Nov. 19, 2021 -- If you're confused about the science behind many popular anti-aging diets, you're not alone.

Although evidence points to some gains in healthspan and lifespan with intermittent fasting, protein restriction and other “anti-aging” diets, most findings come from animals and other organisms studied in a laboratory.

It becomes less clear how the benefits translate to extending human longevity, in part because weight loss from these diets also can translate to health benefits that could help people live longer.

Despite limited evidence in humans, there is some promise: studies reveal some common mechanisms across the different diets that could someday produce more robust and precise therapies to combat the effects of aging.

Confusion Abounds

With the growing popularity of anti-aging diets and multiple options also comes some confusion. With that in mind, senior study author Matt Kaerberlein, PhD, and his colleagues reviewed the evidence for diets that claim anti-aging effects compared to a standard caloric restriction approach.

Their “Antiaging diets: Separating fact from fiction” Review paper was published online this week in Science.

The investigators looked at ketogenic diets, intermittent fasting, fasting-mimicking diets, time-restricted feeding and protein restriction, as well as diets that restrict specific amino acids – methionine, tryptophan or branched chain amino acids.

"Over the past several years, there has been a mainstream popularization of many dietary interventions [claiming] to impact the aging process based on studies in laboratory animals," Kaerberlein tells Medscape Medical News.

"Because these diets are being recommended to the general public, we felt it was important to perform an unbiased evaluation of the evidence supporting their impact on aging in preclinical and clinical studies," says Kaerberlein, who is also a professor in the Department of Laboratory Medicine and Pathology and Director of the Healthy Aging and Longevity Research Institute at the University of Washington School of Medicine in Seattle.

"I found the article to be a very comprehensive, scoping review of the various antiaging diet methods and the results," Lauri Wright, PhD, chair of the Department of Nutrition & Dietetics and Director of the Center for Nutrition & Food Security at the University of North Florida in Jacksonville, tells Medscape Medical News.

"It was an extremely accurate snapshot, presenting the results while acknowledging the complexities of this type of research and the gaps in knowledge," says Wright, who is also a national spokesperson for the Academy of Nutrition and Dietetics, formerly known as the American Dietetic Association.

Dispelling Myths

Kaerberlein and colleagues also address several common fictions regarding antiaging diet strategies, including:

Caloric restriction always 'works.' Although there are many reports of lifespan and healthspan extension from caloric restriction, there are also multiple published examples in which caloric restriction did not extend lifespan, including studies in mice and rhesus monkeys.

Individual macronutrients are 'good' or 'bad' for aging. A focus only on macronutrients like protein or carbohydrates might miss the big picture. Dietary composition, total caloric intake, and feeding interval all have the potential to affect longevity and healthspan.

Caloric restriction extends lifespan only by preventing cancer. Although multiple rodent studies report anticancer effects, caloric restriction also delays age-related declines in immune, brain, heart, muscle, kidney, reproductive and other tissues.

Some Surprises

As for any unexpected findings, "most surprising to me was how weak the actual evidence for benefits on lifespan and healthspan is in mice for many of these interventions once caloric restriction is controlled for,” Kaerberlein says.

In other words, most of the laboratory studies on intermittent fasting, protein restriction or time-restricted feeding also significantly restricted calories the animals consumed. That study design makes it more difficult to separate out any anti-aging effects from gains associated with a 20% to 40% decrease in overall calories.

But when researchers run experiments under “isocaloric conditions,” where calorie counts remain constant, "the effects are generally quite small or non-existent," Kaerberlein says.

"The one exception among the dietary interventions we examined may be methionine restriction and branched chain amino acid restriction, but those dietary strategies haven’t been studied as extensively in laboratory animals and are, at this point, not practical to implement in people."

Fitting in Your Genes

Another surprise for Kaerberlein "was the large impact of genetic background on outcomes in pre-clinical dietary intervention studies, and the fact that this has been largely ignored." A lot of these studies were done in inbred lines of mice, for example.

But other research in organisms with greater genetic diversity – including wild mice, fruit flies and budding yeast – show that "a subset of genetic backgrounds show no response in terms of lifespan and some have their lifespan shortened," he says.

"While it’s not surprising that genotype and environment would both influence individual response to a particular dietary intervention, we do think it is surprising that an intervention that is often presented in reviews of the scientific literature and in books written for the general public as universally beneficial is actually harmful in about 25% of the genetic backgrounds tested."

Other Caveats

The researchers also caution people against going too far.

"Although many people tend to assume that dietary interventions are safe, the biological effects of these antiaging diets are profound and generally less specific than pharmacological interventions," the authors wrote. "Like any drug, dietary interventions have a dose-response profile and at high enough 'doses' will lead to substantial adverse effects and ultimately death."

The loss of libido and sexual dysfunction, psychological problems, chronic fatigue, poor sleep, muscle weakness, susceptibility to infection, impaired wound healing, and social isolation are among the potential side effects of caloric-restriction-like diets, the researchers said.

"In the case of protein restriction, there is also evidence that it may be harmful, at least for all-cause mortality, in older adults," Kaerberlein says, referring to evidence for people older than 65.

More research into adverse effects, particularly over the long-term, is warranted.

"All of these dietary strategies have multiple side effects – even hunger is a side effect – that, as far as we could find, have not been carefully evaluated in laboratory animals or in people," Kaerberlein says.

The overall advice for now is "caveat emptor” or "buyer beware" when it comes to these and other diets, Kaerberlein says.

"There’s not yet a lot of evidence in preclinical or clinical studies that any of these diets will significantly move the needle in terms of healthy longevity for people who aren’t overweight and exercise moderately."

That said, "certainly, if people are overweight, then some of these diets can be helpful in getting down to a healthy weight, especially if combined with exercise,” he says. “And that’s obviously a good thing.”

It's Not Only Quantity, It's Quality

Despite most of the evidence for anti-aging diets coming from non-human studies, "I believe that [the review] still demonstrates the role of diet in aging healthfully," Wright says.

"While we don’t have enough evidence for some of the extremes in diets that were discussed, we do have evidence that shows eating patterns that support not only longevity but quality aging," she continues.

The recommendations may sound familiar: maintain a healthy body weight, consume an abundance of vegetables and fruits, choose whole grains while avoiding added sugars, eat lean proteins including fish and more plant-proteins such as beans, and choose unsaturated fats while avoiding saturated and trans fats.

The American Heart Association recently updated its guidance with 10 evidence-based diet recommendations, which overlap in terms of recommending more whole grains, plenty of fruits and vegetables and minimizing added sugars. The AHA guidance also recognizes the challenges from environmental and other impediments to healthy nutrition, including structural racism, segregated neighborhoods and areas where unhealthy choices are the default option for many people.

Researchers Have More on Their Plate

Moving forward, "I hope the research – and particularly the way it is portrayed in literature reviews and the public domain – becomes a bit more rigorous, but I’m honestly not holding my breath,” Kaerberlein says.

He would like to see research move toward more personalized nutrition.

"I hope we see progress in understanding how individual genotype and environment impact the response to different dietary interventions in people toward the goal of optimizing health benefits at the individual level," Kaerberlein says.

Another avenue of future work "where I think we will definitely continue to make progress,” he says, is research into the mechanisms behind how these diets work in animals and other organisms that could directly translate into beneficial effects on aging in people.

"We highlighted the mTOR pathway or network in our review and I think that’s where the best bets are at," he says, "but there’s a lot to learn still and perhaps other nodes in that network or elsewhere that can be tweaked to get bigger benefits with lower risk of side effects."