Immunity & Ageing ( IF 5.2 ) Pub Date : 2021-07-06 , DOI: 10.1186/s12979-021-00242-z Graham Pawelec 1, 2
For many years, a major question in ageing research has been whether organismal ageing processes affect all tissues similarly, or whether ageing of one organ system drives deficits in others, as originally proposed by Roy Walford in the context of autoimmunity a half-century ago [1]. Yousefzadeh et al. now report that engineering defective DNA repair exclusively in hematopoietic stem cells (HSCs) increases the accumulation of DNA damage in immune cells and results in their early senescence as reflected by higher expression of p16 and p21 [2]. They further show that there were many similarities between these Ercc1-deficient animals at younger ages and naturally aged mice at older ages. Moreover, strikingly, p16 and p21 expression was higher in many non-immune tissues of animals deficient for Ercc1 only in cells derived from HSCs, resulting in widespread tissue damage. These data provide strong support for a modern version of the “immunological theory of ageing” in that senescence limited only to the immune system in this model drives the ageing phenotype and occurrence of degenerative diseases of ageing to a striking degree. This important conclusion rests upon the absolute limitation of Ercc1-deficiency solely to HSCs. Here there may be some provisos to this model which are intrinsic to the use of tissue-specific transgenes to inactivate a gene of interest in a certain organ or tissue. First, there may be leakage of expression of the CRE-expressing transgene in other tissues, inactivating the gene of interest in (a fraction of) cells of that tissue as well, compromising the tissue-specificity of the gene inactivation technique. This was addressed by Yousefzadeh et al. excluding massive leakage but a minor loss of Ercc1 in other tissues is difficult to exclude with the techniques applied and may have been missed, especially in older animals. Second, in a small fraction of cells, inactivation of the floxed gene may not occur and these cells may outgrow the majority that has inactivated the gene of interest, if the wild-type cells have a growth advantage. Both phenomena may apply to tissue-specific Ercc1 mutants. Some other instances of “leakage” in a different context include increased levels of the oxidative DNA lesion 8-oxo-guanine in Ercc1-deficient immune cells, despite the fact that these lesions are repaired by BER, which is not affected by the Ercc1 repair defect. This may suggest “knock-on” effects to other DNA repair mechanisms. Conversely, DNA damage as manifested by cyclopurines was not affected by Ercc1-deficiency but this would normally be expected because these lesions are usually repaired by Ercc1. Nonetheless, these intriguing results make a major contribution to the question of whether immunosenescence drives ageing of other tissues in that even if there is some “leakage” the main effect seems clearly to be due to the activities of immune cells rather than senescence in general, as seen when Ercc1 is knocked out in the whole organism [3].
In the second part of the paper, the authors take this notion a step further, by showing that the premature organismal ageing phenotype of Ercc1-deficient mice could be prevented in several tissues by infusion of splenocytes from normal young mice. Reciprocally, transfer of splenocytes from either younger Ercc1-deficient animals or unmanipulated old animals induced senescence in several tissues of young mice [2]. These are remarkable data suggesting that deficits in only one DNA repair mechanism in only one stem cell compartment can result in immune senescence that is shown to impair not only both cellular and humoural immunity but also to indirectly affect the apparent ageing phenotypes of non-HSC-derived tissues, and moreover paralleling many degenerative changes seen in naturally ageing mice. These fascinating findings raise many questions, not least of which is in how far these findings in mice might also apply to humans. This is not susceptible to investigation because Ercc-1 mutations in humans are exceedingly rare, cause severe developmental dysfunction and are not limited to HSCs. Nonetheless, there is a long-standing school of thought that “inflammageing” links organismal and immune ageing via inflammatory mediators produced by senescent immune cells (but also many other senescent cell types and known as the “senescence-associated secretory phenotype”, or SASP) [4]. Yousefzadeh et al. now provide strong supporting evidence that it may indeed be senescent immune cells and not senescent cells in general that drive inflammageing. If so, a declining ability of immune cells to clear other senescent cells [5] as they themselves become senescent could constitute a vicious circle feedback. Hence, the “anti-ageing” effect of infusions of young splenocytes into Ercc1-deficient mice might be mediated by the capacity of the young cells to clear both senescent immune and nonimmune cells. This remains to be explored.
Not applicable.
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The author thanks Prof. J. H.J. Hoeijmakers, Rotterdam, The Netherlands for his generous advice on DNA repair and the role of Ercc1.
