Can we improve how we age and how long we live by restricting what we eat? Nearly all signs point to yes. In this article, I will describe three major categories of dietary restriction that have been explored: caloric restriction, alternate-day fasting, and prolonged fasting. I will explore the evidence of their efficacy as well as some of the limitations that stand in the way of our understanding of this topic. (In case you missed it, the first blog in this series is available here.)

Numerous studies on a diverse range of organisms, including bacteria, yeast, worms, flies, rodents, and primates, have shown that dietary restrictions, such as chronic or intermittent fasting, can slow down biological aging and increase maximum lifespan substantially, by up to 50% in some protocols. Some of the mechanisms by which these different dietary restriction regimens work have been identified. Many of them are metabolic pathways that are shared across species, including humans. It is, therefore, reasonable to think that the beneficial effects on lifespan, in a worm or mouse, for example, could also occur in humans. Definitively proving this, however, is difficult because longevity studies to utilize any intervention in humans inherently require decades of adherence to a protocol, along with decades of follow-up by the research team. That’s why we love to do aging research in worms that have a twenty-day lifespan! But ultimately, to move from non-human intervention to safe and effective human application, we need to study promising interventions in humans. The good news is that human studies have been carried out, but instead of directly measuring lifespan, biomarkers are used. Biomarkers are biological characteristics that can be objectively measured today that can predict important health outcomes—in this case, biological aging.

 

Caloric restriction

Caloric restriction in rodents and primates involves the reduction of caloric intake by 20-40% than that of ad libitum intake, which can be interpreted as the amount of food intake that happens when food access is unrestricted. Despite the reduced caloric intake, the animals are provided sufficient amounts of nutrients and vitamins to avoid malnutrition. Most studies on animals initiate caloric restriction during the weaning phase and continue throughout the animal’s lifespan, but some studies have tested its effects in as little as ten days. In these animals, the greater the magnitude and duration of caloric restriction are, as long as malnutrition and starvation do not occur, the greater the benefits on longevity become. Beneficial effects are seen in biomarkers that indicate better functioning of the cardiovascular, glucose regulating, and immune systems, as well as reduced oxidative stress and inflammation. In animals, caloric restriction also maintains nerve function, reduces tumor growth, and reduces sarcopenia, which is the loss of muscle tissue and size in response to aging.

The majority of studies that look at reduced calorie intake in humans involve healthy, middle-aged, non-obese men and women, where calories are restricted to about 75-80% of normal intake, and typically instituted for 6-12 months. Instead of directly measuring longevity, biomarkers associated with biological aging are used. The results show that calorie restriction in humans lowers total cholesterol, triglycerides, blood pressure, and carotid wall thickness, and attenuates the age-related decline in diastolic function (the phase of the heartbeat when the heart muscle relaxes and allows the chambers to fill with blood). It also decreases circulating insulin and glucose levels while increasing insulin sensitivity. Studies also indicate reduced oxidative stress and enhanced verbal memory. Overall, these improvements are expected to contribute to extended lifespan in humans.

The combination of caloric restriction plus exercise has also been explored. Animal studies, most often on male rats on voluntary wheel-running, show that caloric restriction plus exercise does not extend lifespan further than does calorie restriction alone. The results on biomarkers are mixed, generally showing benefits in cardiovascular health, muscle function, and age-related muscle loss, but showing no additional benefits on degrees of inflammation or oxidative stress. The effects of varying exercise types, intensities, volumes, and frequencies require much more investigation to understand better the potential benefits of this combination of healthy aging strategies.

Human caloric restriction plus exercise studies typically induce total caloric reduction by 25%, with 12.5% coming from exercise-induced expenditure and another 12.5% coming from reduced caloric intake. Exercise is usually aerobic, done several days per week. Again, findings on biomarkers are mixed. However, caloric restriction plus exercise has an advantage over calorie restriction alone in that it allows for a more manageable reduction in food intake. My guess is that a high satiety-per-calorie diet, like Stephan Guyenet, Ph.D. and I created in the Simple Food Diet for the Ideal Weight Program, would also make for an excellent longevity diet because it allows for adequate satisfaction from food on fewer total calories per day, theoretically. Additional modifications to this eating pattern, like for example protein restriction or even specific amino acid restriction, could yield additional benefits.

