Studies from the early 1990s that analyzed the impact of reduced food intake on life span in rats indicated delayed development and increased adult life span in such animals. Other works by Walford, Masoro, and Weindruch made the concept of caloric restriction (CR) an important factor for anti-aging intervention in both mice and rats. These studies also suggest that along with an increase in life span, CR reduces the disease burden and slows down many functional declines of old age.

Review: Antiaging diets: Separating fact from fiction. Image Credit: alphaspirit.it / Shutterstock

The CR definition in such studies is "reduced caloric intake in the absence of malnutrition." However, the exact mechanism of food limitation, degree of restriction, and timing of initiation varied. Similar studies also took place in invertebrate models, but due to different culture conditions across species, these interventions were termed "dietary restriction" (DR). These studies helped identify a highly conserved growth-promoting and nutrient-sensing network capable of regulating biological aging in several different organisms. Some of the important proteins of this network involved the mechanistic target of adenosine 5′-monophosphate (AMP)–activated protein kinase (AMPK), rapamycin (mTOR), insulin and insulin-like growth factor 1 (IGF-1)–like receptor, nicotinamide adenine dinucleotide (NAD)– dependent sirtuin deacetylases, as well as FOXO-family transcription factors.

Following this, research focused on identifying small molecules that could mirror the effects of CR on health and lifespan without reducing food consumption. A few "CR mimetics" included the antidiabetes drug metformin, the mTOR inhibitor rapamycin, the intestinal a-glucosidase inhibitor acarbose, sirtuin-activating compounds, and the glycolytic inhibitor 2-deoxyglucose. However, most of them have been unable to match CR's health and lifespan benefits.

A new review published in the journal Science aimed to summarize the commonly studied anti-aging dietary interventions and their impact on human health and longevity.

Rise of anti-aging diets

Anti-aging diets can be categorized into two groups; CR and isocaloric nutrient restriction. Diets such as fasting-mimicking diets (FMDs), intermittent fasting (IF), and ketogenic diets (KDs) fall under the CR group, while protein restriction (PR), time-restricted feeding (TRF), and amino acid restriction fall under the isocaloric nutrient restriction group.

Ketogenic diets (KDs)

These diets involve compositions that maintain a constant state of ketogenesis. This leads to ketosis, a state of elevated ketone bodies in the blood. These ketone bodies can be taken up and metabolized by other tissues. The most common KD in humans is mostly very low in carbohydrates, while other variations, such as the popular high-protein Atkins diet, are also available. The long-term health impacts of KDs and the benefits of low- versus high-protein KD diets in humans are still debatable.

Two 2017 studies reported that a low-carbohydrate, low-protein KD can increase mean health and life span in mice. Reduced incidence of cancer, as well as improvement in memory and motor function, were also observed. Moreover, reduced mTOR activity was observed in longer-lived mice consuming a KD. However, whether KD effects are brought about by ketone bodies directly is still unclear. Recent studies indicated ketone esters can have anti-aging properties but require further research.

Fasting-mimicking diets (FMDs), intermittent fasting (IF)

FMDs induce ketogenesis through the restriction of simple carbohydrates and proteins and the maintenance of high-fat levels. Initial studies in rodent models indicated that bimonthly 4-day FMD could lead to a reduction in the body and organ size along with the improvement of several age-related parameters. Cyclic FMD has been reported to induce quiescence and atrophy, followed by stem cell activation and vigorous regeneration in many tissues. Cycles of FMD have also been reported to be beneficial in multiple sclerosis, cancer, and autoimmune diseases.

Previous research has highlighted that true isocaloric IF implemented as fasting and feeding days can also induce ketogenesis and improve stress resistance, metabolic homeostasis, and inflammation markers. However, all such studies are limited in duration and scope. Therefore, further studies are required to analyze whether FMDs or isocaloric IF can provide long-term benefits on longevity and health in rodents as well as people.

Time-restricted feeding (TRF)

TRF is a variant of IF where people receive food daily but only during a specific time window. Studies on isocaloric TRF in rodents suggest improvement in many metabolic parameters. Additionally, isocaloric TRF has been observed to maintain and promote intrinsic circadian rhythms in mice. Although the results of TRF studies are quite promising in animals, they are mixed in the case of human studies. Some studies indicate mild improvements, while others report harmful effects on glucose homeostasis. More extensive studies are required to determine whether TRF benefits metabolic homeostasis and aging in humans.

Protein restriction (PR) and amino acid restriction

Previous research has indicated PR delays signs of aging, sexual duration, and development in rats. Many studies have since shown that PR causes age-related pathology and increases lifespan in rodents. Under ad libitum conditions, many studies have shown that dietary protein may improve longevity in insects and mice.

Moreover, several studies have also reported that restriction of certain essential amino acids that come from diet and cannot be synthesized can lead to life span extension through inhibiting mTOR signaling. A few of these amino acids include tryptophan, methionine, isoleucine, valine, and leucine. Additionally, along with mTOR inhibition, the hormone fibroblast growth factor 21 (FGF21) has been reported as an essential factor that mediates longevity benefits from PR and amino acid restriction. Secretion of FGF21 takes place in response to reduced dietary protein in both humans and mice. Induction of FGF21 can also take place through KDs and methionine restriction. Modulation of life span in mice by FGF21 occurs mainly by reducing IGF-1 signaling and growth hormone in the liver.

Do anti-aging diets work?

There has recently been an increase in anti-aging diets in mainstream society. A CR researcher Roy Walford attempted to popularize CR in the 1980s. However, it did not grow beyond a few followers due to the severe discipline needed to maintain the CR lifestyle. However, several less stringent CR variations, such as KDs, TRF, PR, and IF, have gained popularity. However, it is still unclear whether CR-like diets affect biological aging in people.

Two lines of evidence that support the anti-aging effects of CR in humans are studies of Okinawans and the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) studies. However, laboratory nutrition studies might sometimes not apply to humans. Genetic background effects might also impact translation from laboratory models to humans. Moreover, differences in age and lifespan-associated nutritional requirements between laboratory rodents and humans make translation of anti-aging diets difficult. CR-like diets could improve longevity in some individuals while shortening lifespan in others. The nutritional strategy for longevity varies for different individuals, and only a few studies have explored the long-term and short-term side effects of anti-aging diets in adults.

mTOR inhibition

mTOR is reported to be an important molecular transducer of diet-induced anti-aging signals. mTOR is a kinase that uses mTORC1 and mTORC2 complexes to mediate nutrient response signaling. Inhibition of mTORC1 has been observed to delay or reverse age-related phenotypes in mice across multiple tissues. Several studies indicate that the anti-aging diets discussed above can inhibit mTORC1 signaling via indirect and direct mechanisms. The processes that help to mediate the life span–extending effects of CR downstream of mTORC1 inhibition include inhibition of mRNA translation, activation of autophagy, improved stem cell function, increased ketogenesis, attenuation of senescence-associated inflammation, and enhanced mitochondrial function. However, whether mTORC1 inhibition is a beneficial therapeutic strategy to combat aging in humans is still unclear.

Conclusion

Research on several anti-aging dietary interventions that increase health and life span has helped to understand the mechanism of biological aging. Several molecular targets have been identified to improve longevity and decrease the burden of human disease. However, the outcomes and risks of long-term implementations of such diets are still unknown. Further research is required to understand anti-aging diets' molecular and cellular mediators and the effects of environmental and genetic variation on diet-associated health outcomes.

Journal reference:

• Lee, M.B. et al. (2021). Antiaging diets: Separating fact from fiction. Science. doi: 10.1126/science.abe7365. https://www.science.org/doi/10.1126/science.abe7365