Caloric Restriction and Intermittent Fasting: Benefits, Risks, and Biological Impact

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• Caloric Restriction vs Obesity Prevention
• Human Application and Potential Risks
• Case Study: Roy Walford
• Intermittent Fasting and Caloric Intake
• Dietary Interventions as Dirty Drugs
• Full Transcript

Caloric Restriction vs Obesity Prevention

Dr. Matt Kaeberlein, MD, addresses a fundamental question about caloric restriction and aging. He explains that the benefits likely extend beyond simple obesity prevention. Research in laboratory rodents shows lifespan benefits even when comparing calorically restricted animals to those at healthy weights. Dr. Matt Kaeberlein, MD, states his personal view is that caloric restriction probably has positive effects on biological aging in people. However, he cautions that human studies are extremely difficult due to our long lifespans.

Human Application and Potential Risks

Dr. Matt Kaeberlein, MD, emphasizes the critical importance of considering risk-reward ratios for longevity strategies. He notes that humans live in complex environments with genetic heterogeneity, unlike laboratory animals. Significant risks accompany long-term caloric restriction, including potentially increased susceptibility to infections like influenza or COVID-19. Dr. Kaeberlein warns that diet gurus often fail to evaluate these potential negative consequences and side effects. He stresses that nutritional strategies do have side effects, a fact culturally overlooked.

Case Study: Roy Walford

Dr. Anton Titov, MD references famous caloric restriction researcher Roy Walford, who authored "The 120-Year Diet" but died at age 79. Dr. Matt Kaeberlein, MD, confirms Walford suffered from ALS, though any connection to his dietary practices remains speculative. This case highlights the challenge of interpreting anecdotal data from small numbers of individuals practicing extreme dietary interventions. Notably, no documented examples exist of long-term caloric restriction practitioners reaching even 110 years of age.

Intermittent Fasting and Caloric Intake

Dr. Anton Titov, MD questions whether intermittent fasting and fasting-mimicking diets are simply rebranded caloric restriction. Dr. Matt Kaeberlein, MD, explains that animal studies show most benefits from intermittent fasting actually result from accompanying caloric restriction. In isocaloric situations (where total calorie intake remains unchanged), time-restricted feeding may provide only small lifespan benefits compared to true caloric restriction. For humans, Dr. Kaeberlein believes these strategies are valuable primarily for maintaining normal body weight rather than providing additional anti-aging benefits.

Dietary Interventions as Dirty Drugs

Dr. Matt Kaeberlein, MD, introduces the crucial concept of dietary interventions as "dirty drugs." He explains that while pharmacological interventions have recognized side effects, people rarely consider the side effects of dietary changes. Hunger, malnutrition, and infection susceptibility represent real side effects of caloric restriction. Dr. Matt Kaeberlein, MD, emphasizes that any dietary intervention is biologically far "dirtier" than even the most promiscuous pharmaceutical drug, affecting hundreds of proteins and causing immense downstream biological changes. This perspective helps contextualize the complex biological reality of nutritional interventions.

Full Transcript

Dr. Anton Titov, MD: So, in your recent science feature article about diets and aging, there are several very interesting finer points that you make with your co-authors. One of them is: is it possible that all caloric restriction does is help us perhaps avoid obesity? So there is perhaps no magic in it? What can you comment on that?

Dr. Matt Kaeberlein, MD: I think that's a reasonable question. My personal feeling is that it's very unlikely to be the case. Obesity, whether in laboratory rodents or in people, is associated with and almost certainly causal for a variety of negative health outcomes during aging. Maintaining normal body weight certainly helps. In mice, you get further benefits for lifespan from caloric restriction, as opposed to what we would consider a normal or healthy body weight with moderate adiposity.

So my personal feeling is it's very unlikely that the effects of caloric restriction are simply due to preventing obesity. In humans, it's a harder question to answer. Humans age so slowly and live a long time. Really, nobody can do long-term controlled studies of caloric restriction. In that context, it's harder to know whether moderate or even severe long-term caloric restriction in people would positively impact the biology of aging.

It's a guess. As long as we recognize that it's a guess, then I'm comfortable saying my guess is that caloric restriction, beyond just preventing obesity, probably has positive effects in people on biological aging. My concerns are that because people live in a very complicated environment and are genetically heterogeneous, there is a risk associated with severe or even moderate long-term caloric restriction that is not appreciated based on mouse and rat studies in the laboratory.

When you're thinking about strategies to maximize healthy longevity, you always need to think about the risk-reward ratio. We know that there are potentially big rewards from positively modifying the biological aging process and enhancing lifespan. But there are also risks associated with any strategy we take.

In the context of caloric restriction, one obvious example would be that if you're chronically calorically restricted, there's a reasonable chance you're going to be at higher risk of infection, or at least failure to fight off an infection once infected. That's speculation, but I think it's reasonable. If that's the case, it doesn't do you any good if you're aging more slowly but get infected with influenza or COVID-19 and die because you're in a nutritionally restricted state that isn't able to fight off the infection effectively.

I just say that to make the point that it's hard to answer your question definitively. Even if caloric restriction has significant benefits in the context of aging, I'm not convinced that the benefits will offset the risk that goes along with long-term caloric restriction in people. That was another point we tried to make: some diet gurus that get on the internet and try to sell their favorite diet don't really evaluate the potential negative consequences and side effects.

