Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative pathogen of deadly Coronavirus disease-19 (COVID-19) pandemic, which emerged as a major threat to public health across the world. Although there is no clear gender or socioeconomic discrimination in the incidence of COVID-19, individuals who are older adults and/or with comorbidities and compromised immunity have a relatively higher risk of contracting this disease. Since no specific drug has yet been discovered, strengthening immunity along with maintaining a healthy living is the best way to survive this disease. As a healthy practice, calorie restriction in the form of intermittent fasting (IF) in several clinical settings has been reported to promote several health benefits, including priming of the immune response. This dietary restriction also activates autophagy, a cell surveillance system that boosts up immunity. With these prevailing significance in priming host defense, IF could be a potential strategy amid this outbreak to fighting off SARS-CoV-2 infection. Currently, no review so far available proposing IF as an encouraging strategy in the prevention of COVID-19. A comprehensive review has therefore been planned to highlight the beneficial role of fasting in immunity and autophagy, that underlie the possible defense against SARS-CoV-2 infection. The COVID-19 pathogenesis and its impact on host immune response have also been briefly outlined. This review aimed at revisiting the immunomodulatory potential of IF that may constitute a promising preventive approach against COVID-19.
Fasting and autophagy
Autophagy is exclusively important during periods of stress and starvation because of its role in furnishing cells with nutrients and energy by recycling fuel-rich macromolecules. Autophagy initiates with the triggering of Unc-51-like kinase (ULK) complex which is regulated by the mechanistic target of rapamycin (mTOR) that can sense nutrient levels in the environment. Under nutrient-rich conditions, mTOR phosphorylates ULK1/2 leading to the inhibition of autophagy. On the contrary, mTOR detaches from the ULK complex during periods of fasting or starvation leading to the activation of autophagy. In addition, AMP-activated protein kinase negatively regulates mTOR, and also directly activates ULK1 complex, thereby acting as a positive regulator of autophagy in response to nutrient depletion. Fasting also upregulates several other autophagy-related proteins such as Atg6, Atg7, Atg8, LC3-II, Beclin1, p62, Sirt1, LAMP2, and ATG101 and thus potentially modulates autophagy.
Autophagy inhibition positively influences viral replication or virulence. Many viruses inhibit autophagy by blocking autophagy-inducing pathways, AKT1/BECN1, for example, to promote virus replication. A recent study has validated that SARS-CoV-2 infection also suppressed autophagy. This study also demonstrated that the pharmacological intervention aimed at autophagy induction showed potentiality against this infection. Similarly, intermittent fasting (IF) that causes nutrient depletion, the most potent known physiological autophagy-stimulator, can induce autophagy. One study found that in rats that were starved for 24−46 h, most of the cells in almost every vital tissue had an increased number of autophagosomes . Autophagy inhibition abrogated the anti-aging effects of fasting, indicating that fasting mediates autophagy induction. Another study demonstrated that nutrient deprivation promoted longevity through the Sirtuin-1-dependent induction of autophagy. The beneficial roles of fasting-mediated autophagy promotion have also been reported in functional homeostasis of many organs and tissues. In addition to priming the host immune system, fasting-induced autophagy can improve cellular resistance to stress by increasing the metabolic buffering capacity of cells and thus preparing the human body to deal with various stresses
Fig. 2. Fasting mediates autophagy. Autophagy receives fasting signals through two metabolic sensors such as mTOR and AMPK. Under the condition of nutrient depletion, mTOR detaches from the ULK1 complex leading to the activation of autophagy. Whereas, AMPK negatively regulates mTOR, and also directly activates ULK1 complex, thereby acting as a positive regulator of autophagy in response to nutrient depletion. Beclin1 complex is another autophagy activator that is negatively regulated by mTOR. Once autophagy is initiated, cytoplasmic elements (cargo) to be recycled are engulfed into double-membrane vesicles, termed as autophagosomes, which fuse with lysosomes forming autolysosomes, where cargos are degraded. Autophagy is a multistep process that includes (1) initiation, (2) membrane nucleation and phagophore formation, (3) phagophore elongation, (4) docking and fusion with the lysosome, and (5) degradation, which are regulated by autophagy-related proteins (ATGs). mTOR, mechanistic target of rapamycin; AMPK, AMP-activated protein kinase.
