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Potential Synergy of MOTS-c or Humanin with Senolytics

“product By Nemo 3 months ago

Raising detectability of senescent cells

"Cellular senescence also makes an important impact on the progression of age-related diseases. It is usually accompanied by the production of senescence-associated secretory phenotypes (SASPs). SASPs sustain the progression of the cell cycle and induce adjacent cells to become senescent or carcinogenic in a paracrine manner. Kim et al. found that MOTS-c affected the transformation of SASPs by regulating mitochondrial energy metabolism, and played a cytoprotective role in aging-related diseases, thereby alleviating senescent symptoms and prolonging health period. 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." (2)

MOTS-c and Humanin boost SASP factors

"Next, we examined the levels of a small subset of SASP factors in non-senescent (quiescent) and senescent cells following humanin and MOTS-c treatment. Exposure to these peptides increased production of the SASP factors IL-6, IL-1β, IL-8, IL-10 and TNFα (Table 1). We also examined the effects of humanin and MOTS-c in replicatively senescent cells. Humanin and MOTS-c treatment increased the level of these SASP factors in replicatively senescent cells (Table 2)." (3)

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 was transiently 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)

Sourcing Studies

(1) Loaiza, N. and Demaria, M. (2016). Cellular senescence and tumor promotion: Is aging the key? Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, [online] 1865(2), pp.155–167. Available at: https://eriba.umcg.nl/wp-content/uploads/2017/08/D... [Accessed 8 Mar. 2020].

(2) Yang, Y., Gao, H., Zhou, H., Liu, Q., Qi, Z., Zhang, Y. and Zhang, J. (2019). The role of mitochondria-derived peptides in cardiovascular disease: Recent updates. Biomedicine & Pharmacotherapy, [online] 117, p.109075. Available at: https://www.sciencedirect.com/science/article/pii/....

(3) Kim, S.-J., Mehta, H.H., Wan, J., Kuehnemann, C., Chen, J., Hu, J.-F., Hoffman, A.R. and Cohen, P. (2018). Mitochondrial peptides modulate mitochondrial function during cellular senescence. Aging, 10(6), pp.1239–1256. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046248/

(4) Baar, M.P., Brandt, R.M.C., Putavet, D.A., Klein, J.D.D., Derks, K.W.J., Bourgeois, B.R.M., Stryeck, S., Rijksen, Y., van Willigenburg, H., Feijtel, D.A., van der Pluijm, I., Essers, J., van Cappellen, W.A., van IJcken, W.F., Houtsmuller, A.B., Pothof, J., de Bruin, R.W.F., Madl, T., Hoeijmakers, J.H.J., Campisi, J. and de Keizer, P.L.J. (2017). Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell, [online] 169(1), pp.132-147.e16. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28340339.

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