Metabolic Autophagy
Page 10
These measurements aren’t definitely indicative of autophagy or anabolism or something like that. However, they can give you a glimpse into your metabolic health and what state your body is in.
If you combine a lower insulin to glucagon ratio with a lower glucose ketone index while you’re in a fasted state with depleted liver glycogen, then you can predict the degree of autophagy you’re in. It wouldn’t tell you about autophagy if you’d been eating because calories will suppress autophagy and you can be anabolic with higher mTOR while still maintaining a low insulin to glucagon ratio and vice versa. You can only predict it if you’re in a fasted state because that’s the surest way we know to increase autophagy.
You don’t want to be autophagic all the time either because it would prevent growth and repair of your body. Too much autophagy may lead to muscle wasting and dysfunctional cell death, which is why you want to balance catabolism with anabolism. Maintaining lean muscle is incredibly important for longevity and increased healthspan.
But is autophagy good or bad then?
Autophagy promotes cellular survival in response to stressful conditions such as hypoxia, starvation, mitochondrial damage, and infections[241]. That can be a double-edged sword as both the good and bad cells can get stronger from this.
Whether or not autophagy will be good or bad for you depends on the other lifestyle factors such as the circadian rhythms, overall biomarkers, the amount of body fat, muscle mass, methylation, microbiome and so much more. Fortunately, this book teaches you to optimize all of them. These components are dependent of autophagy to some degree which is why prevention is the best medicine.
Autophagy should be seen as a life-long process of maintenance and repair that needs to be conditioned and kept active so that you’d prevent it from becoming dysfunctional or inadequate.
Balancing Autophagy and mTOR
Both mTOR and Autophagy are amazing. It’s fortunate that the human body has evolved with these metabolic pathways that promote survival and growth. However, they’re not always optimal for our health and longevity in the context of a modern society.
The main idea of this entire book is that by regulating and controlling the expression of certain nutritional factors you can get drastic results in your body composition as well as expected lifespan. Let’s take a look at the Protein Kinase Triad once again:
mTORC1 (mammalian/mechanistic target of rapamycin complex 1) – it’s the main regulator of cell growth and anabolism through upregulating protein synthesis
mTORC2 (mammalian target of rapamycin complex 2) – it’s a multiprotein complex of TOR that regulates the actin cytoskeleton, which is a network of filaments and fibers, extending throughout the cytoplasm of cells
AMPK (AMP-activated protein kinase) – it’s the main fuel sensor that helps to mobilize the body’s internal energy stores in situations of energy deprivation
ULK1 (Unc-51-like kinase 1) – it’s a protein that’s involved with activating autophagy and other catabolic reactions to amino acid deficiencies
These 3 pathways (mTOR/Autophagy/AMPK) sense the energy status of the body and determine whether your cells will be favoring anabolic processes of growth or catabolic processes of self-devouring and preservation.
Figure 36 The Protein Kinase Triad that regulates nutrient signaling pathways
There’s always an evolutionary trade-off between anabolism and catabolism as well as growth and repair.
Being too anabolic and growing rapidly may speed up your biological clock so to say by causing oxidative stress to the mitochondria and simply making your other organs work harder. If you grow fast you’ll inevitably age faster as well.
Being too catabolic and degrading at a quicker rate than you can repair will also damage vital cells and other processes in the body. In this case, you’ll die sooner just by virtue of physical deterioration.
Both of them are necessary for health and longevity. You want to have enough lean muscle mass and bone structure to support vitality but you also want to be efficient with catabolizing your body’s own internal fuel sources as to not waste unnecessary energy.
Being at a balance, on the other hand, is a myth because you’ll never be completely stagnant and balanced. What you have to do is simply understand that certain things make you more anabolic and others catabolic so you can know how to structure your lifestyle based on what you want to accomplish.
Basically, the expression of mTOR and its precursors is the most important signaling pathway in our body because mTOR will tell the body what’s its energy status. If your physiology is in a state of nutrient deprivation and starvation, your body recognizes that it’s not the best time grow.
Whatever the research tells us, it’s clear you don’t want to be stimulating mTOR throughout the day because it’s going to offset the balance towards too much anabolism. As I said, there is no such thing as being in balance as that would entail you’re 50-50 on autophagy and mTOR. It’d be much better for longevity to be recycling your own cells most of the time and then when you stimulate mTOR you do it only briefly and with a larger effect. That’s why I follow a nutrient dense high satiety diet as well – I’m able to suppress mTOR the majority of time and trigger it only for building muscle.
Anti-Aging expert Ron Rosedale MD, who was one of the first people in the scientific community to point out the dangers of eating too much protein due to mTOR, has said that:
Health and lifespan are determined by the proportion of fat versus sugar people burn throughout their lifetime. The more fat that one burns as fuel, the healthier the person will be, and the more likely they will live a long time. The more sugar a person burns, the more disease ridden and the shorter a lifespan a person is likely to have.[242]
But there’s a caveat to the ketogenic diet as well because research has shown that some tumors and cancers can also feed off ketone bodies[243]. So, ketosis or the ketogenic diet themselves won’t help you live longer. Neither will just autophagy. You have to know how to alchemically regulate your own metabolic pathways and be mindful of what direction you’re heading with your dietary practices.
