A new study by American researchers from Intermountain Medical Center-Utah, Stanford University-California, University of Utah, Rocky Mountain University of Health Professions-Utah and University of California San Diego has found that intermittent fasting helps prevent the risk of COVID-19 disease severity.
The study findings were published in the peer reviewed British Medical Journal Nutrition, Prevention & Health.
In patients who previously enrolled in the INSPIRE registry and subsequently tested positive for SARS-CoV-2 in 2020 or early 2021 prior to widespread vaccination, subjects who reported engaging in routine periodic fasting for an average of >40 years had a lower risk of hospitalisation or mortality after COVID-19 onset.
This result was found in younger and older individuals, was present regardless of race or ethnicity, and did not depend on other cardiac risk factors, comorbidities or behaviours. Periodic fasting did not, however, predict whether or not a subject would be infected by SARS-CoV-2.
The degree to which COVID-19 resulted in hospitalisa- tion and mortality throughout the world varied substan- tially during the pandemic. This is due to many health, medical, biological and healthcare issues, as well as social and political challenges, that resulted in a complex patch- work of differences in risk of hospitalisation and mortality across populations.
Some of the factors involved in that variation include a population’s age distribution, its racial and ethnic composition, cardiovascular risk factor preva- lences, and the distribution of comorbidities.19 20 Various mitigating factors specific to populations may also have lowered the severity of COVID-19.
Prior to SARS-CoV-2 vaccines, Utah and Alaska were the only US states with a COVID-19 case fatality rate <1% (both were 0.5%).21 Alaska has the 49th largest state population and before December 2021 had 47th highest number of COVID-19 cases.21 Its low case fatality could be anticipated because it is a geographical isolate to which COVID-19 arrived relatively late.
Alaska’s public health officials had time to prepare and execute an aggressive mitigation programme that delayed widespread infection. Further, Alaska has the lowest number of nursing home beds in the USA (at 700 beds, vs Utah’s 8500 beds).22
Utah has the 30th largest state population and before December 2021 had 28th highest case count,21 and shares some characteristics with Alaska that are relevant to COVID-19 severity: Utah has the lowest median age in the USA (Alaska has the second lowest) and is ranked as the state with the fourth lowest rate of coronary heart disease (Alaska is ranked eighth lowest).23
A low case fatality rate in Utah could also have occurred because the state has the lowest smoking rate in the USA, has a limited racial/ ethnic diversity (39th highest proportion of minorities), and had various healthcare system efforts that may have limited the severity of cases. Finally, Utah has the lowest per capita ethanol consumption in the USA that may have limited the spread of COVID-19 at bars and other social locales, but a connection of alcohol to COVID-19 severity is unconfirmed.
Given those characteristics of the Utah population, when survival analyses adjusted here for age, smoking, alcohol, race, ethnicity, CAD history, MI history, HF history and other factors, periodic fasting remained an independent predictor of a lower risk of hospitalisa- tion or mortality. Because >60% of Utah residents are members of the LDS Church, routine periodic fasting is a common practice in the state.
In this and previous studies at Intermountain, 27%–36% of all patients reported routinely engaging in periodic fasting,13–15 and had done so for more than four decades on average (with age averaging >60 years).15 Although these data suggest that only about a third of the Utah population engages routinely in periodic fasting, this is substantially higher than in other US states and may have contributed to the low COVID-19 case fatality rate for the state.
Periodic fasting was previously reported to be associ- ated with lower mortality and lower HF incidence in a cohort of almost 2000 patients.15 A trend towards lower MI incidence was also found in that study.15 Further, peri- odic fasting was associated with a lower risk of CAD and a lower risk of diabetes in cross-sectional studies.13 14 In the present study, in addition to the association of periodic fasting with a lower risk of hospitalisation or mortality, various factors including many comorbidities were asso- ciated with a greater risk of hospitalisation or mortality. These findings support published predictors of COVID-19 severity,19 20 and extend the list by adding routine fasting as a predictor of lower COVID-19 severity.
Previously in a study of 24-hour water-only intermittent fasting, fatty acids including linoleic acid were increased during fasting.4 Linoleic acid locks the spike protein of SARS-CoV-2 in a conformation that is not conducive to the effective binding to ACE2.5 Elevated linoleic acid during fasting may, thus, lessen the number of infected cells or the number of SARS-CoV-2 virions in cells and thereby decrease the severity of COVID-19.
Ketogenic diets that cause a switch of energy source from glucose to fatty acids/ketones should also provide this benefit. This provides one mechanism in which fasting may directly enhance immune function related to COVID-19 mitiga- tion, while other more general immune-related mecha- nisms exist.
