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Can viral replication be reduced with MOTS-c and FOXO4-DRI by killing zombie (senescent) cells?

“product By Nemo 2 months ago

Senescent cells increase replication of a DNA virus in vitro.

“A significant increase in viral replication efficiency was detected by replicative senescence during IFV and VZV infection. ... As one of possible mechanisms for the increase in viral replication in senescent cells, a reduction in interferon (IFN) response after viral infection may account for it.” (2)

The concentration of this DNA virus in senescent cells is 300% more infected than non-senescent cells.

300% increase of viral infection in senescent cells

MOTS-c: Blocking SIRT1 increases viral plaque formation during influenza virus infection and AMPK activates DNA sensing pathway.

"SIRT1 can be considered as the most well-known anti-aging gene known so far but the effect of SIRT1 during viral infection has not been fully investigated. Thus, we investigated whether modulation of SIRT1 activity would have an impact on influenza viral replication. Nicotinamide (NAM) was used as a SIRT1-specific inhibitor and sodium butyrate (NaB) was used as an inhibitor of histone deacetylation in cultured cells." (2)

Consistent with these findings, the knockdown of SIRT1 also led to a significant increase in viral plaque formation (Fig. 4E). Thus, these results suggest that SIRT1 can contribute to antiviral effect against influenza virus infection." (2)

MOTS-c promoted AMPK and SIRT1 (anti-senescence) activation and suppressed LPS-induced ERK, JNK, p65, and STAT3 activation in the lung tissues of LPS-induced ALI mice.” (6) AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling. (7)

Cell senescence is regulated by innate DNA sensing.

“Cells in the body or in cultures eventually stop replicating. This phenomenon is called "senescence" and is triggered by shortening of telomeres, oxidative stress or genetic damage to the cells, either acute or simply due to the cell growing "old." (1)

"EPFL scientists have now discovered that a DNA-sensing mechanism of the innate immune system -- which is pivotal for the immediate defense against pathogens -- controls cellular senescence. When cells senesce, they undergo profound changes, including the secretion of several inflammation-mediating proteins (cytokines, chemokines, extracellular-matrix proteins, growth factors). The production of this "senescence-associated secretory phenotype" controls a number of biological processes such as wound healing and tissue repair, but also tumor formation and some age-related disorders. But although we know how senescence increases the activity of the genes for these proteins, we know very little about how the entire process begins in the first place.” (1)

“The lab of Andrea Ablasser at EPFL found that senescing cells use a mechanism of the innate immune system to regulate the secretion of inflammation-mediating molecules. The innate immune system includes fast-acting but non-specialized cells (macrophages, neutrophils, mast cells etc.) that provide the first line of defense against the millions of potential pathogens to which humans are constantly exposed. The innate immune cells use a host of pattern recognition receptors to sense and identify foreign parts of an invading pathogen, such as the DNA of a virus. DNA-sensing is accomplished through a two-receptor system comprising an enzyme called cGAS and an adaptor molecule called STING. Once activated, the cGAS-STING pathway triggers the production of inflammatory proteins that help fight off the pathogen." (1)

"Unexpectedly, the researchers now found that senescent cells in the body use the cGAS-STING pathway to regulate and facilitate their secretion of inflammation mediators. But in the context of senescent cells, it is the cell's own DNA that activates cGAS because of defects in the nuclear envelope integrity. (1)

cGAS-STING activating SASP factors

DNA-sensing pathway triggers immune system SASP factors by activating "stimulator of interferon genes" (STING).

