Antiaging Diets: What Science Really Says About Eating for Longevity

Table of Contents

• Key Points
• Introduction: The Long History of Caloric Restriction
• What Does "Antiaging" Actually Mean?
• Two Types of Antiaging Diets: Low-Calorie vs. Isocaloric
• Ketogenic Diets (KDs)
• Intermittent Fasting (IF) and Fasting-Mimicking Diets (FMDs)
• Time-Restricted Feeding (TRF)
• Protein Restriction and Essential Amino Acid Restriction
• Caloric Restriction Mimetics: Drugs That Mimic Fasting
• Key Findings at a Glance
• Clinical Implications: What This Means for Patients
• Study Limitations: What Science Can't Yet Prove
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• Many popular diets, like intermittent fasting and ketogenic diets, reduce calories, so benefits may not come from diet composition.
• Caloric restriction extends lifespan in rodents but effects in humans are unclear and depend on genetics.
• Time-restricted feeding may extend lifespan in mice by about 11%, but humans show mixed results.
• Drugs like rapamycin are being studied as potential caloric restriction mimetics, but none are proven antiaging treatments.

Introduction: The Long History of Caloric Restriction

The idea that eating less can help you live longer is not new. Modern aging research traces its roots back to studies from the early 1900s that examined the effects of reduced food intake on lifespan in rats. These pioneering experiments showed that reducing calories in laboratory-reared animals delays development and results in a substantial increase in adult lifespan. The work of researchers like Weindruch, Masoro, Walford, and others in the 1970s, 1980s, and 1990s expanded and popularized this area of research in both rats and mice, establishing caloric restriction (CR) as the dominant paradigm for antiaging intervention for the rest of the 20th century.

Caloric restriction is defined as "reduced caloric intake in the absence of malnutrition." In early studies, this was typically accomplished by limiting food by a fixed amount while supplementing with vitamins and micronutrients. The precise method of food limitation varied, as did the timing of initiation (before or after weaning) and the degree of restriction. These foundational studies provided strong evidence that CR not only increases lifespan in rodents but also reduces disease burden and delays many functional declines of old age.

The data from these studies support the idea that, at least in some common laboratory strains of both mice and rats, total caloric intake correlates inversely with lifespan up to about 50 to 60% restriction — as long as essential nutrition is maintained. The research also showed that starting earlier in life gives larger effects on lifespan than starting later in life.

What Does "Antiaging" Actually Mean?

Before diving into the science, it's important to understand how researchers define "antiaging." The phrase is greatly abused in popular culture, often for the purpose of marketing cosmetic procedures or unproven nutritional supplements purported to slow or reverse aging. In this review, the authors define "antiaging" as delaying or reversing biological aging by targeting established molecular mechanisms of aging — what scientists call the "hallmarks" or "pillars" of aging.

Effective antiaging interventions in laboratory animals must do two things:

• Increase both median and maximum population lifespan
• Broadly delay the onset and progression of many age-related functional declines and diseases (this is called "extending healthspan")

Recent studies show that at least some antiaging interventions, such as the drug rapamycin, can actually reverse functional declines across multiple tissues in aged animals. However, there are as yet no clinically validated antiaging interventions in humans. There is, however, some evidence consistent with antiaging effects for caloric restriction and related diets in humans, as well as a small number of putative geroprotective compounds, including metformin and rapamycin.

Two Types of Antiaging Diets: Low-Calorie vs. Isocaloric

One critical but often overlooked consideration when evaluating different antiaging diets is the relative caloric intake of control and experimental groups. Antiaging diets can be divided into two broad groups:

1. Low-calorie interventions: These include classic caloric restriction (daily reduction of calories by 20 to 50%, without malnutrition), intermittent fasting (IF), fasting-mimicking diets (FMDs), and ketogenic diets (KDs).
2. Isocaloric diets: These include protein restriction (PR), essential amino acid restriction, and time-restricted feeding (TRF), where the experimental group consumes the same number of calories as the control group.

