Western countries are in the privileged situation of food surplus. The future snack is always just the next snack bar or supermarket away. However, the most common eating behavior in modern societies, three meals plus snacks a day, is not the rule from an evolutionary perspective. In evolution, periods of high nutrition were always followed by periods of low nutrition - there were simply no permanent surpluses.
The consequences of the status quo, thanks to fast food, range from cardiovascular diseases to diabetes and various cancers. Science has made serviceable findings from this context. Data from current and past studies on animal models and humans suggest that fasting can improve health indicators and counteract disease.
How is fasting done?
Humans fast by ingesting no to minimal amounts of food or caloric beverages for periods typically ranging from 12 hours to a few weeks. This principle is by no means new. Fasting rituals are part of most human populations and cultures, including Buddhism, Christianity, Hinduism, Judaism and Islam. Traditionally, fasting is practised at specific time intervals or on specific days of the week. However, the consequences of this behaviour, apart from the favour of the gods, remained largely speculative for centuries. It was not until the 20th century that researchers penetrated the molecular basis of fasting.
However, fasting is not just fasting. First and foremost, it must be distinguished from starvation. Starvation means chronic nutritional insufficiency, which is sometimes mistakenly used as a substitute for the word fasting, but is rather an extreme form of fasting that can lead to degeneration and death. A look across the Aegean provides insight into this sad circumstance.
In fasting, a rough distinction is made between two principles. On the one hand, there is the so-calledcaloric restriction. This means a permanent reduction of the daily calorie intake by 10-50% without causing malnutrition. In humans, there is research that a caloric reduction of 15% a day is most effective against age-related mortality. Bryan Johnson - tech CEO with a desire to stop aging - uses a calorie reduction of about 24% in "Blueprint."
Did you know? The vast majority of fasting methods that exist today did not originate in science. They either came from religious customs, such as Ramadan, or were established for simplicity. For example, the popular 16/8 model tries to accommodate a three-meal society by simply skipping one meal. Which fasting periods are ideal for individuals is still being researched.
Okinawa and the diet of 100-year-olds
At this point, we'll take a little trip to Okinawa, Japan - one of the world's five Blue Zones. The long-lived population of Japan's southernmost province is one of the best-studied links between calorie reduction and improved healthspan. Residents of Okinawa understand how to combine above-average exercise with below-average food intake like no other population. However, when families living there moved to Brazil, they adapted to Western lifestyles that affected both their diet and physical activity. The consequences were weight gain and a decrease in life expectancy by a whopping 17 years.
However, there are some things to keep in mind when reducing calories. A permanent reduction will sooner or later lead to weight loss. This can be desirable for overweight people, but the collective of normal weight people is naturally also affected by aging. Here, additional weight reduction can have a negative effect depending on the initial weight.
Besides calorie restriction, there is a second well-known fasting principle: time restriction = time restricted eating (TRE) . Probably the best known form is intermittent fasting, also called interval fasting or short-term fasting. This is the name given to a form of diet in which there is a constant alternation, in a specific rhythm, between fasting and the normal intake of food. In recent years, this form of fasting has become increasingly popular. Probably for one simple reason: it is easy to apply. You do not have to change your eating habits, but only limit the time for food intake.
Accordingly, in contrast to calorie reduction, there is no significant weight loss. The average in the studies was about 3-5%. Nevertheless, interval fasting is a sensible start. Probably the most popular model is the 16/8 principle. Here, food is eaten within eight hours and then followed by a 16-hour fasting period. The eating time window can be divided according to personal needs or working hours - but should remain constant.
This type of fasting has resulted in a number of beneficial effects on healthspan in studies of mouse models of minimizing the risk of developing age-associated diseases. These include neurodegeneration, cardiovascular disease, and cancer. In similar animal studies, periodic fasting attenuated the deleterious consequences of Alzheimer's disease, Parkinson's disease, and Huntington's disease. In cancer treatment, parallel fasting during selected chemotherapies partially helped "starve" the tumor.