A loss of appetite is a typical response to infection, which may indicate that the human body has intrinsic mechanisms for initiating fasting in order to activate the immune system, as proposed by an animal study.24 While that finding requires testing in humans, other evidence supports the activation of general immune responses and autophagy by fasting.25 26
Interestingly, small human studies reveal that intermittent fasting blunts CD4+ T cell responsiveness during fasting by upregulating insulin- like growth factor binding protein 1 and FOXO4/ FK506-binding protein 5,27 28 and that fasting generally suppresses the production of proinflammatory cyto- kines.25 Often in severe COVID-19 the human immune system over-reacts to SARS-CoV-2 infection and the consequent hyperinflammation can result in respiratory failure.29
Fasting during an active infection could, thus, bolster the immune response through pathways not involved in the standard inflammatory response to infec- tion while minimising severe inflammatory outbursts. It may also counteract the inhibition of autophagy that is caused by SARS-CoV-2.30 31 Immunomodulation by fasting and its effects on autophagy with respect to COVID-19 require further study.
Very frequent intermittent fasting such as alternate-day fasting or uninterrupted multiple-day fasting is chal- lenging. Even lower frequency or shorter duration fasting (eg, 16-hour time-restricted eating18 or 24-hour once- per-week fasting32) over a long period of time (ie, years/ decades) may prevent chronic disease onset or reduce the severity of existing chronic diseases13–15 and, thus, prepare the body to prevent severe COVID-19 outcomes.26
This may occur as fasting prevents or treats morbidities13–15 32 33 that increase the risk of severe COVID-19 outcomes, such as CAD, MI, HF and diabetes.19 20 A variety of mechanisms may be involved in the long-term prevention and treat- ment of those diseases (which mechanisms are beyond the scope of this study),4 6 16–18 26 30–37 and, as a preventive health practice, periodic fasting may indirectly prevent severe COVID-19 by its long-term impacts on those disease mechanisms and comorbidities.25 26 38
Finally, a periodic fasting lifestyle may condition the body by elevating basal levels of key physiological parameters in preparation for insults such as infection. A randomised human study of low-frequency (once-per- week) 24-hour water-only intermittent fasting showed that fasting increased basal galectin-3 level over a moderate term (6 months).6
Galectin-3 is integrally involved in host defence to infectious diseases.7 11 12 Further, galec- tin-3 stimulates anti-inflammatory effects by modulating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome,8 which should inhibit the hyperinflammation associated with COVID-19.
The routine practice of once-per-month fasting for >40 years that is reported here is lower-frequency fasting over a longer term and may have conditioned the body by elevating basal galectin-3 and optimising basal levels of other factors that aided in preventing severe complica- tions of COVID-19. Further study is needed of how fasting may impact the human immune system.
This study is potentially limited by the observational nature in which subjects engaging in periodic fasting were not randomised to the behaviour. Incomplete adjustment for important confounders or failure to measure some confounders may have limited the ability to correctly assign risk to the variables under study.
However, 36 covariables were evaluated and none of them substantially modified the association of periodic fasting with hospitalisation/mortality, including smoking and others that may share some covariation with periodic fasting in the study population. The enrolment of study partic- ipants at the time of angiography may have introduced selection biases that further limit the study; figure 1 and online supplemental table S1 provide information about enrolment characteristics.
Fasting history was self-reported after years of partici- pation in the practice, which may have caused data to be imprecise due to recall bias; however, the vast majority of people who report fasting also report membership in the LDS Church (89%–92% in past evaluations13 15) and fast routinely for religious purposes, thus the average definition of periodic fasting here is a 24-hour fast once per month that was followed consistently for an average of 40.4 years (see Results).
More than 60% of Utahns identify as members of the LDS Church; however, since fewer than half of LDS Church members report that they engage in periodic fasting,13 15 many of the other factors that may be systematically shared in the Utah population (eg, not smoking, not drinking alcohol, being married) were shared by both those who engaged in fasting and those who did not.
Consequently, confounding from systematically shared religion-related characteristics is less of an issue for this study than may be commonly assumed. Additionally, adjustment for variables such as smoking, alcohol use, marital status and other factors corrected for shared health-related characteristics that could confound the association of periodic fasting with study outcomes.
The case fatality rate in the USA was around 3% prior to the advent of SARS-CoV-2 vaccines,21 and this study’s mortality rate was similar: 6 of 205 subjects (2.93%) died. This partly reflects that this population was a higher-risk group than the general population due to the prevalence of morbidities, older age and existence of cardiovascular conditions requiring medical care.
Thus, the findings of this study may not generalise to the overall population and interpretation should be made with caution. Unfortunately, no data on common side effects of fasting such as muscle loss were available here and such potential side effects should be considered in future studies.
As with all medical interventions, assessment of the risks and not just the benefits of intermittent fasting should be made when considering its use for health purposes, including for people with chronic diseases.39