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

Abstract

Heterochronic blood sharing rejuvenates old tissues, and most of the studies on how this works focus on young plasma, its fractions, and a few youthful systemic candidates. However, it was not formally established that young blood is necessary for this multi-tissue rejuvenation. 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.

Plasma dilution improves cognition and attenuates neuroinflammation in old mice

“…As we investigate and form an evolutionary conserved paradigm of systemic rejuvenation, our data demonstrated that young blood is not the primary determinant, and instead, dilution of old blood plasma yields a robust resetting of the systemic signaling milieu to youth and health, rejuvenating multiple tissues [18]. The study of the brain in that report was limited to hippocampal neurogenesis; here we expand the work to other important facets of brain health: neuroinflammation and cognition.…”

“…Cognitive capacity of old mice is improved through a single NBE procedure Young (2-4 months) and old (22-24 months) male C57/ B6 mice underwent one NBE procedure, as published [18]. Isochronic exchanges between young mice (young exchanged with young, YY) and old mice (old exchanged with old, OO) were performed, as controls for the procedure.…”

“…4a). Neurogenesis and neuroinflammation were examined in the brains of these animals as published [18,21,29] and shown in Fig. 2.…”

“…Neurogenesis occurs in the subgranular zone (SGZ) of the DG declines with age and is shown to be influenced by systemic factors [5,9,10,18,21,29]. Proliferation of neural precursor cells (NPCs) that are born in the SGZ of the DG was assayed by immunofluorescence Fig.…”

“…Several systemic proteins and young plasma infusions were suggested to influence the plasticity of brain aging [9,[11][12][13][14][15][16][17], albeit with some controversy to the actual age-specific levels of some of these candidate factors, such as GDF11, B2M, CCL11, and TIMP2 [9,[18][19][20][21][22][23][24]. There was also a lack of health span increase in young plasma infusion studies [25]; and while safety trials were successful, the young blood approaches have not been demonstrated to be effective in improving the health of the brain or any other tissue in clinic [26].…”