Water fasting, FMD, short-term fasting - a guide to different forms of fasting.
In addition to the two concepts, calorie and time restriction, there is an abundance of other forms of fasting. The medical society Heilfasten and nutrition registered association compiles at present in the context of the guideline production exact definitions for the different forms of chamfering. For a better overview, here are the four most important ones:
- Prolonged fasting: In this form, participants are only allowed to consume liquids. Prolonged fasting is when the fasting period is at least 4 days long.
- Short-term fasting: Similar to prolonged fasting, but the duration is limited to 1-3 days.
- Water fasting: Here you are only allowed to consume water. The length is not fixed
- FMD (Fasting Mimicking Diet): This fairly new form of fasting was designed by American Dr. Valter Longo. Here, one is allowed to eat some foods, especially vegetables and healthy fats. The composition of the food is supposed to molecularly imitate fasting without fasting. In addition to an appropriate diet, fasting-mimicking supplements such as spermidine, glucosamine or berbersome are also discussed.
Fasting - religious hype or is there more to it?
Fasting has been anchored in various cultures for centuries, but in (orthodox) medicine it is still pretty much in its infancy. Often labeled as "esoteric" and "non-effective," fasting has eked out a niche existence. Only recent research results - on animals and on humans - shed more light on the beneficial biochemical and molecular genetic processes that take place in our bodies during fasting. We want to go into more detail about that here. Don't be put off by the many abbreviations and complicated names. In the end, the deeper knowledge will help you to evaluate different fasting methods for you and your longevity.
Did you know? The tradition of fasting can be traced back to the Greek philosopher and physician Hippocrates. He lived from 460-370 before Christ. He believed in the body's ability to heal itself through proper nutrition and a healthy lifestyle. Direct recommendations for fasting are not found in his writings, but his dietary prescriptions were very similar to a modern fast.
AMPK - the "energy sensor" of our cells
While Hippocrates still had to "believe" back then, we are already further along nowadays. With the help of detailed studies, we can understand the individual signaling pathways in our body that are activated during fasting.
An important protagonist is AMPK - one of the four longevity pathways. The abbreviation stands for AMP-activated protein kinase. The suffix -ase tells us that AMPK is an enzyme. You can think of its role in the body as a kind of "sensor". AMPK measures energy levels by measuring the ratio between AMP (adenosine monophosphate) and ATP (adenosine triphosphate). AMPK is activated by fasting or intense exercise.
What follows is a series of changes in the energy balance of the cell. Glucose is increasingly absorbed into the cells, which increases your insulin sensitivity. This mechanism of action is also behind the diabetes drug metformin. It also breaks down fatty acids, which helps you lose weight. AMPK not only activates countless energy pathways in your cells, higher levels of AMPK also seem to have an anti-inflammatory effect on your body.
A final, important aspect of AMPK, in the context of fasting, is its ability to stimulate cell autophagy. Autophagy is when your cells go into "recycling mode." Everything that is no longer needed comes out. What sounds like a molecular form of "spring cleaning" is actually an important process for cells to stay healthy for as long as possible.
Meanwhile, the molecule spermidine and autophagy are often mentioned in the same sentence. Researchers expect the substance to directly activate recycling processes in the body. The Bruneck study of the Medical University of Innsbruck has already established a strong positive connection between a spermidine-rich diet and longevity! Dr. David Sinclair and Bryan Johnson both rely on a corresponding dietary supplement.
Did you know? The recycling of old cellular components is more important than was thought a few years ago. Certain diseases, such as Alzheimer's and cardiovascular diseases, but also cancer, are associated with inefficient autophagy. In particular, as we age, our capacity for autophagy decreases. Read more about this topic here.
mTOR - another important sensor
The next molecule, with a complicated abbreviation. mTOR, short for mammalian target of rapamycin) is, like AMPK, an enzyme connected to many different processes in our body.
