Defining and comparing the different food limiting modalities | Valter Longo
A growing body of evidence suggests that fasting and limiting food intake are beneficial in slowing the processes of aging. However, the term "fasting" can comprise a variety of subtypes. Intermittent fasting, a term lacking specificity, usually refers to interventions such as alternate-day fasting, fasting one day per week, or a five:two eating pattern (fasting for two days per week). Caloric restriction pertains to chronically limiting calories below the level that is needed to maintain a healthy body weight. Time-restricted eating involves limiting food intake to certain hours of the day. Finally, prolonged fasting typically exceeds 48 hours and may be more appropriate to practice under the guidance of a physician. In this clip, Dr. Valter Longo defines the different fasting modalities, and compares and contrasts the variations of each in duration and degree of restrictiveness.
Rhonda: There's been a really big interest in fasting and also in limiting food intake, and limiting food intake is actually one of the probably most, I would say, reproducible interventions that's been shown to modulate the aging process across multiple organisms.
So, I was wondering if you could maybe describe...define and sort of describe some of the common denominators between various modalities of limiting food intake like caloric restriction, intermittent fasting, prolonged fasting.
Valter: Right. Yes. So, I think that we're at the point where we have to start...we have to stop using terms like intermittent fasting, because it covers almost everything, right? I mean, at least in the journalist mind, when they talk about intermittent fasting, it covers from two hours food...not eating, to one month. And of course they're completely different practices and they have completely different effects. And so I think it's important to start qualifying what it is that we're talking about.
So, intermittent fasting, I guess it could be a way to include let's say alternate day fasting, and include what's called the five-two, so having two days a week of a very restricted diet, and maybe it could also include the one day a week of fasting, of complete fasting. I think it would be fair to include those three in intermittent fasting, even though they can have very different effects.
Now, of course time-restricted feeding is time-restricted feeding, which refers to let's say how long of a time you eat per day. So 8 a.m., 8 p.m., that would be 12 hours of feeding and 12 hours of fasting.
And then calorie restriction is that...of course you can say some people use calorie restriction to define everything that is calorie restricted, but the people in the field talk about calorie restriction, when they hear calorie restriction, they think of chronic reduction of calories below the normal level. So, below the level that will allow you to maintain a normal weight, and so chronically, so if you do this all the time.
And then periodic prolonged fasting instead is what we mostly work on, and it's very different, and it's not intermittent in the sense that it's not something that has to happen in any type of cycles, frequent cycles. It can be done once a year, it can be done 10 times a year, it can be done 20 times a year, and it refers to let's say at least 2 days of fasting or longer, or 2 days of a fasting-mimicking diet or longer.
So, what do they have in common? I mean, some things may be in common, but they are very different interventions, and they each do something different. I mean, I think we know now from the calorie restriction field that the diet...I mean, the restriction of calories like that can have incredible effects on diseases, diabetes particularly, but also cancer, cardiovascular diseases. So this is really unbelievable effects. I mean, the monkeys, we know that it can wipe out diabetes completely. It can reduce cardiovascular disease and cancer by 50%.
But the monkeys either live a little bit longer, or don't live longer at all. And this is what we and others, a few at least suspected for a long time. I was a student of Roy Walford back in the early '90s, and it was...I mean, being around calorie-restricted people, it was very clear to me that this was going to have problems, but it was also very clear that this was going to have huge effects on health.
Rhonda: For the monkey studies that you're referring to, there were two published, correct? One from the University of Madison and one from the NIH?
Rhonda: And neither of them increased lifespan, but they increased healthspan?
Valter: No, no, no. The Wisconsin increased lifespan. Richard Weindruch was also a student of Roy Walford. So, yeah, that increased lifespan. But if you look at the lifespan that is based on the disease-dependent lifespan, so the mortality caused by major age-related diseases, that was...there was a huge effect. If you look at the overall survival due to where all causes of mortality were taken into consideration, then the survival curves are very close to each other.
Rhonda: Would that be considered maximum lifespan? This one [inaudible 00:05:39]
Valter: No, this will be mean lifespan, mean and maximum, right?
Valter: So, small effect. They don't have maximum because I think they will have taken...at some point they had to stop it so they couldn't really get to full lengths. It already took 25 years to do that. So, I think it would have been difficult to get maximum lifespan.
But the mean lifespan was extended in Wisconsin, it was not extended at the NIA. Of course the Wisconsin study had a controlled diet that was much worse than the NIA-controlled diet. So the NIA had somewhat of an ideal diet, at least ideal monkey diet, and the Wisconsin didn't. The Wisconsin was a reasonably good model for the western diet.
Rhonda: That's interesting. Okay, so there's no really...I think there was also maybe some different genetic backgrounds as well from the monkeys but who knows?
Valter: Yes, probably genetic...
Rhonda: Do you know if in these studies did they see common pathways...and I want to talk about this with you. Genetic pathways that are known to be modulated by caloric restriction, were those changed? For example, did IGF...were IGF-1 lowered or mTOR?
Valter: Yeah, now I haven't looked at those papers in a while, but almost for sure, I mean, those were affected. I mean, calories are cut by 30%, so that would mean 30% less proteins and 30% less sugars. So, yes, I will assume that both of them showed effects on the nutrient-signaling pathways and including TOR and IGF-1.
