Preprints.org · Oct 19, 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) is defined as the difference when an epigenetic clock shows a higher age than the birth certificate. EAA is associated with neurological disease, amongst many other diseases. A series of studies, indexed in Medline, identify that SARS-CoV-2 infection, COVID-19 and long COVID are all associated with EAA. The main mechanism of SARS-CoV-2 to induce pathogenesis in the organism is via the spike protein S2 subunit (SP2). Through the Toll Like Receptor 2 (TRL2) and MyD88-mediated response, the spike protein, via the canonical pathway, activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which initiates the pro-inflammatory response and thereafter promotes inflammation. In turn, NF-κB mediates EAA. The SARS-CoV-2 infection (through its spike protein) causes methylation and demethylation profile alterations in DNA and telomere attrition, which associates with COVID-19 severity. Moreover, the post COVID-19 syndrome is associated with EAA and telomere attrition. Alteration of the methylome, i.e. the methylation and demethylation of the DNA and the nucleosome during EAA, contributes to cellular senescence, which is linked to autoimmunity, and, furthermore, to cancer. In this paper, we investigate the role of NF-κB activation to cause and promote EAA. We identify that nucleosome alterations can occur not only with COVID-19 but also following administration of the mRNA vaccines coding for the SARS-CoV-2 spike protein (post COVID vaccine syndrome; PCVS). We therefore analyse in depth the mechanisms that implicate NF-κB to cause methylome and nucleosome alterations and contribute to EAA. 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 and senescence. Moreover, we point to the consequences that the NF-κB-mediated EAA and inflammaging can have on the overall health of the human population. The mRNAs in the vaccine and the transcribed spike protein persist in time, promoting a chronic activation of NF-κB and other pathogenic pathways.

doi.org/10.20944/preprints202610.1754.v1Open accessMechanisms