One task of mTOR is to detect the availability of nutrients. mTOR is particularly sensitive to two types of molecules: sugar, in the form of glucose, and proteins, in the form of amino acids. Put simply, with the help of mTOR, our body knows how much amino acids and sugar are available to it. However, this is a very gross simplification. There are several subtypes of mTOR whose exact properties and roles are not yet fully understood. Excessive activation of mTOR is associated with various diseases, for example cancer.
Fasting causes the opposite - namely an inhibition of mTOR. Due to the self-induced "stress", the cells switch to recycling (autophagy) and survival mode. For this reason, the "disarming" of mTOR is considered to have great potential for longevity in research. Many animal studies have already shown that lower mTOR levels lead to longer life.
One drug that achieves this is rapamycin. It comes from the immunosuppressor family - in other words, it suppresses our immune system - and is used in organ transplants. The idea of using rapamycin as a "longevity drug" already exists and is being discussed by, among others Peter Attia among others. However, we currently know too little about the effects on the various mTOR groups. Too low levels, as achieved by high doses of rapamycin, may do us more harm than good due to the immune suppressive effect. Here, at least it seems, fasting can provide a natural middle ground.
Did you know. Some studies provided evidence that phytochemicals such as quercetin or resveratrol can downregulate mTOR. Resveratrol also interacts with sirtuins and thus seems to have great potential as a fasting mimetic.
Sirtuins: an elementary building block for the longevity effects of fasting
The term sirtuins covers a group of proteins of which mammals, according to current research, possess seven different ones (SIRT1-SIRT7).
During fasting, SIRT1 plays an important role. Caloric restriction activates SIRT1 and thus its potentially health-promoting properties. Sirtuins can promote cell health and increase their resistance to "stressors." In addition, SIRT1 activates AMPK in the liver. As mentioned above, AMPK plays an important role in energy balance.
Intensive research is currently being conducted on sirtuins, as they show great potential in animal studies to extend life span and health. SIRT1 in particular seems to be a promising candidate.
However, the relationships are complicated by the complex, biochemical mechanisms involved. One example is the functioning of the sirtuins. A quick heads up, it's going to be very detailed again, but then you've done the excursion into the physiology behind fasting:
Sirtuins possess a so-called enzymatic deacetylase activity. This means that they can cleave acetyl groups (=a chemical structure consisting of one oxygen, two carbon and three hydrogen atoms) from one molecule and transfer them to another. One place where this happens is at histones. You find these in the nuclei of your cells.
So where does that leave us? Think of histones as the wrapping string around a gift. Sirtuins can loosen this wrapping string with the help of their enzyme activity and thus expose the DNA underneath. So your "gift" can now be unwrapped and used. In this way, our body can "decide" which genes are currently being read and which are not. Sirtuins work especially on the genes that promote longer life. The catch. Sirtuins need a partner, namely NAD+.
Sirtuins and NAD+ - it takes both
NAD stands for nicotinamide adenine dinucleotide and the + describes the active form of the molecule. You can read more about NAD here read.
Back to the sirtuins: They need NAD+ as a partner to do their job. Unfortunately, as we age, our NAD+ levels continue to decline. Our body therefore has visibly less energy available. One way to counteract this is to supplement the precursors of NAD+. This may increase the effects of fasting. One of the leading researchers on this front, who also fasts and has integrated NAD boosters into his supplement plan, is the renowned aging researcher Dr. David Sinclair.
If you want to know even more about the different signaling pathways after this, admittedly deep insight into the physiology of our body, you can read more about the four molecular pathways to the fountain of youth here.
Did you know? Besides fasting, there is another way to activate SIRT1 in your body. Resveratrol, a secondary plant compound found in red wine, among other things, can also contribute to a longer life, according to research by Prof. Sinclair on the activation of SIRT1. The Harvard researcher himself takes 1 gram each of resveratrol and NAD booster daily for breakfast.
