It may be helpful to have a deeper understanding of cellular autophagy and its regulation in mammals. Autophagy is considered an evolutionarily conserved response to cellular stressors. Particularly the absence of nutrients and growth factors as in calorie restriction are strong inducers of autophagy. Other forms of stress that induce autophagy are DNA or protein damage, reactive oxygen species (ROS), or pathogens. To quote a recent review, “Autophagy is a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is generally thought of as a survival mechanism, although its deregulation has been linked to non-apoptotic cell death. Autophagy can be either non-selective or selective in the removal of specific organelles, ribosomes and protein aggregates. In addition to elimination of intracellular aggregates and damaged organelles, autophagy promotes cell surface antigen presentation, protects against genome instability and prevents necrosis, giving it a key role in preventing diseases such as cancer, neurodegeneration, cardiomyopathy, diabetes, liver disease, autoimmune diseases and infections”.
https://www.nature.com/articles/cddis2017161
Given the central role of autophagy in maintaining healthy cell function and intracellular pathogen clearance, it is not surprising that it is under tight regulation and that many viruses seek to alter or disrupt autophagy. Nonetheless, autophagy is also essential for basal homeostatic maintenance, as shown in animal models in which autophagy is disrupted in a tissue-specific fashion, leading rapidly to the massive accumulation of damaged proteins and organelles within autophagy-deficient tissues. The regulation of autophagy by signaling pathways overlaps the control of cell growth, proliferation, cell survival and death. The evolutionarily conserved TOR (Target of Rapamycin) kinase complex 1 plays an important role in the control of autophagy by growth factors, nutrients, calcium signaling and in response to stress situations, including hypoxia, oxidative stress and low energy. The Beclin 1 (Atg6) complex, which is involved in the initial step of autophagosome formation, is directly targeted by signaling pathways.
Autophagy is responsive to metabolic regulation by sirtuin family proteins whose functions are involved in specific aspects of longevity, stress response and metabolism. Sirtuins act as cellular energy sensors and direct the cell to match energy needs to energy production and consumption. Sirtuins, particularly SIRT1 and SIRT3, can be activated by fasting and further exhibit their effects in insulin response, antioxidant defense, and glycolysis. SIRT1, an NAD-dependent deacetylase, plays a role in regulation of autophagy. SIRT1 increases mitochondrial function and reduces oxidative stress, and has been inversely correlated with advanced-age related reactive oxygen species (ROS) generation, which is highly dependent on mitochondrial metabolism. Metabolic stress can lead to changes in the redox state of nicotinamide adenine dinucleotide (NAD), a co-factor in a variety of enzymatic reactions and thus trigger autophagy that acts to sequester intracellular components for recycling to support cellular growth. Likewise, autophagy is activated by oxidative stress to selectively recycle damaged macromolecules and organelles and thus maintain cellular viability.
In human embryonic stem cells, H2O2 induces oxidative stress and autophagic cell death through interference with Beclin 1 and the mTOR signaling pathways. Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell proliferation. It interacts with many cofactors to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes, thereby inducing autophagy. In contrast, the BH3 domain of Beclin 1 is bound to, and inhibited by Bcl-2 or Bcl-XL. This interaction can be disrupted by phosphorylation of Bcl-2 and Beclin 1, or ubiquitination of Beclin 1. Interestingly, caspase-mediated cleavage of Beclin 1 promotes crosstalk between apoptosis and autophagy. Beclin 1 dysfunction has been implicated in many disorders, including cancer and neurodegeneration.
The body’s circadian clock regulates mitochondrial oxidative metabolism. I quote from a Nov 2013 Science paper by Peek, et al. We examined the role of the circadian clock in 24 hour oxidative cycles by determining whether fatty acid oxidation (FAO), measured by the rate of oxidation of [14C]oleate to [14C]CO2, displayed an endogenous circadian rhythm. We monitored FAO and NAD+ in liver homogenates every 4 hours over the course of 48 hours from fasted wild-type mice maintained in constant darkness . We observed ~24-hour oscillations of FAO with peaks occurring near the end of the <day> that coincided with the rhythms of total cellular NAD+ (Fig. 1A, dashed yellow line) and mitochondrial NAD+ (fig. S3A).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963134/
There are many implications for triggering autophagy to potentially promote SARS-CoV-2 viral clearance. Obviously, the regulation of autophagy is controlled by many inputs. Resveratrol has been suggested to modulate autophagy by activating key metabolic sensors/effectors, including AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) [56,63]. While Quercitin may help to induce autophagy by the inhibition of proteasomal activity and mTOR signaling. Intermittent fasting also promotes autophagy by down regulating insulin, insulin-like growth factor, and switching cellular metabolism to fat burning (ketosis) instead of glucose burning (gylcolysis). Increasing NAD+ levels via nicotinic acid, nicotinamide or nicotinamide riboside supplementation, alters the NAD+/NADH oxidative balance and also promotes autophagy. Finally, the circadian regulation of NAD+ may tie in with my observation that induced inflammation of one or more virally infected organs frequently happens in the evening or at night while fasting or while inducing autophagy with Resveratrol + Quercitin (or Resveratrol + Quercitin + Nicotinamide riboside). And of course fasting for more than 24 hrs is known to induce autophagy. Caloric restriction and time restricted eating over an extended period are also thought to promote autophagy.
Some YouTube videos on Autophagy
Finally a ketogenic diet may help induce autophagy. From McCarty et al. “Autophagy may mediate some of the neuroprotective benefits of ketogenic diets. Brain-permeable agents which activate AMP-activated kinase, such as metformin and berberine, as well as the Sirt1 activator nicotinamide riboside, can also boost neuronal autophagy, and may have potential for amplifying the impact of ketogenesis on this process. Since it might not be practical for most people to adhere to ketogenic diets continuously, alternative strategies are needed to harness the brain-protective potential of ketone bodies. These may include ingestion of medium-chain triglycerides or coconut oil, intermittent ketogenic dieting, and possibly the use of supplements that promote hepatic ketogenesis – notably carnitine and hydroxycitrate – in conjunction with dietary regimens characterized by long daily episodes of fasting or carbohydrate avoidance.”