Eat Less, Live Longer? Insights into the Geroprotective Effects of Calorie Restriction and Prolonged Fasting on Metabolic Health & Longevity

Introduction

It is well-established that calorie restriction can improve metabolic health in multiple preclinical models, as well as delay or at least slow down the rate of biological aging by reducing the incidence of developing age-related pathologies. Other dietary manipulations, such as complete fasting and/or time-restricted feeding, have also gathered attention as alternative approaches to improve metabolic flexibility and lifespan.

In a landmark publication in Nature Metabolism, Professor Dudley Lamming’s research group at the University of Wisconsin-Madison, a PhD student at the time, Dr. Heidi Pak, Ph.D., now a postdoctoral researcher in the Takahashi lab at the University of Texas Southwestern Medical Center, conducted an intricate study to decipher the effect of these various diets.

Here, we provide you with an overview of this study and the benefits and negatives of certain dietary models of calorie restriction. Moreover, we will briefly touch upon translating these findings to humans.

Background

Traditional life extension and longevity interventions are largely based on pharmacological therapeutics, such as Rapamycin [1], Acarbose [2], and Metformin [3], among several other drugs tested by the NIH’s Interventions Testing Program. However, a non-pharmacological and free alternative to these therapeutics could be as simple as restricting the number of calories you eat per day or the time window in which you eat your meals.

Calorie restriction is arguably one of the most powerful anti-aging and longevity-enhancing interventions [4]. The idea of calorie restriction is nothing new, and, in fact, dates back to the 1930s when the mechanisms were first pioneered by Professor Clive McKay, where he observed a life extension effect in male & female rats following a calorie-restricted diet compared to a standard ad libitum diet [5].

Since then, several research groups around the world have shown this in multiple preclinical models, such as worms, flies, mice, and non-human primates. As worms, flies, and mice are far from human-like, the closest possible species in which to study life extension therapies is non-human primates, such as Rhesus Monkeys.

These monkeys share 93% of their DNA with humans, and several aspects of their physiology, anatomy, endocrinology and immunology are directly parallel to that of humans.

A seminal 20-yearlong study published in Science Magazine by the team at The University of Wisconsin-Madison’s Primate Research Centre showed that simply providing 30% fewer calories per day to Rhesus Monkeys resulted in a reduction in age-related mortality by ~24%, as well as delayed onset of age-related pathologies such as cancer, cardiovascular disease, brain atrophy, overall showing a significant slowing of the aging process [6].

Alternatively, another dietary method, “Time Restricted Feeding” or “Intermittent Fasting”, has become increasingly popular over recent years, as it allows for the maintenance of normal caloric intake [7]. However, those calories can only be consumed within a limited ‘eating window’. Thereby, this method has an extended fasting period of up to 18 hours per day, with only a 6-hour period in which to consume your meals [8]. It is reported that this lengthened fasting period is responsible for improvements in metabolic health and favorable changes in body composition (i.e., reductions in fat mass and maintenance of lean mass) [9].

Interestingly, time-restricted feeding feeding has undergone recent advances, in which scientists are now attempting to align feeding patterns with circadian rhythms to further enhance its effect. A recent landmark paper in Science Magazine showed that caloric restriction, plus intermittent fasting in the morning (and eating at night), improved metabolic health & longevity compared to evening fasting (and morning eating) [10]. Thereby observing a new idea of aligning diets to biological rhythms. Unfortunately, the topic of circadian rhythms is being saved for another Healthspan article, where we will provide a more detailed review of them – So stay tuned!

Overall, both dietary methods work by minimizing the amount, or at least the time in which an individual is eating. In a world where access to cheap, high-calorie, and highly palatable foods is plentiful, the ability to overconsume these foods is relatively easy, resulting in the obesity epidemic across North America. Therefore, strategically minimizing caloric intake is an easy lifestyle change that can result in favorable changes to body composition and metabolic health, as well as potential life extension and reduction in age-related diseases.

Calorie Restriction vs Intermittent Fasting: Which is Better?

As part of her PhD thesis under Professor Dudley Lamming at the University of Wisconsin-Madison, Heidi sought to determine the differences between these diets and how they infer their metabolic and geroprotective effects [11].

One of the controversies Heidi wanted to solve was the role of fasting in the calorie-restricted diet. In traditional studies of calorie restriction in mice, they are subjected to a prolonged fast of ~22 hours and generally eat their 30% calorie-restricted diet within a ~2-hour window, therefore displaying a hybrid diet of combined calorie restriction and intermittent fasting.

In a series of elegantly controlled studies, she was able to determine the effect of the two feeding strategies – Here’s what she found.

It is notable, and important for context, to describe the FOUR dietary interventions Heidi provided these mice. The first diet was the standard ad libitum diet, in which the mice have access to as much food as they want to consume throughout each day.

