires the concerted efforts of different cells and tissues. Over time, the efficiency of these pathways may decline, leading to disruptions in metabolic homeostasis that contribute to the broader process of aging.
Research on metabolic pathways and their regulation provides valuable insights into the processes of aging, healthspan, and longevity. Metabolic pathways, including the Somatotropic Axis, IGF-1/Insulin, mTOR, AMPK, and Ras/ERK pathways, collectively influence cellular health and metabolic balance
These pathways, pivotal in lifespan and healthspan regulation, are influenced by interventions such as calorie restriction, emphasizing their central role in metabolic balance. As we continue to unearth the depth of these pathways and their interactions, we come closer to understanding the complexities of aging and, potentially, to interventions that can enhance health and longevity.
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