COVID-19, ferrosenescence and neurodegeneration, a mini-review

Exacerbation of cognitive, motor and nonmotor symptoms have been described in critically ill COVID-19 patients, indicating that, like prior pandemics, neurodegenerative sequelae may mark the aftermath of this viral infection. Moreover, SARS-CoV-2, the causative agent of COVID-19 disease, was associated with hyperferritinemia and unfavorable prognosis in older individuals, suggesting virus-induced ferrosenescence. We have previously defined ferrosenescence as an iron-associated disruption of both the human genome and its repair mechanisms, leading to premature cellular senescence and neurodegeneration. As viruses replicate more efficiently in iron-rich senescent cells, they may have developed the ability to induce this phenotype in host tissues, predisposing to both immune dysfunction and neurodegenerative disorders. In this mini-review, we summarize what is known about the SARS-CoV-2-induced cellular senescence and iron dysmetabolism. We also take a closer look at immunotherapy with natural killer cells, angiotensin II receptor blockers (“sartans”), iron chelators and dipeptidyl peptidase 4 inhibitors (“gliptins”) as adjunct treatments for both COVID-19 and its neurodegenerative complications. SARS-CoV-2 exploitation of ACE-4, DPP4 and furin augment host intracellular iron, inflicting DNA and p53 damage, causing NK cells ferrosenescence. (CD147-induced mitochondrial damage and iron release are not shown). Disabled NKCs fail to clear senescent, virus-infected cells and α-synuclein, predisposing COVID-19 critical illness and neurodegenerative disorders. [Display omitted] •To proliferate in host cells, the SARS-CoV-2 virus requires iron.•To acquire iron and lower host immunity, the virus inflicts mitochondrial damage.•Iron-linked DNA, mtDNA and p53 disruption triggers ferrosenescence in NK cells.•Dysfunctional NK cells are incapable of eliminating senescent cells, leading to neurodegeneration.•Immunotherapy with NK cells and ferrosenescence-lowering drugs may facilitate the clearance of aged cells.