Dr. Valter Longo: “The Fasting Mimicking Diet Activates Yamanaka Factors”
- © Nils Osmar 2025. May 9, 2025
- This post is not intended as, and should not be taken as, medical advice.
- See full Medical Disclaimer
Dr. Valter Longo spent over a decade developing what he calls the Fasting Mimicking Diet (FMD), which has been found in several studies to reduce biological age.
What the FMD is and isn’t
The FMD is not a diet you can “live on.” If you tried doing so for very long, you would die.
Most temporary “diets” designed for weight loss try to lower calories while maximizing nutrients; but Longo’s FMD (which has different goals) is designed to be extremely low in nutrients. An FMD is very similar to a water fast, but has a (very) few specific foods added back in, not so much as to provide needed nutrients, as to minimize hunger and increase the odds of compliance, since so many people give up after just a few hours of water fasting.
The foods that are included are not high in nutrients; protein, for example, is deliberately kept as low as possible because in its absence the body goes into deep autophagy, a sort of “deep cleaning” taking place in our cells, in which the human body finds, recycles and removes components such as viruses, bacteria and protein fragments that have accumulated in the nuclei of our cells.
Benefits of a well-designed FMD can include weight loss (in particular loss of harmful abdominal fat), improved metabolic health, reduced inflammation, and possible longevity benefits. Recent studies have clarified that FMDs also reduce epigenetic age and activate mechanisms that may actually be reprogamming our genes.
A Recent Claim
I was surprised, when watching two recent interviews with Dr. Longo, to find him making the statement that his FMD activates the Yamanaka Factors. If this is accurate, it would appear to be a major breakthrough.
The Yamanaka Factors
The Yamanaka factors are a set of four specific proteins (called transcription factors) that can reprogram adult cells back into a stem cell-like state. They were discovered by Dr. Shinya Yamanaka in 2006 and earned him a Nobel Prize in 2012. The four factors are:
- Oct4
- Sox2
- Klf4
- c-Myc
When these factors are introduced into mature cells, they essentially “reset” the cell’s identity, making it more like an embryonic stem cell. This process is called cellular reprogramming and can theoretically reverse cellular aging.
Traditionally, the thinking has been that they can only be activated by gene therapy or cellular reprogramming. It’s well established, though, that an FMD that lasts the full five days can result in not only deep cellular cleaning, but the rejuvenation of the immune system, in which a flood of T cells are released from our bone marrow. It sounds like Longo may be saying that the activation of the Yamanaka Factors is what causes this to occur.
Longo’s Recent Statements
The idea that fasting or fasting mimicking diets (FMDs) could activate the Yamanaka factors comes from research on how caloric restriction and nutrient deprivation affect cellular processes. Dr. Longo recently claimed that fasting mimicking diets do, indeed, activate the YF. In a recent interview with Gordon Lithgow, this exchange took place:
Gordon: You know, as you look around now at the field, um, it’s really moved so far from where we started. What do you think is the most exciting thing right now in aging biology?
Valter: Um, I mean, I-I really like the-the, epigenetic reprogramming. You know, Belmonte, and David Sinclair, and others, and uh, yeah, so I think that’s-that’s really exciting. Un, and of course, we didn’t talk about it, but, you know, the fasting mimicking diet, one of the things that does in the — in the shrinking starvation process is it turns on Yamanaka factor, right?
So — we’re very interested in, our cells in, um, you know, tapping into that and-and is it, can-can this starvation refeeding cycle, um, activate some of this, um, reprogramming? Epigenetic reprogramming mechanisms. And, yeah, so I-I-I really like that, but of course, there’s lots of different ideas and, um, and so, I think that, that’s good, you know? And we’ll see what-what happens in the next 10 years. It’s a very exciting moment to-to think different, yeah.
Gordon : Yeah, no, I have to agree with you, Valter. This is really exciting. We actually had David Sinclair on the — on the podcast, recently. And, you know, his amazing work as you point out on-on-on sort of reprogramming and-and, recovery of function. And just to hear the-the-the work that went into that. Uh, you know, post-doc slaving away trying different factors in different ways has been fascinating. Um, so it’s-it’s fantastic that you’re now connecting with that entire area, in this relationship between diet and reprogramming.
Valter: Yes, so we-we actually started a while ago, and, um, I think the first paper was, 10 years ago where we look at the blood system, and we were using chemotherapy, and fasting, and fasting mimicking diet. And we saw the [unintelligible] stem cell being turned on and-and-and having a clear advantage if the mice were fasting and, you know, generating — and self-renewing so stem cells making more stem cells.
And then, eventually, w-we started to see what looked like reprogramming in the pancreas and, in another paper, this was 2016 – I believe, and-and we saw that we could damage the pancreas. The pancreas stopped making insulin, and then we would start fasting mimicking diet refeeding cycle, and we would see the-the, um, the pancreatic cells be reprogrammed into making insulin again even though they were, you know, terminally damaged, right?
So then, um, then we started looking at the genes, and some of these genes were in fact, the Yamanaka factor, right? So — and it would be turned on, temporarily, and then for maybe one or two days, and then — and then come down. And then, we went on to show this in the gut. Um, now, we’re about to publish about the-the kidney. Uh, we’ve shown some of the same effects in the nervous system. Yeah, so we’ve published actually many papers on this, um, on this FMD fasting-dependent, turning on of-of these, what seems to be, you know, epigenetic reprogramming or certainly, cellular reprogramming leading to, a rejuvenated, more functional state, yeah.