Fasting and immune responses
IF reduces inflammation and thus could offer some promising health benefits in certain disease conditions such as obesity, asthma, and rheumatoid arthritis, to which inflammatory response is crucially implicated. Fasting enhanced insulin sensitivity and promoted cellular stress resistance, and thus help evolve resilience in immune response. IF improved clinical outcomes and caused a reduction of the biomarkers of inflammation (serum TNF-α) and oxidative stress (8-isoprostane, nitrotyrosine, and protein carbonyls) in asthma patients. IF, an age-old obligatory practice by Muslims during the Holy month of Ramadan (over 14 h daily for 30 consecutive days from dawn to sunset), caused upregulation of key regulatory proteins of metabolism, DNA repair, and immune system and resulted in a serum proteome protective against inflammation and associated lifestyle diseases. The potential molecular mechanism of fasting involves the triggering of adaptive cellular stress responses that prime host defense to confront with upcoming severe stress and counteract pathogenesis.
Reduction in fat mass correlates with a decline in serum pro-inflammatory cytokines, which indicates that approaches designed to promote fat loss could have beneficial outcomes, in particular, overcome the pro-inflammatory conditions associated with obesity. One such approach could be the IF that helps normalize the systemic inflammatory status of the body by suppressing proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and decreasing fat mass and circulating levels of leukocytes. Supporting these findings, another study showed that intermittent CR positively modulates pro-inflammatory cytokine pathways by reducing the serum cytokine (IL-6 and TNF-α) and adipokine (leptin and IGF-I) levels in wild type female C57BL6 mice. CR induces lipolysis resulting in the reduction of adipocyte size, increase adiponectin secretion, and reduce leptin, IL-1β, IL-6, VEGF-α, MCP-1, and CD-68 expression in white adipose tissue. CR also enhances functional beige fat in mice. CR reduces the numbers of circulating monocytes, as well as reduces monocyte metabolic and inflammatory activity in healthy humans and mice. In addition, fasting upregulates gene expression of type 2 cytokines (Il-4, Il-5 and Il-13) that are important for the polarization of M2 macrophage (anti-inflammatory).
Moreover, the potential immune-evading mechanism of SARS-CoV-2 that involves viral ORF3a-mediated persistent activation of NLRP3 can also be modulated by IF. During IF, conventional energy metabolism switches preferably towards fat catabolism with the production of ketones bodies as instant energy sources. The β-hydroxybutyrate (BHB), a major ketone body that fuels many vital organs during fasting/starvation, may also help mitigate inflammation by blocking NLRP3 inflammasome overactivation. As evident in experimental models, BHB reduced the production of IL-1β and IL-18 mediated by NLRP3 inflammasome in human monocytes and suppressed caspase-1 activation and IL-1β production in the mouse. These findings suggest that the anti-inflammatory effects of CR may be mechanistically linked to BHB-mediated inhibition of the NLRP3 inflammasome, and point to the potential use of interventions, IF as an example, that elevate circulating BHB against NLRP3-mediated proinflammatory diseases
Prospects of fasting against COVID-19 and future directions
Since the symptoms of COVID-19 are more severe in individuals with pre-existing conditions and deficient in immunocompetence, the possible preventive measures are to control prevailing diseases and to boost up immune system. As already proposed here, IF could be an effective approach that may help prevent SARS-CoV-2 infection. This strategy of dietary restriction can directly (by activating immune response ) or indirectly (by inducing autophagy) stimulate body surveillance system and boost up immunity, and thus prime host defense to cope with the confronting stresses. However, there is currently no experimental evidence that described the impacts of fasting against SARS-CoV-2 infection. Even no review proposed fasting as a preventive strategy against this disease. With addressing some salient physiological impacts of fasting on the host defense system, this review presents an insight into the potential benefits against SARS-CoV-2 infection that could be attained through observing . However, individuals with pre-existing conditions should be aware of the possible complications of IF as CR may worsen their disease conditions. Moreover, even among seemingly healthy individuals, unplanned fasting can sometimes lead to unexpected consequences. COVID-19 patients are strongly advised not to fast during the course of infection as these dietary restrictions may put them at risk of nutritional deficiencies essential for their immune system. Although the health-promoting potentials of fasting are supported by several experimental evidences, a detailed investigation is warranted with an appropriate experimental model to exploit the full advantages of fasting in the prevention of SARS-CoV-2 infection.
While IF is in practice in various religions and some of them have been proven to have potential health benefits, an appropriate fasting plan can also be adjusted on an individual basis. Along with observing IF, other health-benefiting practices such as exercise and meditation that help improve immunity are also highly recommended. Besides, a healthy diet enriched with functional ingredients that possess strong antioxidant, anti-inflammatory, and immunomodulatory properties should always be incorporated in the dietary chart. During fasting, care should be taken to ensure an adequate amount of essential micronutrients such as vitamin C, vitamin D, and zinc that help boost up the immunity and anti-stress mechanisms.
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