This distinction matters enormously. Several of the most prominent antiaging diets — such as IF, FMDs, and KDs — generally fall under the caloric restriction umbrella because the experimental group typically consumes 20 to 40% fewer calories than the control group. This makes it challenging to determine whether the benefits come from the specific dietary composition or simply from eating fewer calories. Other interventions, such as TRF and protein restriction, are somewhat better characterized under isocaloric conditions.

Ketogenic Diets (KDs)

Ketogenic diets are designed to maintain a constant state of ketogenesis — the metabolic production of ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone) as a by-product of fat metabolism in the liver. When carbohydrates are restricted, the liver switches to burning fat, producing ketone bodies that enter the bloodstream and can be taken up and metabolized by other tissues. In humans, the most common ketogenic diets are typically very low in carbohydrates (less than 30 to 50 grams per day), with roughly 75% of calories derived from fats. Many other variations are possible, so long as carbohydrate levels remain low enough to induce ketogenesis, including the popular high-protein Atkins Diet.

Ketogenic diets have been studied in humans for many decades as a treatment for epilepsy and have achieved mainstream popularity because of their palatability and effectiveness at inducing weight loss. The long-term health consequences of KDs in humans, and the relative merits of low-protein versus high-protein KD variations, are still vigorously debated within the nutrition community.

What the Mouse Studies Found

KDs recently gained recognition for potential effects on biological aging with two pivotal 2017 papers that reported a low-carbohydrate, low-protein KD is sufficient to increase mean lifespan and healthspan in mice.

In the first study, a 0%-carbohydrate KD that achieved high levels of β-hydroxybutyrate in blood was initiated at 12 months of age and given to mice either continuously or in a cyclic fashion (interspersed with control food on a weekly basis). The results were striking:

• The continuous KD failed to increase lifespan
• The cyclic KD increased mean (but not maximum) lifespan
• Cyclic KD improved both memory function and metabolic parameters late in life

In the second study, a low-carbohydrate diet (12% carbohydrates) or a KD (less than 1% carbohydrates) was initiated at 12 months of age. Both diets appeared to increase median lifespan relative to control-fed animals. The KD resulted in a 13% increase in median lifespan and showed a trend toward a smaller increase in maximum lifespan, though that trend did not reach statistical significance. Improvements in memory, motor function, and reduced cancer incidence were observed in the mice fed a KD in this study. Importantly, both studies observed reduced activity of mTOR — a key nutrient-sensing protein complex — in the longer-lived mice eating a KD.

Do Ketone Bodies Themselves Have Antiaging Properties?

An important question is whether KD effects are mediated by ketone bodies directly. Ketone bodies produced by the liver enter circulation and are taken up by other tissues, where they can enter the tricarboxylic acid (TCA) cycle through acetyl–coenzyme A, bypassing the need for glycolytic breakdown of glucose. The ketone body β-hydroxybutyrate has also been implicated as a signaling molecule that can act through extracellular receptors to regulate histone acetylation and thereby impact gene expression.

One study reported that β-hydroxybutyrate supplementation could extend lifespan in Caenorhabditis elegans (roundworms) through a mechanism linked to reduced mTOR signaling. Additionally, ketone esters have been reported to:

• Reduce anxiety-like behaviors and decrease amyloid-β and amyloid-τ deposits in a mouse Alzheimer's disease model
• Reduce blood insulin and glucose levels
• Inhibit mTOR signaling

These findings are highly suggestive that ketone esters themselves could have antiaging properties, but there is not yet direct evidence that ketone body metabolism alone is sufficient to increase lifespan in mice.

Intermittent Fasting (IF) and Fasting-Mimicking Diets (FMDs)

Fasting has long been touted for its putative health benefits across different cultures, and recent years have seen a resurgence of research on possible antiaging effects of diets that incorporate fasting or "fasting-mimicking" components. However, the authors note a critical issue: reviews of this topic often make blanket statements about the health benefits of IF for numerous age-related conditions in mice, but the experimental protocols used generally amount to caloric restriction.

