Magnesium and Rapamycin in Long Covid and Longevity: Mechanistic (Part A) and Therapeutic (Part B) Proposals

A global shortfall in magnesium (Mg) is linked to long Covid and a shortened lifespan. The mTOR (mammalian or mechanistic target of rapamycin)/AMPK (AMP-activated protein kinase) ratio increases with age and these kinases are inversely related. A balanced mTOR:AMPK ratio, promoted by rapamycin (RAP), is linked to healthy aging. mTOR is anabolic and AMPK is catabolic. Mg and RAP are synergistic collaborators in suppressing this ratio. Mg is bottom up, while RAP is top down. Any inhibition of mTOR by RAP may upregulate kinases that activate mTOR via alternate pathways. Whether this occurs with low-dose, intermittent RAP is unknown. But Mg is perfectly placed to block this. Efficacies may merge at the IFN-γ -> indoleamine dioxygenase (IDO) -> kynurenine -> aryl hydrocarbon receptor (AhR) sequence. Persistence of any intracellular pathogen, e.g., SARS CoV2, can prolong IFN-γ activation of IDO, e.g., LC. IDO metabolizes tryptophan (T) and upregulates the kynurenine (K) pathway. Elevated K/T and mTOR/AMPK are linked to cancer, autoimmune disease, cardiovascular disease, dementia, diabetes, and obesity. Furthermore, Mg-dependent vitamin D immunomodulates IFN-γ. Calcium (Ca) competes with Mg for the same transcellular receptor (calcium sensing receptor) for physiologic balance. However, absorption, resorption, and diffusion to and from the vascular and extracellular spaces is predominantly paracellular through tight junctions. RBC Mg sits at the nexus between intracellular Mg and serum Mg. RBCs, like all mesenchymal cells, have no tight junctions but do have cell membrane TRPM7 channels (chanzymes) that sense extracellular Mg and respond appropriately. They also serve as a reservoir for Mg to maintain serum Mg within tight limits. This enables convenient determination of serum Ca:Mg that reflects their intake ratio, their intracellular ratios, and general health status, when converted from mg/dL to mmoles/L of iMg. While developed countries (and cities) ingest too much Ca, the Third World ingests too little. Unfortunately the maximum recommended Ca:Mg intake (weight to weight) of 2:1 was based on total body weight {m/1964-1989/}, but has encountered an American lifestyle. Mean American adult weight has grown from 70 in the mid 60s to 85 in the 2020s. Soil depletion and the increase in dietary UPFs have conspired to further compromise Mg intake. The ionized component of serum Mg has dropped from about 72% to about 62% over the last several decades. This component can be easily determined by comparing the reference range limits for serum Mg with their ionized counterparts. The discussion is technical, and in the interest of clarity the article is partitioned into Part A (proposed mechanism) and Part B (proposed therapeutics).