Fight Aging!

Over the past fifteen years, studies emerging from work on heterochronic parabiosis, in which the circulatory systems of an old mouse and a young mouse are linked, have given rise to a busy and expanding portion of the field of aging research. At first, researchers focused on possible factors in young blood that might beneficially alter the aged environment. That side of the house gave rise to Elevian's focus on GDF-15, transfusion studies in which old people were given blood fractions from young donors, and ongoing work to try to find some form of blood fraction that produces meaningful benefits. Later, researchers focused more on harmful factors in old blood, and this led to efforts focused on blood dilution as a therapeutic strategy. Hybrid approaches to adjust specific connections of signals in the blood, such as increasing oxytocin while decreasing TGF-β, have also arisen.

Still, while one can certainly find ways to obtain blood dilution or plasma transfer treatments in the clinical marketplace, none of this has made much progress towards validation in clinical trials and consequent widespread use. In the case of plasma transfusions, this may be because it just isn't that great as a mode of therapy; those trials that have taken place did not produce great results. In the case of plasma dilution, we may just need to wait for longer for larger trials to take place and more than proof of concept data to emerge. Today's open access review of the state of development in the world of old blood versus young blood is very much on the side of plasma dilution as the right way forward, which is no surprise given the identity of the authors.

The dominance of old blood, and age-related increase in protein production and noise

Over the past 20 years research in aging and longevity has suggested that aging is caused by an excess of certain systemic proteins, which while at young levels are needed for healthy tissues, become counterproductive when persistently elevated. This work narrowed the effects of blood heterochronicity to dilution of old plasma being sufficient for tissue rejuvenation. Young blood or young blood factors, while potentially efficacious, do not seem to be necessary, because dilution of the age-elevated proteins breaks the inhibitory feed-backs in cell-cell signaling pathways, consequentially restoring the levels of the age-diminished proteins in tissues and systemically.

After neutral blood exchange (NBE), there is robust rejuvenation of old muscle with less fibrosis; in liver, fibrosis is also reduced, and adiposity diminished; in brain, hippocampal neurogenesis becomes increased, neuroinflammation and SA-βGal+ senescence decline, and cognitive capacity improves. Thus, this rejuvenation is to the whole body, simultaneously affecting multiple aspects of multiple tissues, in which for many parameters the old animals become statistically the same as young. In old people, an analogous procedure of therapeutic plasma exchange (TPE), resets to a younger state the blood proteins that control homeostasis and regeneration, immune responses, brain health and function, similar to the NBE effects in mice. Moreover, TPE rejuvenated the immune system and reduced measured human biological or health age.

In TPE and NBE, the red blood cells and white blood cells are returned to the patient, and the plasma is disposed, composed mostly of saline, albumin, immunoglobulins, fibrin, and soluble signaling factors. A replacement fluid is added back, consisting of a saline with added purified albumin, and immunoglobulins may also be added. Albumin itself interacts with or binds weakly to many circulating proteins and modulates their activity and specificity. The robust rejuvenation of multiple old tissues described above, is unlikely to be established by rare proteins bound to the introduced albumin, as this is a biochemically purified protein, it isn't "young" or "old". Yet, it might be that the purified albumin, cleaned of other interacting proteins, is now free to interact with endogenous blood proteins and modify their activity, e.g., attenuating the effects of age-elevated proteins.

In this review we emphasize the potential of diluting age-elevated proteins as the way to re-calibrate the systemic proteome to its younger state without donor blood. Furthermore, we introduce modulation of proteome noise, as an important part of understanding tissue aging and as a critical mechanism for tissue rejuvenation. We discuss studies on the dominance of aged systemic milieu in promoting progeric phenotypes in young cells, in vitro, and in multiple tissues of young animals, in vivo. We support our arguments with evidence showing a significant age-related increase in protein synthesis, in noise of newly synthesized proteomes, and in the rapid induction of these aging phenotypes in young muscle by exposure to aged tissue. We summarize the significance of these findings for future research on aging and longevity.