NAD⁺ Controls Circadian Reprogramming through PER2 Nuclear Translocation to Counter Aging

Area of Science:

• Circadian biology
• Metabolic science
• Aging research

Background:

• Aging disrupts sleep-wake and molecular circadian rhythms, linked to metabolic disease and reduced NAD⁺.
• The role of nucleotide metabolism in controlling circadian rhythms during aging is not well understood.

Purpose of the Study:

• To investigate whether NAD⁺ precursor supplementation can restore circadian rhythms and metabolic function in aging.
• To elucidate the molecular mechanisms by which NAD⁺ influences the circadian clock.

Main Methods:

• Supplementation with nicotinamide riboside (NR), an NAD⁺ precursor, in aged mice.
• Analysis of BMAL1 chromatin binding, PER2 protein modification (deacetylation and phosphorylation), and transcriptional oscillations.
• Assessment of mitochondrial respiration rhythms and behavioral activity (late evening activity).

Main Results:

• NR supplementation restored youthful NAD⁺ levels and markedly reprogrammed age-associated metabolic and stress-response pathways.
• NR inhibited the clock repressor PER2, enhancing BMAL1 chromatin binding via PER2^K680 deacetylation.
• NR treatment restored dampened BMAL1 chromatin binding, transcriptional oscillations, mitochondrial respiration rhythms, and late evening activity in old mice.

Conclusions:

• NAD⁺ repletion with NR effectively restores circadian behavioral and genomic rhythms in aging mice.
• NR influences the spatiotemporal control of the molecular clock, impacting metabolism and the circadian system during aging.
• These findings highlight the potential of targeting nucleotide metabolism to combat aging-related circadian and metabolic dysfunction.