How Intermittent Fasting Impacts Longevity: A Summary of the Research

Intermittent fasting (IF) has risen in popularity, as numerous studies continue to illustrate its many benefits. In humans, intermittent fasting improves weight, insulin resistance, inflammation, dyslipidemia, and hypertension.[1] IF has also reduced tumor growth, boosted stem cell production, and increased lifespan in mice.[2] One compelling explanation for these outcomes relates to a term called adaptive stress—a type of physiological stress that elicits positive responses. During fasting, cells undergo adaptive stress, which activates different pathways in the body, resulting in a range of effects, including increased production of antioxidants, DNA repair, autophagy (the removal of damaged or dead cells), and decreased inflammation.[1]



Some scientists believe these responses could translate into a healthier, longer life for humans. So, what does the clinical evidence show? Do these cellular mechanisms really lead to detectable longevity changes in humans? This article examines the research on intermittent fasting and human longevity, as well as the mechanisms that may link the two.

Before we dive in, here is a quick overview of three types of IF widely studied in humans:

• Time-Restricted Feeding (TRF): eating is limited to a specific time window (i.e., 10 am-6 pm) followed by an overnight extended fast. 
• Alternate Day Fasting (ADF): fasting or a restricted caloric intake (~<20%) occurs every other day.
• 5:2 Intermittent Fasting: fasting takes place two days of the week while regular food intake happens on the other five. 



Intermittent fasting improves markers of oxidative stress, a measure of longevity

Many scientists agree that cellular oxidative stress can significantly influence the rate at which we age. Oxidative stress stems from an imbalance between free radicals and antioxidants in the body. Free radicals are generated by both external sources and internal metabolic pathways, and can damage cells, proteins, and DNA. Antioxidants, substances produced by the body and found in various foods, help neutralize free radicals' harmful effects. Scientists and experts agree that, by limiting free radicals and increasing antioxidant content in the body (thereby reducing oxidative stress), we can help slow down the aging process. 

A study from 2007 analyzed markers of oxidative stress and inflammation in ten overweight adults. The subjects followed an alternate day fasting approach, where they consumed less than 20% of their normal caloric intake (around 300-400 calories) every other day. After two months, participants displayed significant reductions in oxidative stress markers (protein carbonyls, nitrotyrosine, and 8-isoprostane) and an increase in the antioxidant uric acid. Participants also lost 8% of their body weight and had improved cholesterol, triglycerides, and inflammation markers.

In 2018, researchers sought to learn about the effects of IF (including oxidative stress) independent of weight loss. The supervised controlled trial involved 100 men with prediabetes who followed an early time-restricted feeding window (eTRF, 6-hour feeding period, last meal before 3 pm) for five weeks, then switched to a control schedule (12-hour feeding period) for an additional five weeks. While eTRF did not improve glucose levels or LDL and HDL cholesterol, it did significantly improve insulin sensitivity, blood pressure, and appetite. The early TRF also improved the oxidative stress marker, 8-isoprostane, but mainly because this marker worsened during the control period. Of note, this study provided subjects with calorie-dense meals to maintain their weight, including pretzels, alfredo pasta, and dinner rolls with butter. Administration of more nutrient-dense meals may have resulted in more positive results.  

Only a limited number of studies examining IF’s effects on oxidative stress have been performed, but a few clinical trials like this one are underway.

Figure 1. Effects of Early Time-Restricted Feeding observed in clinical trials Reprinted from "Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even Without Weight Loss in Men with Prediabetes,” Sutton, et al. 2018, Cell Metabolism vol. 27,6.



Intermittent fasting can protect humans from age-related diseases, according to two reviews

As we age, we become more susceptible to disease. Metabolic processes slow down, the immune system weakens, and the production of essential enzymes and antioxidants declines. The rate at which we age also depends on our lifestyle choices such as diet and exercise. This combination make us more susceptible to certain illnesses, including cardiovascular disease, diabetes, Alzheimer’s Disease, and cancer.