In fact, modern IF protocols are largely a rebranding of classic CR methods. In early CR studies, mice were often fed only three times per week — which is, by definition, an intermittent fasting protocol. Hungry laboratory mice (and any CR researcher will tell you that their mice are hungry) will typically eat all of the available food in their cage quickly compared with control-fed mice. This means that even in a CR study where mice are fed daily, the restricted mice will typically be fasting for at least 18 hours between meals. This is not meant to downplay the potential importance of the physiological changes associated with the fasting state, but it makes it difficult to separate the effects of IF from those of CR.

Fasting-Mimicking Diets

Fasting-mimicking diets are a more recent innovation: cyclic CR protocols in which a low-calorie ketogenic diet is provided during the restricted phase. In mice, FMD cycles are typically 3 to 4 days followed by 3 days of refeeding. Studies in both mice and humans have shown that key biomarkers of fasting — including reduced insulin-like growth factor 1 (IGF-1), glucose, and ketone bodies — change during the FMD phase and return to control levels during a regular feeding regimen.

There is substantial clinical interest in FMDs based on the rationale that their cyclic nature will increase patient compliance relative to traditional diets. In one randomized controlled crossover study, trimonthly FMD cycles of 5 days each:

• Reduced body mass index (BMI)
• Reduced fasting blood glucose
• Reduced blood pressure

These benefits were observed in obese, prediabetic subjects and in subjects with hypertension. Cycles of FMD also appear potentially beneficial in other clinical contexts, such as multiple sclerosis, autoimmune diseases, and cancer.

FMDs and Chemotherapy

One particularly active area of research is the use of FMDs to improve outcomes in combination with chemotherapy. Initial studies indicated that FMDs increase tumor sensitivity to chemotherapy in mouse models of breast cancer and melanoma while reducing collateral toxicity to healthy cells. However, a recent clinical trial failed to detect any difference in the specificity of chemotherapy in breast cancer patients undergoing FMD cycles — possibly due to low compliance among participants.

The authors also caution that like IF, most FMD studies have been performed under conditions where the experimental group consumed fewer calories than the control group. The extent to which isocaloric IF or FMDs have a substantial impact on lifespan or age-related pathology remains unclear. Some FMD studies report that FMD and control mice consume energetically equivalent amounts of food when normalized to body weight, but because FMD mice weigh less than control mice, their total caloric intake is still lower.

Time-Restricted Feeding (TRF)

Time-restricted feeding involves restricting ad libitum feeding to a specific period of the day. In people, a common TRF protocol is 16:8 (16 hours fasting, 8 hours feeding). In mice, a 12:12 protocol has been tested.

Isocaloric TRF studies in rodents suggest improvements in several metabolic parameters, including:

• Glucose and insulin homeostasis
• Energy expenditure
• Liver pathology
• Resistance to different obesogenic (obesity-promoting) diets

Intriguingly, isocaloric TRF seems to promote and maintain intrinsic circadian rhythms in mice — a phenomenon also associated with caloric restriction.

The Only Lifespan Study So Far

To the best of the authors' knowledge, only one study has attempted to carefully examine the effect of isocaloric TRF on lifespan and age-related health outcomes in mice. In that report, which was limited to male mice, the TRF animals were trained to eat all of their food within a 12-hour window each day. The TRF mice were fed a diet intended to be isocaloric to the control ad libitum group; however, the TRF animals still ended up eating slightly less than the ad libitum–fed animals.

The results were notable:

• The TRF group lived about 11% longer than the ad libitum group, on average
• A separate 30% CR group (in which mice ate all of their food in a 3-hour window each day) showed a 28% increase in mean lifespan
• Circulating levels of β-hydroxybutyrate were higher in the CR group but not in the TRF group

Mixed Human Results

Despite the promising results of TRF in animal models, human studies are mixed. Some studies show only mild improvements, even when subjects naturally restricted themselves to 75 to 80% of their daily intake during the feeding window. Other studies indicate detrimental effects on glucose homeostasis. The authors note that many of these human studies designed their feeding windows without regard for circadian variation — meaning they may not have aligned eating periods with the body's natural daily rhythms, which could be an important factor in TRF's effectiveness.

