Naviaux Robert K
The Mitochondrial and Metabolic Disease Center, Departments of Medicine, Pediatrics, Pathology, University of California, San Diego School of Medicine, San Diego, CA 92103, USA.
Biology (Basel). 2019 May 11;8(2):27. doi: 10.3390/biology8020027.
The rate of biological aging varies cyclically and episodically in response to changing environmental conditions and the developmentally-controlled biological systems that sense and respond to those changes. Mitochondria and metabolism are fundamental regulators, and the cell is the fundamental unit of aging. However, aging occurs at all anatomical levels. At levels above the cell, aging in different tissues is qualitatively, quantitatively, and chronologically distinct. For example, the heart can age faster and differently than the kidney and vice versa. Two multicellular features of aging that are universal are: (1) a decrease in physiologic reserve capacity, and (2) a decline in the functional communication between cells and organ systems, leading to death. Decreases in reserve capacity and communication impose kinetic limits on the rate of healing after new injuries, resulting in dyssynchronous and incomplete healing. Exercise mitigates against these losses, but recovery times continue to increase with age. Reinjury before complete healing results in the stacking of incomplete cycles of healing. Developmentally delayed and arrested cells accumulate in the three stages of the cell danger response (CDR1, 2, and 3) that make up the healing cycle. Cells stuck in the CDR create physical and metabolic separation-buffer zones of reduced communication-between previously adjoining, synergistic, and metabolically interdependent cells. Mis-repairs and senescent cells accumulate, and repeated iterations of incomplete cycles of healing lead to progressively dysfunctional cellular mosaics in aging tissues. Metabolic cross-talk between mitochondria and the nucleus, and between neighboring and distant cells via signaling molecules called metabokines regulates the completeness of healing. Purinergic signaling and sphingolipids play key roles in this process. When viewed against the backdrop of the molecular features of the healing cycle, the incomplete healing model provides a new framework for understanding the hallmarks of aging and generates a number of testable hypotheses for new treatments.
生物衰老的速率会随着环境条件的变化以及感知并响应这些变化的发育控制生物系统而周期性和阶段性地变化。线粒体和新陈代谢是基本调节因素，而细胞是衰老的基本单位。然而，衰老发生在所有解剖层面。在细胞之上的层面，不同组织的衰老在性质、数量和时间上是不同的。例如，心脏的衰老可能比肾脏更快且不同，反之亦然。衰老的两个普遍的多细胞特征是：（1）生理储备能力下降，以及（2）细胞与器官系统之间功能通讯的衰退，最终导致死亡。储备能力和通讯的下降对新损伤后的愈合速率施加了动力学限制，导致愈合不同步和不完全。运动可减轻这些损失，但恢复时间会随着年龄增长而持续增加。在完全愈合之前再次受伤会导致不完全愈合周期的叠加。发育延迟和停滞的细胞在构成愈合周期的细胞危险反应（CDR1、2和3）的三个阶段中积累。被困在CDR中的细胞会在先前相邻、协同和代谢相互依存的细胞之间形成物理和代谢分离缓冲区域，通讯减少。错误修复和衰老细胞积累，不完全愈合周期的反复迭代会导致衰老组织中细胞镶嵌体逐渐功能失调。线粒体与细胞核之间以及相邻和远距离细胞之间通过称为代谢因子的信号分子进行的代谢相互作用调节愈合的完整性。嘌呤能信号传导和鞘脂在这一过程中起关键作用。从愈合周期的分子特征背景来看，不完全愈合模型为理解衰老的特征提供了一个新框架，并为新的治疗方法产生了许多可测试的假设。