 

Alternate-day fasting

Alternate-day fasting is the best-characterized form of fasting in rodents and humans. 24-hour periods of ad libitum intake (“feast”) alternate with 24-hour periods of partial or complete restriction of caloric consumption (“fast”). As such, these regimens do not necessarily limit total caloric intake over time. In animal trials, alternate-day fasting causes reductions in resting heart rate and blood pressure and improvements in heart rate variability. Increased insulin sensitivity and glucose tolerance, as well as lower fasting glucose and insulin concentrations, are also seen. Such improvements in cardiovascular function and the regulation of blood glucose, along with the delayed development of cancers in these animals, are thought to explain how alternate-day fasting extends lifespan. Interestingly, a newer mechanism by which this fasting pattern may benefit our health is by increasing brain-derived neurotrophic factor – best known by its acronym, BDNF – which acts on existing neurons to keep them healthy, and also helps in the development of new neurons and synapses. And remember, healthy nerve functioning is critical to healthy non-brain organ function, too!

In human trials, subjects are usually allowed to eat 0-50% of the estimated daily energy required to maintain body mass during fast periods. Few human alternate-day fasting studies last longer than 20 weeks and many trials have lasted only a few days. Most people can comply with the regimens and few experience complications related to the dietary restrictions. However, subjects often report hunger and irritability during fast days as measured with questionnaires, making such interventions difficult to sustain. Despite being allowed to eat ad libitum on feast days, human subjects sometimes experience weight loss as a result of the regimen. This is in contrast to animals, which often maintain body weight by gorging themselves during feast periods. An 8-week long alternate-day fasting regimen on overweight asthmatic subjects showed improved peak expiratory flow rates within two weeks, with greater benefits from albuterol administration and improved quality of life following the full alternate-day fasting regimen. Albuterol is an inhaled β2-receptor agonist, which is a class of drugs used as first-line treatment for bronchial asthma. Over the course of several years of following more than 500 subjects who underwent alternate-day fasting, Johnson and colleagues noted benefits in: insulin sensitivity, seasonal allergies, autoimmune diseases such as rheumatoid arthritis, osteoarthritis, infectious diseases of viral, bacterial, and fungal origin, inflammatory central nervous system lesions involved with Tourette’s syndrome and Ménière’s disease, cardiac arrhythmias, and menopause-related hot flashes.

 

Prolonged fasting

Prolonged fasting is well-investigated in rodents. For mice, water but not food is consumed for two or more consecutive days, at least one week apart. In humans, prolonged fasting can be carried out as infrequently as once a month. In both animals and humans, prolonged fasting has similar benefits as alternate-day fasting regarding benefits on cardiovascular, glucose regulation, and immune function, and levels of inflammatory and oxidative stress. A testament to its efficacy in controlling inflammation is that when prolonged fasting is followed by a vegetarian diet, it can reduce both inflammation and pain in patients who have rheumatoid arthritis. Studies also suggest that it may decrease the adverse effects of chemotherapy in humans, a finding now being tested in multiple larger randomized clinical trials. One difference between alternate-day fasting and prolonged fasting is that the former causes more frequent but less pronounced changes in the molecular markers of the potential age-extending pathways. It remains to be studied how these factors can be optimized to extend lifespan.

Alternate-day fasting and prolonged fasting have few adverse effects, but because both require more intense restrictions in energy intake, they could be dangerous for those who are of very low BMI, those who are frail and old, and patients with diabetes receiving insulin or insulin-like drugs. Although major adverse effects with these interventions are rare and usually reversible, it is not advisable for such individuals to undergo these regimens. Medical supervision by a health professional familiar with such interventions is recommended.

 

Conclusion

These interventions, although promising, will be challenging for many to adhere to, and may be difficult for many (if not most) people to sustain for very long, even if in the future they were to be proven effective. Given my proclivity towards the behavioral aspects of health, I’m always keen to see compliance rates. I also often refer to something called “interventional impact,” which refers to the net benefit of a therapy considering participant compliance plus interventional efficacy. If, for example, you have a therapy that is 80% effective, but only 5% of people can comply with it, you do much more good with a therapy that is half as effective but more people can adhere to it. In the next article, we will look at two other forms of dietary restriction that I think will be better options for more people and, therefore, are therapies that will likely exhibit greater interventional impact.

 

References

1. Longo VD, et al., (2015) Review: Interventions to Slow Aging in Humans: Are We Ready? Aging Cell 14, 497-510.

3. Trepanowski JF, et al., (2011) Review: Impact of caloric and dietary restriction regimens on markers of health and longevity in humans and animals: a summary of available findings. Nutrition Journal 10:107.
4. Johnson JB, et al., (2006) The effect on health of alternate day calorie restriction: eating less and more than needed on alternate days prolongs life. Med Hypotheses 67:209-211.