Fasting

Periodic Vs Intermittent Fasting: Which Is Better For Health And Longevity?

Posted on 15 March 2021

Dietary restriction (achieved by either reducing food intake without causing malnutrition or by eliminating specific dietary components) is emerging as a way to not only treat and prevent age-related diseases, but also to affect the molecular processes that are fundamental to cellular ageing. Dietary restriction (DR) can put our cells into a kind of ‘survival mode’, encouraging them to repair damage that is associated with ageing. While the long term effects of DR on human lifespan are still uncertain, there is strong evidence that animals – from worms to monkeys – live longer when placed on a such a diet.

Dietary restriction is a powerful and cost-free strategy you can adopt to reduce your risk of age-related disease and potentially live longer. However, there is a range of different dietary restriction methods, and not all of them are equal in terms of their benefits, risks, and achievability. Here, we are going to focus primarily on two of these methods, intermittent fasting and periodic fasting, and attempt to summarise the advantages and disadvantages of both. Please note, however, that this article is not medical advice, and that it is best to consult with a doctor before making significant changes to your diet.

Why Fasting?

Fasting diets are going mainstream — ahead of the science. Here's why. - Vox

Broadly speaking, dietary restriction could be divided into three categories: calorie restriction (a reduction in calorie intake, usually between 20% and 40%), restriction of specific dietary componenets (such as protein), and fasting (a significant reduction or complete elimination of food intake over a period of time).

All of the above methods have been associated with health benefits in humans, however, the first two have some drawbacks that may make them less favourable strategies. Prolonged calorie restriction of 15% can cause unwanted weight loss in humans, and more extreme calorie restriction can make mice more susceptible to certain infectious diseases. Strategies like protein restriction may not be safe for older individuals, as low protein intake is associated with greater frailty and disease in those over the age of 65.

Fasting practices are emerging as safer and potentially more effective forms of dietary restriction. Past research on DR has focussed on the effects of continuous calorie restriction, but fasting offers a different approach in which shorter periods of restriction are separated by periods of unrestricted feeding. This means that fasting doesn’t necessarily entail an overall reduction in calorie intake (you could fast one day but consume two days worth of calories the next, thought this doesn’t usually happen in practice). There’s also evidence suggesting that some of the benefits of fasting are not seen in continuous calorie restriction because they depend on these ‘refeeding’ phases.

The Main Fasting Strategies

There are two broad approaches to fasting: periodic fasting (PF) and intermittent fasting (IF). As their names may imply, these approaches are mainly defined by the duration and frequency of the fasting period.

Changes during a 24-hour fast. Glucose from glycogen stores remains the body’s primary fuel source.
Zero: The Physiology of Fasting

Intermittent fasting involves severely restricting or eliminating calorie intake for anywhere between 12 and 48 hours, usually repeated once a week or more depending on the duration and strictness of the fasting period. Some of the most common approaches to IF include:

  • Alternate day fasting (ADF): Complete fasting every other day.
  • Modified alternate day fasting: Very low calorie consumption every other day.
  • The 5:2 diet: Fasting or very low calorie consumption (500-700kcal/day) for two days a week (not necessarily consecutively).
  • Time restricted feeding: Restricting food intake to a limited time window each day, usually 6-12 hours long.
Changes during a 1-3 day fast. Glycogen is depleted, and ketone bodies produced from fat stores become the main energy source. A small amount of glucose is produced from non-carbohydrates for use by the brain.
Zero: The Physiology of Fasting

Periodic fasting, on the other hand, involves calorie restriction or complete fasting for 48 hours to a full week, or even longer in some cases. It is usually practised far less frequently than intermittent fasting (rarely more than once every two weeks), and is sometimes carried out on an ‘as needed’ basis rather than at specific intervals. The main PF methods are:

  • Prolonged fasting: Complete fasting for an extended period, often 3 days or longer.
  • Fasting-mimicking diet (FMD): A diet designed to have similar metabolic effects to fasting, with 30-50% reduced calorie intake for 4-7 days.
Changes during a 3-5 day fast. A steady state of ketosis is reached.
Zero: The Physiology of Fasting

Now that we have covered the basic fasting methods, it’s time to ask the important question: can the evidence tell us which of these strategies is likely to be the most effective for health and longevity in humans?

IF vs PF: Effects on Ageing

Fasting can undoubtedly extend lifespan in animal models, but to say whether fasting practices can actually slow ageing or extend human lifespan is more challenging. It is not feasible to study the long term effects of fasting in humans in the same way we do for animals – we can’t force a group of humans to practise fasting for their entire lives.

While we can study longevity in populations and individuals who already fast, this introduces all kinds of confounding factors. Another way in which we can approximate the effects of fasting on humans is to study risk factors for age related diseases and/or biomarkers of ageing. These are measurable changes that are associated with the biological ageing of a person’s tissues, rather than their chronological age – the number of years since birth. While this doesn’t necessarily tell us how long an individual will live, it does help us to understand whether their tissues are behaving like old tissues, and how this is affected by fasting.

