The Fountain of Youth: A Tale of Parabiosis, Stem Cells, and Rejuvenation

Abstract

Transfusion (or drinking) of blood or of its components has been thought as a rejuvenation method since ancient times. Parabiosis, the procedure of joining two animals so that they share each others blood circulation, has revitalized the concept of blood as a putative drug. Since 2005, a number of papers have reported the anti-ageing effect of heterochronic parabiosis, which is joining an aged mouse to a young partner. The hallmark of aging is the decline of regenerative properties in most tissues, partially attributed to impaired function of stem and progenitor cells. In the parabiosis experiments, it was elegantly shown that factors derived from the young systemic environment are able to activate molecular signaling pathways in hepatic, muscle or neural stem cells of the old parabiont leading to increased tissue regeneration. Eventually, further studies have brought to identify some soluble factors in part responsible for these rejuvenating effects, including the chemokine CCL11, the growth differentiation factor 11, a member of the TGF-β superfamily, and oxytocin. The question about giving whole blood or specific factors in helping rejuvenation is open, as well as the mechanisms of action of these factors, deserving further studies to be translated into the life of (old) human beings.

Keywords: Blood; Brain; CCL11; GDF11; Liver; Muscle; Oxytocin; Parabiosis; Rejuvenation.

Figure 1

Parabiosis. Two mice are stitched together sharing a common bloodstream. Heterochronic parabiosis is when a young mouse is surgically joined to aged partners, while isochronic parabiosis is referred to pairs of young-young or old-old animals. Modified from ref. [36] with permission of Nature Publishing Group.

Figure 2

Ageing of muscles, liver and brain in old mice and rejuvenation by heterochronic parabiosis. The regeneration of skeletal muscle upon injury is linked with the up regulation of the Notch ligand Delta, that is lost with age (upper panels). Hepatocyte proliferation in young animals correlates with the decrease of cEBP-α-brahma (cEBP-α-Brm) complex as compared with aged mice (middle panels). While young animals can increase their neurogenesis and angiogenesis in the subventricular zone of the brain, where neural stem cells are present, aged animals cannot (lower panels). In principle, the heterochonic parabiosis reverts all phenotypic and molecular hallmarks of ageing by transferring soluble factors and cells.

Figure 3

Proposed model describing age-related changes in osteoblastic cell niche and HSCs, and how these changes may be reverted by heterochronic parabiosis. Age-specific changes in autocrine or paracrine effects of IGF-1 on osteoblastic niche cells are signaled by circulating soluble factors which themselves change with age. IGF-1 signaling in aged osteoblastic niche cells (a) directly contributes to age-related dysfunction in HSCs, including HSC over-accumulation and skewed B lymphoid (B cell)/myeloid (My) fate choice. Following heterochronic parabiosis, or after neutralization of IGF-1 signaling in vivo (b), the “youthful” activity of aged niche cells is restored, such that they no longer induce over-accumulation or lineage skewing of HSCs. From ref. [11] with permission of Nature Publishing Group.