IGF-1 and Cancer – The Double-Edged Sword of Health

IGF-1

 

Before we dig into the article on IGF-1, or insulin-like growth factor, let’s touch upon a couple issues. IGF-1 is an extremely complicated topic, paralleled by the fact that a simple Google search will inform you that it will cause cancer and kill you, bless you with bigger muscles and stronger bones, make you smarter and more attractive, and shorten your life, all at the same time. It is beyond confusing and figuring out how to maximize our IGF-1 levels leaves many unanswered questions, including whether we even want to affect those levels. This article tries to distill the confusion and provide some tangible takeaways, and it still gets nuanced (and boring) at times. Strap in, drink some coffee, and enjoy.

 

Japanese legend has it that around 700 AD, the legendary sword maker, Amakuni Yasutsuna, forged the first single-edged longsword, known as the tachi. Like all legends, different versions of the story have developed, but Amakuni was apparently the head of the Japanese swordsmiths working directly for the emperor of Japan.

Adding to his legacy, he is credited with the creation of the double-edged katana, known as Kogarasu Maru. Yet, no swords signed by Amakuni exist, nor are there modern reproductions like his original sword. This double-edged sword is shrouded with both legend and controversy.

Legend has it that half of the swords used by the emperor’s troops had broken in a famous battle. Amakuni realized he was to blame, and in his shame, retired to his shop to pray for seven days and seven nights. With the help of his son, he then used the best ore he could find and forged it into nearly indestructible steel, working for 31 tireless days and nights. The revolutionary swords were perfect in shape and form, single-edged, and led to many victories in battle by the emperor’s warriors.

As with what happens often in legends, the somewhat believable story becomes a little far-fetched when Amakuni gains immortality from the massive amount of blood spilt from his masterful swords.

At this point, you are probably wondering about the relevance of this lesson on Japanese history and what Samurai swords have to do with insulin-like growth factor, or IGF, a mundane hormone that tells our body, muscles, and bones to repair and grow. Well, like Amakuni’s double-edged sword – based on much legend and storytelling – discussions of IGF have miraculously morphed into a one-sided argument that can provide us either immortality or death through much bloodshed.

This last sentence may be too dramatic, but read on to learn more about IGF, the double-edged sword that our body requires for health and optimal functioning, but may lead to some health issues when in excess. Let’s dig in to the basics so we can leave with some tangible takeaways on how we can manipulate our IGF for optimal health.

IGF-1

Like Amakuni’s initial sword, discussions of IGF should always be two-sided as we still have much to learn.

IGF-1 – The Basics

Before we can dig too deep into the how and why to manipulate our IGF-1 through lifestyle and diet, we should review some basics. IGF was first described in the 1950’s, when two scientists found that a mysterious factor within the blood appeared to incorporate sulfur into cartilage, supporting its growth.1 This factor was driven by growth hormone and also had a remarkable ability to pull glucose from the blood and into cells, much like insulin.

Not surprisingly, IGFs are proteins that closely resemble insulin, the hormone our pancreas secretes to lower blood sugar by stimulating our cells to extract it from the blood. To recap, the hormone insulin binds to a receptor on our cells, flicking an “open” switch on the protective castle wall-like cellular membrane, opening the flood gates to allow sugar to come pouring in. IGF works similarly, and there are several different IGF ligands (which bind to things) and receptors (which things bind to). The most common of each is IGF-1 and the IGR-1R (R for receptor), respectively. To keep things simple, I will only discuss these two, as a more nuanced conversation is unnecessary and boring, and this is already a deep topic that requires some intestinal fortitude just to get through.

Release of growth hormone from the pituitary signals to the liver to secrete IGF-1, which then commands the growth of nearly every cell within our body, including bones, cartilage, muscles, nerves, blood cells, and organs. Other cell types can produce IGF-1, but the liver does the lion’s share of production. Growth is basically the main action of IGF-1, as can be attested by our Major-League Baseball home run champions with their large muscles (and large jaw lines).

IGF-1 also signals back to the pituitary to stop releasing growth hormone, a process known as negative feedback, which serves as a method of regulation. IGF-1 levels are highly dependent on growth hormone, and can be low due to growth hormone deficiency and malnutrition.2 Other normal activities, like sleep, increase IGF-1 levels.3

Protein, Cancer, and IGF

Typical teenagers illustrate the “growth” in insulin-like growth hormone as they consume massive amounts of food to satisfy their large appetites, which increases circulating IGF-1, commanding the bones to grow larger and longer. IGF-1 levels are high during these years, then reach a plateau around age 30 and begin to drop off quickly at age 60, until our final resting days. Low rates of IGF-1 in the elderly are associated with weak bones and fractures,4 a higher risk of dying,5 increased body fat, thinning of the skin and decreased muscle mass.6 This last fact is responsible for the numerous popup ads with incredibly muscular bald old men and younger bikini-clad women in one hand and a bottle of IGF-1 in the other.

protein, cancer, and IGF

IGF-1 levels steadily increase throughout childhood, peak around age 20, plateau, and then steadily drop off as we age.

Not surprisingly, IGF-1 levels in children are correlated with height.7 IGF-1 also stimulates brain development and supports brain function, and children with higher levels of IGF-1 generally have higher IQs.8 After childhood, IGF-1 continues to support the brain by repairing damage and aiding our neurons (brain cells) for optimal function and survival.9 IGF-1 also helps to degrease the brain of amyloid, the tiny plaques that can accumulate and gunk up the brain, leading to Alzheimer’s Disease and dementia.10

Finally, IGF-1 supports our heart and blood vessels, and dilates arteries to protects them from damage.11 Some reports have shown that IGF-1 decreases arterial plaques, decreases inflammation (IL-6 and TNF),12 and reduces oxidative stress in animal studies.13 Furthermore, the protective effect of IGF-1 within the brain may be from its ability to protect the mitochondria, our cellular powerhouses, from oxidative (free radical) stress and damage by promoting our cellular antioxidant system.14 When IGF-1 is given to aging mice, it improves their metabolic function by aiding the breakdown of sugar and fat during metabolism, along with supporting antioxidant production within the brain and liver. As too much sugar, fat or free radicals are damaging, IGF-1 supports the metabolism of all three, a vital cellular process.

