What do IGF-1, mTOR, and PKA have to do with your health and longevity?

When these pathways detect certain nutrients, they send signals to various parts of the body, instructing them to use energy, regulate metabolism, repair and grow cells, plus so much more.

NSPs must activate during periods of growth (like when we are growing in adolescence, for instance), over activation of NSPs when growth is not required (e.g. ages 18-65), can accelerate the aging process. As such, regulation and balance of NSPs is essential for optimal health throughout life, and as we age.

Insulin-like growth factor (IGF-1)

This protein pathway is crucial for growth, tissue, muscle maintenance, and overall body function. IGF-1 levels and signaling have been implicated in aging processes. Reduced IGF-1 signaling has been associated with increased lifespan and dysfunctional signaling has been implicated in several cancers

What is IGF-1?  

In simple terms, IGF-1, or insulin-like growth factor 1, is a natural substance in our body that plays a crucial role in helping us grow, develop, and maintain our tissues. It's called "insulin-like" because it has some similarities to insulin, which is known for regulating blood sugar.  

IGF-1 is mainly produced in the liver and is stimulated by growth hormone. It acts like a messenger, signaling cells to grow and divide. This is essential for normal growth during childhood, and it continues to be important throughout our lives for maintaining our muscles, organs, and overall body function.  

Think of IGF-1 as a key player in the complex system that keeps our bodies in good shape. It helps repair tissues, build muscles, and keeps everything in balance. However, just like with many components of our body, having too much or too little IGF-1 can lead to health issues. It's all about finding the right balance to keep our bodies functioning at their best.  

Too high or too low: The delicate balance of IGF-1  

Striking the right balance in IGF-1 levels is crucial for maintaining optimal health and well-being. So, what exactly is the optimal level? The effects of IGF-1 can vary among individuals, and the impact of high or low levels may depend on factors such as age, overall health, and the specific context of each person. However, finding the right equilibrium of IGF-1 is essential—enough to support muscle protection and repair but not so much that it tips the scale toward increased risks of age-related diseases like cancer or cardiovascular diseases. This delicate balance underscores the intricate interplay between IGF-1 and our body's complex systems.  

When IGF-1 levels are too high or too low, certain health risks are at stake:  

Too High IGF-1:  

• Increased Cancer Risk: Elevated levels of IGF-1 have been linked to an increased risk of certain types of cancer. This is because IGF-1 promotes cell growth, and when it's too high, it may contribute to the uncontrolled growth of cells, potentially leading to cancer.  

• Tumor Growth: High IGF-1 levels have also been associated with the growth of tumors. The excessive stimulation of cell division can lead to the development and progression of tumors in various tissues.*  

  
  

*A series of studies have shown that high levels of IGF-1 are associated with an increased risk of tumors including prostate, pre- and postmenopausal breast, lung, thyroid, and colorectal cancers (Ma et al.,1999; Renehan et al.,2004; Shi et al.,2001). Furthermore, in worms, flies, and mice insulin/IGF-1 signaling reduces lifespan and healthspan (Bartke et al.,2013; Fontana et al.,2010; Kenyon,2010; Podshivalova et al.,2017). 

In humans, studies on patients with Laron syndrome (LS), whose IGF-1 levels are extremely low, have reported a reduction in pro-aging signaling, cancer, diabetes, and cognitive decline (Guevara-Aguirre et al.2011; Nashiro et al.2017). Steuerman et al. (2011) also surveyed 230 individuals with LS and found no cases of cancer.  

In fact, a study investigating the relationship between protein consumption and mortality discovered a significant and direct relationship between high protein intake, high IGF-1 levels, and increased hazard ratios for all-cause mortality (Willett & Ludwig,2020).

Too Low IGF-1:  

• Muscle Wasting and Frailty: Insufficient levels of IGF-1 can result in decreased muscle mass and strength, leading to frailty. This is particularly relevant in aging populations, where low IGF-1 levels may contribute to muscle wasting.  

• Bone Density Reduction: IGF-1 plays a role in maintaining bone density, and low levels may lead to decreased bone mass, increasing the risk of fractures and osteoporosis.*  

*Several studies have found a connection between low levels of IGF-1 and conditions such as cardiovascular diseases (CVD), diabetes mellitus, osteoporosis, and sarcopenia (Garnero et al.,2000; Higashi et al.,2010).  (Brioche et al.,2014; Katsanos et al.,2001; Lenk et al.,2010; Saki et al.,2017).  

What factors influence IGF-1 levels?  

IGF-1 levels are influenced by a variety of factors, including nutrition, exercise, and growth hormone. When we consume food, especially meals rich in protein, our body responds by releasing insulin and growth hormone. This growth hormone then signals the liver to produce IGF-1.   

Amino acids, the building blocks of proteins, play a crucial role in this process. Certain amino acids, including leucine, arginine, and methionine, can play a big role in IGF-1 stimulation. Intriguingly, many studies using mice suggest that restricting methionine in the diet can extend the lifespan and enhance overall health by lowering IGF-1 levels.  

Protein sources matter. Numerous studies have observed a correlation between the consumption of animal proteins and elevated levels of IGF-1 in the body.* 

Conversely, plant-based proteins such as legumes, naturally have lower levels of methionine, leucine, and arginine compared to their animal counterparts. Proteins derived from peas, chickpeas, and black beans not only provide essential amino acids, crucial for muscle health, but also work to limit excessive IGF-1 levels.  