Claude AI Weighs In
I was curious for Claude.ai‘s reaction to Longo’s claim that the FMD had activated the Yamanaka Factors. So I asked it “How can an individual activate the Yamanaka Factors?”
It first replied:
The Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc, collectively known as OSKM) are transcription factors that can reprogram somatic cells into induced pluripotent stem cells (iPSCs). While this technology has significant potential for regenerative medicine and aging research, it’s important to understand that individuals cannot and should not attempt to “activate” these factors in themselves. Here’s why:
- Laboratory-based technology: Yamanaka factor reprogramming is performed in controlled laboratory settings using specialized techniques like viral vectors or small molecule compounds.
- Research stage: While partial reprogramming (brief, controlled exposure to Yamanaka factors) shows promise in animal models for improving tissue function and potentially addressing age-related decline, this research is still experimental.
- Safety concerns: Full reprogramming can lead to teratoma formation (tumors), and even partial reprogramming requires precise control to avoid harmful effects.
I then shared Longo’s claims to have activated the YF with Claude. It replied:
Based on Dr. Longo’s statements, it appears that his research team has observed some activation of Yamanaka factors in specific tissues during the fasting-refeeding cycles associated with the FMD. Here are the key points from his interview:
- Temporary activation: According to Longo, they observed certain Yamanaka factors being “turned on temporarily” for “maybe one or two days” during the fasting-refeeding process, followed by deactivation.
- Tissue-specific effects: He mentions observing these effects in multiple organ systems including the pancreas, gut, kidney, and nervous system.
- Partial reprogramming: This appears to be a form of partial or transient reprogramming, not the complete cellular reprogramming that would revert cells to a fully pluripotent state.
- Regenerative outcomes: The research suggests this temporary activation contributes to tissue regeneration and functional improvement in damaged organs (like insulin production in damaged pancreatic cells).
This is significant because it suggests the FMD might naturally induce a controlled, transient activation of some reprogramming factors that could contribute to tissue rejuvenation without the risks associated with complete cellular reprogramming.
My Experience
I’ve done FMDs several times, though not for a few years. I found them challenging but possible. Some major health problems cleared up permanently after my fourth one. ‘
After doing some FMDs, I tried following Dr. Longo’s so-called “Longevity Diet” (a very low protein version of the Mediterranean Diet) for a while. It did not work well for me; in fact, I found myself losing muscle mass visibly and drifting toward sarcopenia when I was on it. I resolved this by adding more meat back into my diet. (Of course, others’ experiences may vary.)
It’s interesting to note, BTW, that all of the successful trials of the Fasting Mimicking Diet were conducted on people who were not eating his Longevity Diet; they ate their “usual” diets before doing an FMD then resumed their usual diets afterwards, and still got all of the benefits.
For what it’s worth, what works best for me these days is to eat a high protein animal-based diet most of the time, in particular because I’m working on building a reserve of muscle before I get any older. Based on my experience his “Longevity Diet” is not a diet I’d personally recommend to anyone. I plan to do an FMD again soon, but to follow it with several days of eating a very high nutrient, largely animal-based diet.
My current approach is working well enough for me that, according to blood tests which have been analyzed by the PhenoAge calculator (which compares a range of blood biomarkers with our risk of mortality), I am currently 13.,9 years younger than my biological age.
This isn’t to say I don’t like the Fasting Mimicking Diet. My experiences with it have all been good. (But again, it’s designed to be temporary.) I would highly recommend learning more about FMDs if you’re new to the concept, with the usual admonition that Longo recommends checking in with your doctor before doing one.
More about FMDs
If you consider doing an FMD, remember that it is intended to be a temporary diet on which calories and macronutrients are kept deliberately low to force the body into deep autophagy: It lasts three to five days, after which you stop it and resume eating your usual diet.
- It’s important to be aware that that FMDs are essentially starvation diets.
- Anyone who tried living on an FMD permanently would starve to death in a few weeks.
The specifics:
People eating Longo’s version of an FMC need to completely avoid animal foods and most seeds, legumes and grains, for the 3-5 days of the diet. They also need to avoid plant foods high in protein, and foods which involve amino acids such as leucine. (Romaine lettuce is not allowed, because it’s too high in nutrients; iceberg lettuce, which is essentially just water wrapped in cellulose with very low nutrients, and celery and cucumbers, are fine.)
- Day 1: About 1,100 calories (11% protein, 46% fat, 43% carbs)
- Expressed in grams: Day 1: 30g protein, 56g fat, 118g carbohydrates
- Days 2-5: About 700-800 calories (9% protein, 44% fat, 47% carbs)
- Expressed in grams: Days 2-5: 16-18g protein, 35-40g fat, 85-90g carbohydrates
Not medical advice
This article is not intended as, and should not be taken as, medical advice. I’m not advising that people eat any particular diet or take any particular supplement(s), just reporting on what I’m doing. Supplements, like medications and other interventions, can have side effects; I would encourage people to research both possible benefits and side effects before starting on any supplementation regimen, and consult with a medical professional about any issues which might have a medical component. See full Medical Disclaimer
Other resources
- My Youtube channel Pathways to Longevity
- My Facebook group: Anti-Aging and Life Extension,