Protein, IGF, and Cancer

While insulin binds to both the insulin receptor and IGF-1R, stimulating cellular growth, IGF-1 binds mostly to the IGF-1R. Furthermore, fat and liver cells only have insulin receptors on their surface, while muscles contain both the insulin and IGF-1 receptor. Knowing that too much growth could be detrimental, the body creates circulating IGF-binding proteins (IGFBP) to latch onto IGF-1 and block its ability to bind to these receptors. As a result, while this bound IGF-1 may be present in our system, it is inactive. IGFBP-3 is the most common of these inhibitors, and binds around 75-90% of circulating IGF-1.

Protein, Cancer, and IGF

The Insulin/IGF-1 Axis: Green arrows promote the pathway while red arrows inhibit it.

Any discussion of IGF-1 without taking IGFBP into consideration is missing a critical element of the pros and cons of increasing or decreasing our body’s IGF-1. When the pituitary gland secretes growth hormone and stimulates the release of IGF-1 from the liver, it also sparks the production of IGFBP-3. Insulin, on the other hand, decreases both the total amount of IGFBP-1 and its bioavailability.15 It also significantly increases levels of bioactive IGF-1. In other words, the more insulin we have floating around in our blood, the less IGFBP is available to bind and inactivate excess IGF-1.15

Estrogen also blocks IGFBP-3 production, and drugs that block estrogen may provide a dual cancer treatment as estrogen can signal growth in some cancers. Antiestrogens increase IGFBP-3, disarming excessive IGF-1 and preventing it from signaling growth in breast cancer cells.16 IGFBP-3 even blocks the cancerous growth of cells via mechanisms that are independent of IGF-1,17 and some have even referred to it as a tumor suppressor.18 As a side note, exercise seems to increase IGFBP-3, while overtraining may cause levels to fall off.19

Combining all of these issues, many now consider the ratio of IGF-1/IGFBP-3 to be perhaps the most important predictor of cancer risk.20 However, even studies looking at these ratios remain mixed.

 

Conclusion: IGF-1 is vital in supporting our cellular growth and repair. Too much, however, can have detrimental effects and a result, the body creates IGFBPs to offset bioavailable IGF-1.

 

 IGF-1 and Aging

Like many aspects of our health and Amakuni’s initial sword, IGF-1 is double-edged when it comes to our health, with the potential to provide much benefit or harm: too little, and we do not develop properly, we lose muscle mass, bone strength diminishes, and our cognition declines as we age; too much, and our cells can grow out of control, leading to cancer and potentially, premature aging. A recent analogy that has gained notoriety is that of telomeres, the protective caps at the end of our DNA. If our telomeres are too short, cells age and diseases of old age spring up prematurely. However, telomeres that are too long can promote cellular immortality and cancer. Much like telomeres, balancing IGF-1 is a delicate process, and for optimal health we need to avoid tipping the scale too far in either direction.

The insulin/IGF-1 axis supports cellular growth, a phenomenon that can also lead to cellular “burnout” and premature aging. Scientists have even shown that blocking this pathway in animals can enhance longevity. For instance, when the insulin receptor is deleted from fatty tissue in mice, they live longer.21 As insulin is strongly stimulated via dietary carbohydrates, this may be one reason why sugar and yeast restriction increases lifespan in fruit flies (irrespective of calories),22 and glucose restriction increases lifespan in roundworms23 and yeast.24

Similarly, protein and amino acid restriction in fruit flies enhances longevity,25 and protein restriction in mice – and specifically the amino acid methionine – modestly increases longevity. Exposing cells to continuously high levels of IGF-1 can damage their mitochondria and interfere with their function, leading to premature aging.26

While dietary changes can alter the IGF-1 pathway and promote or limit longevity in an array of insects and small animals, as you will read below, mutations of the IGF-1 pathway may provide the greatest longevity benefits. Mice with impaired IGF-1 signaling and function live longer – along with tendencies to have dwarfism, further illustrating the double-edged sword of IGF-1.27

 

IGF-1 in Centenarians

In elderly human studies shown that mutations and decreased signaling of the insulin and IGF-1 pathway are a common occurrence in those of us that outlive our peers.28,29 Studies in centenarians – those individuals defying death past the age of 100 – reveal frequent mutations in the IGF-1 pathway. For instance, some Ashkenazi Jewish centenarians have higher amounts of IGF-1 floating around in their blood, yet this IGF-1 is not pulled into cells due to a genetic “defect” in the IGF-1R gene (remember IGF-1R is the receptor that binds IGF-1).30 There may be more IGF-1 present, but if it is unable to bind to the cell, the amount is insignificant. A massive study in Italy, a country with a hefty supply of prosciutto, wine, and centenarians, has confirmed that IGF-1R mutations are most common in individuals that outlive the rest of us.31

Centenarians also often have double the insulin sensitivity when compared to other individuals.32 In other words, they need roughly half as much insulin to reduce an equal amount of blood sugar when compared to the rest of the population. As excess insulin can lead to a plethora of health complications, including cancer, this metabolic benefit may be a large contributor to their longevity.

We must also keep in mind that many of these animal and population longevity studies often use models with mutations that result in extremely high or low levels of IGF-1, in animals very different from humans, and with levels that are unachievable through diet and lifestyle. As a result, many of these studies are interesting, but irrelevant for most of us.

Furthermore, while reducing IGF-1 may enhance longevity, low levels may increase our risk of developing diabetes, cardiovascular disease, osteoporosis and neurodegenerative diseases earlier in life.33 Some have even questioned growth hormone (to stimulate IGF-1) as a method to combat aging and its accompanying diseases.34

At the end of the day, when it comes to longevity, dietary fat seems to be the odd man out, as limiting it does not appear to extend lifespan.35 Interestingly, when the protein versus carbohydrate wars are being waged, there seems to be a mysterious void of any discussion including fat. So, while generally speaking, dietary carbohydrates most strongly stimulate insulin and protein most strongly stimulates IGF-1, fat remains the odd man out. Along these lines, when scientists create a strain of mice with a mutated insulin receptor and feed them a high-fat diet, they live significantly longer.36

If you are confused, you’re not alone. It seems like all the macronutrients, protein, carbohydrates, and even fat, could affect the insulin/IGF pathway to reduce longevity, depending on who we want to demonize. However, the irony is that the largest dietary enemy in recent years – fat – may be the one macronutrient with the smallest effect.

 

Conclusion: While IGF-1 supports many vital functions as we age, those with genetic alterations that decrease active IGF-1 appear to live longer. Current dietary recommendations conflict with cellular pathways that affect longevity.

