Preprints.org · Nov 3, 2026

The Activation of NF-κB by the SARS-CoV-2 Spike Protein and Its Role in Epigenetic Age Acceleration, Inflammaging, and, Finally, Senescence

By Kyriakopoulos AM, Seneff S

Epigenetic age acceleration (EAA) occurs when an individual's DNA methylation-predicted biological age is older than their actual chronological age. EAA is associated with neurological disease, amongst many other diseases. A series of studies, indexed in Medline, identify that COVID-19 and long COVID are both associated with EAA. Pathogenesis occurs primarily via the spike protein (SP). Through Toll Like Receptor 2 (TRL2) and MyD88-mediated response, SP activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), to initiate pro-inflammatory responses and promote inflammation. SARS-CoV-2 infection causes methylation and demethylation profile alterations in DNA and telomere attrition, which associates with COVID-19 severity. Post COVID-19 syndrome (Long COVID) is also associated with EAA and telomere attrition. Alterations of the methylome during EAA contribute to cellular senescence, which is linked to autoimmunity, and, furthermore, to cancer. In this paper, we investigate the role of NF-κB activation in EAA. We identify that nucleosome alterations can occur not only with COVID-19 and Long COVID but also following administration of the SARS-Cov-2 mRNA vaccines. We analyse in depth the mechanisms that implicate NF-κB to cause these alterations. We identify the critical role of long non-coding RNAs (lncRNAs), which regulate NF-κB activation through scaffolds, decoys, and feedback loops, in modulating type I interferon expression, premature aging, inflammaging and senescence. We discuss the consequences of these processes on the overall health of the human population. The mRNAs in the COVID-19 vaccine and the transcribed spike protein persist in time, promoting chronic activation of NF-κB and other pathogenic pathways.

doi.org/10.20944/preprints202610.1754.v2Open accessMechanisms