In addition to resveratrol, there are other molecules that can activate SIRT1. One of these is glucosamine. This substance occurs naturally in our bodies - primarily in joint fluid and cartilage. For this reason, glucosamine has been studied in the treatment of knee pain - with mixed results. In animal studies, however, glucosamine has been shown to have life-prolonging effects, so further studies will follow. One of the presumed mechanisms is the activation of SIRT1 and the resulting increased autophagy of cells. In addition, glucosamine blocks a step in carbohydrate metabolism, which also stimulates recycling in our cells.
FMD - Fasting benefits without having to fast?
After this excursion into the biochemical background, you may better understand the (molecular) ways in which fasting can contribute to a healthier and longer life. The question remains, which type of fasting is the best?
This question can hardly be answered in such a general way. However, the following rule of thumb can be derived from the studies: If one wants to achieve the health-promoting effects of mTOR, AMPK and SIRT1, a longer fast of at least 2 days is probably required. Intermittent fasting can also achieve corresponding effects, but to a lesser extent.
Now not everyone wants to go without food for several days at a stretch. This is absolutely understandable, because it is not always possible to reconcile a longer fasting episode with our everyday tasks. The side effects, such as fatigue and hunger attacks, are usually most pronounced in the first two days.
To prevent this, there is a relatively new concept. Dr. Valter Longo from the USA has postulated the FMD (Fasting mimicking diet) and describes it in detail in his book "The Longevity Diet". The principle behind it is that the body is "tricked". By combining different foods, especially high-quality fats such as omega-3, hunger can be satisfied and yet the molecular signaling pathways of fasting can be activated.
Fasting also works molecularly
Get fasting benefits without actually fasting? That sounds almost too good to be true. However, through precise research into molecular signaling pathways, we can now "trick" our bodies to a certain extent and pretend that we are fasting.
With the help of glucosamine for example, SIRT1 can be activated. Supporting this Spermidinebecause spermidine is not only a potent autophagy promoter, according to studies it has a positive effect on your heart health and has an anti-inflammatory effect. This is especially important because SIRT1 is less likely to be activated in an inflammatory environment. Berberine is a useful supplement due to its positive influence on carbohydrate metabolism and insulin sensitivity.
Disclaimer: Please note. You can take both Spermidine and Glucosamine during a true fast. Caution is advised with Berbersome. If you do not consume carbohydrates, the additional intake of Berbersome may cause dangerous hypoglycemia. It is always advisable to do fasting under medical supervision.
Fasting and diabetes - why the liver plays an important role
Research is currently being conducted on many fronts in medicine. For example, it has been shown that in some breast cancer patients, fasting during chemo resulted in a better response to therapy. However, caution is advised here. The results must not be generalized and applied to all types of cancer.
Another condition where fasting therapy can be useful is in people with diabetes mellitus type 2. Affected individuals can no longer adequately regulate their blood glucose levels. A suspected cause behind this condition is visceral fat, which is stored in the pancreas and liver. This fat, although not visible from the outside, is responsible for a number of "bad" signals. Unlike our skin fat, visceral fat can send out a whole armada of hormones and signaling substances. This is one of the main reasons why visceral fat makes us sick.
A little tip: Subcutaneous fat can usually be touched with two fingers (for example, on the abdomen or hips). The much more harmful visceral fat, on the other hand, is located "in the belly" and is accordingly not tangible.
The problem with visceral fat is the fact that you can hardly get rid of it. However, fasting can help here, especially prolonged fasting. The long period of abstinence from food leads to the activation of AMPK in the body. Our metabolism changes its energy utilization - it switches from sugar to "fat burning". This process can take between 12 and 36 hours. If we manage not to eat food during this time, we force our body to burn its own fat. And this is where visceral fat is used first and then storage fat. This is probably one of the reasons why fasting can help with insulin resistance and diabetes. Perhaps in the future fasting will be fixedly integrated into the treatment plans of sufferers.
Attention: If you have diabetes, please consult your doctor before fasting! Discuss with him all the medications that you should possibly discontinue for the time of fasting. In the worst case, you could suffer from life-threatening hypoglycemia if left unattended!
