Minimum fasting length required for autophagy | Guido Kroemer
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A key regulator of the process of autophagy is a drop in cellular levels of acetyl CoA, an end product of nutrient metabolism. As one would expect, fasting – the abstention from all nutrients – is a potent inducer of autophagy. This is especially true in mice, which begin to experience autophagy within a few days of fasting. However, critical metabolic differences between mice and humans make it difficult to extrapolate these findings to humans. In this clip, Dr. Guido Kroemer describes the current state of knowledge about the minimum amount of time required for fasting-induced autophagy in humans.
-Rhonda: So it kind of brings up another question I had which related to when you started talking about how you can fast, and fasting in organisms like rodents and also in some human volunteers does induce autophagy. And the question that I had for you is, like, I've talked with Dr. Valter Longo, he was on the podcast, and he talked quite a bit about his research on prolonged fasting in both rodents and also in humans and how the prolonged fast, at least, in rodents is 48 hours, which in humans is around 4 days, 4 to 5 days. And that was able to very robustly, not only activate autophagy, but also cell death, and that was followed by a regeneration period. But, the question is do we know what the minimum amount of fasting time is for humans or rodents that can activate autophagy? So for example, when I'm not pregnant, I usually followed a very time-restricted eating schedule where I like to eat all of my food within at least 10 hours, and then I fast for 14 hours every night. Some people do even more strict. They eat within 8 hours and they fast for 16 hours. Does that 16-hour fast induce any autophagy in any of our tissues? Is there any evidence, do we know?
Dr. Kroemer: We don't know. So, Craig Thompson published a paper on circadian variations in hepatic autophagy. So you know that mice don't eat during the day and they eat during the night, and so, the entire cycle is inversed. And he observed that as a result of not eating during the day, there was more autophagy in the liver. So this result is intriguing. It has not been, to my knowledge, extrapolated to other organs. And it still certainly requires more profound studies.
Rhonda: Okay. When you say during...
Dr. Kroemer: So what we did on circulating leukocytes is that we needed to wait for three or four days to see a massive induction of autophagy. There's a fundamental difference between rodents and humans, and so, the two days that you have been alluding to cause a 20% weight loss in mice, that are, at this time point, at the verge of death. Another day would potentially kill them. And so, 20% is a lot, so imagine this for yourself.
Rhonda: In two days.
Dr. Kroemer: In four days, a human being only loses one to two percent of his or her weight.
Rhonda: Is that because they have a higher metabolism, rodents do, or...?
Dr. Kroemer: Yeah, it's certainly linked to the change in the surface volume ratio that is classically associated with an accelerated metabolism.
Acetyl coenzyme A is a molecule that was first discovered to transfer acetyl groups to the citric acid cycle (Krebs cycle) to be oxidized for energy production. Now it is known to be involved in many different pathways including fatty acid metabolism, steroid synthesis, acetylcholine synthesis, acetylation, and melatonin synthesis.
An intracellular degradation system involved in the disassembly and recycling of unnecessary or dysfunctional cellular components. Autophagy participates in cell death, a process known as autophagic dell death. Prolonged fasting is a robust initiator of autophagy and may help protect against cancer and even aging by reducing the burden of abnormal cells.
The relationship between autophagy and cancer is complex, however. Autophagy may prevent the survival of pre-malignant cells, but can also be hijacked as a malignant adaptation by cancer, providing a useful means to scavenge resources needed for further growth.
A diet that mimics the effects of fasting on markers associated with the stress resistance induced by prolonged fasting, including low levels of glucose and IGF-1, and high levels of ketone bodies and IGFBP-1. More importantly, evidence suggests these changes in the cellular milieu are associated with a sensitization of cancer cells to chemotherapeutic drugs while simultaneously also conferring greater stress resistance to healthy cells.[1] Evidence also continues to emerge that properties of the fasting-mimicking diet, particularly its ability to cause immune cell turnover, may also make it useful in the amelioration of auto-immune diseases like multiple sclerosis.[2]
Fasting-Mimicking Diet Breakdown
- Day 1 - consists of 1,090 total calories (10% protein, 55% fat and 34% carbohydrate)
- Days 2 through 5 - consists of 725 total calories (9% protein, 44% fat and 47% carbohydrate)
[1] Cheng, Chia-Wei, et al. "Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression." Cell Stem Cell 14.6 (2014): 810-823. [2] Choi, In Young, et al. "A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms." Cell Reports 15.10 (2016): 2136-2146.
A type of white blood cell. Leukocytes are involved in protecting the body against foreign substances, microbes, and infectious diseases. They are produced or stored in various locations throughout the body, including the thymus, spleen, lymph nodes, and bone marrow, and comprise approximately 1 percent of the total blood volume in a healthy adult. Leukocytes are distinguished from other blood cells by the fact that they retain their nuclei. A cycle of prolonged fasting has been shown in animal research to reduce the number of white blood cells by nearly one-third, a phenomenon that is then fully reversed after refeeding.[1]
- ^ Cheng CW; Adams GB; Perin L; Wei M; Zhou X; Lam BS, et al. (2014). Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell 14, 6.
The thousands of biochemical processes that run all of the various cellular processes that produce energy. Since energy generation is so fundamental to all other processes, in some cases the word metabolism may refer more broadly to the sum of all chemical reactions in the cell.
A type of intermittent fasting that exceeds 48 hours. During prolonged periods of fasting, liver glycogen stores are fully depleted. To fuel the brain, the body relies on gluconeogenesis – a metabolic process that produces glucose from ketones, glycerol, and amino acids – to generate approximately 80 grams per day of glucose [1]. Depending on body weight and composition, humans can survive 30 or more days without any food. Prolonged fasting is commonly used in the clinical setting.
[1] Longo, Valter D., and Mark P. Mattson. "Fasting: molecular mechanisms and clinical applications." Cell metabolism 19.2 (2014): 181-192.
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