Immunosenescence and COVID-19
Interview with Dr. Philip McMillan April 25, 2020 [link posted June 27, 2022 on substack.com].
Please see video posted at Youtube for a better understanding of how to reverse and prevent immunosenescence to reduce your risks of COVID-19 severity.
More details on the protection protocol can be found here, which had been originally posted on LinkedIn on March 5, 2020 (before I became ostracized in fall of 2021):
With time, prevention and/or early treatment COVID-19 protocols also included ivermectin, a putative alpha-fetoprotein antagonist which may prevent and reverse immunosenescence [Laderoute M. Ivermectin may prevent and reverse immunosenescence by antagonizing alpha-fetoprotein and downmodulating PI3K/Akt/mTOR hyperactivity. Open Heart, April 29, 2021. https://openheart.bmj.com/content/8/1/e001655.responses#ivermectin-may-prevent-and-reverse-immunosenescence-by-antagonizing-alpha-fetoprotein-and-downmodulating-pi3k-akt-mtor-hyperactivity].
Ivermectin was integrated into the prevention and/or early treatment protocols by the fall of 2020 (see Image 1 below) spearheaded by Drs. Paul E. Marik and Pierre Kory (FLCCCA) and Dr. Peter A. McCullough (Association of American Physicians and Surgeons). These later protocols share the usage of zinc, flavonoids and ivermectin each with putative anti-immunosenescence/ AFP antagonistic properties.
Image 1: Anti-immunosenescence interventions using alpha-fetoprotein (AFP) antagonists (which behave as ‘anti-virals’) were predicted to be the optimal approach to prevent COVID-19 severity on March 5, 2020 six days before the COVID-19/SARS-COV-2 pandemic was declared by the WHO on March 11, 2020; by a global ‘immunosenescence and HERV-K102’ authority, Dr. Marian Laderoute Ph.D. Medical Sciences-Immunology.
Since that time, accumulating evidence has shown that immunosenescence associated with age, stress and/or co-morbidities, and/or vitamin D deficiencies are the key contributing factors to risk of COVID-19 severity [Laderoute M submitted and see also: 1) Cox LS, Bellantuono I, Lord JM, Sapey E, Mannick JB, Partridge L, Gordon AL, Steves CJ, Witham MD. Tackling immunosenescence to improve COVID-19 outcomes and vaccine response in older adults. Lancet Healthy Longev. 2020 Nov;1(2):e55-e57. doi: 10.1016/S2666-7568(20)30011-8. Epub 2020 Nov 9.; and 2) Al Kiyumi MH, Kalra S, Davies JS, Kalhan A. The impact of vitamin D deficiency on the severity of symptoms and mortality rate among adult patients with COVID-19: a systematic review and meta-analysis. Indian J Endocrinol Metab. 2021 Jul-Aug;25(4):261-282. doi: 10.4103/ijem.ijem_115_21.].
Immunosenescence (of macrophages) has been defined as the failed lytic release of HERV-K102 particles from foamy macrophages [Laderoute M, Discovery Medicine, 2015, see Image 2 below].
Image 2. The New Immunosenescence Paradigm, 2015
Immunosenescence which causes chronic diseases associated with aging, and which involves the failed lytic release of HERV-K102 particles from the pro-inflammatory foamy macrophages, also places the host at risk from viral infections such as COVID-19 severe disease. Fortunately, this condition can be reversed by alpha-fetoprotein (AFP) antagonists such as zinc, flavonoids, DHEA (or preferably 7-keto-DHEA in women which cannot be converted to male hormones in women), and now putatively ivermectin. It is important to note that several lines of evidence shows SARS-CoV-2 infection of myeloid cells induces immunosenescence and that SARS-CoV-2 infection upregulates AFP at the mRNA and protein levels [Appelberg S, Gupta S, Svensson Akusjärvi S, Ambikan AT, Mikaeloff F, Saccon E, et al. Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells. Emerg Microbes Infect. 2020 Dec;9(1):1748-1760. doi: 10.1080/22221751.2020.1799723. and and Dr. Ujjwal Neogi, personal communication].
It is notable that vitamin D deficiency affects HERV-K102 particle production by not being able to prevent the switching of lipid body negative (Oil Red O negative), pro-inflammatory M1-like foamy macrophages (which produce the HERV-K102 particles) to the lipid body positive (Oil Red O strongly positive) anti-inflammatory M2-like foamy macrophages [Oh J, Weng S, Felton SK, Bhandare S, Riek A, Butler B, et al. 1,25(OH)2 vitamin D inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus. Circulation. 2009 Aug 25;120(8):687-98. doi: 10.1161/CIRCULATIONAHA.109.856070.] which interestingly is favored in those with diabetes.
As well, Tallam et al [Tallam A, Perumal TM, Antony PM, Jäger C, Fritz JV, Vallar L, et al. Gene regulatory network inference of immunoresponsive gene 1 (IRG1) identifies interferon regulatory factor 1 (IRF1) as its transcriptional regulator in mammalian macrophages. PLoS One. 2016 Feb 12;11(2):e0149050. doi: 10.1371/journal.pone.0149050. ] have shown that the vitamin D receptor (VDR) blocks IRF1 induction of IRG1 (a highly inflammatory mediator released by macrophages upon LPS/TLR4 exposures) where IRF1 induces HERV-K102 provirus full-length transcription [Manghera M, Ferguson-Parry J, Lin R, Douville RN. NF-κB and IRF1 induce endogenous retrovirus K expression via interferon-stimulated response elements in its 5' long terminal repeat. J Virol. 2016 Sep 29;90(20):9338-49. doi: 10.1128/JVI.01503-16].
Of relevance, Ren X et al, Cell 2021 have shown: a) the TLR4 response becomes activated with progression to severe COVID-19 but not with progression to moderate and; b) the recovery myeloid cells; Macro_c5-WDR74 (foamy macrophage putative producers of HERV-K102 particles) and Mono_c4-CD14-C16 (monocyte putative progenitors of the Macro_c5-WDR74 foamy macrophages) both uniquely express VDR (no other cell type in moderate or severe BALF expresses VDR by single cell RNA sequencing).
It may be quite relevant that at the time of acute COVID-19 hospital admission an analysis of circulating monocytes revealed that those patients with upregulated IRF1 and an M1 profile were less likely to be admitted to ICU or were at significantly reduced risk of death [Utrero-Rico A, González-Cuadrado C, Chivite-Lacaba M, Cabrera-Marante O, Laguna-Goya R, Almendro-Vazquez P, et al. Alterations in circulating monocytes predict COVID-19 severity and include chromatin modifications still detectable six months after recovery. Biomedicines. 2021 Sep 17;9(9):1253. doi: 10.3390/biomedicines9091253.]. This further substantiates the importance of IRF1 for early clearance of SARS-CoV-2 and/or recovery and supports the hypothesis that HERV-K102 activation (induced by IRF1 see Manghera et al 2016 quoted above) is needed for recovery from COVID-19.
In summary, the importance of reversing and preventing immunosenescence cannot be understated to avoid COVID-19 severity and as well for healthy longevity. Hopefully this link to the 40 minute April 25, 2020 interview with Dr. Philip McMillan can help clarify these and other points around how ivermectin (also considered an anti-viral against many if not most viruses) may strengthen the HERV-K102 response for COVID-19 recovery by reverting and preventing immunosenescence.
Immunosenescence and COVID-19
Excellent. I am going to have to read and reread time 4-5 but this is excellent, and explains a lot to me, just in what I have been able to digest so far. THANK YOU for posting on substack.