 

At this point, you are probably feeling much like my dog below. If so, put the article down and come back to it tomorrow. If not, you are a trooper, so congrats, and keep on reading.

IGF-1 and Cancer

IGF-1 derives its ability to stimulate cellular growth and support our bones and muscles via several cellular pathways, including one called AKT and a further downstream pathway called mTOR. If you decide to dig deeper after reading this, these may be the two that you encounter frequently. Through these signaling pathways, IGF-1 promotes cellular growth and allows cells to evade apoptosis, the process of programmed cell death that is necessary to rid the body of potentially dangerous and even cancerous cells.

Potential danger accompanies these otherwise normal mechanisms. More simply put, IGF-1 fosters cellular growth and cancer is the process of unregulated growth. The potential issue here is obvious. As a result, it is not surprising that cancer cells place IGF-1R receptors on their surface, which can attract and bind IGF-1 to promote their growth. However, even normal cells contain this receptor, and in these ordinary cells, IGF-1R has an uncanny ability to push the gas pedal on uncontrolled growth and the conversion to cancer – along with protection from apoptosis – thus circumventing the body’s naturally pruning process of suspicious cells.37 Well known cancer researchers, like Renata Baserga, have found that IGF-1R is so vital for cancer initiation and growth, that cells without the receptor are nearly resistant to transformation to cancer.37

Protein, Cancer, and IGF

If IGF-1R is needed for cancer growth, blocking it can hinder cancer development and enable our cells to engage in normal apoptosis. This in turn will command faulty cells to fall on their own swords (known technically as programmed cell death). Initial enthusiasm for targeting IGF-1R as a cancer treatment was high, as it was felt that blocking it may be lethal to cancer cells while sparing normal cells. How well this may work is another story.

The connection between the IGF-1 and the insulin receptor only helps to strengthen the view that blocking these targets, or limiting the amount of circulating IGF-1, could decrease or prevent cancer. Along these lines:

  1. IGF-1 circulates throughout the body and can bind to both the IGF1-R and the insulin receptor, though it prefers the former.
  2. Just as too much insulin can bind to the insulin receptor, signaling excessive growth in our normal cells or cancer cells, IGF-1 provides the same concern.
  3. Insulin, much like IGF-1, can also directly stimulate the growth of cancer cells, providing a direct impetus as a fuel for cancerous growth and indirectly, by offsetting IGFBPs.38

 

Conclusion: IGF-1, especially in excess, can promote cellular growth and may fuel cancer growth.

 

Impacting IGF-1 Through Our Lifestyle

So how does our diet affect IGF-1? The amount of IGF-1 in our blood is largely related to both our overall dietary energy intake and protein consumption.39 However, like most aspects of the interaction between our diet and physiology, it’s more complicated than just calories and macronutrients. For instance, even dietary calcium increases IGF-1 and decreases IGFBPs, signaling our cells to grow.40 IGF-1 is also increased by several vital nutrients and vitamins, including zinc, selenium, and magnesium.41

High amounts of dairy can increase circulating IGF-1, which has led many to chastise it. The exact mechanisms are unclear, but the actual IGF-1 found in dairy does not appear to make it through the digestion process and into our system. It is also unclear if it is simply broken down during digestion or if perhaps our bowel bacteria somehow denature it. If the latter is the case, any subsequent effect on our bowel bacteria is unclear. More likely, the high amount of protein in commonly consumed dairy products – low-fat milk and low-fat cheese – is simply a large protein source, which, much like breast milk during infancy, increases IGF-1 and signals our cells to grow.

Studies confirm this and point to animal protein as a stronger stimulus of IGF-1. These are mostly epidemiologic studies, but some have recommended a vegetarian diet to lower IGF-1 as a result. The data, however, paints a different picture. Meat eaters and vegetarians have the same serum IGF-1 levels in several studies in both men42 and women.43 Those on a vegan diet, however, may have a modestly lower IGF-1 level (18.5 vs. 20.1 nmol/L in men and 27 vs. 30.9 nmol/L), at least in these studies. IGF-1 levels were again correlated to animal protein and the “meat eaters” were consuming a standard western diet. As a result, it remains unknown how those eating a plant-heavy diet including healthy and well-sourced animal products or animal sources higher in fat would have compared. The topic remains so polarizing, that I doubt these studies will ever be performed.

At the end of the day, it appears that, like most protein, dairy protein increases our IGF-1. Dairy in itself seems to have less of an effect. For instance, when athletes were supplemented with bovine colostrum, the milk high in antibodies and growth hormones secreted after the first few days of calving, they experienced no increase in their serum IGF-1.44

Milk intake in children is associated with a higher level of IGF-1, and boys that drink more milk have longer leg length (remember, IGF-1 is a growth factor).45 In this study, which further provides evidence that there is no magical element of dairy that raises IGF-1, the higher IGF-1 was related to the protein content and not the IGF-1 within the milk. Soy protein isolate increases IGF-1 as well, further stressing the effect of protein on IGFs.46 According to some data, soy protein is even more potent at increasing IGF-1 than milk protein, further exonerating dairy.47 The IGF-1 to IGFBP3 ratio is also increased in women receiving soy protein powder.48

A Primer on Recombinant Bovine Growth Hormone (rBGH)?

RBGH is a growth hormone that acts much like IGF-1, and is often given to cows to increase their milk production. This “cheat” is not without its issues, as rBGH encourages cellular growth and replication and excess cellular growth and replication can lead to cancer. The higher levels of circulating rBGH in their milk are of further concern, as we eventually consume dairy products made with this milk.

Yet, current studies have absolved rBGH as it appears to be inactive in humans, potentially minimizing the obvious concern here. However, cows treated with rBGH have higher amounts of circulating IGF-1, which, if it makes it through the digestion process, would be concerning as it could be passed along. Furthermore, it is unclear if rBGH can more easily pass through the digestive system in those with inflammatory bowel issues or damaged digestive tracts.

Aside from these potential issues, cows given rBGH experience higher rates of infections and must receive antibiotics, leading to multiple health issues and an increase in antibiotic resistant infections. Overall, it seems prudent from both a health and ethical stance to avoid dairy from cows given rBGH.

