Heterochronic parabiosis for the study of the effects of aging on stem cells and their niches

Abstract

Aging is unmistakable and undeniable in mammals. Interestingly, mice develop cataracts, muscle atrophy, osteoporosis, obesity, diabetes and cognitive deficits after just 2-3 postnatal years, while it takes seven or more decades for the same age-specific phenotypes to develop in humans. Thus, chronological age corresponds differently with biological age in metazoan species and although many theories exist, we do not understand what controls the rate of mammalian aging. One interesting idea is that species-specific rate of aging represents a ratio of tissue attrition to tissue regeneration. Furthermore, current findings suggest that the age-imposed biochemical changes in the niches of tissue stem cells inhibit performance of this regenerative pool, which leads to the decline of tissue maintenance and repair. If true, slowing down stem cell and niche aging, thereby promoting tissue regeneration, could slow down the process of tissue and organismal aging. In this regard, recent studies of heterochronic parabiosis provide important clues as to the mechanisms of stem cell aging and suggest novel strategies for enhancing tissue repair in the old. Here we review current literature on the relationship between the vigor of tissue stem cells and the process of aging, with an emphasis on the rejuvenation of old tissues by the extrinsic modifications of stem cell niches.

Figure 1. Aging and rejuvenation of adult myogenesis. In young muscle, injury upregulates the Notch ligand, Delta-like 1, which activates Notch signaling. Active Notch promotes a G₀ to G₁ transition in muscle stem cells after an injury; interplay between Notch and Wnt controls myogenic cell proliferation and differentiation. In old muscle, which regenerates poorly, in addition to a suppression of activation of Notch pathway following injury, there is also an excess of signaling via the TGFβ and Wnt pathways, leading to a suppression of myogenesis and a promotion of fibrosis. Notch, Wnt and likely other signaling pathways are regulated by systemic niche / circulatory milieu, such that in the aged environment, systemic signals contribute to the activities that inhibit myogenesis and promote fibrosis. By contrast, in the setting of heterochronic parabiosis, young systemic factors restore more youthful states and are able to rejuvenate the aged stem cells and stem cell niches to promote enhanced muscle regeneration. .

Figure 2. The role of the stem cell niche in stem cell performance (A) The young niche induces productive stem cell responses and, as a result, young tissues regenerate efficiently. (B) By contrast, the old niche inhibits stem cell responses. Rather than effective tissue regeneration, there is sustained inflammation and resulting fibrosis, perhaps further suppressing stem cell function and leading to apoptosis, senescence, or aberrant cell fate. (C) Promisingly, exogenous molecules that boost the regenerative responses of tissue stem cells, perhaps in part by rejuvenating the aged niche, promote effective repair of aged tissues, overriding the inhibitory influence of the old niches.