Heterochronic parabiosis is the name given to the linking of circulatory systems between old and young mice. The old mouse benefits, showing signs of rejuvenation of function, while the young mouse suffers early signs of aging. Initially it was argued that beneficial factors in young blood produce this effect, and a number of efforts moved ahead to produce clinical therapies based on this concept. Some companies like Alkahest have trialed plasma transfer from young to old patients, with so far poor results. Others, like Elevian, are focused on specific factors thought to mediate the effects, GDF11 in that case, and appear to be doing better in their preclinical work.

A presently important debate in the research community is whether or not the benefits of parabiosis are mediated by factors in young blood, or whether it is merely a case of diluting bad factors in old blood. Irina Conboy and Michael Conboy put forward a compelling demonstration a few years ago, using much more controlled method of exchanging blood between old and young animals. It provided very strong evidence for the “bad old blood” hypothesis. Yet there continues to be evidence on the other side suggesting that factors in young blood can produce benefits. Parabiosis is an interesting area of research in this sense.

In the open access paper I’ll point out today, the Conboys report on their latest demonstration that parabiosis benefits are the result of dilution of harmful factors in old blood. They develop a means of diluting blood in animals without major disruption to metabolism, and show that it produces very similar benefits to a transfer of young blood. This is, again, quite a compelling argument for the primacy of harmful factors in old blood rather than beneficial factors in young blood in the matter of parabiosis.

Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin

Historically, the phenomena of heterochronic parabiosis and blood exchange remained unconfirmed with respect to the key assumption as to whether the addition of young factors is needed for rejuvenation, and if premature aging of young mice stemmed from the introduction of old blood factors or a simple dilution of young factors. To answer these questions in a well-controlled experimental set-up, we took advantage of our recently developed small animal blood exchange model.

Here, using our recently developed small animal blood exchange process, we replaced half of the plasma in mice with saline containing 5% albumin (terming it a “neutral” age blood exchange, NBE) thus diluting the plasma factors and replenishing the albumin that would be diminished if only saline was used. Our data demonstrate that a single NBE suffices to meet or exceed the rejuvenative effects of enhancing muscle repair, reducing liver adiposity and fibrosis, and increasing hippocampal neurogenesis in old mice, all the key outcomes seen after blood heterochronicity.

Comparative proteomic analysis on serum from NBE, and from a similar human clinical procedure of therapeutic plasma exchange (TPE), revealed a molecular re-setting of the systemic signaling milieu, interestingly, elevating the levels of some proteins, which broadly coordinate tissue maintenance and repair and promote immune responses. Moreover, a single TPE yielded functional blood rejuvenation, abrogating the typical old serum inhibition of progenitor cell proliferation. Ectopically added albumin does not seem to be the sole determinant of such rejuvenation, and levels of albumin do not decrease with age nor are increased by NBE/TPE.

A model of action (supported by a large body of published data) is that significant dilution of autoregulatory proteins that crosstalk to multiple signaling pathways (with their own feedback loops) would, through changes in gene expression, have long-lasting molecular and functional effects that are consistent with our observations. This work improves our understanding of the systemic paradigms of multi-tissue rejuvenation and suggest a novel and immediate use of the FDA approved TPE for improving the health and resilience of older people.