In the Journal of Translational Medicine, researchers have published the results of a randomized, controlled clinical trial demonstrating that plasma proteins from young donors have beneficial effects against inflammation in a surgical context.
From parabiosis experiments to the clinic
It has been documented for two decades that giving young blood to older animals, a process known as heterochronic parabiosis, has been found to rejuvenate them in multiple respects [1]. This work has been confirmed multiple times, with researchers finding that it has benefits for the brain [2], the kidneys [3], and bone tissue [4]. While some of these effects have been attributed to the simple dilution of proteins that originate from older tissue, some proteins from young tissue have been found to have benefits: for example, tissue inhibitor of metalloproteinase 2 (TIMP2), which is derived from umbilical cord blood, restores cognitive function in older mice [5].
However, as these researchers note, plasma from young donors has not been confirmed as a clinical treatment. In fact, back in 2019, the FDA warned consumers against receiving plasma for rejuvenation purposes, as neither safety nor efficacy could be guaranteed and some of the people marketing it were untrustworthy.
A controlled trial for human plasma proteins
These researchers, however, did not test raw plasma itself. Instead, they tested GRF6021, a proprietary 5% plasma fraction that is derived from young donors and has been approved by the FDA; the batch of GRF6021 used in this trial was derived from people with an average age of 35. Using simple saline as a control group, this trial tested GRF6021’s effects on inflammation among older people who had received hip and knee replacements (joint arthroplasty), as a poor inflammatory response slows down healing [6].
A total of 697 patients were assessed for participation in this trial; however, a great many of them were unable to participate due to having serious medical conditions or substance abuse. Furthermore, as this study was conducted during the COVID pandemic, some of the planned surgeries were cancelled. Of the 164 eligible patients, only 55 consented to the trial, and only 36 made it through to the end of this study.
The surgeries were conducted as normal, except that lidocaine, corticosteroids, and ketamine were all prohibited from being used as infusions, as all three have been reported to affect the immune response. GRF6021 was administered four times: one day before surgery, immediately before and after surgery, and one day after surgery.
Biomarkers were significantly affected
The treatment did not appear to have any significant effects on the proteome on the two administrations before surgery. However, immediately and one day after surgery, the effects were statistically significant and highly noticeable. Pathways relating to inflammation were strongly affected, including PI3K-AkT, cytokine receptors, and the cytokine-related JAK-STAT.
GRF6021’s effects on the immune system, as expected, matched these proteomic effects. Before surgery, there were no significant effects; after surgery, JAK-STAT and MAPK signaling pathways were significantly affected. There were significant effects on the adaptive immune system, including a decrease in inflammatory factors released by monocytes; innate immune cells, on the other hand, seemed to be unaffected. NF-κB signaling, which is often affected by aging, was also unaffected by this treatment.
Unfortunately, and possibly due to the limited number of participants, there were few significant differences in the patients’ quality of life, and the researchers could find no correlations between immune and patient outcomes. There were trends towards a more rapid reduction of pain and fatigue. Opioid use for pain relief was significantly less in the treatment group, and the effects here seemed to be strongest in the patients experiencing the most pain. The researchers hold that “while speculative, this observation is compatible with the view that patients at risk for a prolonged and impaired recovery may benefit most from” this administration of GRF6021.
The authors of this paper present this study as a proof of principle, demonstrating that proteins from relatively young donors have beneficial immune effects. They note that the donors, with an average age of 35, were not particularly young; other sources, such as umbilical cord blood, may have had stronger effects. They also note that it is not clear which proteins in the proprietary GRF6021 cocktail were responsible for the effects seen in this study; if these proteins can be identified, it may be possible to synthesize them, better controlling the intervention and removing the need for donor plasma.
Literature
[1] Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., & Rando, T. A. (2005). Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature, 433(7027), 760-764.
[2] Villeda, S. A., Luo, J., Mosher, K. I., Zou, B., Britschgi, M., Bieri, G., … & Wyss-Coray, T. (2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature, 477(7362), 90-94.
[3] Huang, Q., Ning, Y., Liu, D., Zhang, Y., Li, D., Zhang, Y., … & Chen, X. (2018). A young blood environment decreases aging of senile mice kidneys. The Journals of Gerontology: Series A, 73(4), 421-428.
[4] Baht, G. S., Silkstone, D., Vi, L., Nadesan, P., Amani, Y., Whetstone, H., … & Alman, B. A. (2015). Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin. Nature communications, 6(1), 7131.
[5] Castellano, J. M., Mosher, K. I., Abbey, R. J., McBride, A. A., James, M. L., Berdnik, D., … & Wyss-Coray, T. (2017). Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature, 544(7651), 488-492.
[6] Gaudillière, B., Fragiadakis, G. K., Bruggner, R. V., Nicolau, M., Finck, R., Tingle, M., … & Nolan, G. P. (2014). Clinical recovery from surgery correlates with single-cell immune signatures. Science translational medicine, 6(255), 255ra131-255ra131.
