Posted on 4 July 2023
Over 100 years ago, scientists discovered a way to extend the lifespan of rats, and it was remarkably easy. Simply restrict the rats’ food intake sharply, and they would live significantly longer than their counterparts on a normal diet. This dietary restriction works in many other organisms including yeast, fruit flies and worms. Unfortunately, as animals become more and more complex, the effects of dietary restriction on health and lifespan get harder to study. Despite extensive research, we still don’t really know whether dietary restriction extends lifespan in humans, though it certainly seems to be beneficial for health.
There are countless different strategies for performing dietary restriction. How many calories you cut, what time of day you choose to eat and for how long, and what kinds of foods your calories come from are all factors that need to be considered when we study dietary restriction in humans. That last point is often overlooked: not all calories are equal, and that problem is the focus of the following article.
This review was published in Cell Metabolism, and summarises what we currently know about dietary restriction and its effects on healthy ageing. We’ll summarise the key points below – if you’re interested in practising dietary restriction for health and longevity, but aren’t sure what approach to take, you’ll probably find this information useful.
Important definitions and abbreviations:
One of the concerns surrounding CR in humans is the possibility that it might weaken the immune system, since studies in mice and some primates show they get more infections when calorie restricted. However, CR seems to be capable of strengthening the immune system in healthy humans. CALERIE II was a phase II randomised trial of calorie restriction lasting two years, and included 238 participants aged 21-50. Participants who reduced their caloric intake by 25% had a healthier thymus (the organ where immune cells are ‘trained’). They also had less inflammation and oxidative stress, as well as improved cardiovascular health and various metabolic benefits. These benefits didn’t depend on the timing or frequency of participants’ meals.
CALERIE II is also not the only study suggesting that moderate calorie restriction is safe and healthy, though some studies have reported downsides like reduced bone mass at similar levels of CR. A loss of bone mass is common during extreme weight loss, but seems to occur in CR even in people who aren’t overweight, which is a concern in older people who are already more at risk of fractures. However, at least some (if not all) of this bone loss is the result of reduced intake of important nutrients (like calcium and vitamin D) as part of the CR diet, rather than the calorie restriction itself. Studies suggest that supplementing with these nutrients as well as engaging in physical exercise during CR can prevent bone loss, but have so far only looked at young obese people.
While protein is an important component of a healthy diet, there’s evidence that some of the amino acid building blocks that proteins are made of are harmful, and that their elimination from the diet explains some of the benefits of CR. Specifically, methionine and branched-chain amino acids seem to be associated with worse metabolic health, leading to increased risk of obesity and diabetes. The evidence for this is stronger in animals than it is in humans, but suggests that reduced intake of proteins containing these amino acids can reduce risk of age-related disease, even if calorie intake remains the same.
These amino acids are generally most abundant in meat and dairy products, which may explain some of the health benefits of a vegan diet. However, older people need to be cautious about restricting their protein intake due to the associated risk of sarcopenia (muscle wasting). The effects of restricting specific amino acids require further study.
A ketogenic diet entails consuming little to no carbohydrates and usually eating more fat instead. In a ketogenic diet, the liver converts fat and protein into ketone bodies, which fulfil a similar role to glucose derived from carbohydrates. Ketone bodies will also be produced during a fast as the body runs out of stored carbohydrates.
Ketogenic diets seem to be beneficial for health and longevity, even when the number of calories consumed is unchanged. Mouse studies suggest that ketogenic diets reduce inflammation and improve cognitive function. These benefits are probably linked to both the ketone bodies themselves (which bind to receptors on cells to elicit positive effects) and to the elimination of glucose (lower blood glucose is generally associated with delayed ageing). More work needs to be done on the effects of ketogenic diets in humans.
TRF is a popular method for reducing calorie intake, and involves limiting feeding to a specific time window each day. Even though no limitation is placed on calorie consumption, the practice of TRF tends to reduce caloric intake. In human studies, restricting feeding to an 8-10 hour window seems to be the sweet spot: most people are able to adhere to it long term, and it still produces significant health benefits. Those benefits include reduced risk of cardiovascular disease and weight loss. Most TRF studies have been done in overweight participants, but the health improvements observed are disproportionately larger than those that might be expected from the observed weight loss, suggesting that there are other, intrinsic benefits to TRF.
So, where within the day should the eating window fall? That has been a very difficult question to answer, and there’s a lot of conflicting evidence. For example, some studies find that skipping breakfast is associated with health problems, suggesting that the eating window should fall earlier in the day. There are issues with this interpretation, however. If you want to read about this research in more detail, you can find a more in-depth article here.
What is the best way to harness diet to improve human health and lifespan? We still have a long way to go before we can answer that question. For example, our understanding of how sex and genetics interact with dietary restriction is still very lacking. Another problem is the effect of age. For example, we know that calorie restriction is less beneficial in old mice than in young mice, while protein restriction in old mice can be harmful, resulting in a loss of muscle mass.
As we touched on already, how the timing of dietary restriction affects health benefits also needs further study. Metabolic activity is tied to the circadian rhythm – the body’s 24 hour internal ‘clock’ that regulates sleep and many other processes. Not only can the time of day influence how we handle our calories, but anything that disrupts the circadian rhythm can also impact how diet (including DR) affects our health.
Finally, and perhaps most importantly, we still do not know whether any form of DR actually slows ageing or extends lifespan in humans. To show that it does, we would need clinical trials lasting many years, but getting people to adhere to DR for that long is hard and might not even be safe. Scientists are currently trying to develop drugs that mimic some of the beneficial effects of DR strategies, such as ‘ketodrugs’ (which seem to mimic the consumption of a ketogenic diet). If these drugs are safe and effective, they may provide us with the answers we’re looking for.
When a calorie is not just a calorie: Diet quality and timing as mediators of metabolism and healthy aging https://doi.org/10.1016/j.cmet.2023.06.008
2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial https://doi.org/10.1016/S2213-8587(19)30151-2
Decline in Bone Mass During Weight Loss: A Cause for Concern? https://doi.org/10.1002/jbmr.2754
Title image by mdjaff on Freepik