That’s why intermittent fasting is still the most powerful component of this. Honestly, it’s an irreplaceable part of life extension and balancing mTOR with autophagy. Any diet that doesn’t include intermittent fasting is pro-mortality and it’s very difficult to side-step this. You can gain some of the benefits of autophagy by eating ATG-boosting compounds and restricting protein but the effects of that aren’t nearly as good you’d get from simply fasting. A therapeutic ketogenic diet may mimic a fasted physiology by keeping insulin and glycogen low but for the full benefits of autophagy, you need periods of energy deficit.
The process of autophagy resembles life itself – almost every organism on the planet is in a symbiotic relationship that more often than not entails eating each other. That is how predation occurs in the wild. That is how different ecosystems balance their species diversity. That’s how cells within your body eat themselves and make them reborn.
In many mythologies of the world, there is a creature called the Ouroboros that represents the entire idea of autophagy perfectly. It’s the snake biting its own tail – eating itself as to leave behind the old. Paradoxically, the serpent moves in a cyclical manner that entails constant death and rebirth.
Metaphorically, the Ouroboros represents not only autophagy but any other form of personal transformation. In order to grow and become a new person, you have to leave behind the old. To promote the functioning of your healthy cells, you need to eliminate the dysfunctional ones. Inside your body, these processes happen inside a network of collective intelligence that includes your mitochondria, bacteria, cells, and physiological states. In your personal life, you have to be the one who’ll bite their own tail and assimilate the weaker parts of yourself so you could become stronger and reborn into the greatest version of yourself.
Chapter V
Squaring the Curve
“I think you
should always bear in mind that entropy is not on your side.”
Elon Musk
When you look at the world around you, then you can see how everything functions in a cyclical manner with death and deterioration complementing life. The Universe itself seems to be moving towards greater complexity, chaos, and entropy, which may have potentially unwanted consequences on our subjective personhood.
However, entropy is never on your side, as the quote above pointed out. You’re always on the verge of disappearing into nothingness. Whether or not that’s a bad thing is a different question with many nuances. Instead of giving you immortality, this book seeks to help you live more fulfilled and have higher quality experiences.
In Chapter One, we talked about how age-related diseases have to do with a loss in mitochondrial functioning, decreased autophagy, cellular turnover, and pure physical damage.
Although the human body has its biological limitations that inevitably will reach its end, there are still many things you can do today to postpone that process. Aging doesn’t have to be something that’s guaranteed as most of it is relievable with lifestyle. It sure as hell doesn’t have to cause you suffering but joy instead.
In the coming chapters, I’m going to be walking through how to promote longevity with resistance training, and how to maintain lean muscle tissue as you age. Take up your arms as we now begin to combat entropy.
Muscle and Longevity
“The best activities for your health are pumping and humping.”
Arnold Schwarzenegger
Living organisms consist of many organic molecules and different tissues. Up to 60% of your body is made of water and it’s found in muscle, organs, the brain, adipose tissue, and even bones.
A healthy body composition includes more muscle mass in relation to fat mass. About 30-40% of a fit person’s total body weight is made of skeletal muscle tissue. This may increase up to 45% in advanced athletes and people who do strength training. Women tend to have less while men have more.
In 1972, Ancel Keys and others published a paper in the Journal of Chronic Disease where they coined the term Body Mass Index (BMI) to describe a person’s ratio of bodyweight to squared height[244]. Keys said that the BMI is: "...if not fully satisfactory, at least as good as any other relative weight index as an indicator of relative obesity".
BMI has been used for decades in attempts to measure an individual’s weight status and categorize them as either underweight, normal, overweight, or obese. The formulas are as follows:
Metric BMI Formula: BMI = weight (kg) ÷ height2 (m2)
Imperial BMI Formula: BMI = weight (lb) ÷ height2 (in2) × 703
Let’s take me as an example. I’m a 173 cm male who weighs 77 kilograms. This would lead us to calculate my BMI with these results:
Convert my height into meters: 173 cm = 1,73 m
Calculate my BMI: 77 ÷ (1,73)2 = 25,6
That gives me the BMI of roughly 26. Common BMI ranges are: <18 underweight, 18-25 normal, 25-30 overweight, 30-40 obese, and <40 severely obese. Based on industry standards, I’m borderline overweight and in the yellow zone for increased health problems.
Figure 37 Congratulations! You may be borderline overweight or even obese
if you happen to have some muscle
No doubt that overweight and obese people are at a greater risk of metabolic syndrome and dying prematurely. However, BMI isn't really a reliable indicator of lifespan. In a 2014 meta-analysis, people who were categorized as overweight and ‘fat-but-fit’ had similar chances of dying as those who were in the normal weight-fit range[245]. Someone who’s carrying a bit of extra fluff but exercises a lot may still be healthy in the long term.
However, having higher body fat isn’t definitely healthier nor optimal. Excess adipose tissue, especially visceral fat, increases the risk of heart disease, diabetes, fatty liver, insulin resistance, and hypertension.