"The activation of cGAS, in turn triggers the production of SASP factors via Stimulator of interferon genes (STING), thereby promoting paracrine senescence. We demonstrate that diverse stimuli of cellular senescence engage the cGAS-STING pathway in vitro and we show cGAS-dependent regulation of senescence upon irradiation and oncogene activation in vivo. Our findings provide insights into the mechanisms underlying cellular senescence by establishing the cGAS-STING pathway as a crucial regulator of senescence and the SASP." (3)

"The cGAS‐STING pathway in senescence‐associated secretory phenotype (SASP) regulation. Various stressors such as reactive oxygen species (ROS) or UV irradiation cause accumulation of DNA fragments from nucleic double‐strand breaks (DSB), termed cytoplasmic chromatin fragments (CCF), in senescent cells. Damaged mitochondria release mtDNA into the cytoplasm. Long‐interspersed element‐1 (LINE‐1) transcription is upregulated, thereby promoting cDNA production in senescent cells. These DNA fragments are recognized by cGAS to generate 2′3′‐cyclic GMP‐AMP (2′3′‐cGAMP). 2′3′‐cGAMP activates both STING and TANK‐binding kinase 1 (TBK1), resulting in phosphorylation of IRF3. 2′3′‐cGAMP also activates IκBa. These transcription factors enter the nucleus and induce expression of type‐I interferon (IFN) and inflammatory cytokines. Both IRF3 and NF‐κB induce senescence‐associated secretory phenotype (SASP) factors such as IFN‐β, IL‐6 and IL‐8, which are known to induce ROS and maintain cellular senescence." (4)

What are the characteristics of senescent cells and their secretions?

“Senescent cells arrest at the G0/G1 phase of the cell cycle and are characterized by distinctive phenotypic alterations, including enlarged and flattened morphology, enlarged and multinucleated nuclei, and increased senescence-associated beta-galactosidase (SA-beta-gal) activity. In addition, senescent cells secrete a variety of factors to the extracellular environment, collectively known as the senescence-associated secretory phenotype (SASP). This SASP serves to reinforce the senescence arrest in an autocrine manner, but it can also induce growth arrest in a paracrine manner. SASP components are mainly proinflammatory cytokines and chemokines, growth factors, and extracellular matrix remodeling enzymes that can alter the tissue microenvironment and interact with the immune system promoting the recognition and clearance of senescent cells, thereby facilitating the resolution of the damage.” (5)

cGAS-STING activating SASP factors

Potential Synergy of MOTS-c or Humanin with Senolytics

Previous Peptide Sciences article: https://www.peptidesciences.com/blog/potential-synergy-of-mots-c-or-humanin-with-senolytics

"Similarly, Andrew et al. showed that by increasing SASP phenotype, MOTS-c could make senescent cells more easily detected and then cleaned by the immune system, thus protecting normal cells."

Sourcing Studies:

(1) ScienceDaily. (n.d.). Cell senescence is regulated by innate DNA sensing. [online] Available at: https://www.sciencedaily.com/releases/2017/07/1707...

(2) Kim, J.-A., Seong, R.-K. and Shin, O.S. (2016). Enhanced Viral Replication by Cellular Replicative Senescence. Immune Network, 16(5), p.286. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC50864...

(3) Glück, S., Guey, B., Gulen, M.F., Wolter, K., Kang, T.-W., Schmacke, N.A., Bridgeman, A., Rehwinkel, J., Zender, L. and Ablasser, A. (2017). Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nature cell biology, [online] 19(9), pp.1061–1070. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC58265...

(4) Loo, T.M., Miyata, K., Tanaka, Y. and Takahashi, A. (2020). Cellular senescence and senescence‐associated secretory phenotype via the cGAS‐STING signaling pathway in cancer. Cancer Science, [online] 111(2), pp.304–311. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC70045...

(5) Baz-Martínez, M., Da Silva-Álvarez, S., Rodríguez, E., Guerra, J., El Motiam, A., Vidal, A., García-Caballero, T., González-Barcia, M., Sánchez, L., Muñoz-Fontela, C., Collado, M. and Rivas, C. (2016). Cell senescence is an antiviral defense mechanism. Scientific Reports, [online] 6. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC51111...

(6) Xinqiang, Y., Quan, C., Yuanyuan, J. and Hanmei, X. (2020). Protective effect of MOTS-c on acute lung injury induced by lipopolysaccharide in mice. International Immunopharmacology, [online] 80, p.106174. Available at: https://www.sciencedirect.com/science/article/pii/...

(7) m.jbc.org. (n.d.). JBC : Journal of Biological Chemistry. [online] Available at: http://m.jbc.org/content/292/1/292.full

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