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.
Highlights
Heterochronic parabiosis has been used for decades in laboratory animals to investigate the effects of shared blood, organs and environmental enrichment, on the surgically connected partners [1, 2, 3,4,5]
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 confirm these findings and to explore their evolutionary conservation, we took advantage of the fact that there is a procedure for human patients analogous to neutral” blood exchange (NBE) where most of the plasma is replaced by physiologic solution, supplemented with commercial human albumin, called Therapeutic Plasma Exchange, therapeutic plasma exchange (TPE), which is FDA approved and routinely used in the clinic [16,17,18]
Summary
Heterochronic parabiosis has been used for decades in laboratory animals to investigate the effects of shared blood, organs and environmental enrichment, on the surgically connected partners [1, 2, 3,4,5]. Muscle fibrosis was not different between YY and young control mice that did not experience blood exchange or OO and old control mice; regeneration was slightly better in YY than Y and in OO than O cohorts; and YY/Young cohorts had higher regeneration and lower fibrosis than OO/Old cohorts (Supplementary Figure 1) To confirm these findings and to explore their evolutionary conservation, we took advantage of the fact that there is a procedure for human patients analogous to NBE where most of the plasma is replaced by physiologic solution, supplemented with commercial human albumin, called Therapeutic Plasma Exchange, TPE, which is FDA approved and routinely used in the clinic [16,17,18]. We did not find antioxidative difference between Pre and PostTPE serum (Supplementary Figure 3) These results establish that NBE and TPE have positive effects on adult myogenesis and that ectopic albumin does not rescue the old serum-imposed inhibition of myogenic proliferation. We performed the analyses of hippocampal neurogenesis and liver health (degree of adiposity and fibrosis) to examine whether in addition to skeletal muscle, there might be rejuvenative effects in the absence of young blood
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