Metabolic Autophagy
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Testosterone and androgens can also signal mTOR and induce muscle hypertrophy[309][310]. Testosterone has many anti-catabolic as well as anabolic properties, which is why high cortisol tends to wreak havoc on this hormone.
These nutrient and growth signals are picked up by receptors on the surface of cells, such as insulin receptors, and by the energy availability throughout the cellular matrix via AMPK and its ATP:AMP:ADP ratios.
mTOR and Aging
Overexpression of mTOR or its dysfunction is often related to various cancers and genetic disorders[311]. Suppressing mTOR with diet or certain supplements like Metformin and Rapamycin are common ways of treating cancer and tumor growth.
Rapamycin inhibits mTORC1, which is thought to increase life expectancy in animal studies.
Disrupting mTORC2 with rapamycin may induce insulin resistance as well as symptoms of diabetes and glucose intolerance[312].
Increased glycolysis, which is the metabolism of glucose into lactate, is often found to be higher in cancer cells, also known as the Warburg Effect[313]. In 1924, Otto Warburg discovered that cancerous tumor cells primarily meet their energy demands from glycolysis. Akt regulates Hexokinase 2, which is thought to cause this enhanced glycolysis in cancer cells. mTOR promotes the activation of insulin receptors and IGF-1 receptors[314][315], which is in most cases accompanied by glucose and glycolysis. Hence the association of mTOR with cancer.
Inhibiting mTOR also promotes autophagy. High mTOR activity may promote tumor growth because of stopping autophagy from removing cancerous cells[316]. Patients with Alzheimer’s disease also show dysregulated mTOR activity in the brain and connection with beta-amyloid proteins[317][318]. That’s because of autophagy suppression.
Reduced mTOR expression has been found to increase lifespan in different yeast species, bacteria, and mice[319][320][321]. Whether or not it’s related to insulin or mTOR specifically is something I’d pay more attention to.
Methionine restriction could be beneficial for longevity as well. SAM (S-Adenosyl-Methionine) is the 2nd most common cofactor in enzymes after ATP, which detects the presence of methionine-related nutrients in the body. One of the methionine sensors SAMTOR (S-adenosylmethionine upstream of mTORC1) inhibits mTORC1 signaling. Methionine restriction lowers SAM and increases SAMTOR, which improves glucose homeostasis and can promote longevity along the lines of caloric restriction. One of the reasons why it’s thought that restricting calories and methionine extends life is because of decreased mTOR and insulin.
Due to its potent anabolic growth effects, mTOR signaling during early life is very beneficial and necessary for proper development. However, it may not be ideal as you become older. Likewise, people wanting to build muscle or improve physical performance would also want more anabolism. Unfortunately, most of the fitness and nutrition advice you hear on social media doesn’t even consider the downstream effects of that nor what to do about it.
The free radical theory of aging states that reactive oxygen species (ROS) and oxidative stress damage the mitochondria, which decreases ATP production[322]. By lowering mTOR you preserve ATP that would otherwise be used for protein synthesis and thus have more resources for mitochondrial repair. Low TOR signaling also upregulates autophagy, which helps to remove ROS and recycle old cells back into energy thus slowing down aging.
mTOR may promote intestinal inflammation[323] as well as skin acne, which is more proof to how high mTOR all the time accelerates aging. However, this effect is probably due to a poor microbiome and other inflammatory lifestyle factors not necessarily mTOR itself. mTOR simply makes things worse in some cases because of its anabolic effects.
What Inhibits mTOR
Here are the mTOR inhibition mechanisms:
Dietary protein restriction lowers mTOR[324]. Amino acid deficiency, in particular, regulates mTOR[325].
Calorie restriction lowers mTOR and promotes autophagy[326]. Ghrelin the hunger hormone activates AMPK in the hypothalamus and inhibits mTOR[327].
Fasting lowers glucose, insulin, and suppresses mTOR while raising AMPK. This is the most effective method of inhibiting mTOR. It also raises autophagy and promotes ketosis.
Ketogenic Diets are moderate in protein and low glucose, which lowers mTOR activity[328]. Glucagon, which is a hormone that raises in the presence of low glucose and insulin, activates AMPK and represses mTOR[329].