So, how do the effects of intermittent and periodic fasting stack up? Both appear to be beneficial, even in healthy individuals. However, it is difficult based on current evidence to point to one strategy and say definitively that it is superior overall in terms of health benefits. What follows is a summary of some of the effects of these methods. However, until the evidence is more clear, it is arguably more important to choose a fasting regimen based on its safety and on how difficult it is to adhere to.

Intermittent Fasting:
All of the aforementioned methods of intermittent fasting have shown significant benefits (in many cases more so than calorie restriction) on a variety of biomarkers. Alternate day fasting, for example, has beneficial effects on markers of cardiovascular health, inflammation and low-density lipoprotein (LDL), also known as ‘bad cholesterol’. It also reduced fat mass. This was true even in healthy individuals who weren’t obese, whether they maintained their fasting pattern short term (4 weeks) or long term (6 months).

Graphical summary of the effects of ADF in healthy, non-obese humans.
Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans

Other intermittent fasting strategies have also proven to be effective for overweight individuals and those suffering from metabolic disease. Time-restricted feeding limits weight gain, improves sleep, reduces age-related cardiovascular problems, and improves the body’s ability to control blood sugar. In healthy midlife and older adults, restricting feeding to an 8 hour window for 6 weeks did not improve cardiovascular function, but did improve blood sugar control modestly and did not affect lean mass.

The 5:2 diet, meanwhile, seems appears to be roughly as effective as 25% calorie restriction in terms of weight loss, but more effective at reducing waist circumference and improving blood sugar control. The cardiovascular benefits of this diet are less certain, however.

Periodic Fasting:
Periodic fasting can produce similar kinds of changes as intermittent fasting strategies. In one study including 1,422 non-obese individuals aged between 18 and 99, participants reduced their calorie intake to 200–250 kcal for 4-21 days. This significantly reduced weight, abdominal circumference, blood pressure, blood sugar, LDL, triglyceride and cholesterol levels. Perhaps unsurprisingly considering the more extreme nature of PF, these changes were generally more significant than those observed in IF studies.

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Changes in lipid metabolism for fasting periods from 5-20 days. A: Triglycerides (TG) B: Total cholesterol (TC) C: High-density lipoprotein cholesterol (HDL-C) D: Low-density lipoprotein cholesterol (LDL-C).
Safety, health improvement and well-being during a 4 to 21-day fasting period in an observational study including 1422 subjects

The fasting-mimicking diets appear capable of achieving similar (though possibly less significant) benefits in healthy individuals. Three 5-day FDM cycles reduced weight and lowered blood pressure, as well as various other markers for age-related diseases. These changes were comparable to the effects of alternate day fasting in healthy individuals, but didn’t have much affect on fat metabolism in individuals at lower risk of age-related disease.

Both intermittent and periodic fasting strategies can be effective at reducing markers of age related disease even in healthy individuals, but periodic fasting has the potential to achieve more rapid and possibly more significant effects. There is also some evidence from animal studies suggesting that a minimum of 72 hours is required to achieve some of the cellular benefits of fasting. However, it’s not clear to what extent this would translate to health benefits in humans, and more research is needed to study how long the benefits of prolonged fasting persist after returning to a normal diet. Prolonged fasting is also limited by the frequency with which which it can be carried out, and is challenging to adhere to. For these reasons, it is difficult to single out a fasting strategy as superior in terms of health benefits alone.

IF vs PF: Safety

It is important to consider the potential side effects and dangers of each fasting strategy as these could in some cases reduce or even outweigh the potential health benefits. This is arguably the most important consideration when it comes to choosing a fasting method.

Managing Fasting Ketosis: Common Signs of Ketosis From Fasting
Symptoms of ketosis (aka ‘keto flu’) experienced by some people.
Perfect Keto

Intermittent Fasting:

Being the less extreme of the two approaches, intermittent fasting appears to be safer in general, though there is variability depending on the specific conditions of the fast. For example, one study found that alternate day fasting produced no side effects in healthy, non-obese individuals, even after 6 months. Time-restricted feeding periods of 12 hours or less also appear to be safe.

The safety of time restricted feeding lasting longer than this is less clear. There is some suggestion that it may be associated with negative health consequences, but it this may be due to factors outside of the fasting itself. For example, one of the most commonly used methods to fast for over 12 hours is to skip breakfast, which has been associated with increased mortality from all causes. We don’t currently know if this is caused by the fasting itself, or whether skipping a different meal would eliminate this risk. It’s also not known to what extent the effects of skipping breakfast are due to confounding factors – for example, those who skip breakfast may have more stressful jobs.

Periodic Fasting:

Prolonged fasting has the potential to be unsafe outside of a clinical environment because of the rapid decline in weight, blood pressure and blood sugar. Additionally, fasting can make existing nutrient deficiencies worse (such as vitamin D deficiency, estimated to be relatively common even in developed countries).

