Poljsak Borut
Laboratory of Oxidative Stress Research, Faculty of Health Sciences, University of Ljubljana , Ljubljana, Slovenia .
Rejuvenation Res. 2018 Jun;21(3):210-224. doi: 10.1089/rej.2017.1975. Epub 2017 Sep 8.
The biological age of organisms differs from the chronological age and is determined by internal aging clock(s). How cells estimate time on a scale of 24 hours is relatively well studied; however, how biological time is measured by cells, tissues, organs, or organisms in longer time periods (years and decades) is largely unknown. What is clear and widely agreed upon is that the link to age and age-related diseases is not chronological, as it does not depend on a fixed passage of time. Rather, this link depends on the biological age of an individual cell, tissue, organ, or organism and not on time in a strictly chronological sense. Biological evolution does not invent new methods as often as improving upon already existing ones. It should be easier to evolve and remodel the existing (circadian) time clock mechanism to use it for measurement or regulation of longer time periods than to invent a new time mechanism/clock. Specifically, it will be demonstrated that the circadian clock can also be used to regulate circannual or even longer time periods. Nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide adenine dinucleotide (NAD+) levels, being regulated by the circadian clock, might be the missing link between aging, cell cycle control, DNA damage repair, cellular metabolism and the aging clock, which is responsible for the biological age of an organism. The hypothesis that NAMPT/NAD+/SIRT1 might represent the time regulator that determines the organismal biological age will be presented. The biological age of tissues and organs might be regulated and synchronized through eNAMPT blood secretion. The "NAD World 2.0" concept will be upgraded with detailed insights into mechanisms that regulate NAD-mediated aging clock ticking, the duration and amplitude of which are responsible for the aging rate of humans.
生物体的生物学年龄不同于实际年龄，它由内部衰老时钟决定。细胞如何在24小时的时间尺度上估算时间已得到相对充分的研究；然而，细胞、组织、器官或生物体如何在更长的时间段（数年和数十年）内测量生物学时间，在很大程度上仍是未知的。目前明确且被广泛认同的是，与年龄及年龄相关疾病的联系并非基于实际年龄，因为它不取决于固定的时间流逝。相反，这种联系取决于单个细胞、组织、器官或生物体的生物学年龄，而不是严格意义上的时间。生物进化并不经常发明新方法，而是常常改进现有的方法。相较于发明一种新的时间机制/时钟，进化和重塑现有的（昼夜节律）时钟机制以用于测量或调节更长的时间段应该更容易。具体而言，将证明昼夜节律时钟也可用于调节年节律甚至更长的时间段。由昼夜节律时钟调节的烟酰胺磷酸核糖转移酶（NAMPT）介导的烟酰胺腺嘌呤二核苷酸（NAD+）水平，可能是衰老、细胞周期控制、DNA损伤修复、细胞代谢与衰老时钟之间缺失的环节，而衰老时钟决定了生物体的生物学年龄。将提出NAMPT/NAD+/SIRT1可能代表决定生物体生物学年龄的时间调节器这一假说。组织和器官的生物学年龄可能通过细胞外烟酰胺磷酸核糖转移酶（eNAMPT）的血液分泌来调节和同步。“NAD世界2.0”概念将通过对调节NAD介导的衰老时钟滴答作响机制的详细洞察得到升级，该机制的持续时间和幅度决定了人类的衰老速度。