 

Amidst all the smoke and mirrors when it comes to discussions of dairy’s effect on our health, it should be noted that the issues with dairy come into play from the amount of protein, especially in fat-free dairy, and the high amounts of insulin-stimulating sugar in skim milk. The benefits of dairy are largely contained within the fat, including cancer-fighting conjugated linoleic acid and butyric acid. The same can be said for the benefits of dairy regarding the insulin and IGF-1 pathways.

 

Skim milk, the “healthy” dairy recommendation for decades – made up of mostly sugar and protein – leads to total insulin/IGF-1 stimulation. High fat Italian cheese – the same kind that has been shunned for decades – is nearly 75% calories based on fat, with a much smaller amount of insulin/IGF pathway-promoting protein.

For instance, trans-palmitoleate, the fatty acid found in dairy fat, is associated with higher insulin sensitivity, less abdominal obesity, higher HDL, lower triglycerides, and lower markers of inflammation, like C-reactive protein.49 Dairy fat consumption has even been associated with a strong decrease in the risk of diabetes. These factors would act to lower the insulin and IGF-1 pathway. Furthermore, when we check blood levels for biomarkers of milk fat consumption, those with high levels also have a lower risk of heart attack.50

An assessment of nearly 27,000 individuals revealed that full-fat, but not low-fat, dairy was associated with a significantly decreased risk of type II diabetes.51 As a reminder, type II diabetes is a state of metabolic dysfunction whose victims experience harmfully high levels of blood glucose and insulin, along with elevated inflammation – all of which are consistent with higher rates of cancer.52 Dairy fat also has many healthy elements that may protect our cells from cancer.

 

Conclusion: High protein diets can increase IGF-1. Dairy is often demonized in this regard, but the issue with dairy is likely pointing to low-fat/high-protein dairy sources. Associative studies show that a vegan diet is modestly associated with lower levels of IGF-1 than Western diets, and vegetarian and Western diets appear to be associated with similar levels of IGF-1, but these are only correlative studies.

 

Decreasing IGF-1 Through Food (or Lack Thereof)

At this point, it is clear that excessive dietary protein can increase IGF-1. Yet, effective methods to decrease IGF-1 – at least in humans – have proven more difficult. Calorie restriction reduces IGF-1 in animals, but is unsuccessful in humans at lowering either IGF-1 or the IGF‐1:IGFBP‐3 ratio.53 On the other hand, extreme calorie restriction through malabsorption, gastrointestinal issues, or severe malnourishment significantly depresses IGF-1 (low IGF-1 is actually a method to test for these disorders).54,55

Many benefits of severe calorie restriction in animals – like an improved metabolism, longevity, and decreasing cancer risk – have failed to translate to humans. Lowering IGF-1 can be added to the list. Protein restriction seems to be the one dietary aspect that may be effective at lowering IGF-1 humans. For instance, when a group of study participants ate a diet that reduced their protein intake from a daily average of 1.67 g/kg of body weight to 0.95 g/kg for 3 weeks, their serum IGF-1 dropped from 194 ng/mL to 152 ng/mL.56

 

Severe calorie restriction may increase lifespan in an array of insects and animals, but thus far in humans all it seems to increase is misery.

 

Per above, population studies reveal that IGF-1 levels are lower in vegans on a low protein diet versus standard American dieters,57 likely because A) plant protein is low in methionine, an essential amino acid that can increase IGF-158 and B) animal protein is more bioavailable than plant protein. Yet, no study to my knowledge, has compared a switch from an animal to plant protein diet to test changes in IGF-1. Studies have tested other metabolic factors that increase the risk of diabetes, and when individuals were randomized to a plant protein versus animal protein diet, there were no major differences, though insulin and blood sugar were improved in the animal protein consumers.59

Since general calorie restriction has thus far failed to reduce IGF-1, attempts have turned to intermittent fasting. Unfortunately, fasting has also been relatively unsuccessful in reducing IGF-1 in the real-world setting (including reasonable fasts). Fasting, however, greatly decreases insulin (which will increase IGFBP-1), increases ketones, and downregulates the insulin/IGF-1 pathway.60 This can even be accomplished in more reasonable fasts, like 15 hour periods.

 

IGF-1

 

Fasting mice for 3 or more days can lower IGF-1,61 but in humans, we likely require a much longer fast,62 a practice unbearable by, well, nearly everyone. Furthermore, after the fast, levels appear to normalize in both mice and men, and there may even be a period of excessive hormone production. Intermittent fasting studies in young overweight women elicited an improvement in several metabolic factors, and while it increases some IGF binding proteins, it has a minimal effect on IGF-1.63 While fasting may fail to cause significant changes in IGF-1, keep in mind that it can lower blood sugar and insulin levels – decreasing the insulin/IGF pathway – and improve multiple metabolic and inflammatory factors that can increase cancer risk.

Finally, attempts to lower IGF-1 with a lower fat and higher carbohydrate diet have, not surprisingly, failed. In fact, when postmenopausal women were randomized to a low-fat, high-fat, or low-fat diet with omega-3 fats, the low-fat diet increased both IGF-1 and the IGF-1/IGFBP ratio.64 Decreasing fat in the diet and instead relying on carbohydrates to minimize either insulin or the IGF-1 pathway makes little sense.

 

Conclusions: Protein restriction can decrease IGF-1 in humans, but calorie restriction and fasting have yet to show a consistent change. Fasting can, however, decrease the insulin/IGF-1 pathway through its reduction in glucose and insulin.

 

IGF-1 and Exercise

Pinning down the exact effect of exercise on IGF-1 levels can be difficult, if not impossible. For instance, weight lifting and resistance training play a role in modifying IGF-1 levels, but much like the “inflammatory hormones” that are secreted during workouts, this seems to be a local phenomenon with systemic levels remaining relatively unaffected over the long term.

Stressing our muscles with weights leads to the anabolic process of muscle growth, and this hypertrophy follows increases in IGF-1 production within the exercised muscle.65 The key word is within the exercised muscle. Much like the increase in the “inflammatory” hormone IL-6 that accompanies exercise, systemic levels do not always correlate with local levels within the muscle. Even stretching our muscles increases in IGF-1 production within the stretched muscle.66

 

Muscles Cancer

Exercising muscles increases potentially damaging IL-6, only to sensitize our muscles to it. IGF-1 may work similarly.