Protein Restriction and Essential Amino Acid Restriction

In mice and rats, isocaloric protein restriction (PR) has been reported to extend lifespan, but the effects appear to be much smaller than those of caloric restriction. A recent report found that PR increased lifespan in male mice but not in female mice, suggesting the effects may be sex-specific.

Beyond general protein restriction, researchers have studied diets restricted for specific essential amino acids — amino acids that the body cannot produce on its own and must obtain from food. These include:

• Methionine restriction: typically involves reducing methionine by about 80% in mouse diets
• Tryptophan restriction: typically involves reducing tryptophan by about 40%
• Branched-chain amino acid (BCAA) restriction: typically involves reducing BCAAs by about 67%

It remains unclear to what extent these interventions share similar mechanisms. The authors note that these diets are difficult to follow for humans in practice, and most of the evidence comes from rodent studies.

Caloric Restriction Mimetics: Drugs That Mimic Fasting

As the molecular underpinnings of CR became established, research attention shifted toward identifying small molecules that could mirror the effects of CR on lifespan and health without requiring reduced food consumption. These "CR mimetics" include:

• Rapamycin — an mTOR inhibitor (originally developed as an immunosuppressant)
• Metformin — an antidiabetes drug that activates AMPK
• 2-deoxyglucose — a glycolytic inhibitor
• Acarbose — an intestinal α-glucosidase inhibitor
• Sirtuin-activating compounds — including resveratrol, which activates sirtuin proteins

The results so far are mixed. Most putative CR mimetics — with the possible exception of rapamycin — have thus far failed to match the magnitude of lifespan extension and healthspan benefits seen with CR. For example, metformin (a nonspecific AMPK activator) and resveratrol (a nonspecific sirtuin activator) primarily improve measures of metabolic health during aging in mice, including increased insulin sensitivity and reduced cancer incidence, but they do not reproducibly extend lifespan. These discrepancies likely reflect a still-incomplete understanding of the varied and diverse effects of CR, which have yet to be fully recapitulated pharmacologically.

Key Findings at a Glance

Here is a summary of the evidence for each diet, based on the review's assessment of rodent studies:

• Classic caloric restriction (CR): Strongest evidence. Daily reduction of calories by 20-50% robustly increases lifespan and healthspan across species.
• CR without protein restriction: Strong evidence (similar to classic CR).
• Intermittent fasting (IF): Strong evidence, but many classic CR studies actually used IF protocols, so the effects are hard to separate from CR.
• Fasting-mimicking diets (FMDs): Moderate evidence; cyclic protocols show promise but most studies involve reduced calorie intake.
• Ketogenic diets (KDs): Weakest evidence among low-calorie interventions; effects depend on cyclic versus continuous administration, and results on lifespan are modest.
• Protein restriction (PR): Small effects, possibly sex-specific (benefits seen in male mice but not female mice in a recent study).
• Essential amino acid restriction: Small effects; unclear if mechanisms overlap with other interventions.
• Time-restricted feeding (TRF): Small effect (11% lifespan extension in one study), but the TRF mice also ate slightly fewer calories.
• Isocaloric IF: Small effect (13% lifespan extension in one study under roughly isocaloric conditions).

Clinical Implications: What This Means for Patients

So what does all this mean for someone hoping to live a longer, healthier life? The authors are careful to strike a balanced tone. Human studies, both correlative and controlled, are consistent with health benefits conferred by a CR diet. Epidemiological data from human populations generally supports the idea that lower caloric intake is associated with increased life expectancy. However, it remains unresolved whether these benefits are a consequence of modulating the aging process itself, or are simply the result of avoiding obesity.

