Mitochondrial use of fatty acids as mechanism for cancer cell death during fasting | Valter Longo
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Fasting can have a multi-level effect in helping the body rid itself of cancer cells. During fasting, once the available glucose has been depleted, cancer cells must obtain their energy from fat. As this is not their preferred metabolic pathway, they become desperate, leading some cells to die. Furthermore, the cancer cells become more immunogenic, capable of provoking an immune response. Fasting can also alter proteins on the surface of cancer cells which normally allow them to hide from the immune system. In essence, fasting makes cancer cells less able to escape detection by the immune system. In this clip, Dr. Valter Longo explains how the use of fatty acids instead of glucose not only weakens cancer cells but also makes them more susceptible to being cleared by the immune system.
Rhonda: So, do you think that part of the fasting of the cancer cells, and, sort of, causing them to then use fatty acids, which can only be used by the mitochondria to generate energy as a byproduct, then making reactive oxygen species, do you think that's part of the killing, I mean, in addition to the immune system, which you also showed...
Valter: Yeah, I think it's all connected. You know, I think it's all connected. So, yes, yes we publish a paper calling the fasting-dependent anti-Warburg effect. And so, basically, normally, the cancer cells can rely on glucose, and once that glucose is lower, they have no choice but to try to go back to oxidative phosphorylation, and using the mitochondria to get energy, because there's no other way around, right? And that's great because, then, they become desperate, essentially, and that condition makes them undergo suicide. Because now, like you said, you know, you produce a lot of free radicals, but the cell is not set up to be protected. So, it's a very bad combination, and this, we believe, leads to the extent of that, and then, in mice, can cause cancer-free survival. But also, we think that probably that is involved in allowing the immune cells to move in and kill them, or it allows the cells to become more immunogenic, so, then, now, they're easier to be recognized by the dendritic cell, etc., and to be set up to cause an immune response, the normal.
Rhonda: Yeah. I think you actually showed that the...maybe it was the fasting-mimetic diet itself was able to increase cytotoxic T lymphocyte number, and play an important role in killing cancer cells.
Valter: Yeah. Not just increase the number, which is very much consistent with our older paper, but more or so making the cancer cells exposed to it, right? So, it's more about making the cancer cell more unable, like you were saying now, than normally, the cancer cell figures out how to deal with the immune system, and has proteins that say, "I'm one of yours," right? And tricks the immune system in that sense. And so, the fasting takes that away, and this is really, again, interesting because this is coordinated multi-level approach that the fasting is causing. Which makes you think, again, that some of these programs, some of these effects may have been evolved effects to get rid of, let's say, precancerous cells, right?
Rhonda: Right.
Valter: Because fasting was something that was normal for human beings, kinda like sleep. And then, maybe it was utilized for protection. And then, eventually when we stopped doing it, we lost this feature, we lost this help that the fasting had always given us. And maybe, that also caused us to be now, you know, exposed to this very high incidence of diseases that we earlier did not have.
A type of white blood cell that kills cancer cells, cells that are infected (particularly with viruses) or are otherwise damaged.
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 molecule composed of carboxylic acid with a long hydrocarbon chain that is either saturated or unsaturated. Fatty acids are important components of cell membranes and are key sources of fuel because they yield large quantities of ATP when metabolized. Most cells can use either glucose or fatty acids for this purpose.
The ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human or animal.
Tiny organelles inside cells that produce energy in the presence of oxygen. Mitochondria are referred to as the "powerhouses of the cell" because of their role in the production of ATP (adenosine triphosphate). Mitochondria are continuously undergoing a process of self-renewal known as mitophagy in order to repair damage that occurs during their energy-generating activities.
The process of generating energy that occurs when mitochondria couple oxygen with electrons that have been derived from different food sources including glucose, fatty acids, and amino acids.
Oxygen-containing chemically-reactive molecules generated by oxidative phosphorylation and immune activation. ROS can damage cellular components, including lipids, proteins, mitochondria, and DNA. Examples of ROS include: peroxides, superoxide, hydroxyl radical, and singlet oxygen.
A related byproduct, reactive nitrogen species, is also produced naturally by the immune system. Examples of RNS include nitric oxide, peroxynitrite, and nitrogen dioxide.
The two species are often collectively referred to as ROS/RNS. Preventing and efficiently repairing damage from ROS (oxidative stress) and RNS (nitrosative stress) are among the key challenges our cells face in their fight against diseases of aging, including cancer.
The observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.
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