 

The key difference here is between growth hormone-stimulated IGF-1 – or in other words IGF-1 produced by the liver in response to growth hormone secreted by the pituitary gland – and the local production of muscle-derived IGF-1. Remember, the liver produces IGF-1 in response to growth hormone stimulation and it also remains the major determinant of our serum IGF-1. For instance, increasing IGF-1 production in a specific muscle leads to hypertrophy of that muscle without an increase in serum IGF-1 or an effect on the growth of other organs throughout the body.67 It appears that the muscle itself and local area is creating the IGF-1. Furthermore, the “burn” that we get from working out – the acidic environment surrounding the muscle – causes IGFBP-3 to release from IGF-1, which increases the amount of free-floating and locally bioavailable IGF-1.68

Resistance exercise is an anabolic stimulus and our muscles respond with hypertrophic adaptation, i.e. more muscle growth. While the health benefits of bigger muscles are plenty, the relationship between the process of gaining these muscles and our hormones is not as clear cut (though it is hard to imagine it could result in negative health effects due to the massive benefits of both lifting weights and having more muscle).

Both high and low-intensity resistance exercise immediately increase serum IGF-1 by around 20-25%, which may be at least partially responsible for the benefits of exercise on brain function and bone strength.69 However, much like the potentially harmful inflammatory hormone IL-6 that is increased during exercise, our muscles absorb this released IGF-1 to aid in their repair and growth,70 sensitizing them to future elevated levels of IGF-1. Along these lines, studies show that even after 12 weeks of strength and endurance training, serum IGF-1 levels can decrease.71

In healthy men who routinely strength train, the effect on IGF-1 gets more confusing as weight training may not change serum levels over time.72 While controversial, many believe that chronic exercise results in adaptation to the high levels of IGF-1. Other studies suggest that more fit individuals who exercise more often, have a lower baseline IGF-1 and a higher spike in IGF-1 after resistance training.73 Still other studies show that exercise lowers IGF-1 and insulin levels in overweight and obese postmenopausal women.74 In other words, it depends on our age, sex, health status, exercise status, and when levels are measured. In other words, depending on the methods of the study, we can find drastically different results.

The transient increase in IGF-1 during exercise appears to be countered by an increase in IGFBPs.75 The increase in IGF-1 is not long-lasting, and within 20 minutes after a workout, levels drop, and as early as the next morning they normalize.76 Yet, the exact influence of exercise seems to depend on the study – some show an increase, decrease, or no change in serum IGF-1 over the long term.77

Furthermore, during and after exercise, IGF-1 is pulled from the blood and into the brain to support its function,78 one of the many ways in which exercise improves cognition. In fact, the benefits of exercise-derived IGF-1 are so strong that if we block IGF-1 uptake into the brain, it eliminates the cognitive and neuroprotective benefits of exercise.79

Exercise signals to many IGFBPs to release their IGF-1, which is then used to promote muscle growth and repair. The remaining IGF-1 then becomes bound again as levels drop back to normal. It is as though we can exercise off excess IGF-1. Also, much like the way in which exercise pulls sugar from our blood and into our cells to be burned as fuel, improving our insulin sensitivity, the same may be true of exercise and IGF-1.

On the other hand, IGF-1 levels naturally decrease in the elderly, which can lead to multiple health issues, prompting attempts to increase them. Exercise80 and increased protein consumption81 in the elderly can increase levels of IGF-1 and improve their health, including decreasing risk of cancer and improving cognition.

 

Conclusions: Exercise has many benefits, but its effect on IGF-1 remains relatively unclear. It transiently raises our IGF-1, and seems to “push” IGF-1 to our brain and muscles to improve the function of both. Exercise and protein consumption can benefit the elderly by raising IGF-1.

 

Elderly individuals experience a significant drop of IGF-1, decrease in bone strength, and muscle loss. This may be a population where increased protein is necessary. Studies have shown that protein consumption in the elderly is less associated with cancer, and may serve to improve multiple health factors.

Interestingly, as we get older, our physique tends to resemble a mild form of cachexia (severe muscle loss). IGF-1 levels drop, muscle wasting occurs, fatigue sets in, and weakness ensues. In these individuals, it may be prudent to consume larger amounts of protein to increase IGF.

 

IGF-1 – Muscles, Amino Acids, and Health Benefits

While the connection between IGF-1 and cancer is concerning, it’s worth reminding that IGF-1 serves many vital purposes that antagonize its villainous side. IGF-1 helps to build muscle and reduce adipose (fat) tissue, which provides many anticancer effects. As we have already discussed, muscles – and specifically contracting those muscles – secrete anti-inflammatory hormones that sensitize our cells to insulin, decreasing cancer-promoting inflammation, blood sugar, and insulin. Adipose tissue also increases inflammation, dysregulates our blood sugar control, and secretes several hormones that can aid in cancer initiation and  growth. However, like most aspects of our health, there are two sides to the coin.

The amino acids in protein appear to provide the major stimulus of IGF-1 secretion. These same amino acids are vital to our health and the repair of our cells and organs, and their requirement further illustrates the double-edged sword of dietary protein – simply avoiding protein and amino acids is a shortsighted recommendation. Even the ways in which these vital amino acids affect IGF-1 is less than clear, as there is worrisome IGF-1 – like excess IGF-1 in our blood – and beneficial IGF-1 – like that required for repair and growth of our skeletal muscles.

Skeletal muscle-derived IGF-1 is stimulated from the amino acid leucine. Furthermore, leucine also stimulates mTOR, that pesky pathway that often gets blamed with fueling cancer. Yet, even this increase may be more within the muscles and less so the worrisome cancer pathways that IGF-1 can increase.82 Studies suggest that in exercising individuals, leucine in the diet is used for muscle repair and growth, and not stimulation of mTOR. In fact, leucine appears to be the key regulator of skeletal muscle growth, an important fact since muscles work like an endogenous organ, secreting beneficial anti-inflammatory hormones during exercise. In those individuals who do not engage in muscle-stimulating exercise, the interactions are less clear.

After we engage in intense physical activity, skeletal muscle metabolizes leucine at a high rate. Protein is broken down and branched-chain amino acids (BCAAs: leucine, isoleucine, and valine) are oxidized (broken down for energy). The amount of leucine found in our blood significantly decreases. Leucine is even pulled from non-muscular sources, like the liver and gastrointestinal tract, and shuttled to our muscles for fuel.83 Both dietary leucine and foods that increase insulin, like excess carbohydrates, increase the mTOR pathway to enhance protein synthesis, especially after exercise.