The authors highlight several unresolved questions that suggest caution when considering whether to recommend or implement any of these diets among the healthy general public:

1. Genetic variation matters: The effects of CR on lifespan are highly dependent on genotype. In some cases, CR actually causes reduced survival — even though it is often presented as uniformly beneficial.
2. Environmental variation matters: Understanding how environmental factors modify diet response is critical, especially in understudied populations and in the context of environmental challenges such as a global viral pandemic.
3. Diet composition vs. calories: Many studies fail to control for reduced caloric intake in the diet group, making their effects impossible to separate from simple calorie reduction.
4. Model system limitations: Human aging is difficult to model in mammals that are ultimately quite different from humans, which poses fundamental limitations to translating these findings to people.

From a pragmatic perspective, the authors are blunt: even if these scientific challenges can be overcome, widespread adoption of dietary interventions for healthy longevity seems unrealistic. They therefore suggest that alternative, non-dietary strategies with the potential for public uptake should be pursued.

Study Limitations: What Science Can't Yet Prove

This review article itself acknowledges several important limitations in the existing body of research:

• Caloric confound: Many studies of popular antiaging diets (IF, FMDs, KDs) do not properly control for the fact that the diet groups consume fewer calories overall. This makes it impossible to know if benefits come from the specific diet composition or from caloric restriction itself.
• Genotype dependence: The effects of CR on lifespan are highly dependent on the genetic background of the animal. Some genotypes actually show reduced survival under CR — a reminder that "one size fits all" does not apply.
• Sex differences: A recent report found that protein restriction increased lifespan in male mice but not female mice, suggesting that sex-specific responses are an underappreciated factor.
• Model organism limitations: Much of the evidence comes from yeast, worms, flies, and rodents. These model systems are evolutionarily distant from humans, and human aging involves complexity (genetic diversity, environmental variation, lifestyle factors) that cannot be fully replicated in laboratory animals.
• Short-term human data: Most human studies are short-term and measure biomarkers (like blood glucose, blood pressure, insulin sensitivity) rather than actual lifespan or healthspan. No antiaging diet has been clinically validated to extend human lifespan.
• Compliance issues: The one clinical trial of FMDs in breast cancer patients during chemotherapy failed to detect benefits, possibly because participants did not adhere closely to the diet — a real-world challenge for any dietary intervention.

Recommendations for Patients

Based on this review, here is what patients should consider when evaluating antiaging diets:

1. Be skeptical of sensational claims: The term "antiaging" is frequently abused in marketing contexts. No dietary intervention has been clinically proven to slow or reverse aging in humans.
2. Weight loss vs. aging: Many benefits attributed to antiaging diets may simply reflect the health benefits of avoiding obesity. If you are overweight, any diet that helps you achieve a healthy weight will likely improve metabolic health — but that is not necessarily the same as slowing biological aging.
3. It's not just the calories: If you are considering a specific diet (like a ketogenic diet or intermittent fasting), ask whether the benefits are proven independent of calorie reduction. For most popular diets, this is still unknown.
4. Timing matters for TRF: If you practice time-restricted feeding, pay attention to circadian rhythms — some human studies that failed to show benefits designed their feeding windows without regard for the body's natural daily rhythms.
5. Cyclic vs. continuous: In mouse studies, cyclic administration of a ketogenic diet extended lifespan while continuous administration did not. This suggests that how a diet is implemented may matter as much as what the diet contains.
6. Individual variation: Genetic and environmental factors influence how your body responds to dietary changes. What works for one person may not work for another — and could even be harmful, given that CR reduces survival in some genotypes.
7. Watch for future research on "CR mimetics": Drugs like rapamycin and metformin are being studied for their ability to mimic the molecular effects of CR without requiring dietary changes. Rapamycin, in particular, has shown promise in animal studies. These "precision geroscience" approaches may eventually offer a more practical path than extreme diets.
8. Don't undertake extreme restriction without supervision: The research on caloric restriction involves carefully controlled conditions with vitamin and micronutrient supplementation to prevent malnutrition. Extreme calorie cutting without medical supervision can be dangerous.