Exercise inhibits mTORC1 in liver and fat cells[330]. This is great because you’ll be preventing fat gain while promoting longevity and muscle growth. The post-exercise time window, however, facilitates muscle protein synthesis in muscle cells because of the mechano-overload. That’s another mechanism by which resistance training is great for increasing lifespan – more mTOR in muscles and less mTOR in fat cells.
Glucocorticoids and cortisol get elevated during physiological stress[331]. Cortisol helps to mobilize glycogen and fatty acids. This shifts the body into a more catabolic state.
Metformin is a potent anti-diabetic drug that lowers blood sugar and insulin, thus lowering mTOR[332]. Berberine is a medicinal compound that has similar effects.
Rapamycin is an immunosuppressing drug that lowers mTOR[333]. It’s been used to fight cancers and tumors in humans.
Resveratrol is a compound found in certain fruit and red wine that has a longevity-boosting effect[334]. Part of it has to do with sirtuins and autophagy.
Curcumin inhibits mTOR signaling in cancer cells[335]. Reishi fights tumors as well by blocking mTOR[336]. Rhodiola Rosea[337] and astragalus too[338].
Anthocyanins found in blueberries and grape seed extract promote AMPK and block mTOR[339]. Pomegranate as well[340].
Alcohol activates AMPK and regulates the mTOR complex[341]. It doesn’t go to say that drinking is going to boost your longevity. Remember that mTOR inhibition is just a single piece of the puzzle.
Oleanolic acid contributes to anti-tumor activity[342]. Main food sources of oleanolic acid are apples, pomegranates, bilberries, lemons, grapes, bilberries, and olives.
Carnosine inhibits the proliferation of human gastric carcinoma cancer cells by retarding mTOR signaling[343]. Carnosine is an amino acid with anti-aging and antioxidant benefits that fights free radicals as well. Interestingly, it’s found the most in animal foods and meat.
Although there’s some evidence showing how mTOR can have negative side effects, it’s still an essential pathway for cellular growth and maintenance. So, is mTOR bad for you?
Benefits of mTOR
Here’s the light side of TOR:
mTOR is required for protein synthesis and skeletal muscle hypertrophy[344]. Suppressing mTOR for too long or having too much autophagy leads to muscle atrophy and loss of lean tissue through sarcopenia, which can contribute to aging and metabolic disorders[345].
mTORC2 regulates the distribution of mitochondria and mTORC2-activated AKT is linked to mitochondrial proliferation[346][347]. mTOR also promotes mitochondrial biogenesis by activating PGC1-alpha[348]. mTORC2 localizes mitochondria-associated endoplasmic reticulum (ER) and mitochondria-associated membrane (MAM)[349]. This localization is stimulated by PI3K growth factors.
mTORC2 deficiency creates a defect in MAM, which causes an uptake of calcium in the mitochondria. Probably not good for atherosclerosis and plaque formation.
mTOR can also help you lose weight and be healthier. mTORC2 regulates glucose homeostasis via Akt. Akt promotes glucose uptake by increasing GLUT4 translocation to the membrane in adipocytes[350]. The same effect is also true because of increased muscle mass and insulin sensitivity that’s accompanied by muscle. If you have too low mTOR then you won’t be able to build muscle thus having poorer metabolic flexibility and thus actually predisposing yourself to disease.
mTOR also contributes to neural plasticity and learning memory development[351]. Neuroplasticity is a key factor in learning, skill acquisition, and memory retention. It seems that both too low levels of mTOR and overexpression of mTOR cause impaired learning and cognitive decline. Activa
ting mTOR in prefrontal neurons by HMB inhibits age-related cognitive decline in animals[352]. mTOR also helps to grow synaptic connections.
All in all, mTOR signaling seems to be more problematic in people who already have a certain disease such as cancer, tumors, diabetes, or Alzheimer’s. The reason is that mTOR inhibits autophagy which would help to fight the disease by clearing out the diseased cells. If you’re sick and keep stimulating growth factors in the body, you’ll keep feeding the disease while simultaneously stopping the healing processes. That’s why strict fasting for an extended period of time seems to help treat a lot of diseases and cancers.
