...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Experimental Gerontology >The reserve-capacity hypothesis: evolutionary origins and modern implications of the trade-off between tumor-suppression and tissue-repair.
【24h】

The reserve-capacity hypothesis: evolutionary origins and modern implications of the trade-off between tumor-suppression and tissue-repair.

机译：储备能力假说：肿瘤抑制与组织修复之间权衡取舍的进化起源和现代意义。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Antagonistic pleiotropy, the evolutionary theory of senescence, posits that age related somatic decline is the inevitable late-life by-product of adaptations that increase fitness in early life. That concept, coupled with recent findings in oncology and gerontology, provides the foundation for an integrative theory of vertebrate senescence that reconciles aspects of the 'accumulated damage' 'metabolic rate', and 'oxidative stress' models. We hypothesize that (1) in vertebrates, a telomeric fail-safe inhibits tumor formation by limiting cellular proliferation. (2) The same system results in the progressive degradation of tissue function with age. (3) These patterns are manifestations of an evolved antagonistic pleiotropy in which extrinsic causes of mortality favor a species-optimal balance between tumor suppression and tissue repair. (4) With that trade-off as a fundamental constraint, selection adjusts telomere lengths-longer telomeres increasing the capacity for repair, shorter telomeres increasing tumor resistance. (5) In environments where extrinsically induced mortality is frequent, selection against senescence is comparatively weak as few individuals live long enough to suffer a substantial phenotypic decline. The weaker the selection against senescence, the further the optimal balance point moves toward shorter telomeres and increased tumor suppression. The stronger the selection against senescence, the farther the optimal balance point moves toward longer telomeres, increasing the capacity for tissue repair, slowing senescence and elevating tumor risks. (6) In iteroparous organisms selection tends to co-ordinate rates of senescence between tissues, such that no one organ generally limits life-span. A subsidiary hypothesis argues that senescent decline is the combined effect of (1) uncompensated cellular attrition and (2) increasing histological entropy. Entropy increases due to a loss of the intra-tissue positional information that normally regulates cell fate and function. Informational loss is subject to positive feedback, producing the ever-accelerating pattern of senescence characteristic of iteroparous vertebrates. Though telomere erosion begins early in development, the onset of senescence should, on average, be deferred to the species-typical age of first reproduction, the balance point at which selection on this trade-off should allow exhaustion of replicative capacity to overtake some cell lines. We observe that captive-rodent breeding protocols, designed to increase reproductive output, simultaneously exert strong selection against reproductive senescence and virtually eliminate selection that would otherwise favor tumor suppression. This appears to have greatly elongated the telomeres of laboratory mice. With their telomeric failsafe effectively disabled, these animals are unreliable models of normal senescence and tumor formation. Safety tests employing these animals likely overestimate cancer risks and underestimate tissue damage and consequent accelerated senescence.
机译：对抗性多效性是衰老的进化理论，它认为与年龄相关的体细胞衰弱是适应性的不可避免的晚期生命副产物，其增加了早期生命的适应性。这个概念，再加上最近在肿瘤学和老年医学上的发现，为脊椎动物衰老的综合理论奠定了基础，该理论调和了“累积损害”，“代谢率”和“氧化应激”模型的各个方面。我们假设（1）在脊椎动物中，端粒失效保护通过限制细胞增殖来抑制肿瘤形成。 （2）同一系统导致组织功能随着年龄的增长而逐渐退化。 （3）这些模式是进化的拮抗多效性的表现，其中外在的死亡原因有利于肿瘤抑制和组织修复之间的物种最优平衡。 （4）以折衷为基本限制，选择可以调节端粒的长度，较长的端粒可提高修复能力，较短的端粒可提高肿瘤抵抗力。 （5）在外在性死亡频繁发生的环境中，针对衰老的选择相对较弱，因为很少有人寿命足以遭受实质性表型下降。抗衰老的选择越弱，最佳平衡点就越朝着较短的端粒和增加的肿瘤抑制方向发展。抗衰老的选择越强，最佳平衡点就越朝着更长的端粒移动，从而增加了组织修复的能力，减缓了衰老并增加了肿瘤风险。 （6）在同种异体生物中，选择趋于协调组织之间的衰老率，以至于没有一个器官通常会限制寿命。辅助假设认为，衰老下降是（1）细胞代偿性失代偿和（2）组织学熵增加的综合作用。由于通常调节细胞命运和功能的组织内位置信息的丢失，熵增加。信息损失受到正反馈的影响，产生了等速脊椎动物衰老特征的不断加速的趋势。尽管端粒侵蚀是在发育早期开始的，但衰老的发生通常应推迟到首次繁殖的物种典型年龄，在此折衷选择的平衡点应使复制能力耗尽，从而超过某些细胞线。我们观察到，旨在增加生殖产量的圈养啮齿动物繁殖方案，同时对生殖衰老发挥了强大的选择作用，实际上消除了否则会有利于肿瘤抑制的选择。这似乎大大延长了实验小鼠的端粒。由于有效禁用了端粒失效保护功能，这些动物是正常衰老和肿瘤形成的不可靠模型。使用这些动物的安全性测试可能高估了癌症风险，并低估了组织损伤和随之而来的加速衰老。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号