The authors conclude with a vision for the future: validated biomarkers of biological aging are needed to match interventions to each person's distinct genetic and environmental context, thereby optimizing individual healthy lifespan. Future research directed at clarifying the underlying mechanisms of how CR elicits longevity-promoting responses — and how these differ among individuals — should one day help realize a true "precision geroscience" approach to healthy aging.

Frequently Asked Questions

What is the difference between low-calorie and isocaloric antiaging diets?

Low-calorie diets, such as classic caloric restriction, intermittent fasting, and fasting-mimicking diets, reduce total calorie intake. Isocaloric diets, like protein restriction or time-restricted feeding, aim to keep calories the same as a control group. This distinction matters because many studies cannot separate the diet's specific effects from simple calorie reduction.

Does intermittent fasting extend lifespan?

In mice, intermittent fasting shows strong evidence for lifespan extension, but many classic caloric restriction studies actually used fasting protocols, so the effects are hard to separate. In humans, studies are short-term and mixed. One isocaloric intermittent fasting study in mice found a 13% lifespan increase, but compliance in human trials is often low.

What are fasting-mimicking diets and do they help?

Fasting-mimicking diets are cyclic low-calorie ketogenic diets given for 3–5 days, followed by normal eating. In a randomized crossover study, trimonthly cycles reduced body mass index, fasting blood glucose, and blood pressure in obese, prediabetic, or hypertensive subjects. However, most studies involve fewer calories, and a chemotherapy trial found no benefit, possibly due to low compliance.

Do ketogenic diets slow aging?

Evidence is the weakest among low-calorie interventions. In mice, one study found cyclic ketogenic diets extended mean lifespan, but continuous feeding did not. Another study showed a 13% increase in median lifespan. Effects appear modest and may depend on how the diet is implemented. Long-term human data are lacking.

Are there drugs that mimic fasting or caloric restriction?

Researchers study compounds like rapamycin, metformin, resveratrol, and acarbose as caloric restriction mimetics. Rapamycin has shown promise in animal studies, but most candidates fail to match the lifespan benefits of caloric restriction. These drugs are not approved for antiaging purposes in humans and require more research.

When should a patient considering an antiaging diet seek a second medical opinion?

No antiaging diet has been clinically validated to extend human lifespan. Many popular diets—such as intermittent fasting, ketogenic diets, and fasting-mimicking diets—have not been proven to work independently of calorie reduction. Genetic variation matters: caloric restriction reduces survival in some genotypes, so a diet that helps one person may harm another. Extreme calorie restriction without medical supervision can be dangerous. A second opinion can help evaluate whether a proposed diet is safe and appropriate for your individual health profile. Diagnostic Detectives Network provides independent expert second opinions.

When should a patient considering an antiaging diet seek a second medical opinion?

No antiaging diet has been clinically validated to extend human lifespan. Many popular diets—such as intermittent fasting, ketogenic diets, and fasting-mimicking diets—have not been proven to work independently of calorie reduction. Genetic variation matters: caloric restriction reduces survival in some genotypes, so a diet that helps one person may harm another. Extreme calorie restriction without medical supervision can be dangerous. A second opinion can help evaluate whether a proposed diet is safe and appropriate for your individual health profile. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Antiaging diets: Separating fact from fiction

Authors: Mitchell B. Lee, Cristal M. Hill, Alessandro Bitto, and Matt Kaeberlein (corresponding author, email: kaeber@uw.edu)

Journal: Science, volume 374, article eabe7365 (2021). DOI: 10.1126/science.abe7365

Author affiliations: Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Pennington Biomedical Research Center, Baton Rouge, LA, USA.

Publication date: November 19, 2021

This patient-friendly article is based on peer-reviewed research. It has been written to make the original scientific findings accessible to a general audience while preserving all key data, statistics, and conclusions from the original publication. Patients should consult their healthcare providers before making significant changes to their diet or lifestyle.