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Department of Immunology, University of Tübingen, Tübingen, Germany
Graham Pawelec
Health Sciences North Research Institute, Sudbury, Ontario, Canada
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Pawelec, G. Does immunosenescence drive organismal ageing via inflammageing?. Immun Ageing 18, 31 (2021). https://doi.org/10.1186/s12979-021-00242-z
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DOI: https://doi.org/10.1186/s12979-021-00242-z
中文翻译：
免疫衰老是否通过炎症驱动机体衰老？
多年来，衰老研究中的一个主要问题一直是机体衰老过程是否对所有组织产生类似的影响，或者一个器官系统的衰老是否会导致其他器官系统的缺陷，正如 Roy Walford 最初在半个世纪前在自身免疫背景下提出的那样。 1]。Yousefzadeh 等。现在报告称，专门在造血干细胞 (HSC) 中进行工程缺陷 DNA 修复会增加免疫细胞中 DNA 损伤的积累，并导致其早期衰老，这反映在 p16 和 p21 的较高表达上 [2]。他们进一步表明，这些缺乏 Ercc1 的年轻小鼠与自然衰老的小鼠之间存在许多相似之处。此外，引人注目的是，在缺乏 Ercc1 的动物的许多非免疫组织中，p16 和 p21 的表达仅在源自 HSC 的细胞中更高，导致广泛的组织损伤。这些数据为现代版本的“衰老免疫学理论”提供了强有力的支持，因为该模型中的衰老仅限于免疫系统，在显着程度上推动了衰老表型和衰老退行性疾病的发生。这一重要结论基于 Ercc1 缺陷仅对 HSC 的绝对限制。在这里，该模型可能有一些附带条件，这是使用组织特异性转基因使某个器官或组织中感兴趣的基因失活所固有的。首先，表达 CRE 的转基因在其他组织中的表达可能会泄漏，从而使该组织（部分）细胞中的目标基因失活，从而影响基因失活技术的组织特异性。Yousefzadeh 等人解决了这个问题。排除大量渗漏但其他组织中 Ercc1 的轻微损失很难用所应用的技术排除，并且可能会被遗漏，尤其是在老年动物中。其次，在一小部分细胞中，如果野生型细胞具有生长优势，则可能不会发生 floxed 基因的失活，并且这些细胞可能会超过大多数已失活目的基因的细胞。这两种现象都可能适用于组织特异性 Ercc1 突变体。在不同情况下的其他一些“泄漏”实例包括 Ercc1 缺陷免疫细胞中氧化性 DNA 损伤 8-氧代鸟嘌呤的水平增加，尽管这些损伤由 BER 修复，而 BER 不受 Ercc1 修复的影响缺点。这可能表明对其他 DNA 修复机制的“敲击”效应。反过来，由环嘌呤引起的 DNA 损伤不受 Ercc1 缺陷的影响，但这通常是可以预料的，因为这些损伤通常由 Ercc1 修复。尽管如此，这些有趣的结果对免疫衰老是否会导致其他组织衰老的问题做出了重大贡献，因为即使存在一些“泄漏”，主要影响似乎显然是由于免疫细胞的活动而不是一般的衰老，正如当 Ercc1 在整个生物体中被敲除时所见 [3]。
在论文的第二部分，作者将这一观点更进一步，表明可以通过输注来自正常年轻小鼠的脾细胞在多种组织中预防 Ercc1 缺陷小鼠的过早机体老化表型。相反，从年轻的 Ercc1 缺陷动物或未经处理的老年动物转移脾细胞会诱导年轻小鼠的几个组织衰老 [2]。这些显着的数据表明，只有一种干细胞区室中只有一种 DNA 修复机制的缺陷会导致免疫衰老，这不仅会损害细胞和体液免疫，还会间接影响非 HSC-的明显衰老表型。衍生组织，而且与自然衰老小鼠中观察到的许多退行性变化平行。这些引人入胜的发现提出了许多问题，其中最重要的是，这些在老鼠身上的发现在多大程度上也适用于人类。这不容易进行调查，因为人类中的 Ercc-1 突变极为罕见，会导致严重的发育功能障碍并且不仅限于 HSC。尽管如此，有一个长期存在的学派认为，“炎症”通过衰老免疫细胞（以及许多其他衰老细胞类型，称为“衰老相关分泌表型”或 SASP）产生的炎症介质将机体衰老和免疫衰老联系起来。 ) [4]。优素福扎德等人。现在提供强有力的支持证据表明它可能确实是衰老的免疫细胞而不是一般的衰老细胞驱动炎症。如果是这样的话，免疫细胞清除其他衰老细胞的能力下降 [5]，因为它们本身变得衰老，这可能构成恶性循环反馈。因此，将年轻脾细胞输注到 Ercc1 缺陷小鼠中的“抗衰老”作用可能是由年轻细胞清除衰老免疫细胞和非免疫细胞的能力介导的。这还有待探索。
不适用。
- 1.
沃尔福德 RL。自身免疫现象在衰老过程中的作用。Symp Soc Exp Biol。1967；21：351-73。
CAS PubMed 谷歌学者
- 2.
Yousefzadeh MJ、Flores RR、朱 Y、Schmiechen ZC、Brooks RW、Trussoni CE 等。老化的免疫系统会导致实体器官衰老和老化。自然。2021；594（7861）：100–5。https://doi.org/10.1038/s41586-021-03547-7。
CAS 文章 PubMed Google Scholar
- 3.
Schumacher B、Pothof J、Vijg J、Hoeijmakers JHJ。DNA 损伤在衰老过程中的核心作用。自然。2021；592（7856）：695-703。https://doi.org/10.1038/s41586-021-03307-7。
CAS 文章 PubMed Google Scholar
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Franceschi C、Capri M、Monti D、Giunta S、Olivieri F、Sevini F 等。炎症和抗炎：从人类研究中得出关于衰老和长寿的系统观点。机械老化开发 2007;128(1):92-105。https://doi.org/10.1016/j.mad.2006.11.016。
CAS 文章 PubMed Google Scholar
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Kale A、Sharma A、Stolzing A、Desprez PY、Campisi J。免疫细胞在去除有害衰老细胞中的作用。免疫老化。2020；17(1):16。https://doi.org/10.1186/s12979-020-00187-9。
文章 PubMed PubMed Central Google Scholar
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作者感谢荷兰鹿特丹的 JHJ Hoeijmakers 教授对 DNA 修复和 Ercc1 作用的慷慨建议。
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德国图宾根大学免疫学系
格雷厄姆·帕韦莱克
加拿大安大略省萨德伯里健康科学北方研究所
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Pawelec, G. 免疫衰老是否通过炎症驱动机体衰老？。免疫老化 18, 31 (2021)。https://doi.org/10.1186/s12979-021-00242-z
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