Excess leucine (and protein and amino acids in general) could potentially fuel cancer growth, but is also vital for normal physiologic function, especially in individuals that weight train. Due to the enormous anti-cancer and overall health benefits of exercise, resistance training, and muscle hypertrophy, engaging in all three is the best strategy, even though these activities require an adequate source of leucine and protein for optimal recovery.

The intricate balance of leucine and protein is best exemplified by cachectic cancer patients. Cachexia, a state of severe muscle loss, weakness, fatigue, and anorexia, is often seen in cancer patients and is difficult, if not impossible, to combat. Even consuming massive amounts of calories often fails to offset the potentially lethal loss of muscle mass. As a result, leucine supplementation has been a potential target to offset this muscle loss. Yet, recent animal studies – limitations aside – have shown that leucine supplementation may fuel pancreatic cancer growth.84

 

Adding further confusion is the fact that other preclinical data – limitations aside as well – reveal that leucine restriction in breast cancer cells lines, may decrease mTOR, but increase a survival mechanism in the cancer cells, known as AKT.85

 

Yet, all these issues aside, when mice are supplemented with BCAAs, they can paradoxically live longer.86 Oddly enough, the increase in lifespan comes from promotion of the same mechanisms that are activated when we decrease the insulin/IGF-1 axis through diet and lifestyle. BCAAs activate several genes that provide protection from free radical damage, known as oxidative damage. Furthermore, BCAAs promote the creation of new mitochondria and an increase in the size of current mitochondria, which serve as powerhouses of our cells and producers of detoxifying enzymes and antioxidants.

But, the relationship is not that simple. When mice are given BCAAs, they place the mitochondria on overdrive, forcing the production of energy through a process called oxidative phosphorylation. The exact details are less important, but the significance lies in the byproducts of this process: free radicals known as reactive oxygen species (ROS), which are simply reactive chemicals containing oxygen. These ROS are potentially dangerous to our cells, causing everything from cancerous DNA damage to premature aging. In response to these threats, our cells have created a major mechanism to offset this damage known as the ROS defense system. As our mitochondria run on full throttle from the BCAAs, the excessive production of ROS activates these antioxidant enzymes. Paradoxically, this leads to an overall decrease in the amount of free radical damage. As a result, the mice live longer and experience improved muscle function and physical endurance.

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BCAA supplementation also increases expression of PGC-1α, a regulator of the ROS defense system and mitochondrial production that is intimately connected with AMPK. AMPK is our cells’ energy accountant—when stores are getting low, it switches on some processes that stop cellular growth, which inhibits mTOR and the insulin/IGF-1 pathway, and increases the breakdown and recycling of faulty parts and cells, known as autophagy. Exercise, fasting, and other activities that deplete our fuel stores turn on AMPK, which activate the mitochondria to produce more energy.

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Much of this activity is occurring within our muscles. Countering the effects of BCAAs within our muscles is the effect of increasing insulin/IGF-1, which disarms the “stress response” of the antioxidant defense system.87 In other words, while ROS production during our mitochondrial overdrive helps our cells fight free radicals in the grand scheme of things, insulin and IGF-1 can block our cells’ ability to put up this fight.88 This is one of the mechanisms by which carbohydrate restriction can increase longevity in animal experiments.89

 

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The resistance to oxidative stress is shut off by excessive amounts of insulin and IGF-1,90 and as a result, oxidative and free radical damage occurs, our cellular parts break down, I get gray hair, and we all age. But that fact that leucine – an amino acid that can increase IGF-1 and mTOR, which would potentially age us and increase our risk of cancer – improved muscular function in mice and allowed them to live longer merely illustrates the massive interplay between these processes. It is also why anyone who is trying to single out a specific protein or pathway may find themselves focusing too closely or even in the wrong direction with their recommendations.

 

Conclusions: The benefits and potential risks of dietary branched-chain amino acids merely illustrate the double-edged nature of IGF. However, the ability of BCAA to upregulate several anticancer pathways in our muscles and improve lifespan in mice is unexpected and intriguing. The benefits likely outweigh the risks in individuals who exercise, lift weights, and have a healthy amount of muscle mass.

IGF-1 and Stress

There is both good stress and bad stress. Chronic stress wears us down and weakens our immune system. Acute stresses can stimulate our immune system to help fight infections and cancer. However, there are other, much smaller stressors that we often fail to consider. Certain diet and lifestyle activities, like exercise, fasting, eating spices and cruciferous vegetables, and drinking tannic wines can stress our cells on the microscopic levels.

I dedicated a chapter of Misguided Medicine to these stressors, along with an old article from my blog. Physical activity, sulfur-containing vegetables, spices, and even red wine mimic danger to our cellular sensors and rouse a physiologic response that triggers our cells to upregulate several defensive pathways, a process that acts much like troops preparing for battle. There are many ways to “stress” our cells, nudging them to produce many antioxidants to neutralize potentially damaging free radicals. The key is how our mitochondria respond to this nudging, especially since they spend their fair share of time creating actual stresses to our cells in the form of free radicals.

This leads to another enormous double-edged sword: our mitochondria are vital for life as they churn out energy like a hydroelectric dam, but with more power comes more potentially harmful free radical byproducts that can damage the mitochondria and its sensitive parts. The fix, which has been designed, built, and perfected over several million years, is the antioxidant defense system. It is not by coincidence, that the more we “stress” our mitochondria with ROS, the more they fight back.

Dr. Rainer Klement has extensively researched and reviewed the effects of protein and carbohydrate within the diet and the capacity of insulin and IGF-1 to promote cancer.91 What he found, was that both humans and mice are sensitive to dietary carbohydrates and protein and their effect on insulin and IGF-1. However, mice seem to be exquisitely sensitive to protein, while humans are more sensitive to carbohydrates, which is sensible since humans have been omnivores for most of their evolution and consumed generally low-carbohydrate diets, while the diet of mice has been nearly the opposite.

This raises several points: 1) Recommendations that consistently rely on mouse studies or even worse, epidemiologic studies, with little mechanistic evidence in humans, must be taken with caution. Protein is likely a target for reducing IGF-1, but the exact impact of the relationship remains unknown as human studies are limited.  2) In terms of reducing the insulin/IGF-1 pathway, humans may still get more bang for their buck from keeping insulin levels low by restricting dietary carbohydrates to varying degrees than excessively focusing on protein.

