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

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

"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."

MOTS-c Vascular Calcification and Insulin Resensitization

By Nemo 3 months ago

AMPK Activation Targets Vascular Calcification and Metabolic Homeostasis

"Recently, MOTS-c, a novel bioactive mitochondrial-derived peptide, has been demonstrated to activate the AMPK pathway to promote metabolic homeostasis... Our findings provide evidence that MOTS-c may act as an inhibitor of VC [Vascular Calcification] by activating the AMPK signaling pathway and suppressing the expression of the AT-1 and ET-B receptors." (1)

"Angiotensin II type 1 (AT-1) and endothelin B (ET-B) have been found to be involved in the AMPK pathway by binding to the AT-1 and ET-B receptors, respectively. A decreased level of the AT-1 receptor plays roles in reducing oxidative stress and preventing the development of myocardial contractile dysfunction, while a high level of the AT-1 receptor induces myocardial fibrosis and cardiac dysfunction. AT-1 can induce the relocation and suppression of the AMPK pathway via the AT-1 receptor in the development of diabetic proteinuria. After treatment with metformin, AMPK signaling is activated and AT-1 levels are decreased in the kidney. In epithelial ovarian carcinoma, ET-1 plays a role in epithelial-mesenchymal transition. A decrease in ET-1 receptor activation is beneficial in attenuating biventricular remodeling, and the overexpression of ET-1 causes sustained blood pressure elevation and vascular and renal injury. The activation of the AMPK pathway can also upregulate the ET-B receptor to inhibit autophagy in vascular smooth muscle cells under high glucose conditions." (1)

"Previous reports have shown that MOTS-c can amplify glucose uptake, inhibit the folate cycle and de novo purine biosynthesis following metabolic stress, and regulate nuclear gene expression in an AMPK-dependent manner. MOTS-c treatment dramatically reduced the number of disordered elastic fibers and significantly improved vascular wall structure (Fig. 2c). Moreover, MOTS-c also significantly reduced VDN [Vitamin D3 plus Nicotine] induced calcium phosphate salt deposition in the calcified aortas, as detected by alizarin red S staining and von Kossa staining... Our results showed that MOTS-c reverses VDN-induced AMPK downregulation. In mice with hypoxia-induced pulmonary hypertension, the activation of the AMPK pathway can effectively improve right ventricular systolic pressure and right ventricular hypertrophy due to treatment with liraglutide." (1)

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Potential Synergy of MOTS-c or Humanin with Senolytics

By Nemo 3 months ago

FOXO4-DRI senescent cell remover is potentiated by SASP factors

"SASP factors as IL-6 may be the cause for the observed loss in renal function, and we wondered how FOXO4-DRI would function under such high SASP conditions. In vitro experiments showed FOXO4-DRI to be more potent against senescent cells in which SASP wastransiently boosted by recombinant IL1a/b or lipopolysaccharide (LPS), whereas an IL1 receptor antagonist or the general anti-inflammatory drug cortisol reduced its potency (Figures 6H and 6I). Thus, FOXO4-DRI actually is most effective against senescent cells expressing high levels of SASP and could as such be particularly effective against loss of renal function. Excitingly, while not substantially influencing total body nor kidney weight (Figure S6G), FOXO4-DRI treatment normalized the percentage of tubular cells lacking LMNB1 (Figure 6G), the tubular IL-6 elevation (Figure 6J), and the elevations in plasma urea levels (Figure 6K)." (4)