This 2017 review authored by one of the world's leading longevity scientists, Valter Longo, found intermittent fasting improved several aspects of age-related diseases in humans. Various studies included in the review showed that IF protected against type 2 diabetes and cardiovascular disease. The studies included health indicators measured both at baseline and after periods of two to six months of intermittent fasting. Two years later, a second review published in The New England Journal of Medicine (the world's leading medicine journal) showed similar results. The authors concluded that numerous clinical trials indicate that intermittent fasting has broad-spectrum benefits for many health conditions and age-related diseases, including diabetes mellitus, cardiovascular disease, cancers, and neurologic disorders.

Early time-restricted feeding positively impacts sirtuins and autophagy

In a 2019 crossover study, researchers analyzed numerous markers related to longevity, including blood glucose, autophagy, and oxidative stress. A group of 11 overweight adults followed an eTRF schedule, during which they consumed food only between 8 am and 2 pm for four days. They later switched to a regular TRF schedule of 8 am to 8 pm for another four days. Participants received the same three daily meals during each schedule; no other food or beverages were allowed. On days three and four, participants had to avoid exercise and caffeine. Compared to the control schedule, eTRF significantly improved glycemic control by reducing 24-hour glucose levels and fasting glucose and insulin levels.  Blood glucose is the body's primary source of fuel, and maintaining optimal levels contributes to overall health and longevity. A wealth of peer-reviewed scientific literature suggests that longevity can be predicted by an individual's fasting glucose levels.

Figure 2. Changes in autophagy gene expression during eTRF. Reprinted from "Early Time-Restricted Feeding Improves 24-Hour Glucose Levels and Affects Markers of the Circadian Clock, Aging, and Autophagy in Humans,” Jamshed, et al. 2019, Nutrients vol. 27,3.



Furthermore, the eTRF schedule resulted in higher production of the longevity gene SIRT1 and the autophagy gene LC3A, +10% and 22%, respectively. SIRT1 is the most widely studied of the sirtuin family, a class of proteins involved in longevity and aging. Several studies also indicate that sirtuin activity declines with age.[3] Autophagy is a process in which our body removes dead or damaged cells to make new healthier cells, a form of cellular housekeeping. It plays an essential role in many biological processes and has shown to be protective against age-related illnesses. Therefore, increased autophagy may play a role in anti-aging. This study indicates that eTRF could potentially have anti-aging and longevity effects. Of note, no changes were noted in antioxidant levels related to oxidative stress.

Intermittent fasting increases survival rate

A 2019 abstract, published in the American Heart Association’s’ journal Circulation, analyzed intermittent fasting and its direct effects on longevity. The researchers followed over 2,000 subjects between the ages of 63-67 who underwent cardiac catheterizations. Of the 2000 subjects, 380 described themselves as routine fasters (minimum of five years). The fasters had a greater survival (-49% risk of death) compared to the non-fasters. Interestingly, new adopters of fasting (those who had fasted less than five years) experienced no survival benefit. This study indicates that routine long-term intermittent fasting is associated with greater longevity. The abstract did not disclose the type of intermittent fasting the participants engaged in. 

Please note, intermittent is not for everyone—individuals who are underweight, under 18 years old, pregnant or breastfeeding, have a history or currently struggle with eating disorders, and those with diabetes, or on certain medications should refrain from intermittent fasting. Before beginning intermittent fasting, we recommend consulting with a doctor or dietitian to see if it’s appropriate for you. 

A summary of intermittent fasting's effects on longevity

• During fasting, cells undergo an adaptive stress response that may account for its many beneficial effects.
• Alternate-day fasting improves markers of oxidative stress, a measure of longevity.
• Intermittent fasting has shown to protect against many age-related diseases including diabetes and cardiovascular disease. 
• Early time-restricted feeding (in which the last meal of the day is eaten before late afternoon) can lead to an increase in sirtuin (a key protein family associated with longevity and aging) and autophagy expression (the clearing of unhealthy cells).
• Routine long-term intermittent fasting may result in greater longevity. 
• Consult with a doctor or dietitian before beginning intermittent fasting. 

References

[1] https://www.gwern.net/docs/longevity/2019-decabo.pdf

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627766/

[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112140/