Fluctuating blood sugar levels and insulin resistance are the precursors to diabetes mellitus. To live as healthily as possible for as long as possible, we must prevent excessively high sugar levels from damaging our blood vessels. A good first step in doing this is to eat as healthy a diet as possible, with plenty of legumes and healthy fats. Dr. David Sinclair and Bryan Johnson also rely on the drug metformin, which is available by prescription in Germany. In recent studies, the molecule berberine has shown similar effects to metformin. And berberine, as a secondary plant compound, is available over the counter, unlike metformin. Together with chromium and zinc, highly bioavailable berberine is contained in MoleQlar Berbersome.
Fasting has been practiced for millennia, but only recently have studies shed light on its role in adaptive cellular responses that reduce oxidative damage and inflammation, optimize energy metabolism, and strengthen cellular protection.
While fasting was often offered by alternative practitioners in the past, evidence is mounting that fasting can also have medical benefits. Whether to lower LDL levels, blood pressure or improve insulin sensitivity, all of these factors are desirable effects that today we often just need to address with several tablets at once.
- Longo, V. D., & Mattson, M. P.. (2014). Fasting: molecular mechanisms and clinical applications. Cell metabolism, 19(2), 181-192. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946160/
- Mitchell, S. J., Bernier, M., Mattison, J. A., Aon, M. A., Kaiser, T. A., Anson, R. M., ... & de Cabo, R. (2019). Daily fasting improves health and survival in male mice independent of diet composition and calories. Cell metabolism, 29(1), 221-228. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326845/
- de Cabo, R., Carmona-Gutierrez, D., Bernier, M., Hall, M. N., & Madeo, F. (2014). The search for antiaging interventions: from elixirs to fasting regimens. Cell, 157(7), 1515-1526. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254402/
- Longo, V. D., & Panda, S. (2016). Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan. Cell metabolism, 23(6), 1048-1059. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388543/
- Velingkaar, N., Mezhnina, V., Poe, A., Makwana, K., Tulsian, R., & Kondratov, R. V. (2020). Reduced caloric intake and periodic fasting independently contribute to metabolic effects of caloric restriction. Aging Cell, 19(4), e13138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189989/
- Balasubramanian, P., Howell, P. R., & Anderson, R. M. (2017). Aging and caloric restriction research: a biological perspective with translational potential. EBioMedicine, 21, 37-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514430/
- Hofer SJ, Carmona-Gutierrez D, Mueller MI, Madeo F. The ups and downs of caloric restriction and fasting: from molecular effects to clinical application. EMBO Mol Med. 2022;14(1). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749464/
- Wei M, Brandhorst S, Shelehchi M, et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017;9(377). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816332/
- Brandhorst S, Choi IY, Wei M, et al. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015;22(1). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509734/
- Barbosa MC, Grosso RA, Fader CM. Hallmarks of Aging: An Autophagic Perspective. Front Endocrinol (Lausanne). 2019;9:790. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333684/
- Schiattarella GG, Hill JA. Therapeutic targeting of autophagy in cardiovascular disease. J Mol Cell Cardiol. 2016;95:86-93. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871782/
- Corti O, Blomgren K, Poletti A, Beart PM. Autophagy in neurodegeneration: new insights underpinning therapy for neurological diseases. J Neurochem. 2020;154(4):354-371. https://pubmed.ncbi.nlm.nih.gov/32149395/
- Corti O, Blomgren K, Poletti A, Beart PM. Autophagy in neurodegeneration: new insights underpinning therapy for neurological diseases. J Neurochem. 2020;154(4):354-371. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274804/
- Sadeghian M, Hosseini SA, Zare Javid A, Ahmadi Angali K, Mashkournia A. Effect of Fasting-Mimicking Diet or Continuous Energy Restriction on Weight Loss, Body Composition, and Appetite-Regulating Hormones Among Metabolically Healthy Women with Obesity: a Randomized Controlled, Parallel Trial. Obes Surg. 2021;31(5):2030-2039. https://pubmed.ncbi.nlm.nih.gov/33420673/
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