Is NAD low in CFS?

Nicotinamide adenine dinucleotide (NAD) performs central roles in metabolism as a redox cofactor and enzyme substrate. NAD is synthesised via several pathways; in essence from tryptophan (i.e. de novo pathway) or vitamin B₃ precursors (i.e. Preiss-Handler and salvage pathways), with addition of ribose-phosphate (from PRPP) and AMP (from ATP), and amidation to form NAD ¹. Several enzymes (e.g. sirtuins, PARPs and CD38) catabolise NAD by removing the whole ADP-ribose portion releasing nicotinamide (NAM), which can be recycled to NAD in the salvage pathway, or methylated (via NNMT) and excreted.

NAD metabolism is regulated by circadian rhythms ² and daily activities ³, while levels may decline with ageing ^4,5 and disease ⁶. Several authors have also suggested NAD may be low in ME/CFS, based on suspected pathophysiology ^7–10. Currently, there are scarce studies in this area, but below are some preliminary findings I’ve scraped together.

An initial blood study found low serum NAD(P)H (but no control matching mentioned) ¹¹. A small metabolomics study found significantly lower plasma NAM ¹² (but not another ¹³). Another study found a tendency to lower plasma KYN/TRP ratio and 3-HK ¹⁴, which might suggest altered de novo synthesis. A clinical audit reported a high prevalence of low RBC NAD (vs. lab reference), which increased with nutritional treatment ¹⁵. In muscle samples, increased oxidative DNA damage has been reported ^16,17, which may be expected to increase PARP activity and NAD consumption ^8–10; while in people with idiopathic chronic fatigue (ICF, <Fukuda), there was low mitochondrial content and biogenesis signalling, including SIRT1/3 expression ¹⁸. In cultured muscle cells, impaired AMPK has also been reported ¹⁹, which is a positive regulator of NAMPT (i.e. salvage synthesis) ³. So collectively, these studies may suggest low NAD metabolites in some compartments.

However, the situation may be different in immune cells. An RCT with CoQ₁₀ plus NADH decreased PBMC NAD, but increased NADH, ATP and CS activity ²⁰, all suggesting increased mitochondrial activity (not necessarily content ²¹). Therefore, at baseline there may be slow reduction of NAD to NADH, with energy/redox dysfunction ²². A couple of transcriptome studies on PBMCs found increased expression of genes in NAM metabolism (e.g. PRKAA1 ²³ and NAMPT ²⁴), suggesting increased salvage synthesis. Some studies find changes to NAD-dependant enzymes, such as increased CD8⁺CD38⁺ T cells ^25,26 (negatively correlated CD4/8 ratio and CD19 ²⁶) and PBMC SIRT4 ²⁷ (correlated PDK1, PPAR-A and D). Also, small studies on an older cohort (no control) found PBMC SIRT1 expression correlated negatively with blood DHEA (i.e. sex hormone precursor) and FRAP (i.e. antioxidant capacity) ²⁸, and bidirectionally with various lipid oxidation markers ²⁹. So collectively, these studies may suggest increased NAD turnover in immune cells, in relation to immune, hormone and redox changes.

References

1.           Xiao, W., Wang, R.-S., Handy, D. E. & Loscalzo, J. NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism. Antioxid. Redox Signal. 28, 251–272 (2018).

2.           Nakahata, Y. & Bessho, Y. The Circadian NAD+ Metabolism: Impact on Chromatin Remodeling and Aging. Biomed Res. Int. 2016, 3208429 (2016).

3.           Costford, S. R. et al. Skeletal muscle NAMPT is induced by exercise in humans. Am. J. Physiol. Endocrinol. Metab. 298, E117-26 (2010).

4.           Chini, C. C. S., Tarragó, M. G. & Chini, E. N. NAD and the aging process: Role in life, death and everything in between. Mol. Cell. Endocrinol. 455, 62–74 (2017).

5.           Fang, E. F. et al. NAD+ in Aging: Molecular Mechanisms and Translational Implications. Trends Mol. Med. 23, 899–916 (2017).

6.           Braidy, N., Lim, C. K., Grant, R., Brew, B. J. & Guillemin, G. J. Serum nicotinamide adenine dinucleotide levels through disease course in multiple sclerosis. Brain Res. 1537, 267–72 (2013).