Shutting off IGF-1 and Insulin Further Downstream

While the ability of vital processes like insulin and IGF-1 to block our stress response mechanisms may make us feel helpless at times, we can reengage them through some foods and activities that can stress our cells. The curveball that we can throw IGF-1 is the handful of activities that may not largely effect it, but provide a beneficial downstream effect. In other words, we can minimize the potentially harmful effects of IGF-1 by mitigating the cellular responses that it activates.

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While the above activities may directly affect IGF-1 levels, turning on the regulator of our ROS defense system provides some valuable lessons. When PGC-1α is activated, triggering mitochondrial synthesis, our energy clerk (AMPK), is also activated. By halting the downstream pathways that insulin and IGF-1 activate, we are potentially providing our cells with an escape mechanism.

Fasting, carbohydrate restriction, ketosis, exercise, cold weather, and muscle contraction deplete our cellular energy supplies and these spartan activities intensely activate AMPK. It then relays this message to PGC-1α, leading to a chain reaction that increases the expression of many processes and enzymes that disarm free radicals. Remarkably, as mitochondria produce ROS when stressed, triggering PGC-1α, the antioxidants produced to offset these ROS are so great in number that they lead to lower levels of free radicals than before the stressful event. In other words, a little stress to our cells generates a much larger amount of antioxidant defense.92

Furthermore, many of the procancer pathways that are upregulated in our muscles with protein consumption and exercise are blocked in other tissues by AMPK. As discussed above, AMPK inhibits mTOR and the insulin/IGF-1 pathway, favoring a period of breakdown and recycling of faulty parts and cells, instead of growth.

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Conclusions: Both insulin and IGF-1 may interfere with our stress response and antioxidant defense systems. We can attempt to decrease them through carbohydrate and/or protein restriction. We can also stimulate the stress response system with exercise and by eating “stressors”, or cut off insulin/IGF-1 further downstream by activating AMPK through exercise, fasting, and periods of ketosis and carbohydrate restriction.

Protein, Cancer, and IGF-1 – What’s Left to Eat?

IGF-1 and insulin are the yin and the yang of the dietary world, the push and pull of the “experts.” The push against insulin, chastising of carbohydrates, and promotion of protein often neglects how this will affect IGF-1. Conversely, the anti-protein pushers, often those that promote veganism or vegetarianism, endorse dietary carbohydrates while selectively ignoring the abundance of data revealing the equally (or perhaps even greater) negative effects of a dietary reliance of carbohydrates. After decades of conditioning, both sides fail to discuss one aspect of the diet that avoids this push and pull, the yin and yang.

You may notice that one macronutrient is often, and ironically, left out of the discussion. Fat, the demonized macronutrient that provides the largest calories per gram, aids in the absorption of fat-soluble vitamins, provides essential fatty acids that support our brain and our body cannot make, is used as the building block of our cell walls, and supports hormonal function and production. Many more benefits of this vital nutrient exist, but surprisingly, fat’s ability to directly affect the insulin/IGF-1 pathway pales in comparison to carbohydrates and protein, the infamous macronutrients over which present day health experts are waging an insulin/IGF-1-based war. This seems to have been lost somewhere in the shuffle.

Mechanistically, the vilification of dietary carbohydrates and protein is reasonable. Dietary fat, on the other hand, has only been associated with IGF-1 through shoddy epidemiologic studies and mechanistically continues to be the odd man out. This discrepancy should be remembered when dairy is chastised. Studies assessing the issues with dairy protein, coupled with the potential benefits of dairy, argues that one should consume dairy fat – ideally from a healthy and happy cow that roams the pasture, does not receive hormones and antibiotics, and is not exposed to pesticides. This does not sit well with many of the vegan groups, but the data is the data.

The issues with insulin and IGF-1 parallel the mishandling of red meat and dairy over the past several decades; we have been counselled to avoid the fatty source lest we want our arteries clogged or a plethora of other health issues, and advised to eat lean sources instead. After decades of misguided medicine, we are now being told the high-protein source will kill us.

 

Conclusions: Methods to combat stimulating of the insulin and IGF-1 pathway may ironically promote a higher consumption of dietary fat and less carbohydrates and protein.

IGF-1 – The Problems with Lowering It

After reading the laundry list of the vital functions IGF-1 provides to our cells, muscles, bones, brains, and bodies in general – combined with the fact that it may help physical function and performance – you may be wondering if it is even worth attempting to decrease IGF-1.

The potential anti-cancer and pro-longevity benefits of IGF-1 reduction are thus far unproven in humans. While less cerebral nematodes, flies, mice, and other farm animals may be positively affected through things like extended fasting and severe calorie restriction, as these animals get larger, smarter, and closer to humans, the benefits drop off. As a result, we have plenty of proven benefits of IGF-1 with some potential downsides, albeit the large downsides of reduced longevity and cancer.

On the flip-side, even if successful methods to reduce IGF-1 in animals translated to humans, the potential downsides are plenty. Severe calorie restriction, for example, increases our risk for vitamin deficiency and malnutrition, with still no tangible benefit shown in humans. Severe calorie restriction results in muscle loss and a lifestyle that would be miserable for many. Veganism, another difficult lifestyle to follow, can lead to vitamin and nutrient deficiency if not precisely managed. It also removes many of the vital and healthy sources of dietary fat and cholesterol that the body and brain require to thrive, often replacing them with insulin-stimulating carbohydrates. This is partially why veganism and vegetarian diets are associated with depression, psychologic disorders, and suicide.93–97

Furthermore, veganism is unproven to lower IGF-1 except in population studies where it is shown to be better than the dreadful standard Western diet. Furthermore, following a vegan diet often requires supplementation as it is difficult to obtain certain vitamins and nutrients that are found in animal sources and fats. The precision required to remain proficient in vitamins and nutrients on a vegan diet is so difficult that it may be the reason that population studies reveal a lower IGF-1 in vegans; IGF-1 is increased by vitamins like zinc, selenium, and magnesium41 and levels reflect nutritional status. Along these lines, many vegans are likely malnourished,98–100 which can potently lower IGF-1 levels.

Short-term fasting may have many metabolic benefits, but long-term fasting is unproven and many of us would rather chance it than be miserable. Furthermore, if the fasting schedule is too extreme and does not provide adequate vitamins and minerals, deficiencies can follow. In other words, several of these strategies require extreme precision that is difficult and undesirable for most people to follow, especially considering the unclear benefits.

