Caloric Restriction Mimetics in Aging, Improved Cancer Chemotherapy, Autophagy Anti-Obesity Effect
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Caloric restriction mimetics – compounds that “trick” cells into inducing autophagy even in the setting of sufficient nutrient levels – include resveratrol, which is found in red wine, and spermidine, which is found in cheese. These compounds work by inducing the same biochemical changes within cells that starvation and fasting induce, such as the acetylation and deacetylation of proteins. Emerging research suggests that caloric restriction mimetics, when used in conjunction with chemotherapy, enhance the anti-cancer immune response that makes chemotherapy have lasting effects. In this clip, Dr. Guido Kroemer describes the autophagy-inducing effects of calorie restriction mimetics such as spermidine and resveratrol.
- Rhonda: ... some of your work with the fasting, so-called fasting mimetics like spermidine, hydroxycitrate that you've done. Maybe can you kind of just briefly explain... I'll start with spermidine. What is spermidine? What does it do?
- Dr. Kroemer: Well, it was first start to explain what are these fasting mimetics is as you say and caloric restriction mimetics as we say. So the CRM's, caloric restriction mimetics, are actually inducing the same biochemical changes in the cells as would do starvation or fasting. So, we have been discussing on the importance of acetyl-CoA and protein deacetylation resulting from the inhibition of Acetyl-CoA in the context of fasting. And caloric restriction mimetics, similar induced deacetylation reactions to stimulate autophagy. And this can be actually achieved in three different ways. First, you simply inhibit the generation of Acetyl-CoA. The enzyme that generates Acetyl-CoA in our cells, the most important one for the cytosolic pool, is ATP citrate lyase and hydroxycitrate or pharmacological compounds that inhibit this enzyme cause Acetyl-CoA depletion, deacetylation, and autophagy. And you can have the same effect by inhibiting the protein acetyltransferases, some of them have been identified. Like, EP300 which appears extremely important for autophagy regulation, and specific inhibitors of EP300 such as spermidine and natural compound or C646 which is a pharmacological compound specifically designed for this function. They can also cause deacetylation and autophagy. And finally, it is possible to activate deacetylases or enzymes that remove acetyl groups from proteins and cause hypoacetylation and autophagy. And one example that is well known is resveratrol contained in red wine that induces autophagy through this pathway. So, all these agents, caloric restriction mimetics, have different molecular targets, but it activate autophagy by a final common pathway.
- Rhonda: The protein acetylation seems like that.
- Dr. Kroemer: Yes, exactly.
- Rhonda: Okay. So, with some of the major ones that you've worked with, spermidine. I've read quite a bit about spermidine. I know it's found in high concentrations in natto, the Japanese fermented soybean that doesn't taste like great. But I've seen studies about aging, you know, giving it to even aging mice or something, can then extend their lifespan. Is that true?
- Dr. Kroemer: So spermidine, to come to the source of spermidine is contained in the nuclei of all kind of cells. So, in the nucleoid of bacteria but also the nuclei from yeast cells or from plant cells or animal cells. So, all food items that contain nuclei cells, are actually containing spermidine. Also, there are large variations in the content. So we have to know, on this spermidine, it also is volatile and accounts for the smell of sperm. So, it is frequently found in food items that have some kind of smell like natto or durian fruit or fermented cheese, when it is generated from non pasteurized sources and very rich in bacteria and fungi that are contributing to the fermentation process, which is, of course, smelly cheese. And it's also quite abundant in some vegetables and food where the scent is more agreeable to most people because it is complex to other molecules that reduce its volatility. So spermidine has the capacity to induce autophagy when it is taken up with food or with the drinking water when we take mice. It can also be injected, of course. It is produced by our microbiota. So, one-third of the spermidine in our body is probably produced in the intestine, and you can manipulate a microbiome to increase its production of polyamines, including spermidine.
- Rhonda: Through what? Probiotics? Or through...
- Dr. Kroemer: Yes.
- Rhonda: So you know what strains of bacteria... ?
- Dr. Kroemer: Yeah, there is a Japanese group that has been publishing that specific bacteria overproducing polyamines can be used to reduce the development of colon cancer or to reduce aging.
- Rhonda: Wow, fascinating. That's very interesting. And you've shown with the spermidine, I know we have a limited time here, with the spermidine that's been shown to... Was it spermidine or hydroxycitric, I think, that was shown to synergize with, like you were mentioning before, the chemotherapeutic...
- Dr. Kroemer: Yeah, both of them actually.
- Rhonda: Both? Okay.
- Dr. Kroemer: So the mechanism is that when you combine chemotherapy with caloric restriction mimetics, all the caloric restriction mimetics that I mentioned, including spermidine and hydroxycitrate and resveratrol, will enhance the anti-cancer immune response that makes the therapy durable. So, we have been able to show that inhibition of autophagy in the malignant cells or destruction of the extracellular ATP that is released as a result of autophagy is sufficient to abolish the favorable interaction between caloric restriction mimetics and chemotherapy. And similarly, actually, it is sufficient to remove T-cells from the system. And you will lose any kind of tumor growth reduction induced by chemotherapy combined with caloric restriction mimetics as it proves that the cellular immune response is actually decisive for therapeutic outcome.
- Rhonda: Wow, that's really quite promising, I think, for you know at least in the clinic, if you can somehow test whether or not this caloric restriction or fasting mimetics work in conjunction with some of these immunotherapies, that would be fantastic. But I want to ask you one last thing too about some of these fasting mimetics. Like, if I were to just supplement with hydroxycitric, for example, or if there were spermidine supplement, and I was still eating a normal, you know, healthy diet, but not caloric restricted and not fasting. Do you think that would be sufficient to induce autophagy?
