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Of mice and men

Can fasting or keto slow aging? Scientists are skeptical

Maybe don’t change your diet because it worked for a mouse.

GraphicaArtis/Hulton Archive/Getty Images

The term “anti-aging” has jumped from moisturizer containers and vials of retinol serum to cookbooks and herbal supplements. For these, “anti-aging” is not only a cosmetic effect — smooth skin, clear eyes — but a nutritional strategy that can actually slow the age-related deterioration of the body and brain by fine-tuning our internal molecular process. Or can it?

When it comes to diets, the “anti-aging” label can be misleading — that’s the conclusion of a new, sweeping review article published in the journal Science on Thursday. The review authors call into question the idea that studies done mostly in rodents and non-mammalian subjects can have any implication for human health.

What’s new — One of the major issues the review illuminates is that “anti-aging” diets are ones that also restrict calories and calorie restriction is already known, from animal studies, to increate lifespans. “This makes evaluating the effects of dietary composition challenging to differentiate from the effects of reduced caloric intake,” the authors state.

“Diets are the dirtiest drug you can imagine,” Matt Kaeberlein, one of the co-authors of the review, tells Inverse, “because they are changing thousands of things.” What Kaeberlin means is that the things we put — or don’t — put in our bodies do have material effects on our biology from the molecular level up. At the same time, our genetic makeup comes into play, further twisting our personal physiological responses to diet.

“We are still at the early days of personalized nutrition,” Kaeberlein adds.

The eating trends studied in their review include:

  • Intermittent fasting: Eating every other day, for example.
  • Fasting-mimicking diets: Eating the equivalent of three days worth of food per week, for instance.
  • Time-restricted eating: Eating only between certain hours of a day.
  • Protein restriction: Eating less protein than average.
  • Specific amino acid restrictions: Eating less of specific nutrients than average.
  • Ketogenic diet: A diet of little or no carbohydrates.

In the review, the researchers examine the evidence for each intervention and anti-aging properties. Ultimately, they conclude that there is not enough evidence to support four of the biggest myths around dieting and aging:

  1. Restricting calories “works,” every time, to delay aging.
  2. Restricting calories extends life and healthspan by “preventing cancer.”
  3. Certain nutrients, like fat or protein, are “good” or “bad” in regards to delaying aging.
  4. There is scientific evidence for the claim “anti-aging” diets do delay age-related brain and body changes in humans.

To understand how these myths arose, and why they are so problematic, it helps to understand where the idea of limiting calories results in “anti-aging” effects stems from in the literature — a history these authors get into in their article.

A Brief Guide to Caloric Restriction

In 1935, a Cornell University professor of animal husbandry showed that mice whose chow allotment was reduced lived longer than a control group, opening the field of longevity and diet studies.

Diet aids from yesteryear.Fairfax Media Archives/Fairfax Media Archives/Getty Images

In subsequent studies, other animal models were shown to live longer if they were fed a restricted number of calories — so long as they still got their quota of essential vitamins and nutrients. Depending on the animal and the study, scientists saw increases of between 50 to 300 percent of the average lifespan. Other research, however, showed no effect of diet on aging and lifespan. Interestingly, the degree of effect on aging was more on animals inbred to be used in a lab as opposed to “wild-derived” ones.

“It’s been a constant that the more diverse the genetic background [of the lab animal], the less consistent the benefit of caloric restrict,” Kaeberlein says.

To explain the effect, some scientists theorized that burning calories may speed up the body’s metabolic clock — speeding up the aging process. Another theory was that the free radicals released in the process of burning calories had a life-shorting effect.

Others suspect that caloric restriction only helps in weight management. In this hypothesis, scientists assume that animals left to their own devices would end up at an unhealthy weight.

Pathologist Roy Walford popularized the idea that caloric restriction could affect human longevity in a 1986 book called The 120 Year Diet. (Walford died in 2004, two-thirds the way there at 79.) Walford’s work — while it earned him little fame — helped spawn a wave of fad diets claiming “anti-aging” properties.

Does restricting calories affect aging in humans?

The short answer is that scientists don’t know.

Few people would put up with the eating restrictions put on lab animals, Kaeberlein says. That makes it very hard to do long-term studies on humans testing the claims of diets like keto in regards to aging. Also, of course, the human age span of 70-plus years makes it “unfeasible,” says Kaeberlein (who declined to name names as to who is spreading misinterpretations today).

“Generally, they cut out 30 percent of [the lab animals’] food supply. No one expects people to do that.”

Instead, the diets the review looks at try to replicate the metabolic mechanisms spurred by caloric restriction, by limiting the time span in which the body processes calories (intermittent fasting, fasting-mimicking diets, time-restricted eating) or cutting out specific parts of the diet (ketogenic, low-protein diet, and low-amino-acid diets).

Some of these diets have been tested in rodents. In one study, mice fed a ketogenic diet lived about 14 percent longer than a control group. In another, mice on a diet meant to mimic the effects of the fasting cycle added 11 percent to their lifespans. In another study, mice on a protein-restricted diet lived 15 percent longer than a control group.

The problem of drawing a conclusion from these studies?

“Mice are different from humans,” says Kaeberlein. “It’s just common sense.”

Although scientists gain insight into several bodily mechanisms using lab rodents, they generally consider these findings of limited practical value until they are expanded upon in research involving humans.

Also, the lab animals in these studies are raised their entire lives on one diet — people don’t follow keto from infancy through to the end of their lives.

Lastly, these diets, when followed by people, tend to reduce their calorie consumption — even if counting calories Weight Watchers style is not part of the diet — so it can be hard to tell what is the effect of that particular approach or cutting calories in general, says Kaeberlein.

“It’s a relatively new paradigm where people have shifted from studying caloric restriction to studying these dietary strategies that are similar to caloric restriction but have a different flavor,” he says.

Similarly, these studies have not identified any of the three macronutrients — carbohydrates, fat, and protein — as harmful to health.

“There is always a tendency to make one of them the bad guy,” he says, like keto and carbs, for example. “It’s more complicated to that and somewhat individual.”

There is, however, a purpose to all this work looking at the molecular effects of certain eating regimes on the body’s cells and processes.

“The real power,” Kaeberlein says referring to this murky field of science, “is helping us understand the mechanisms of aging,” and not in yielding a hack for humans to implement in their daily lives.

Abstract: Caloric restriction has been known for nearly a century to extend life span and delay age-associated pathology in laboratory animals. More recently, alternative “antiaging” diet modalities have been described that provide new mechanistic insights and potential clinical applications. These include intermittent fasting, fasting-mimicking diets, ketogenic diets, time-restricted feeding, protein restriction, and dietary restriction of specific amino acids. Despite mainstream popularization of some of these diets, many questions remain about their efficacy outside of a laboratory setting. Studies of these interventions support at least partially overlapping mechanisms of action and provide insights into what appear to be highly conserved mechanisms of biological aging.
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