The second diet was a standard ad libitum diet but with a manipulation via 50% dilution to eliminate fasting.

Thirdly, mice consumed a meal-feeding strategy where mice were fed at three distinct times of the day to mimic traditional eating behaviour and to prevent binge eating.

The last group was fed a standard 30% caloric-restricted diet in the morning, with a prolonged fasting period in between feeding.

So, what did Heidi and the Lamming lab find? They found that a prolonged fast is essential for the metabolic and lifespan-enhancing properties of calorie restriction. Although the group of mice received a 30% calorie-restricted diet, the feeding of three meals daily to mimic traditional dietary food intake blunted the metabolic adaptations associated with traditional calorie restriction.

Notably, the thrice-meal feeding frequency group lost significantly more lean mass than the once-per-day feeding, even though they consumed the exact same number of calories per day.

Eating a thrice daily 30% calorie-restricted diet for 12 weeks resulted in a ~17% reduction in lean mass. However, the once-per-day calorie-restricted feeding resulted in only a ~1.8% decline in lean mass. Similarly, insulin sensitivity was impaired in the same group. The traditional one-per-day calorie-restricted diet improved insulin sensitivity by >40% compared to the multiple-feeding group [11].

In a second mini-study by Heidi, she sought to clarify the importance of the fasting period, independent of calorie restriction. In this study, she had three separate groups: Ad libitum (eat as much as they want), traditional 30% calorie restriction, and the final group could eat as much as they wanted, but only in a three-hour time window, meaning they had a 21-hour fasting period in-between feeding [11].

Rather interestingly, Heidi showed that most of the benefits from calorie restriction were observed in the 3-hour feeding group, independent of how many calories they consumed. Both the calorie-restricted and time-restricted diets lost fat mass, but interestingly, there were differences in lean muscle mass regulation.

Notably, the calorie-restricted diet did not lose muscle mass, which is a good thing. However, the ‘eat whatever you like for 3 hours’ group saw a ~8% gain in lean muscle mass. Glycaemic control and insulin sensitivity were identical between the two groups, as were the ability to ‘burn fat’ through fat oxidation [11].

Overall, it shows that the time between meals is a critical aspect of improving metabolic health, but what about lifespan?

In these cohorts, Professor Lamming’s lab is a world leader in lifespan investigations, so this is exactly what Heidi did utilizing the first dietary interventions we discussed.

So, looking at the effects of traditional one-per-day feeding of a 30% calorie-restricted diet versus a 30% restricted diet, but access to food all day, thereby resulting in no fasting period. These diets can, therefore, tease out if it is the calorie restriction or prolonged fasting that enhances lifespan.

What she showed was that traditional calorie restriction improved lifespan by ~20%. Remarkably the 30% calorie-restricted diet that had food provided throughout the day resulted in a 9% decline in life expectancy!

Overall, this intricate study shows that just maintaining calorie restriction is not enough, and that the prolonged fasting period in between meals is critical to the lifespan-enhancing effects of the diet.

What About Humans?

As we’re all aware, translating something from mice to humans isn’t always as easy as it first seems, particularly when we factor in the major issue of mice traditionally only living until 30 months of age, while humans live to ~80 years of age—thereby making the translation of mice longevity & healthspan incredibly difficult to recapitulate.

Here, we’ll briefly delve into the short-term data in humans to see which diet is better and a more feasible approach to maintain as part of dietary and lifestyle changes aimed at longevity – What, then, does the human data suggest?

Monitoring mice in a laboratory is relatively easy compared to monitoring humans for weeks, months, and years, especially in response to a dietary intervention where adherence can be severely compromised. Nevertheless, the CALERIE: Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy study at Duke University has attempted to determine the effects of a 25% calorie-restricted diet on human health, which has resulted in more than 50 publications related to the project.

Over the last 5-years, they have published several high-impact studies showing improvements in body composition [12], insulin sensitivity [13], and resting metabolic rate [14]. However, this diet has minimal to no effect on molecular biomarkers, i.e., DNA methylation [15] and telomere length [15].

Interestingly, running a dietary study of this length has its own limitations, in particular, ensuring dietary adherence to the caloric restriction [12]. In the CALERIE study, the average calorie restriction was only ~11.9% over, albeit with decreases in fat mass, decreases in waist circumference, and increases in lean mass [12].

Comparing a 2-year study in humans that live until 80 years of age is only looking at 2.5% of their lifespan, compared to starting a calorie-restricted diet in a mouse at 3 months old, until they’re 30 months of age, equating to 90% of their life has been on a diet. Therefore, extrapolating human studies to understand their effects on lifespan and longevity is currently impossible. Therefore, while the mouse data is unequivocally beneficial for understanding potential impacts on longevity, establishing its effect in humans remains a task for future studies.