Dilution is the Solution (to Aging)

In the post on osteocalcin that I can never quite finish I paraphrased a review on the topic that suggested that undercarboxylated osteocalcin may be one of the anti-aging factors present in 'young blood'.  Heterochronic parabioss experiments - wherein the circulatory systems of an old and a young mouse are joined - have shown rejuvenating effects for the old mouse and some age-promotion in the young. This has lead to speculation that there are youth-promoting factors in the blood of the younger mouse that provide benefit to the older mouse.  However the Conboys and their research team, who pioneered heterochronic parabiosis experiments, have proposed that it is actually dilution of pro-aging factors that provides the age-reversing effects. They recently published an article [Mehdipour et al. 2020] showing dilution of the blood of an old mouse is sufficient for rejuvenation.  From the article:

"The above concept fits well with the age-imposed increase in systemic TGF-beta family ligands (GDF11 and TGF-beta 1, for example), which contributes to pro-geronic phenotypes [7, 14, 1544–47] and the fact that attenuation of TGF-beta signaling in old animals has effects that are similar to those of NBE [7, 14, 15, 28, 44]. NBE is also predicted to promote stronger rejuvenation than an Alk5 inhibitor, as that attenuates just one branch of one pathway, and because proteins other than the TGF-beta family that are elevated with age will be re-set to their younger levels of gene expression and/or signaling intensities by NBE/TPE (to be profiled in the future). Fitting the model that is shown in Figure 6 with experimental data on multiple time points after NBE/TPE, for multiple proteins and multiple levels of regulation (mRNA, protein, signaling intensities), is a focus of our long-term work."

"With respect to the proteins that are the same between mice and people, and were modulated in the same direction by the NBE and TPE, an increase in erythropoietin [EPO] is likely to improve the numbers and health of erythrocytes, attenuating age-imposed anemia [69]."

While the last statement undeplays the potential effects of increasing EPO (which probably results from dilution itself), I don't think increased EPO explains the all the treatment effects. EPO has been investigated in rats as an anti-aging treatment and has shown to be modestly effective at moderate doses [Zhai et al. 2012]. I believe it is most likely due to beneficial effects on iron homeostatis; note that Na/K ATPase activity and superoxide dismutase activity were increased by EPO.


References

Mehdipour, Melod, Colin Skinner, Nathan Wong, Michael Lieb, Chao Liu, Jessy Etienne, Cameron Kato, Dobri Kiprov, Michael J. Conboy, and Irina M. Conboy. “Rejuvenation of Three Germ Layers Tissues by Exchanging Old Blood Plasma with Saline-Albumin.” Aging 12, no. 10 (May 30, 2020): 8790–8819. https://doi.org/10.18632/aging.103418.

Zhai, Yue-Fen, Hai-qin Wu, Duo Lü, Hu-Qing Wang, Hui-Yun Wang, and Gui-Lian Zhang. “[The anti-aging effect of EPO and the preliminary probe into its mechanisms].” Sichuan Da Xue Xue Bao. Yi Xue Ban = Journal of Sichuan University. Medical Science Edition 43, no. 5 (September 2012): 679–82, 719.


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