Nicotinamide riboside augments the human skeletal muscle NAD⁺ metabolome and induces transcriptomic and anti-inflammatory signatures in aged subjects: a placebo-controlled, randomized trial

Abstract

Tel: + 44(0)121 414 3917, email: g.g.lavery@bham.ac.uk 26 27 2012), reduction of blood glucose, hepatic steatosis, and neuropathy on high fat diet 64 (Trammell et al. 2016), improvement of cardiac function in genetic cardiomyopathy (Diguet et 65 al., 2018), and prevention of cortical neuronal degeneration (Vaur et al., 2017). Depletion of 66 the enzyme nicotinamide phosphoribosyltransferase (NAMPT), rate-limiting for NAD + 67 biosynthesis, in mouse skeletal muscle severely diminishes NAD + levels and induces 68 sarcopenia. Oral repletion of NAD + with NR in this model rescued pathology in skeletal 69 muscle in a cell-autonomous manner (Frederick et al., 2016). However, recent data in mice 70 tracing NAD + fluxes questioned whether oral NR has the ability to access muscle (Liu et al., 2018). Thus, whether oral NR can augment the human skeletal muscle NAD + metabolome is 72 currently unknown. 73A decline in NAD + availability and signalling appears to occur as part of the aging process in 74 many species (Gomes et al., 2013; Mouchiroud et al., 2013), though there is a paucity of 75 data to confirm that this is the case in human aging. NR and nicotinamide mononucleotide 76 (NMN) are reported to extend life span (Zhang et al., 2016) and enhance metabolism in 77 aged mice (Mills et al., 2016). To date, NR supplementation studies in humans have been 78 reported, focussing on cardiovascular (Martens et al., 2018), systemic metabolic (Dollerup et 79 al., 2018), and safety (Conze et al, 2019) end-points, but have not addressed advanced 80 aging, tissue metabolomic changes, or effects on muscle metabolism and function. 81Herein, we set out to study if oral NR is available to aged human skeletal muscle and 82 whether potential effects on muscle metabolism can be detected. We conducted a 21-day 83 NR supplementation intervention in a cohort of 70 -80 year old men in a randomized, 84 double-blind, placebo-controlled crossover trial. We demonstrate that NR augments the 85 skeletal muscle NAD + metabolome inducing a gene expression signature suggestive of 86 downregulation of energy metabolism pathways, but without affecting muscle mitochondrial 87 bioenergetics or metabolism. Additionally, NR suppresses specific circulating inflammatory 88 cytokines levels. In an additional study, we used 31 P magnetic resonance spectroscopy 89 (MRS) and show that NAD + decline is not associated with chronological aging per se in 90 either human muscle or brain. 91 92 5 RESULTS 93Oral NR is safe and well tolerated in aged adults 94Twelve aged (median age 75 years) and marginally overweight (median BMI 26.6 kg/m 2 ; 95 range 21 -30), but otherwise healthy men were recruited and orally supplemented with NR 1 96 g per day for 21-days in a randomized, double-blind, placebo-controlled crossover design 97 with 21-days washout period between phases. Baseline characteristics of participants are 98 included in Suppl Table 1. NR chloride (Niagen ®) and placebo were provided as 250 mg 99 capsules (ChromaDex, Inc.) and subjects were instructed to take ...

Brain NAD Is Associated With ATP Energy Production and Membrane Phospholipid Turnover in Humans

“…The first 31 P-MRS study to report NAD in the aging human brain found that tNAD, NAD + , and the NAD + /NADH redox ratio decreased with age in the occipital region (Zhu et al, 2015). Similar findings were found for NAD + measured by 1 H-MRS (Bagga et al, 2020), but this was not replicated in a recent 31 P-MRS study in which NAD was not affected by age (Elhassan et al, 2019). When NAD was measured in the frontal lobe of healthy participants (Kim et al, 2017), an age-dependent increase in NADH and decrease in the NAD + /NADH redox ratio was observed, but no change in NAD + was detected.…”

Why Does COVID-19 Disproportionately Affect the Elderly?

“…This decline, exacerbated by COVID-19, might therefore promote hyperactivation of NLRP3 and the trigger cytokine storms in COVID-19 patients [10]. Maintaining NAD + levels may therefore alleviate COVID-19 symptoms, a possibility supported by recent data showing that SARS-CoV-2 proteins hyperactivate poly-ADP-ribose polymerases PARP9, -10, -12, and -14 and deplete cellular NAD + [56] and the ability of NAD precursors to lower inflammation in human subjects [57,58].…”

Combined Metabolic Activators accelerates recovery in mild-to-moderate COVID-19

“…Recently, we performed integrative analysis of multi-omics data on different metabolic conditions and found that combined metabolic cofactors supplementation (CMCS) consisting of L-serine, N-acetyl-L-cysteine (NAC), nicotinamide riboside (NR), and Lcarnitine tartrate may be used for treatment of the patients with non-alcoholic fatty liver diseases (11,12). On the basis of this evidence, we conducted an animal toxicity study and a human calibration study with/without supplementation of combined metabolic cofactors, and demonstrated the safety of the CMCS (13).…”