- The effect of NAD+ and Sirt1 on Major Depressive Disorder
- NAD+ as a moderator in bipolar disorder
- Fluctuations of NAD+ and its effect on the circadian rhythm
Sirtuins are an NAD+ dependent class of enzymes. Seven homologs have been identified, with Sirt1 and Sirt2 being the most studied. Sirtuins are known to have multiple protective roles in pathophysiological pathways such as aging, DNA repair, cardiovascular disease, cell regulation, etc.
Sirtuins have recently been identified as a key factor in the development of various mood disorders such as depression, anxiety, or bipolar disorder. Sirt1 particularly has neuroprotective effects. Their impact is explained through the occurrence of depressive-like symptoms when Sirtuins activity decreases in presence of prolonged stress, and the occurrence of anxiety-like symptoms, when decreased Sirtuins levels cause a decrease in serotonin expression.
It is understood that Sirtuins regulate the expression of monoamine oxidase A, which catabolizes serotonin. Hence a decrease in NAD+ will decrease Sirtuins and consequently result in more serotonin breakdown. A 2004 study in rodents explored the effect of NADH which is a reduced form of NAD+ and found that it had a similar behavioral effect as the antidepressant Fluoxetine. Another 2014 study in rodents with depression-like behavior, found that resveratrol, which is a Sirt1 activator, had a positive antidepressant effect as well.
Bipolar disorders are mainly described as biphasic diseases with alternating episodes of mania and depression. Investigational studies have established an association with energy levels through mitochondrial activity and ATP production. During manic phases, there is increased oxidative stress, intracellular Ca2+, and pro-inflammatory cytokines. During depressive phases, these activities decrease. When cytosolic Ca2+ increases, there is an increase in ATP production through increased NAD+ levels and consequently, Sirt1 activity. This will have a protective effect on mitochondrial function by oxidative phosphorylation.
The circadian rhythm consists of alternating mental and physical behaviors around the 24 hours biological clock. The alternations in the rhythm affect hormonal function, appetite and digestion, body temperature, and sleep. The referred biological clock is located in the hypothalamic suprachiasmatic nucleus (SCN), which comprises CLOCK and BMAL1 which are transcription factors. These factors are activated by Sirt1 that is present in the nervous system, which consequently makes it a regulator of the circadian rhythm. Hence the loss of Sirt1 is associated with a slowed or disrupted rhythm. Sirt1 has also been found to affect the circadian clock by deacetylating central clock components in the hepatic cells of rodents. When it comes to the focused impact of NAD+, it is synthesized in an oscillatory fashion parallel to the circadian rhythm from nicotinamide, NAMPT, and nicotinamide phosphoribosyltransferase. This leads to scheduled Sirt1 activation and mitochondrial activity.
When discussing circadian rhythm, the most common association is sleep. Jet lag occurs when there is rhythm disruption after traveling for long hours and relocating several time zones away, resulting in sleep schedule interruption. Jet lag causes fatigue, mood changes, and indigestion. As mentioned earlier, NAD+ levels follow a circadian pattern, activating Sirtuins similarly.
Sirtuins bring it full circle by regulating mitochondrial activity and the circadian clock itself. NAD+ also impacts dopamine synthesis, and in a 2002 study, it was seen that NADH supplementation during jet lag was able to fight sleepiness and disruption of cognitive behaviors.
NAD+ has the potential to be a multifaceted agent not only in physical ailments but also in mood and cognitive disorders. There is a growing understanding of its different mechanisms that affect mental health and wellbeing. There’s also growing evidence of its effects, either as a mood stabilizer, cognitive regulator, or circadian rhythm modulator.
- Arenas-Jal M, Suñé-Negre JM, García-Montoya E. Therapeutic potential of nicotinamide adenine dinucleotide (NAD). Eur J Pharmacol. 2020;879:173158. doi:10.1016/j.ejphar.2020.173158
- Lu G, Li J, Zhang H, Zhao X, Yan LJ, Yang X. Role and Possible Mechanisms of Sirt1 in Depression. Oxid Med Cell Longev. 2018;2018:8596903. Published 2018 Jan 31. doi:10.1155/2018/8596903
- Morris G, Walder K, McGee SL, et al. A model of the mitochondrial basis of bipolar disorder. Neurosci Biobehav Rev. 2017;74(Pt A):1-20. doi:10.1016/j.neubiorev.2017.01.014
- Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014;24(8):464-471. doi:10.1016/j.tcb.2014.04.002