Observed and self-reported symptoms/adverse effects among 1311 individuals aged 18-99 who fasted for 4-21 days. Self reported symptoms were counted if they occurred at least 3 times during the fasting period.
Safety, health improvement and well-being during a 4 to 21-day fasting period in an observational study including 1422 subjects

Side effects are less likely to occur for shorter fasting periods, but we do not have a good understanding of the long-term effects of extended periods (weeks) of fasting. Periodic fasting also carries a greater risk of falling into a so-called yo-yo diet, in which a person may lose 10% of their body weight during each fasting period, but regain all of said weight during the feeding period. This cycle of weight gain and weight loss has been linked to increased mortality.

Conversely, fasting-mimicking diet cycles that alternate with normal feeding periods appear to be safe in humans while maintaining beneficial effects. However, we are in need of studies investigating the safety of FMD diets when they are carried out repeatedly over an extended period. Until then, it may be prudent to consider frequent periods of FMD as potentially unsafe.

Overall, confounding variables make it challenging to accurately assess the safety of different fasting approaches, but it seems likely that intermittent fasting techniques are safer. In the case of periodic fasting, prolonged fasts of more than 7 days should probably be avoided outside of a clinical setting. In all cases, fasting does not reduce the importance of eating a healthy diet during the feeding period.

The Take Home Message

Not all fasting strategies are equal in terms of health benefits and side effects, but it’s difficult to point to a clear winner based on current evidence. Here is a table summarising my own assessment of the research discussed in this article. Note that the entries in this table are generalisations based on current research, and will vary depending on age, weight, and many other factors. An 80 year-old is not going to be able to fast as safely as a 20 year-old, and someone who is overweight is likely to find fasting more difficult than a lean person.

Fasting MethodWeight LossImpact on age-associated markersDifficultySafety
Alternate Day FastingSimilar to calorie restriction, and may be more effective for the retention of lean mass.Impacts most markers in both healthy and at-risk individuals. AverageProbably safe for long periods.
Time Restricted FeedingSimilar to calorie restriction.Impacts most markers in at-risk individuals and some markers in healthy individuals.AveragePossibly unsafe for fasting periods >12 hours.
5:2 DietPossibly faster than calorie restriction, with a larger effect on waist circumference.Impacts most markers in at-risk individuals, with less well studied effects in healthy individuals.AverageProbably safe.
Prolonged FastingFaster than calorie restriction, but risk of weight returning.Impacts most markers in both healthy and at-risk individuals.HarderPossibly unsafe for >7 days or if practised too frequently.
Fasting Mimicking DietSimilar to calorie restriction.Impacts most markers in at-risk individuals and some markers in healthy individuals.EasierPossibly unsafe if carried out repeatedly over long periods.

If I were to personally choose a fasting strategy to follow based on the current evidence, it would depend on the outcome I wanted to achieve. If I wanted to lose a set amount of weight as quickly as possible, then I would choose prolonged fasting, as this approach produces the most rapid weight loss. I am young and healthy, and therefore less likely to experience adverse effects, and am confident in my ability to fast for an extended period. However, if I wished to fast for the benefits associated with ageing, I would not choose this method due to the fact that it cannot be practised regularly, and we don’t know how long benefits last. I would instead choose a method that can be maintained for long periods – most likely alternate day fasting because it appears to be beneficial regardless of health status, while also being relatively safe.


References

Intermittent and periodic fasting, longevity and disease: https://doi.org/10.1038/s43587-020-00013-3

Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans: https://doi.org/10.1016/j.cmet.2019.07.016

Short-term time-restricted feeding is safe and feasible in non-obese healthy midlife and older adults: https://doi.org/10.1007/s11357-020-00156-6

Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome: https://doi.org/10.1016/j.cmet.2019.11.004

Effects of 4- and 6-h Time-Restricted Feeding on Weight and Cardiometabolic Health: A Randomized Controlled Trial in Adults with Obesity: https://doi.org/10.1016/j.cmet.2020.06.018

The effect of intermittent energy and carbohydrate restriction v. daily energy restriction on weight loss and metabolic disease risk markers in overweight women: https://doi.org/10.1017/s0007114513000792

Caloric restriction decreases survival of aged mice in response to primary influenza infection: https://doi.org/10.1093/gerona/60.6.688

Aging, adiposity, and calorie restriction: https://tinyurl.com/yglnvkw5

Safety, health improvement and well-being during a 4 to 21-day fasting period in an observational study including 1422 subjects: https://doi.org/10.1371/journal.pone.0209353

Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease: https://doi.org/10.1126/scitranslmed.aai8700

Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans: https://doi.org/10.1016/j.cmet.2019.07.016

Association of Skipping Breakfast With Cardiovascular and All-Cause Mortality: https://doi.org/10.1016/j.jacc.2019.01.065

Prevalence of Vitamin D Deficiency and Associated Risk Factors in the US Population (2011-2012): https://dx.doi.org/10.7759%2Fcureus.2741

Body-Weight Fluctuation and Incident Diabetes Mellitus, Cardiovascular Disease, and Mortality: A 16-Year Prospective Cohort Study: https://doi.org/10.1210/jc.2018-01239

Prolonged Fasting reduces IGF-1/PKA to promote hematopoietic stem cell-based regeneration and reverse immunosuppression: https://dx.doi.org/10.1016%2Fj.stem.2014.04.014

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