Culturally, we're not trained to think of diets or nutritional strategies as having side effects, but they do. It's important to appreciate that.

Dr. Anton Titov, MD: I think you also mentioned in the review that the famous caloric restriction researcher, Roy Walford, tried to popularize and did write a very famous book on caloric restriction. He died at 79, quite short of the 120 years that he proposed. Do you know what is the cause of death?

Dr. Matt Kaeberlein, MD: It's my understanding that Dr. Walford suffered from a form of ALS. It's total speculation whether or not that was at all impacted by his quite public adoption of caloric restriction; nobody knows. This is a challenge with interpreting anecdotal data from people who have been practicing caloric restriction because it's always very small numbers of individuals.

But the point is valid: Walford wrote a book called "The 120-Year Diet," making the case that caloric restriction would likely allow most people to reach that threshold of 120 years, which is still viewed as the longest natural lifespan in people. In his case, he didn't make it. As far as I know, there aren't any examples of people who practice long-term caloric restriction who reached even 110 years.

It doesn't disprove the idea that caloric restriction could allow some people to achieve extreme healthy old age, but I don't think there's a lot of data to support that at this point.

Dr. Anton Titov, MD: So that probably explains why there is an interest in intermittent fasting and fasting-mimicking diets. But then again, the question is something you addressed in your numerous publications: the fact that there is no control for the total amount of calories. In fact, intermittent fasting or a fasting-mimicking diet could be just a rebranding of caloric restriction. What is known about those types of dietary modification?

Dr. Matt Kaeberlein, MD: It's important to separate what we know in laboratory animal studies from what we think we know in humans. In laboratory animal studies, there have been a few studies attempting to address this question. With something like intermittent fasting, where mice are fasted every other day, there are studies reporting significant increases in lifespan and healthspan metrics.

If you actually look at those studies, in nearly every case where there was a significant effect on lifespan, those mice were also calorically restricted. They did not make up for the deficit on the day they were fed. So it becomes very difficult to separate whether the beneficial effects were due to caloric restriction or due to the time-restricted nature of feeding.

It's an area that is a little bit murky. Right now, people are doing work with different time-restricted feeding regimens. My take on that body of literature as a whole is that so far, the data are very suggestive that you can get a small lifespan benefit from intermittent fasting in an isocaloric situation, but it's nowhere near the magnitude of the effect achieved by true caloric restriction.

Most of the benefits seen in laboratory animals are due to caloric restriction. There may be some small benefit achieved from isocaloric time-restricted feeding in laboratory animals. In people, nobody has ever done a carefully controlled, even medium-term study of time-restricted feeding, fasting-mimicking diets, or intermittent fasting, so we just don't know.

My personal view is if time-restricted feeding or intermittent fasting helps some people maintain normal body weight and not become obese, that's probably quite valuable. I don't think there's much reason to believe these strategies will have a significant impact beyond the benefit you get simply from not being obese. But I could be wrong; that's my take on what I've seen of the human data so far and the animal studies available.

Dr. Anton Titov, MD: This is very interesting data, because clearly, individuals in the public almost equate dieting or caloric restriction with longevity as a panacea. You rightly highlight that there are risks involved in real-world conditions, like the immune system and various other non-controlled conditions, which for mice are very well controlled.

Dr. Matt Kaeberlein, MD: This is an area I've tried to be vocal about. I think people, researchers and the general public, don't appreciate that when you make a significant change in your dietary intake, there are lots of biological effects that go along with that. It's obvious to say that, and anybody with a basic understanding of biology will recognize it's true.

If you restrict your calories or eat every other day, there are biological effects. What people typically don't appreciate is that there are side effects associated with that kind of intervention, very similar to the side effects associated with a drug. With prescription medicine, we're attuned to the idea that there is a risk of side effects in addition to the targeted effect.

But people don't appreciate that with diets. It's important to make that point. Some side effects associated with caloric restriction can be severe, like susceptibility to infection, which could lead to death. Malnutrition is a potential side effect. But there are more common ones that everybody can appreciate.

Hunger is a side effect. That is not the effect you're going for when you calorically restrict, but it is real and unpleasant for most people. If you took a drug that made you hungry and made your stomach hurt, that would be considered a side effect. People don't think that way about dietary interventions.

I'm not saying that's good or bad; it's just important to recognize. The other piece equally important to recognize is that unlike a small molecule, which can have a very specific biochemical effect, dietary interventions are far "dirtier" than the dirtiest drug. What I mean is that the downstream biological changes when you dramatically change your nutritional intake are immense.

There are probably hundreds of proteins altered at gene expression or biochemical level. Caloric restriction, intermittent fasting, time-restricted feeding are among the dirtiest drugs out there in terms of off-target effects. Again, I'm not saying that's good or bad; it's a biological reality most people don't ever even think about.

Dr. Anton Titov, MD: That's very important to know. When I did my Ph.D. at Rockefeller University, I worked with yeast. When we put yeast in a less nutritious medium overnight and did some of the first gene chip experiments to look at expression pattern changes, I saw very significant effects across thousands of genes. The patterns looked completely different with just mild overnight caloric restriction of the yeast medium, and it was very profound. So that's exactly as you said: the dirtiest effect compared to clean small molecules.