Conclusions: Many of the unproven and potential methods to reduce IGF-1 are difficult to follow, miserable, and may simply lower IGF-1 due to malnutrition and nutrient deficiencies.  

Protein, Cancer, and IGF-1 – How Much Protein is Too Much?

With protein as the major target for reducing IGF-1 and carbohydrates for insulin, it makes sense to avoid consistently overindulging in either of these macronutrients. The exact amount of protein to consume remains elusive. On average, Americans eat 1-1.3 grams of protein per kilogram of body weight per day (or 0.46-0.59 g per pound body weight for those of us not on the metric system), according to the National Health and Nutrition Examination Survey from 2003-2004.101 If you are an 185 pound male, this is about 85-109 g protein per day.

The Institute of Medicine (IOM), which is tasked with the nearly impossible job of creating the Dietary Reference Index recommends 0.8 g per kg body weight daily, or 0.36 g/lb. For a 185-pound male, this would be about 67 g of protein per day, which is much smaller than the amount eaten by your average American. The IOM must take politics, dogma, science, and political pressure, blend them all together, and somehow come up with dietary recommendations for everyone. Regardless, it’s the best we’ve got. Keep in mind, this is also recommended for the average American, of whom less than 20% actually achieve the daily recommended amount of exercise. While it is reasonable to consume between 0.8-1 g/kg of protein per day (0.36-0.59),102 most of us eating a reasonable diet – especially if we are exercising and lifting weights – may not need to worry too much about protein.

Even with these numbers, keep in mind that the effect on IGF-1 may be minimal. In other words, if restricting your protein is interfering with your performance or sanity, it may be more reasonable to keep levels at a moderate amount. For instance, when postmenopausal women eating 1.1 g/kg of protein per day – already higher than the values above – were given a daily 30 g whey protein supplement with the goal of increasing IGF-1, it rose by 5% at year one but then decreased by year two.103 Even at year one, the increase was tiny, and this was in a group where they were trying to raise IGF-1.

However, while protein restriction may be one of the few – and possibly only – tangible ways of decreasing IGF-1 levels, like nearly all aspects of health, viewing it in isolation can get us into trouble. For instance, focusing solely on IGF-1 levels could in theory promote routines like avoiding exercise (which has millions of health benefits), taking estrogens104 (which can increase our risk of cancer), and eating a diet very high in carbohydrates (which can increase the insulin pathway and lead to the same endpoint as high levels of IGF-1). Furthermore, continually referring to shoddy epidemiologic studies to support vegetarian and vegan diets may further cloud objectivity when making rational dietary decisions.

IGF-1, Protein, and Cancer – Conclusions

Like most physiologic aspects of the human body, IGF-1 involves a fine interplay of countless factors that impact our risk of cancer, but also allows us to function optimally with the greatest overall health. The only conclusion we can make from the current state of the data is to avoid too much or too little. Protein over-consumption can enhance IGF-1, even to levels that may promote cancer. Lack of protein consumption can lead to muscle wasting, decreased bone strength, and cognitive decline. Striking a balance is the most sensible approach.

Recommending the switch from animal to plant protein may make sense if we are eating protein in excess, but for those of us that do not overindulge in protein, eat healthy greens and fats, and properly select animal foods that provide a plethora of vital nutrients and vitamins, this endorsement is backed by limited data.

To recommend decreasing IGF-1 to avoid its potential cancer-promoting effects, while ignoring the growth effects of insulin (and vice-versa) is conflicting and inadequate. Instead, consuming a diet with a plethora of healthy leafy greens, berries, well-sourced animal sources (with the fatty portions), and a limited/modest amount of complex carbohydrates like sweet potatoes is likely the most prudent strategy.

IGF-1 is one of the many double-edged swords when it comes to our health. In the diet wars, the vegetarians and vegans tend to use IGF-1 as a reason to avoid all animal foods, while the zero carbers use insulin. In excess, both insulin and IGF-1 can potentially lead to cancer. However, in normal, or possibly slightly low amounts, both are necessary for normal health. To demonize one and blindly promote the other is more often proselytizing agendas than promoting reasonable health recommendations to the masses. While this article is a simplification of a complex subject, hopefully it provides insight to the issues that arise with IGF-1 and dietary recommendations, which often leave us scratching our heads and questioning what’s left to eat.

Further tipping the scale towards health by engaging in plenty of activities to support the free radical defense system – regardless of dietary protein or level of IGF-1 – is a prudent anticancer strategy. In this regard, the self-prescription of a healthy mixture of spartanesque behaviors including intense exercise, resistance training, high levels of background activity, periodic ketosis, intermittent fasting, limiting protein and carbohydrate over-consumption, and eating plenty of foods that “stress” our cells is practical. In other words, a lifestyle that can promote the benefits of reducing IGF-1, while avoiding the downsides may be best.

Amakuni’s double-edged sword provided some valuable lessons: we can maximize our health, longevity, and physical function while training our body to fight cancer by fine-tuning our lifestyle. His initial sword may have failed, but after a Spartanesque month without food or sleep, he made amends. Along these lines, IGF-1 may be a modern double-edged sword, and revealing its benefits requires a deliberate balance of several factors addressed herein and more than just minimizing protein.

 


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4 Comments

  1. Ron Penna

    Excellent article Dr. Champ!

    A fantastic overview of the many players in the game concerning IGF-1. It’s such an important part of health that I’m surprised the Laron people in Ecuador (who can’t make IGF-1 due to a genetic quirk) don’t have more problems than they seem to. While seemingly bulletproof against cancer and diabetes because of this genetic factor, you’d think they would suffer from other health issues (besides dwarfism).

    I have saved your article and will refer to it every time I start oversimplifying things (methionine restriction reduces IGF-1 for instance) to slap myself back to reality.

    These topics are all double edged swords indeed and your recommendations at the end seem to be on point!

    Reply
  2. Benjamin

    A very comprehensive post! What are your views on the strategy of periodic Fast Mimicking Diets such as Prolon as endorsed by Dr Valter Longo to lower IGF. A very compelling body of research supports the concept, and it seems eminently achievable compared to water only fasting.

    Reply
  3. Ben Thomson

    Thanks Colin. Appreciate the work you put into that. The best article on the subject I have ever read (and I read a lot!)

    Reply
  4. Pingback: Forest Bathing - How Nature Stresses Our Cells to Fight Stress

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