COVID-19: NAD⁺ deficiency may predispose the aged, obese and type2 diabetics to mortality through its effect on SIRT1 activity

R. Miller,^c,1 A.R. Wentzel,^a,1,⁎ and G.A. Richards^b,1

Abstract

The SARS-CoV-2 hyperinflammatory response is associated with high mortality. This hypothesis suggests that a deficiency of nicotinamide adenine dinucleotide (NAD⁺) may be the primary factor related to the SARS-Cov-2 disease spectrum and the risk for mortality, as subclinical nutritional deficiencies may be unmasked by any significant increase in oxidative stress.

NAD⁺ levels decline with age and are also reduced in conditions associated with oxidative stress as occurs with hypertension, diabetes and obesity. These groups have also been observed to have high mortality following infection with COVID-19. Further consumption of NAD⁺ in a pre-existent depleted state is more likely to cause progression to the hyperinflammatory stage of the disease through its limiting effects on the production of SIRT1.

This provides a unifying hypothesis as to why these groups are at high risk of mortality and suggests that nutritional support with NAD⁺ and SIRT1 activators, could minimise disease severity if administered prophylactically and or therapeutically. The significance of this, if proven, has far-reaching consequences in the management of COVID-19 especially in third world countries, where resources and finances are limited.

Could zinc and NAD deficiency explain massive inflammation in COVID-19 infection?

An article published in Medical Hypotheses in May 2020 may go a long way toward explaining the cytokine storm, and the endothelial activation/coagulability which is seen in COVID-19 infection.

The authors of this paper looked for a systemic abnormality which might be present in patients who appear to get the sickest when infected with SARS CO-V 2. We know that the ACE2 receptor serves as an open door for the SARS CO-V 2 virus, whose spike protein binds to that receptor which is heavily expressed in the vascular endothelium, kidney and heart tissue as well as small intestine, testis and respiratory epithelium. When the spike protein binds, the entire complex is drawn into the cell, thus reducing expression of the ACE2 receptor on the outside of the cell.

Through a complex interaction involving severe oxidative stress brought on by viral infection of a cell, an NAD-dependent enzymes called PARP 1 (poly ADP ribose polymerase 1) is activated, resulting in depletion of cellular NAD pools and therefore in depletion of ATP, cellular energy loss and eventually cell death.

NAD deficiency in turn decreases the activity of SIRT1 (Silent Information Regulator 1) which normally downregulates ADAM 17 which normally decreases levels of TNF-alpha. With increased levels of TNF-alpha we see increased inflammation, a common component of obesity, diabetes, cancer, ageing and neurodegeneration.

SIRT1 is dependent on the presence of zinc as well as NAD+ for its activation and function.

If oxidative stress is especially severe, another mechanism takes over – the conversion of active iron Fe2+ to the inactive Fe3+ form, stored as ferritin in both liver and macrophages. Hemoglobin is also converted to methemoglobin by this same reaction, resulting in methemoglobinemia and hypoxia.

Upregulation of SIRT1 decrease the ability of the virus to replicate, as well as decreasing levels of TNF alpha. In the presence of deficiency of Zinc and NAD+, the production of TNF alpha is unchecked, resulting in massive inflammation.

Both obesity and diabetes are associated with decrease intracellular NAD+ levels. Multiple other inflammatory conditions – inflammatory bowel disease, renal failure, alcoholism – are associated with Zinc deficiency, and older adults appear to have a marginally adequate intake of Zinc, according to NHANES III study. Thus individuals so affected are in a perfect position to develop the hyperinflammatory state associated with severe COVID-19 infection.

SIRT1 is an effective antioxidant, especially active in cells of the endothelium. Normally the endothelium is lined by a web of glycoproteins. This web separates blood components from the endothelial cells, and maintains the osmotic tension within the blood. Anything which can damage this web of glycoproteins will expose the endothelium to the bloodstream, resulting in activation of platelets and subsequent coagulation.

Does it not seem reasonable that activation of SIRT1 may be essential to prevent the hyperinflammatory and hypercoagulability seen with COVID-19? When SIRT1 cannot downregulate ADAM 17, the result is a hyper-inflammatory state. The diagnosis will depend on the particular organ or organ system involved. But the final common denominator is inflammation.

Does it not seem equally reasonable that nutritional support with both Zinc and NAD+ might be an important factor in lessening disease severity? Not just with SARS CO-V 2 infection, but also with other disease states associated with excessive inflammation – obesity, cardiovascular disease, diabetes, inflammatory bowel disease, asthma, acute pulmonary infections, perhaps even disease associated with mold exposure and water-damaged buildings.

What would be the harm? The benefit might be significant.