The bottom line: Opting for plant-based proteins may not only support overall health but may also promote a longer and healthier life by modulating IGF-1 levels in the body. 

Mechanistic target of rapamycin (mTor)

An amino acids pathway that regulates cellular processes like growth, metabolism, and protein synthesis. mTor has been extensively studied for its impact on glucose metabolism, mitochondrial function, and lifespan.

mTOR: What It Is and How it Affects Longevity

On your health and longevity journey, you may have heard mention of nutrient-sensing pathways.  When activated by certain nutrients, these pathways send signals to various parts of the body, instructing them what to do, such as energy utilization, metabolism regulation, and cell growth or repair. Overstimulating such pathways may accelerate these processes, potentially leading to unwanted outcomes such as speeding up aging.

IGF-1 (a protein pathway), PKA (carbohydrate pathway), and mTOR (amino acids pathway), which are important when we are young and growing, but may speed up aging in adulthood. mTOR, specifically, plays a major role in the body’s aging and growth processes, and when kept low between the ages of 18 - 65, is associated with longevity and healthspan, the period of life spent in good health.  

mTOR- the story 

At its core, mTOR is an enzyme that acts as a master regulator within the body. It plays pivotal roles in regulating many fundamental cellular processes like growth, metabolism, and protein synthesis.

The story of mTOR itself is fascinating: its inhibitor, a molecule that binds to an enzyme and decreases its activity, was discovered before it was! Isolated from soil on the island of Rapa Nui (Easter Island), a compound was found first to have antifungal activities, then immunosuppressive properties, and used successfully to reduce organ rejection with kidney transplantation. Soon, researchers began noticing there were less incidents of cancer in those taking this inhibiting compound (developed into a drug named rapamycin, after the island). Then, in 2009 its implication to potentially increase lifespan was discovered when researchers found that mice fed rapamycin lived an extra six months, equivalent to about 20 years in humans. The enzyme that rapamycin was inhibiting to produce these results, when ultimately identified, was named mTOR: the mechanistic (or mammalian) target of rapamycin. 

How mTOR may speed up aging 

When nutrients, particularly proteins and sugars, are abundant in the diet, mTOR activity spikes, prompting the cells in our body to divide and grow.  We need this during childhood, as it is crucial for growth. However, as we get older, increased mTOR activity is linked with aging, neurological diseases, and malignancies. For example, mTOR is elevated in nearly 100% of advanced human prostate cancers, and higher mTOR expression has been noted in breast cancer tumors associated with more aggressive disease and lower survival rate among breast cancer patients. This has made mTOR inhibition a potential therapeutic target for these diseases. 

An analogy often used likens mTOR to the engine of a car speeding recklessly without brakes. While beneficial in youth to drive growth, the activity of mTOR may turn into a liability in adulthood by accelerating aging. Historically, humans and other animals didn't live as long as we do today; thus, evolution did not equip us with natural "brakes" for this growth engine, which means it's up to us to find ways to slow it down ourselves. 

How to slow down mTOR 

While the drug rapamycin (known as Sirolimus) inhibits mTOR, it has an extensive list of side effects including stomach pain, headache, nausea, diarrhea, constipation, and joint pain, and its widespread use for anti-aging purposes faces challenges due to risk tolerance. However, targeted dietary approaches may play positive roles in regulating these pathways and offer safe “brakes” that are effective for both short- and long-term use. 

• Caloric restriction 

  One effective “brake” that has evolved over time is caloric restriction. Reducing calorie intake, particularly from sugars and animal proteins, has been shown to inhibit mTOR. This response may have evolved to allow organisms to enter a high protection mode when not enough food was available or sufficient for growth or reproduction. When mTOR detects that food is scarce, it slows down cell division and initiates autophagy, the body's way of cleaning house by removing damaged cells and recycling parts for future use - a process vital for cellular health and longevity. Prolon's 5-Day Fasting Mimicking Diet is the only program clinically proven to induce this state of autophagy.

• Low protein diet, emphasizing plant-based foods 

  In both mice and humans, a low-protein diet has shown a reduction in growth factors. Because foods that can trigger mTOR are high in protein, particularly animal products rich in the amino acid leucine such as meat, fish, dairy, eggs, and high-glycemic carbohydrates such as refined grains and sugary foods and drinks, a diet low in animal protein and rich in plant-based foods - including plant-based proteins- may reduce mTOR activation.  

  
  

  Foods such as broccoli, green tea, soy, turmeric, grapes, onions, strawberries, blueberries, mangoes, and cucumber skin all contain natural mTOR inhibitors. Incorporating these foods into your diet, along with following the recommended cycles of Prolon’s 5-Day FMD (three consecutive months initially, followed by three times yearly) can help manage mTOR activity, supporting your longevity. 

With the right dietary approaches, we can turn mTOR from the engine driving us toward accelerated aging into a tool for longevity! 

Protein kinase A (PKA)

A carbohydrate pathway that regulates physiological processes such as metabolism, cell growth, muscle contraction, and more. It also triggers different cellular responses like changes in gene expression, metabolism, and cell growth.