November 3, 2020

Recent studies continue to reveal potential benefits for nicotinamide riboside (NR), a nutritional compound that acts as a precursor to nicotinamide adenine dinucleotide (NAD), a coenzyme that supports cellular energy production and metabolism throughout the body.

In a report published on September 16, 2020 in EMBO Journal, researchers at the National Institutes of Health found a decrease in NAD levels and abnormal NAD consumption in cells from mice with an absence of telomerase (an enzyme that helps maintain telomeres), as well as in fibroblast cells from patients with dyskeratosis congenita, a disease characterized by the presence of short telomeres at a young age. Telomeres are segments of genetic material that cap and protect the end of the cells’ chromosomes by preventing them from being recognized as damaged DNA. Dysfunctional telomeres result in a DNA damage response that leads to cellular senescence (cessation of cell division) or apoptosis (programmed cell death). Like telomere dysfunction, telomere shortening (attrition), which occurs during cellular aging, is also associated with cellular senescence.

Administration of nicotinamide riboside to fibroblasts from dyskeratosis congenita patients helped support normal levels of NAD, which decreased telomere damage, defects in the synthesis of the cells’ power plants known as mitochondria, cell growth retardation and cellular senescence.

“Telomere attrition and mitochondrial dysfunction are hallmarks of biological aging, and defects in telomere maintenance contribute to telomere biology disorders,” Chongkui Sun and colleagues wrote. “Declining NAD levels have recently emerged as a feature of aging in humans and animal models.”

They concluded that NR supplementation decreased mitochondrial and cellular reactive oxygen species (ROS) levels and telomere DNA damage, delayed replicative senescence of dyskeratosis congenita cells, and exerted a protective effect on dyskeratosis congenita fibroblasts, which implicates the involvement of dysregulated NAD metabolome in telomere biology disorders.

A second article, which appeared on August 13, 2020 in the Journal of Clinical Investigation, suggests a role for NR in normalizing inflammation activated by peripheral blood mononuclear cells (PBMCs, which are types of white blood cells) in heart failure patients.

The study included 19 patients hospitalized with final stage heart failure and 19 healthy participants. Reduced mitochondrial respiratory capacity and an increase in proinflammatory gene expression in PBMCs collected from heart failure patients was observed in comparison with those from the healthy group.

Models of inflammation using PBMCs of healthy participants revealed increased expression of proteins known as cytokines (including interleukin-6) whose proinflammatory effect impaired mitochondrial respiration. However, treating these cells with NR improved mitochondrial respiration and reduced proinflammatory cytokine gene expression. Nicotinamide riboside treatment of PBMCs from heart failure subjects also resulted in an increase in mitochondrial respiration and a small reduction in proinflammatory cytokine gene expression, prompting the researchers to note that longer exposure to NR may have been needed.

In a small experiment in which NR was orally administered to end stage heart failure patients for five to nine days, blood levels of NAD+ increased, mitochondrial respiration improved and proinflammatory cytokine gene expression was reduced up to 30-fold in comparison with pretreatment levels.

“This study demonstrates a critical role of mitochondrial function in the inflammatory activation of peripheral immune cells in heart failure with reduced ejection fraction patients,” Bo Zhou and colleagues at the University of Washington wrote.

“Although the human efficacy data is currently lacking, the collective actions of NAD repletion on preserving cardiac function and reducing systemic inflammation may provide a molecular basis for a novel heart failure therapy,” they wrote. “The results pose promising opportunities for future clinical trials to investigate NR’s potential anti-inflammatory effect.”