NAMPT-Mediated NAD Biosynthesis as the Internal Timing Mechanism: In NAD+ World, Time Is Running in Its Own Way.

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.