Dietary restriction ameliorates haematopoietic ageing independent of telomerase, whilst lack of telomerase and short telomeres exacerbates the ageing phenotype
Dietary restriction ameliorates haematopoietic ageing independent of telomerase, whilst lack of telomerase and short telomeres exacerbates the ageing phenotype
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DOI：
10.1016/j.exger.2014.07.010
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发表时间：
2014-10-01
影响因子：
3.9
通讯作者：
Spyridopoulos, Ioakim
中科院分区：
文献类型：
--
作者：
Al-Ajmi, Nouf;Saretzki, Gabriele;Spyridopoulos, Ioakim
衰老与组织和干细胞（包括造血干细胞和祖细胞（HSPC））功能能力的总体下降以及端粒功能障碍有关。饮食限制（DR）是一种公认的抗衰老干预措施，可延长寿命并改善多种生物体的健康状况。为了研究端粒和端粒酶在造血衰老中的作用，我们比较了野生型和端粒酶缺陷小鼠骨髓细胞的HSPC谱和克隆形成能力，以及DR对这些参数的影响。与年轻小鼠相比，老年野生型小鼠表现出HSPC的显著积累（1.3% vs 0.2%，P = 0.002）和粒细胞/巨噬细胞集落形成单位（CFU-GM，26.4 vs 17.3，P = 0.0037）数量增加，与造血的髓系“偏斜”一致。DR能够限制老年野生型小鼠中HSPC数量的增加以及骨髓“偏斜”。为了分析短端粒对衰老表型的影响，我们检查了缺乏端粒酶RNA模板TERC-/-的小鼠。端粒缩短导致与老年小鼠中观察到的骨髓表型相似的骨髓表型，HSPC数量显著增加，所有髓系集落类型的形成增加，但年龄小于野生型小鼠。然而，红系细胞集落（BFU-E）的额外增加也很明显。缺乏端粒酶逆转录酶而没有缩短的端粒的小鼠，TERT-/-，也表现出增加的造血衰老，其被DR改善，表明DR的作用不依赖于HSPC中端粒酶的存在。我们的结论是，虽然缩短的端粒模仿造血衰老的某些方面，缩短的端粒和缺乏端粒酶产生特定的表型，其中一些可以通过饮食限制来预防。(C)2014 Elsevier Inc. All rights reserved.
Ageing is associated with an overall decline in the functional capacity of tissues and stem cells, including haematopoietic stem and progenitor cells (HSPCs), as well as telomere dysfunction. Dietary restriction (DR) is a recognised anti-ageing intervention that extends lifespan and improves health in several organisms. To investigate the role of telomeres and telomerase in haematopoietic ageing, we compared the HSPC profile and clonogenic capacity of bone marrow cells from wild type with telomerase-deficient mice and the effect of DR on these parameters.Compared with young mice, aged wild type mice demonstrated a significant accumulation of HSPCs (1.3% vs 0.2%, P = 0.002) and elevated numbers of granulocyte/macrophage colony forming units (CFU-GM, 26.4 vs 17.3, P = 0.0037) consistent with myeloid "skewing" of haematopoiesis. DR was able to restrict the increase in HSPC number as well as the myeloid "skewing" in aged wild type mice. In order to analyse the influence of short telomeres on the ageing phenotype we examined mice lacking the RNA template for telomerase, TERC-/-. Telomere shortening resulted in a similar bone marrow phenotype to that seen in aged mice, with significantly increased HSPC numbers and an increased formation of all myeloid colony types but at a younger age than wild type mice. However, an additional increase in erythroid colonies (BFU-E) was also evident. Mice lacking telomerase reverse transcriptase without shortened telomeres, TERT-/-, also presented with augmented haematopoietic ageing which was ameliorated by DR, demonstrating that the effect of DR was not dependent on the presence of telomerase in HSPCs. We conclude that whilst shortened telomeres mimic some aspects of haematopoietic ageing, both shortened telomeres and the lack of telomerase produce specific phenotypes, some of which can be prevented by dietary restriction. (C) 2014 Elsevier Inc. All rights reserved.