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

Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 06/2012; 11(12):2260-7. DOI: 10.4161/cc.20437
Source: PubMed

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.

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    • "We injected CTX ( Sigma ) into the TA muscles of 3 - mo - old and 27 - mo - old mice to induce muscle regeneration following a previous - ly described method ( Conboy and Rando 2012 ) . Briefly , TA mus - cles were injected with 50 µL of 20 µM CTX . "
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    ABSTRACT: The myogenic capacity of myoblasts decreases in skeletal muscle with age. In addition to environmental factors, intrinsic factors are important for maintaining the regenerative potential of muscle progenitor cells, but their identities are largely unknown. Here, comparative analysis of microRNA (miRNA) expression profiles in young and old myoblasts uncovered miR-431 as a novel miRNA showing markedly reduced abundance in aged myoblasts. Importantly, elevating miR-431 improved the myogenic capacity of old myoblasts, while inhibiting endogenous miR-431 lowered myogenesis. Bioinformatic and biochemical analyses revealed that miR-431 directly interacted with the 3' untranslated region (UTR) of Smad4 mRNA, which encodes one of the downstream effectors of TGF-β signaling. In keeping with the low levels of miR-431 in old myoblasts, SMAD4 levels increased in this myoblast population. Interestingly, in an in vivo model of muscle regeneration following cardiotoxin injury, ectopic miR-431 injection greatly improved muscle regeneration and reduced SMAD4 levels. Consistent with the finding that the mouse miR-431 seed sequence in the Smad4 3' UTR is conserved in the human SMAD4 3' UTR, inhibition of miR-431 also repressed the myogenic capacity of human skeletal myoblasts. Taken together, our results suggest that the age-associated miR-431 plays a key role in maintaining the myogenic ability of skeletal muscle with age. © 2015 Lee et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & development 07/2015; 29(15). DOI:10.1101/gad.263574.115 · 10.80 Impact Factor
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    • "There is wide evidence, both in animals models and in humans, the Wnt signaling pathway is down regulated with aging and contributes to the progressive reduction in muscle regeneration and repair capacity (Conboy and Rando, 2012). Wnt proteins are a large family (19 members in humans) of secreted glycoproteins that are highly evolutionary conserved. "
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    ABSTRACT: Aging is associated with a progressive loss of muscle mass and strength and a decline in neurophysiological functions. Age-related neuromuscular junction (NMJ) plays a key role in musculoskeletal impairment that occurs with aging. However, whether changes in the NMJ precede or follow the decline of muscle mass and strength remains unresolved. Many factors such as mitochondrial dysfunction, oxidative stress, inflammation, changes in the innervation of muscle fibers, and mechanical properties of the motor units probably perform an important role in NMJ degeneration and muscle mass and strength decline in late life. This review addresses the primary events that might lead to NMJ dysfunction with aging, including studies on biomarkers, signaling pathways, and animal models. Interventions such as caloric restriction and exercise may positively affect the NMJ through this mechanism and attenuate the age-related progressive impairment in motor function.
    Frontiers in Aging Neuroscience 08/2014; 6:208. DOI:10.3389/fnagi.2014.00208 · 4.00 Impact Factor
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    • "Especially in early, mid, and older adults, stem cells reduced or ceased their growth and regeneration capacities to maintain tissue homeostasis or to reduce cancer development risk in aging tissues (Signer and Morrison 2013). Additionally, the current findings in the literature suggest that such biochemical changes in the stem cell niches are responsible for regenerative declines in older mammalians (Conboy and Rando 2012). The MTT assay results of the present study showed that metabolic and cellular activity of the early and mid adult BM-MSCs decreased, such a decrease in the mitochondrial activity, growth, and metabolic rates of the cells of mammalian tissues can influence the rates of the cellular aging at the later stages of the life (Dillin et al. 2002). "
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    ABSTRACT: Stem cell studies hold enormous potential for development of new therapies for tissue regeneration and repair. Bone marrow mesenchymal stem cells (BM-MSCs) can differentiate into a variety of non-hematopoietic tissues and contribute maintenance of healthy hematopoiesis by providing supportive cellular microenvironment into BM. Here, we investigated age-related differences in BM-MSCs by using attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and FTIR imaging together with hierarchical clustering as a novel methods to clarify global alterations in the structure and function of macromolecules in characterized BM-MSCs of different aged donors. The results may contribute to identification of age-related new molecular marker(s) to determine the effects of donor age on MSCs. The spectral results reflected that there were significant increases in the concentration of saturated lipids, proteins, glycogen, and nucleic acids in children and adolescent group BM-MSCs when compared to the infants and early and mid adults. The concentration of mentioned macromolecules in adult (early and mid) BM-MSCs were significantly lower than the concentrations in the children and adolescents. These results were attributed to the increase in the proliferation activity in younger BM-MSCs. The distribution of macromolecules into the cells was shown as in the form of chemical maps by FTIR imaging, and the results are in agreement with the ATR-FTIR spectroscopy results. The cellular activity degree was determined by the thiazolyl blue tetrazolium bromide (MTT) proliferation assay to support ATR-FTIR spectroscopy results. BM-MSCs of five different age groups were discriminated by making the hierarchical cluster analysis where the spectral data according to alterations in structure and composition of macromolecules were considered.
    Journal of the American Aging Association 08/2014; 36(4):9691. DOI:10.1007/s11357-014-9691-7 · 3.39 Impact Factor
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