Dr. Matt Kaeberlein and colleagues recently published a review summarizing anti-aging diets as well as their misconceptions .
Caloric restriction, fasting-mimicking diets, and intermittent fasting
While fasting diets have been practiced for centuries, a recent re-emergence of this research has come to the anti-aging field. The general idea behind fasting diets is to cut back on calories, such as simple carbohydrates and protein. The author’s review of these studies showed that they have multiple health benefits in mice. Some of the health benefits of the fasting-mimicking diet shown by Dr. Valter Longo and collaborators are reduced levels of blood glucose, insulin-like growth factor 1, and insulin-like growth factor binding protein 1 in mice and humans [2,3].
Notably, in the randomized clinical trial, human participants with obesity, prediabetes and hypertension showed that a fasting-mimicking diet for five days every three months reduced fasting blood sugar levels, BMI, and blood pressure . Additional clinical trials show that fasting-mimicking diets may have benefits against cancer, multiple sclerosis, and autoimmune disease [4,5,6]. However, in a recent study with cancer patients undergoing chemotherapy, a benefit was not seen between the regular diet and fasting-mimicking diet group in the DIRECT study . A Nature Communications publication discussed this trial and how the fasting-mimicking diet in addition to chemotherapy had low compliance rates .
Intermittent fasting studies in mice thus far look promising in inducing health benefits. However, these same results have not been seen in humans. A study protocol in which participants had 1 day of fasting and 1 day of feeding for 3 weeks (often called 1:1 intermittent fasting and alternate-day fasting) in lean healthy people revealed that intermittent fasting did not improve metabolic or cardiovascular biomarkers .
The reviewers urged that there needs to be additional research in people and rodents due to the limited timeline and scope of these studies. The reviewers mentioned a similar statement when reviewing time-restricted feeding due to the mixed research results thus far in rodents and humans.
Numerous studies since the 1920s show lifespan extension in rodents fed protein-restricted diets. These results have been proposed to be due to reduced mTOR signaling, insulin-like growth factor 1, and growth hormone [10,11] along with increased hormone fibroblast growth factor 21 . The reviewers discuss a meta-analysis and an additional study in mice and rats that showed that protein restriction had a greater impact on life extension than caloric restriction [13,14].
Another meta-analysis that reviewed 25 studies showed increased lifespan of mice when protein is replaced with carbohydrates . However, to make things more complex, the absolute lifespan of these mice was lower than that of other studies of the same mouse breed, and the lowest-calorie diets did not yield the longest lifespans. Interestingly, they found that out of all the diets, the results in the longest median lifespan, 139 weeks, consisted of approximately 42% protein, 29% carbohydrates, and 29% fat. This illustrates the need for additional research on protein restriction and its influence from other macronutrients and other variables on longevity.
In human studies, the most commonly used ketogenic diet has approximately 75% of daily calories from fat and only roughly 30 to 50 grams per day carbohydrates .
The authors discussed one mouse study, a daily ketogenic diet that had no calories from carbohydrate and failed to increase lifespan. However, a cyclic ketogenic diet that alternates with a regular diet on a weekly basis increased mean lifespan . A different study had the mice eating a low-carbohydrate diet or a ketogenic diet . Median lifespan was increased in both diet groups.
In both of these studies, mTOR activity was decreased in the longer-lived mice that were on the ketogenic diets [17,18]. You can read more about mTOR in our articles on a mouse study, the Dog Aging Project, and a human trial.
Do anti-aging diets from animal studies work in humans?
One area of the paper that the reviewers pointed out very early on is that intermittent fasting, fasting-mimicking diets, and ketogenic diets generally can be considered caloric restriction diets due to typically having 20-40% less calorie intake than the regular diet groups. In some studies, the diets are not matched for calorie intake between the regular diet group and calorie-restricted groups. In these cases, it is obvious that there may be greater weight loss and improved health parameters in the caloric restriction groups. Additionally, it can be hard to determine whether it is the calorie restriction or the dietary composition that induced the health changes. This, along with low adherence rates to these diets, are among the reasons why they are highly debated in the nutrition field.
The final part of the paper goes into weighing the evidence to determine if anti-aging diets work in people. It should be no surprise that when people eat a diet pattern that differs from the typical Western diet and is lower in calories, it will likely result in losing weight. However, there is not yet strong evidence that calorie restriction diets slow aging in people.
Additionally, the reviewers mention that there have been multiple reports of lifespan and healthspan extension from calorie restriction diets as well as multiple reports that calorie restriction diets do not extend lifespan or healthspan. In both human and animal studies, calorie restriction and other diet interventions’ successful outcomes are likely to be dependent on a number of factors that are not fully discovered yet, such as genetic background, gender, stress, and environment.
In one human study, documented side effects included poor sleep, poor temperature fluctuation tolerance, loss of sexual dysfunction and libido, increased risk of infections, psychological problems, muscle weakness, chronic fatigue, social isolation and poor wound healing .
On a personal note, I have been a Registered Dietitian for over a decade. I have often heard clients discuss diets or supplements that they are trying because they were given recommendations by a friend, social media influencer, celebrity, or scientist on diets and/or supplements that are based solely on research studies not yet conducted in humans. I believe that this review is a great example of why pursuing any diet should be met with caution, and to avoid joining the hype before it is established with human data.
I agree with the authors, and I have seen while working with clients, that few people will be able to maintain a caloric restriction, a protein restriction, or a ketogenic diet continuously over their entire adulthood. The eating pattern for longevity will certainly be different in different people. Dr. Matt Kaeberlein and colleagues conclude with a call to action by saying:
Future research should focus on better understanding the cellular and molecular mediators of anti aging diets under highly controlled laboratory conditions as well as the impact of genetic and environmental variation on health outcomes associated with these diets.
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