How Much mTOR is Too Much?
mTOR has its benefits for performance as well as some supportive aspects for longevity. However, it’s not optimal to have it elevated all the time for obvious reasons. That’s why knowing how to cycle mTOR is a vital thing for your long-term health.
You want to activate mTOR in muscle cells, brain cells, and mitochondria instead of fat cells and cancer cells.
Exercise activates mTOR in the brain and promotes skeletal muscle mTOR[353]. Resistance training, in particular, will make you build muscle through the mechanistic stimuli of mTOR.
Time restricting your eating is probably the most effective and most critical thing for controlling mTOR. Even though you may be eating a low mTOR diet you need autophagy as well if you want to promote life-span. If you’re fasting for longer periods of time and you’re eating less often, then you need to make your meals more mTOR stimulating to counterbalance the catabolic effects of fasting and support muscle homeostasis.
If you’re fasting less and you’re eating frequently, then it’s indeed a better idea to keep your foods lower in mTOR as to avoid excess growth.
The mTOR pathway has many functions beyond just muscle growth and anabolism. It regulates the immune system, fat storage, and with AMPK controls whole-body energy balance.
Timing is probably the most critical component to this. Activating mTOR doesn’t guarantee muscle hypertrophy. It doesn’t entail accelerated aging and carcinogenesis either. It’s dependent on the body’s entire nutrient status combined with the presence of growth factors or lack thereof as well as the overall energetic conditions of the individual. You can even add circadian rhythms and the status of the microbiome into the mix. What determines the effect of these pathways is vastly context dependent.
The same applies to AMPK. Elevated AMPK and increased autophagy won’t always lead to lean tissue catabolism and atrophy. You can be effectively efficient at cellular turnover during some periods of the day without jeopardizing muscle or performance over the course of the 24-hour cycle. Likewise, you can have autophagy working in only some preferable regions, such as the liver and brain but not muscle thus preserving lean body mass while fighting disease.
That’s why I’d say the best strategy is to maintain a state of low mTOR most of the day by fasting and then stimulating it in a post-workout setting. This ensures that you’ll be turning on mTOR for its beneficial effects. If you’re raising mTOR without needing to repair your body, then it’s inevitably going to be worse for longevity than if you were to do it post-exercise.
Because of the same reasoning, activating mTOR after waking up isn’t optimal as your body is in a state of deeper ketosis and mild autophagy after the overnight fast. mTORC1 does promote fatty acid storage by inhibiting lipolysis[354]. It also inhibits beta-oxidation and ketogenesis[355]. However, this may be because mTOR activity is often preceded by insulin and glucose. If you were to stimulate mTOR in a state of low insulin-glucagon ratios, then you’d probably avoid the inhibition of ketosis and fat burning. Nevertheless, turning on mTOR right in the morning may prevent you from going back into autophagy for the rest of the day.
Another benefit of restricting mTOR activation is that you’re going to avoid the negative side effects of chronic mTOR elevation. In my opinion, all of the associations of mTOR with cancer and aging stem from having it elevated all the time ala Standard American diet three times a day with constant snacking or the high protein bodybuilder diet with 4-6 meals a day.
Intermittent Fasting and mTOR
There are virtually no studies done on people who follow a fasting focused lifestyle and actively time restrict their food intake. The effects of both mTOR and AMPK would be probably much different in individuals who fast and do resistance training simultaneously. That’s why the arguments that mTOR will accelerate aging as well as that it’s not that big of a deal both may hold water depending on the context. It’s probably not a good idea to be anabolic all day and to optimize your longevity you’d want to express it in only certain situations.
mTOR isn’t like a progressively increasing energy catalyzer, meaning that you’re not going to keep growing more and more cells based upon how much protein or carbohydrates you ate in a meal. mTOR is more like a switch that opens up the valve for many other upstream anabolic hormones supportive of tissue growth and cell proliferation. If you have the valve open all the time then it’s simply going to release more of these growth hormones into the body where they’ll keep building everything they can, including the good and the bad.