- Dr. Kroemer: Well, I can respond for mice...
- Rhonda: Okay. How about in mice?
- Dr. Kroemer: ...that this is certainly the case. I don't know about humans because we have no clinical studies in this field.
- Rhonda: So in mice, it does?
- Dr. Kroemer: It does. And in mice, you actually can give a combination of high-fat diets, that usually would cause obesity, with spermidine to reduce weight gain through mechanisms that we don't understand and that we believe to be autophagy-dependent but have to elucidate in some molecular detail.
- Rhonda: That's very cool. So I'm going to look up those strains of bacteria, you know, to see that can I eat fermented foods to increase that population and get more spermidine. You know, things like that would be very interesting to me as useful little tools.
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 energy-carrying molecule present in all cells. ATP fuels cellular processes, including biosynthetic reactions, motility, and cell division by transferring one or more of its phosphate groups to another molecule (a process called phosphorylation).
An enzyme that converts citrate into acetyl CoA, which leads to protein acetylation and thus inhibits autophagy. The production of acetyl CoA also represents an important step in fatty acid biosynthesis and by converting citrate to acetyl CoA, ATP citrate lyase links the metabolism of carbohydrates, which yields citrate as an intermediate, to the production of fatty acids, which requires acetyl CoA. Hydroxy citrate is a competitive inhibitor of ATP citrate lyase and thereby reduces the cytosolic levels of acetyl CoA.
↓ ATP citrate lyase activity → ↓ Protein Acetylation → Autophagy
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.
The practice of long-term restriction of dietary intake, typically characterized by a 20 to 50 percent reduction in energy intake below habitual levels. Caloric restriction has been shown to extend lifespan and delay the onset of age-related chronic diseases in a variety of species, including rats, mice, fish, flies, worms, and yeast.
Compounds that induce a similar biochemical milieu in the cell as starvation or nutrient deprivation, including the reductions in cytosolic acetyl CoA and increases in protein deacetylation that serve as a trigger for the cellular autophagic machinery. Popular examples of compounds that exhibit this type of effect include: hydroxycitrate (inhibits ATP citrate lyase), spermidine (inhibits Ep300, a protein acetyltransferase), and resveratrol (activates deacetylases called sirtuins).
The aqueous component of the cytoplasm of a cell, within which various organelles and particles are suspended.
Any of a group of complex proteins or conjugated proteins that are produced by living cells and act as catalyst in specific biochemical reactions.
Also known as p300 HAT. A histone acetyltransferase that acetylates proteins in chromatin, causing widespread changes in gene activation. This enzyme can be inhibited by compounds such as spermidine and thereby promote autophagy.
The collection of genomes of the microorganisms in a given niche. The human microbiome plays key roles in development, immunity, and nutrition. Microbiome dysfunction is associated with the pathology of several conditions, including obesity, depression, and autoimmune disorders such as type 1 diabetes, rheumatoid arthritis, muscular dystrophy, multiple sclerosis, and fibromyalgia.
A collective term for the community of commensal, symbiotic, and pathogenic microorganisms that live in a particular environment. The human body has multiple microbiotas, including those of the gut, skin, and urogenital regions.
A chemical reaction that removes an acetyl functional group from a chemical compound. The presence of the acetyl functional group plays an important role in the synthesis, stability and localization of about 85% of human proteins.[1] During fasting, falling acetyl CoA levels in the cytosol initiate protein deacetylation and initiates autophagy. In general, protein deacetylation, whether from so-called caloric restriction mimetics or nutrient deprivation, is an important general inducer of autophagy.
- ^ Arnesen, Thomas; Van Damme, Petra; Martinho, Rui Gonçalo; Helsens, Kenny; Hole, Kristine; Pimenta-Marques, Ana, et al. (2011). NatF Contributes To An Evolutionary Shift In Protein N-Terminal Acetylation And Is Important For Normal Chromosome Segregation PLOS Genetics 7, 7.
A polyphenolic compound produced in plants in response to injury or pathogenic attack from bacteria or fungi. Resveratrol exerts a diverse array of biological effects, including antitumor, antioxidant, antiviral, and hormonal activities. It activates sirtuin 1 (SIRT1), an enzyme that deacetylates proteins and contributes to cellular regulation (including autophagy). Dietary sources of resveratrol include grapes, blueberries, raspberries, and mulberries.
Resveratrol Autophagy ↑ Deacetylases (especially SIRT1) → ↓ Protein Acetylation → Autophagy
A polyamine (an organic compound having more than two amino groups) named for having been isolated in semen. Spermidine has since been found in a variety of different tissue types, as well as foods. It is best known for its role as a potential autophagy and longevity promoter with its effects having been demonstrated in yeast, flies, worms, and human immune cells.[1]
↓ Acetyltransferase activity (especially EP300) → ↓ cytosolic Acetyl CoA → Autophagy
↓ mitochondrial transmembrane potential → ↑ ubiquitination → mitophagy (preferentially targeted)
- ^ Hartl, Regina; Megalou, Evgenia; Laun, Peter; Heeren, Gino; Breitenbach, Michael; Grubeck-Loebenstein, Beatrix, et al. (2009). Induction Of Autophagy By Spermidine Promotes Longevity Nature 11, 11.
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