Visceral Fat – The fat around your abdominals and between the organs. It’s a bit harder to pinch and measure accurately. Often referred to as stubborn belly fat.
Subcutaneous Fat – The fat under your skin. You can pinch it quite easily with your fingers and wobble around. It’s simple – if it jiggles, it’s fat. This one is less dangerous and used more for metabolic activities.
Visceral fat will continuously leach inflammatory cytokines and other metabolic substrates into your system that will promote inflammation and oxidative stress. Being overweight, experiencing too much stress, drinking alcohol, not sleeping enough, insulin resistance, and eating processed foods all contribute to visceral fat gain.
Figure 38 Difference between visceral and subcutaneous fat
Everyone has a combination of both types of fat in different proportions. To determine how much of each you have you can take DNA tests or full body composition scans at a medical facility. Naturally, if you’re already carrying a bit of extra weight then you most likely already have a lot of both. However, even if you’re skinny, you may still have some extra visceral fat, especially if you suffer from the ‘skinny-fat syndrome’. Having a wider more apple-like body shape is also indicative of visceral fat. To lose that you’d simply have to fix your diet, burn some fat, lower your stress, and allow your metabolism to heal.
Healthy body fat percentages range from 8-14% for men and 15-23% in women. Acceptable ranges fall between 15-20% in men and 24-30% in women. In men, you’re considered overweight if your body fat % is above 21 and in women above 31%. Looking at your actual body fat % and relative fitness level is a much more accurate tool for predicting longevity than BMI.
Therefore, for optimal health and longevity, you would want to keep your body fat % always relatively low as to prevent obesity and other ailments. Being fat-but-fit shouldn’t be an argument for staying fat because you’ll always be healthier with slightly less body fat. There is no longevity benefit to having extra fat beyond a healthy range.
However, a lot more important factor for increased lifespan may be higher muscle mass. More muscle promotes chances of survival through many mechanisms but its main benefit comes from combating entropy.
The human body inevitably deteriorates with age. After the age of 30, aging is characterized by a progressive decrease in skeletal muscle. This process is called sarcopenia and it can happen at a rate of 3-8% reduction per decade. From the age of 40, lean tissue and strength get reduced by about 1% per year[246]. Keep in mind that even very athletic people’s bodies consist of 30-40% muscle, which isn’t that much. That makes maintaining your musculature an incredibly vital component of healthy aging and longevity.
Figure 39 Muscle mass peaks during adulthood and drops in older life
Muscle wasting and a decrease in cardiovascular fitness are often attributed to disuse and sedentary living. Elderly people start to move less which makes their body lose its lean tissue. Low muscular fitness combined with inadequate nutrition are major risk factors for disease and mortality from all causes[247].
Loss of muscle is very well illustrated by hospital bed rest and weightlessness in space where astronauts or patients tend to lose a lot of weight. Most of it is valuable lean tissue. This inactivity also decreases muscle protein synthesis (MPS), which makes the body more resistant to anabolic growth and hormones. Age also contributes towards resistance to protein intake.
On the flip side, it’s well demonstrated that acute resistance exercise enhances myofibrillar muscle protein synthesis in both young and older individuals[248]. Even a single bout of resistance training can increase MPS by 2-3 times, which may be enhanced further with a protein-rich diet[249]. What you don’t use you’ll lose, especially muscle and strength.
For anti-aging and heart health, the American Heart Association (AHA) recommends aerobic activities, such as walking, jogging, swimming or cycling[250]. They also propose some strength training, but the vast majority of people aren’t actively engaged in any form of resistance exercise. However, strength training may be much more important for longevity than jus
t aerobics. There’s a lot of research suggesting that muscular strength is inversely and independently associated with all-cause mortality[251]. Essentially, more muscle and strength reduces your chances of dying and can increase your lifespan, especially in older people.
A 2016 paper found that amongst a large cohort of 65 and older, mortality rates were significantly lower in individuals who did regular strength training[252]. This shouldn’t be just encouraging for the elderly to continue exercising but it should also tell younger adults to keep working out as part of their everyday lifestyle.
The common idea of aging is that it’s a gradual process of degradation that involves slowly becoming weaker, more forgetful, obsolete in society, a nuisance to the family, and miserable. How many people do you know who are already showing signs of deterioration in their 40s? Oh...I’m not as supple as I used to be. I’ve got some back pain, I keep forgetting stuff, and I can’t get out of bed easily. Must be old age catching up on me...However, that’s often the result of aging poorly and prematurely.
Aging shouldn’t be thought of as something negative or seen with dismay. Of course, there is the inevitable physical entropy that accompanies the life cycle of your body but it doesn’t have to be such a gruesome process. Like said, most people start aging in their 40s and they accept it as a natural thing. Must be getting old again...
Even if you did live over 100 years old, you wouldn’t want to spend most of that time being disabled or enduring age-related diseases. I don’t know about you but I’d prefer having a shorter life that’s higher in quality VS living extremely long but suffering most of that time. Fortunately, you can get the best of both worlds.