7.           Pietrangelo, T., Fulle, S., Coscia, F., Gigliotti, P. V. & Fanò-Illic, G. Old muscle in young body: an aphorism describing the Chronic Fatigue Syndrome. Eur. J. Transl. Myol. 28, 7688 (2018).

8.           Morris, G. & Maes, M. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Curr. Neuropharmacol. 12, 168–85 (2014).

9.           Pall, M. Explaining Unexplained Illnesses: Disease Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia, Post-Traumatic Stress Disorder, Gulf War Syndrome and Others. (New York: Haworth Medical Press, 2007).

10.        Pall, M. L. Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Med. Hypotheses 54, 115–25 (2000).

11.        Mikirova, N., Casciari, J. & Hunninghake, R. The assessment of the energy metabolism in patients with chronic fatigue syndrome by serum fluorescence emission. Altern. Ther. Health Med. 18, 36–40 (2012).

12.        Germain, A., Ruppert, D., Levine, S. M. & Hanson, M. R. Metabolic profiling of a myalgic encephalomyelitis/chronic fatigue syndrome discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. Biosyst. 13, 371–379 (2017).

13.        Nagy-Szakal, D. et al. Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics. Sci. Rep. 8, 10056 (2018).

14.        Russell, A. et al. Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome. Psychoneuroendocrinology 100, 276–285 (2019).

15.        Myhill, S., Booth, N. E. & McLaren-Howard, J. Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) - a clinical audit. Int. J. Clin. Exp. Med. 6, 1–15 (2013).

16.        Fulle, S. et al. Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome. Free Radic. Biol. Med. 29, 1252–9 (2000).

17.        Pietrangelo, T. et al. Transcription profile analysis of vastus lateralis muscle from patients with chronic fatigue syndrome. Int. J. Immunopathol. Pharmacol. 22, 795–807 (2009).

18.        Wawrzyniak, N. R. et al. Idiopathic chronic fatigue in older adults is linked to impaired mitochondrial content and biogenesis signaling in skeletal muscle. Oncotarget 7, 52695–52709 (2016).

19.        Brown, A. E., Dibnah, B., Fisher, E., Newton, J. L. & Walker, M. Pharmacological activation of AMPK and glucose uptake in cultured human skeletal muscle cells from patients with ME/CFS. Biosci. Rep. 38, (2018).

20.        Castro-Marrero, J. et al. Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? Antioxid. Redox Signal. 22, 679–85 (2015).

21.        Taub, P. R. et al. Beneficial effects of dark chocolate on exercise capacity in sedentary subjects: underlying mechanisms. A double blind, randomized, placebo controlled trial. Food Funct. 7, 3686–93 (2016).

22.        Castro-Marrero, J. et al. Could mitochondrial dysfunction be a differentiating marker between chronic fatigue syndrome and fibromyalgia? Antioxid. Redox Signal. 19, 1855–60 (2013).

23.        Kerr, J. R. et al. Gene expression subtypes in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J. Infect. Dis. 197, 1171–84 (2008).

24.        Sweetman, E. et al. Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Int. J. Immunopathol. Pharmacol. 33, 2058738418820402 (2019).

25.        Broadbent, S. & Coutts, R. Intermittent and graded exercise effects on NK cell degranulation markers LAMP-1/LAMP-2 and CD8(+)CD38(+) in chronic fatigue syndrome/myalgic encephalomyelitis. Physiol. Rep. 5, (2017).

26.        Maes, M., Bosmans, E. & Kubera, M. Increased expression of activation antigens on CD8+ T lymphocytes in Myalgic Encephalomyelitis/chronic fatigue syndrome: inverse associations with lowered CD19+ expression and CD4+/CD8+ ratio, but no associations with (auto)immune, leaky gut, oxidative an. Neuro Endocrinol. Lett. 36, 439–46 (2015).

27.        Fluge, Ø. et al. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome. JCI insight 1, e89376 (2016).

28.        Jason, L. et al. Increased HDAC in association with decreased plasma cortisol in older adults with chronic fatigue syndrome. Brain. Behav. Immun. 25, 1544–7 (2011).

29.        Kubow, S. et al. Novel Associations of F2-Isoprostanes, F3- Isoprostanes and Isofurans in Older Adults with Chronic Fatigue Syndrome: An Exploratory Study. Clin. Res. Open Access ( ISSN 2469-6714 ) 1, 1–4 (2015).