It doesn’t matter how much you restrict protein or carbohydrates because even small amounts of amino acids and energy will activate mTOR to a certain degree. That’s going to have less of an effect on how much growth happens but it’s still activated and thus inhibiting autophagy and catabolic processes. To effectively reap the benefits of low mTOR while eating you’d have to be eating a diet virtually near to starvation. However, that’s just not optimal for muscle preservation nor performance. There are better and smarter ways of doing so.
If mTOR is suppressed most of the time like during fasting, then that’s going to allow autophagy to actually kick in and give you the other lifespan-boosting benefits. It’s much more effective and easier to fast and then stimulate mTOR only within a very small time frame.
I’d say that it’s much more optimal for health and longevity to have a single large spike of mTOR and protein synthesis vs small and frequent blips of mTOR throughout the day because:
(1) Those small blips of mTOR won’t make you build a lot of muscle.
(2) You’ll still have to restrict your protein and calories to hopefully expect increased longevity if you eat very frequently.
(3) Restricting your calories and protein too much will lead to muscle loss and thus promoting aging and atrophy.
(4) A single high mTOR spike will make you build muscle enough and then helps you to go back into a state of autophagy faster for the next day.
I myself aim to fast about 20 hours every day and I’ve been able to build muscle with it. No skin issues, no health problems, no gut disorders, no signs of cognitive decline, supercharged mitochondrial function, energy all day, no hunger, and full vitality.
To be on the safe side, you may want to cycle being more mTOR dominant with periods of higher autophagy throughout the year. For instance, when training harder you naturally would want to be more anabolic. During periods of less activity, you’d want to take advantage of more autophagic conditioning.
Whenever you’re trying to build some muscle you’d need higher mTOR and anabolism. Otherwise, you may find yourself swimming upstream and simply wasting your time. That’s why sticking to a consistent intermittent fasting schedule is such a good idea. Such seasonality can be added to your yearly diet plans as well.
There are probably several ways of cycling mTOR and such but the main idea is that you have to know how to balance these anabolic and catabolic pathways. You can fast in different time frames or throughout different weeklong cycles but it’s still best to focus harder on one end or the other without staying somewhere in the blimpy-zone of still having small amounts of mTOR but not being in autophagy.
Is IGF-1 Good or Bad
Next up, I want to look at another anabolic hormone that’s considered to be bad for longevity and aging. Insulin-Like Growth Factor-1 (IGF-1) is connected to
insulin signaling. So, is IGF-1 actually good or bad?
Most of IGF-1 gets mediated by growth hormone that’s produced in the hypothalamus. When the anterior pituitary gland in the hypothalamus releases growth hormone into the blood, the liver responds by stimulating the production of IGF-1. IGF-1 activates the Akt pathway, which is a downstream activator of mTOR.
Figure 49 Insulin/IGF-1 signaling activates Akt, which turns on mTOR and growth
The role of IGF-1 is to promote the growth, survival, and proliferation of all cells, especially muscle, cartilage, bone, nerves, skin, and neurons, depending on what’s needed. It’s a critical component to childhood growth and it has many anabolic effects on the body.
There are many functional benefits to IGF-1:
IGF-1 supports muscle growth and protects against muscle wasting. It also promotes bone growth and strength. Protein and amino acids increase IGF-1 levels as well independent of caloric intake. This supports anabolism and cellular growth.
IGF-1 regulates glutathione peroxidase, which is one of the most potent antioxidant pathways in the human body[356]. These anti-oxidant benefits can protect against heart disease by clearing out plaques in the arteries[357].
IGF-1 fights autoimmune disorders by increasing T-cells and boosts the immune system[358].
IGF-1 improves blood sugar regulation. Lower IGF-1 is associated with metabolic syndrome and insulin resistance[359].
However, IGF-1 is also said to have its dark side...
The IGF-1 pathway has been found to contribute to some types of cancer[360]. People with Laron Syndrome, which lowers their IGF-1 expression, have a much lower risk of getting cancer. However, clinical drug trials have been unsuccessful and IGF-1s association with cancer is not completely understood.