Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA.
Gerontology. 2018;64(3):300-308. doi: 10.1159/000485320. Epub 2018 Jan 10.
Aging is associated with a significant decline of tissue repair and regeneration, ultimately resulting in tissue dysfunction, multimorbidity, and death. Salamanders possess remarkable regenerative abilities and have been studied with the prospect of inducing regeneration in humans and counteracting regenerative decline with aging. However, epimorphic regeneration, the full replacement of amputated structures, also occurs in mammals. One of the best studied models is digit tip regeneration, which is described for mice, and occurs in humans in a comparable manner. To accomplish regeneration, the amputated digit tip has to undergo three interdependent, overlapping steps: (i) wound healing without formation of a scar; (ii) formation of a blastema, a highly proliferative cell mass; and (iii) spatiotemporally regulated differentiation to generate a pattern similar to the original structure. Aging likely interferes with each of these steps. In this article, we provide an overview of the critical signaling pathways for regeneration, as revealed by investigating mammalian digit regeneration, the possible impact of aging on these pathways, and approaches to induce regeneration in the elderly. We hypothesize that with aging, increased Wnt signaling, NF-κB and tumor suppressor activity, and loss of positional information hampers regeneration. Knowledge about the impact of aging on regenerative mechanisms will enable us to safely activate endogenous regeneration in the elderly, and to generate a regeneration-permissive environment for cell therapies.
衰老是与组织修复和再生能力的显著下降相关的，最终导致组织功能障碍、多种疾病和死亡。蝾螈具有显著的再生能力，一直是研究的热点，有望在人类中诱导再生，并对抗衰老导致的再生能力下降。然而，在哺乳动物中也存在出芽再生，即完全替代被截肢的结构。其中研究得最好的模型之一是指（趾）尖再生，这在小鼠中已有描述，在人类中也以类似的方式发生。为了实现再生，被截肢的指（趾）尖必须经历三个相互依赖、重叠的步骤：（i）无疤痕形成的创伤愈合；（ii）形成一个芽基，这是一个高度增殖的细胞团；以及（iii）时空调节分化，以产生与原始结构相似的模式。衰老是可能干扰这些步骤的。在本文中，我们通过研究哺乳动物指（趾）尖再生，概述了再生所涉及的关键信号通路，以及衰老对这些通路的可能影响，以及在老年人中诱导再生的方法。我们假设，随着年龄的增长，Wnt 信号、NF-κB 和肿瘤抑制因子活性的增加，以及位置信息的丧失，会阻碍再生。了解衰老对再生机制的影响将使我们能够安全地在老年人中激活内源性再生，并为细胞治疗创造一个再生允许的环境。
