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Conboy M.J.,University of California at Berkeley | Conboy I.M.,University of California at Berkeley | Rando T.A.,Stanford University | Rando T.A.,Neurology Service and Rehabilitation Research
Aging Cell | Year: 2013

Pairing two animals in parabiosis to test for systemic or circulatory factors from one animal affecting the other animal has been used in scientific studies for at least 150 years. These studies have led to advances in fields as diverse as endocrinology, immunology, and oncology. A variation on the technique, heterochronic parabiosis, whereby two animals of different ages are joined to test for systemic regulators of aspects of aging or age-related diseases also has almost a century-long scientific history. In this review, we focus on the history of heterochronic parabiosis, methodological considerations and caveats, and the major advances that have emerged from those studies, including recent advances in our understanding of stem cell aging. © 2013 John Wiley & Sons Ltd and the Anatomical Society. Source


Conboy I.M.,University of California at Berkeley | Rando T.A.,Stanford University | Rando T.A.,Neurology Service and Rehabilitation Research
Cell Cycle | Year: 2012

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. © 2012 Landes Bioscience. Source


Rodgers J.T.,Stanford University | Rando T.A.,Stanford University | Rando T.A.,Neurology Service and Rehabilitation Research
EMBO Journal | Year: 2012

Age associated changes in stem cell function are widely implicated as having a causal role to the declines in tissue function, homeostasis and regenerative ability that accompany aging. However, the signals and mechanisms that lead to altered stem cell functionality in aging are unclear. A recent study published in Nature (Chakkalakal et al, 2012) proposes a unique mechanism whereby a signal from the aged niche causes a cell autonomous and persistent change in the ability of a stem cell to maintain the quiescent state, which, over time, leads into impaired tissue regenerative capacity. © 2012 European Molecular Biology Organization | All Rights Reserved. Source


Cheung T.H.,Stanford University | Cheung T.H.,Hong Kong University of Science and Technology | Rando T.A.,Stanford University | Rando T.A.,Neurology Service and Rehabilitation Research
Nature Reviews Molecular Cell Biology | Year: 2013

Subsets of mammalian adult stem cells reside in the quiescent state for prolonged periods of time. This state, which is reversible, has long been viewed as dormant and with minimal basal activity. Recent advances in adult stem cell isolation have provided insights into the epigenetic, transcriptional and post-transcriptional control of quiescence and suggest that quiescence is an actively maintained state in which signalling pathways are involved in maintaining a poised state that allows rapid activation. Deciphering the molecular mechanisms regulating adult stem cell quiescence will increase our understanding of tissue regeneration mechanisms and how they are dysregulated in pathological conditions and in ageing. © 2013 Macmillan Publishers Limited. All rights reserved. Source


Gopinath S.D.,Stanford University | Webb A.E.,Stanford University | Brunet A.,Stanford University | Rando T.A.,Stanford University | Rando T.A.,Neurology Service and Rehabilitation Research
Stem Cell Reports | Year: 2014

Skeletal muscle stem cells, or "satellite cells" (SCs), are required for the regeneration of damaged muscle tissue. Although SCs self-renew during regeneration, the mechanisms that govern SC re-entry into quiescence remain elusive. We show that FOXO3, a member of the forkhead family of transcription factors, is expressed in quiescent SCs (QSCs). Conditional deletion of Foxo3 in QSCs impairs self-renewal and increases the propensity of SCs to adopt a differentiated fate. Transcriptional analysis of SCs lacking FOXO3 revealed a downregulation of Notch signaling, a key regulator of SC quiescence. Conversely, overexpression of Notch intracellular domain (NICD) rescued the self-renewal deficit of FOXO3-deficient SCs. We show that FOXO3 regulates NOTCH1 and NOTCH3 receptor expression and that decreasing expression of NOTCH1 and NOTCH3 receptors phenocopies the effect of FOXO3 deficiency in SCs. We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration. © 2014 The Authors. Source

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