Rhonda: And I guess so that's probably something that's also a common denominator between these other modalities of limiting food such as the periodic prolonged fasting. I guess one of the major differences would be the shift in metabolism to, when you're fasting, to beta-oxidation, to...because that's...is that something that occurs during caloric restriction?
Valter: That probably occurs. There's probably a minimal switch to a ketogenic mode, depending on who it is and what the restriction is. So, it is possible that chronically, when you're chronically restricted, it also depends how you restrict it.
So for example there are human studies where they show that because the people that are restricted were eating high protein, a high vegetable protein diet, and the IGF-1 was not affected. So, it is possible that some of these individuals have a diet that would block entry into even a small ketogenic mode. But overall they're probably not, they're relatively in a standard metabolic mode as far as ketone bodies and fatty acids are concerned.
Alternate day fasting
A type of intermittent fasting in which a person fasts every other day. On “fasting” days, dietary intake is limited to 0–25% of typical caloric intake; on “feeding” days, energy take is not restricted. Scientific evidence suggests that ADF results in weight loss and improved metabolic parameters and may be an effective weight loss strategy in humans.VIEW FASTING TOPIC
The process by which fatty acid molecules are broken down. Beta-oxidation occurs in the mitochondria and produces acetyl-CoA, FADH2, NADH, and H+. Under conditions where glucose is limited, beta-oxidation is an important preceding step for producing the acetyl-CoA needed for ketogenesis.
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.
Cardiovascular disease (CVD)
A large class of diseases that involve the heart or blood vessels, including stroke, hypertension, thrombosis, heart failure, atherosclerosis, and more. Cardiovascular disease is often caused by lifestyle factors. As such, up to 90 percent of cardiovascular disease may be preventable .  McGill, Henry C., C. Alex McMahan, and Samuel S. Gidding. "Preventing heart disease in the 21st century." Circulation 117.9 (2008): 1216-1227.
Fasting-mimicking Diet (FMD)
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. 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.
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)
 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.  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.VIEW FASTING TOPIC
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 years of a person’s life spent free of disease.
Insulin-like growth factor 1 (IGF-1)
One of the most potent natural activators of the AKT signaling pathway, stimulator of cell growth and proliferation, potent inhibitor of programmed cell death, primary mediator of the effects of growth hormone, and has been implicated in contributing to aging and enhancing the growth of cancer after it has been initiated. Similar in molecular structure to insulin, IGF-1 plays a role during childhood for growth and continues later in life to have anabolic, as well as neurotrophic effects. Protein intake increases IGF-1 levels in humans, independent of total caloric consumption.
A broad term that describes periods of voluntary abstention from food and (non-water) drinks, lasting several hours to days. Depending on the length of the fasting period and a variety of other factors, intermittent fasting may promote certain beneficial metabolic processes, such as the increased production of ketones due to the use of stored fat as an energy source. The phrase “intermittent fasting” may refer to any of the following:
- Time-restricted eating
- Alternate-day fasting
- Periodic fasting (multi-day)
Molecules (often simply called “ketones”) produced by the liver during the breakdown of fatty acids. Ketone production occurs during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, or prolonged intense exercise. There are three types of ketone bodies: acetoacetate, beta-hydroxybutyrate, and acetone. Ketone bodies are readily used as energy by a diverse array of cell types, including neurons.
Mechanistic target of rapamycin (mTOR)
A genetic pathway that senses amino acid concentrations and regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. It integrates other pathways including insulin, growth factors (such as IGF-1), and amino acids. mTOR plays a key role in mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain. It is dysregulated in many human diseases, such as diabetes, obesity, depression, and certain cancers. mTOR has two subunits, mTORC1 and mTORC2. Also referred to as “mammalian” target of rapamycin.
Rapamycin, the drug for which this pathway is named (and the anti-aging properties of which are subject to much study), was discovered in the 1970s and is used as an immunosuppressant in organ donor recipients.
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 . 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.
 Longo, Valter D., and Mark P. Mattson. "Fasting: molecular mechanisms and clinical applications." Cell metabolism 19.2 (2014): 181-192.VIEW FASTING TOPIC
Time-restricted eating (TRE)
Restricting the timing of food intake to certain hours of the day (typically within an 8- to 12-hour time window that begins with the first food or non-water drink) without an overt attempt to reduce caloric intake. TRE is a type of intermittent fasting. It may trigger some beneficial health effects, such as reduced fat mass, increased lean muscle mass, reduced inflammation, improved heart function with age, increased mitochondrial volume, ketone body production, improved repair processes, and aerobic endurance improvements. Some of these effects still need to be replicated in human trials.VIEW TIME-RESTRICTED EATING TOPIC
Type 2 diabetes
A metabolic disorder characterized by high blood sugar and insulin resistance. Type 2 diabetes is a progressive condition and is typically associated with overweight and low physical activity. Common symptoms include increased thirst, frequent urination, unexplained weight loss, increased hunger, fatigue, and impaired healing. Long-term complications from poorly controlled type 2 diabetes include heart disease, stroke, diabetic retinopathy (and subsequent blindness), kidney failure, and diminished peripheral blood flow which may lead to amputations.
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