As for other aspects of metabolic regulation, circadian rhythm becomes increasingly disrupted with age. Researchers here provide evidence for falling NAD+ levels to be a proximate cause of this issue. NAD+ is important in the core activity of mitochondria, generation of energy store molecules to power cellular operations, but also acts on numerous other processes in the cell. Unfortunately the various mechanisms of synthesis and recycling of NAD+ falter as tissues age, though it is an open question as to how much of this is a matter of failing to maintain fitness versus more inexorable processes of aging. Data suggests that exercise programs in older individuals can do just as well, if not better, than approaches based on providing NAD+ precursors such as nicotinamide riboside as supplements.
Cellular levels of NAD+ decline with ageing, and boosting NAD+ production by administration of its precursors promotes youthful behavioural and physiological functions in mice. To investigate the role of NAD+ in circadian gene expression in mice, the authors gave mice drinking water that was supplemented with NAD+ precursors for 4 months and analysed circadian gene expression in the liver. This revealed that the expression pattern of approximately half of circadian-regulated hepatic genes changed upon NAD+ increase.
NAD+ is a cofactor for sirtuin deacetylases, which are known to promote healthspan and lifespan. Sirtuin 1 (SIRT1) regulates circadian rhythms by binding to the core clock complex - comprising heterodimeric circadian transcription activator CLOCK-BMAL1 and its repressor PER2 - and driving PER2 deacetylation and subsequent degradation. Liver-specific Sirt1 knockout abrogated the changes in hepatic circadian gene expression that were observed when NAD+ levels were increased.
Next, the authors found that in the liver of old mice, chromatin occupancy of BMAL1 was decreased, which coincided with increased PER2 levels and decreased amplitude of circadian gene oscillations. Administration of NAD+ precursor to the old mice for 6 months restored BMAL1 chromatin binding and function to levels observed in young animals. In addition, late-night locomotor activity, normally reduced in old mice, was restored to youthful levels with NAD+ precursor administration. In summary, elevating NAD+ has the capacity to reverse ageing-associated dysfunction of circadian rhythms.