Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin

Abstract

The capacity for tissues to repair and regenerate diminishes with age. We sought to determine the age-dependent contribution of native mesenchymal cells and circulating factors on in vivo bone repair. Here we show that exposure to youthful circulation by heterochronic parabiosis reverses the aged fracture repair phenotype and the diminished osteoblastic differentiation capacity of old animals. This rejuvenation effect is recapitulated by engraftment of young haematopoietic cells into old animals. During rejuvenation, β-catenin signalling, a pathway important in osteoblast differentiation, is modulated in the early repair process and required for rejuvenation of the aged phenotype. Temporal reduction of β-catenin signalling during early fracture repair improves bone healing in old mice. Our data indicate that young haematopoietic cells have the capacity to rejuvenate bone repair and this is mediated at least in part through β-catenin, raising the possibility that agents that modulate β-catenin can improve the pace or quality of fracture repair in the ageing population.

Report: NIA Workshop on Measures of Physiologic Resiliencies in Human Aging

“…Studies on circulating factors are subject to the caveat that circulating levels may not correlate well with levels in the tissue of interest, but can nonetheless provide insights. Circulating factors that influence tissue repair and whose levels change with age in laboratory animals have been identified through heterochronic parabiosis (23).…”

Homeostatic migration and distribution of innate immune cells in primary and secondary lymphoid organs with ageing

“…This is where heterochronic parabiosis, the surgical union between an adult and an old organism, can be used as a powerful platform to both isolate individual pro-and anti-geronic factors and to understand the complexity of ageing. The anti-geronic effects of heterochronic parabiosis have been demonstrated thoroughly in skeletal muscle [7], central nervous system [8][9][10][11], pancreatic b cell proliferation [12], cardiac tissue [13], bone repair [14] and systemic cholesterol turnover [15]. In some cases, single molecules or pathways were identified as playing a significant pro-or anti-geronic role in the aetiology of ageing in the reported tissue.…”

“…in the case of impaired Schwann cell function [17], impaired T cell subset distribution [18], function [19] and thymic involution [18,20], and in the first two examples pro-geronic effects were noted in the adult animal. Regarding individual pro-geronic molecules, increased levels of CCL11 and b2m with age are associated with decreased brain functions [8,11] and increased b-catenin signalling was implicated in defects in bone repair [14].…”

The Impact of Aging on Mechanisms of Mammalian Epimorphic Regeneration

“…Fracture repair in aged bone was improved by exposing the tissue to a young environment, achieved by surgical connection of the blood circuits of young and old animals (heterochronic parabiosis), or transplantation of young bone marrow into old animals. As in muscle, this effect was shown to involve Wnt inhibition, and is mimicked by the treatment of old mice with DKK1, which still allowed Wnt activation in the fractured bone, but prevented overactivated Wnt [19]. Therefore, systemic Wnt inhibition might be beneficial for the outcome of regeneration, but on a local level, a transient, well-dosed Wnt activation must occur to allow regeneration.…”