NMN supplementation may improve conditions associated with reduced DNA integrity

NMN supplementation may improve conditions associated with reduced DNA integrity

Scientists from multiple institutions, including Baylor College of Medicine, MD Anderson Cancer Center, and the University of Pennsylvania perform experiments on mice, indicating nicotinamide mononucleotide (NMN) supplementation ameliorates cellular conditions associated with reduced DNA integrity and counteracts liver disease.

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Scientists from multiple institutions, including Baylor College of Medicine, MD Anderson Cancer Center, and the University of Pennsylvania perform experiments on mice, indicating nicotinamide mononucleotide (NMN) supplementation ameliorates cellular conditions associated with reduced DNA integrity and counteracts liver disease.

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Image from Amano et al. (2019)

Previous research indicates regions of DNA on ends of chromosomes which shorten with age (telomeres) have reduced length in stem cell decline, formation of excess fibrous connective tissue (fibrotic disorders), and premature aging.  The cellular mechanisms through which these health issues occur remain unclear.1  The authors of this study want to explore whether supplementation with NMN, a nicotinamide adenine dinucleotide (NAD+) precursor, ameliorates effects of dysfunctional telomeres.  If so, the authors want to find out how.

The scientists start with examining the effect of telomere dysfunction on sirtuins, proteins requiring NAD+ for their function.  In order to do so, they generate mice lacking an essential component (reverse transcriptase) of telomerase, an enzyme maintaining telomeres through cell divisions.  The mice develop premature aging as telomeres become progressively shorter, especially in successive generations. The scientists study male mice between eight and 16 weeks of age from the fourth generation of mice with telomere dysfunction.  These mice display characteristics of telomere dysfunction, such as compromised stem cells, regenerative defects in tissues with high cellular turnover, tissue weakening (atrophy), heart muscle disease (cardiomyopathy), and shortened lifespan.1,3

The scientists examine a tissue with high cellular turnover in which previous research implicates telomere dysfunction and sirtuin repression in organ disease– the liver.  Compared to normal mice (wild type), sirtuin proteins have reduced expression levels in the liver of mice with telomere dysfunction. The degree of repressed sirtuin expression depends upon degree of telomere dysfunction as mice with less telomere dysfunction and intermediate telomere length (first and second-generation mice) display only slight sirtuin repression.

In order to examine how telomere dysfunction leads to repressed expression of sirtuins, the scientist focus on p53, a protein involved in the DNA damage response.1,2,3  The group analyzes mice with telomere dysfunction having proficient and reduced levels of p53.  The protein levels of sirtuins increase in mice with telomere dysfunction lacking p53, suggesting p53 plays a role in decreased sirtuin levels in mice with telomere dysfunction.

The scientists test whether NMN, the NAD+ precursor, improves defects in the powerhouse of the cell (the mitochondria) in mice with telomere dysfunction.  Previous studies indicate telomere dysfunction leads to repressed mitochondrial DNA copy number and reduced molecules for energy (ATP) in tissues like the liver.  This suggests mitochondrial dysfunction in mice with telomere dysfunction.1,3  NMN consumption improves NAD+ levels in mice, according to the data from this study.  The data also indicate mice have greater mitochondrial DNA (mtDNA) copy number following NMN consumption.  Greater mitochondria DNA copy number suggests reduced p53 expression upon NMN consumption.

To test whether increased NAD+ levels affect telomere-mediated disease, the scientists examine whether NMN improves telomere-dependent liver fibrosis conditions– telomere-dependent liver fibrosis affects patients with inherited telomerase enzyme mutations.  The scientists inject normal mice (wild type mice) and telomere dysfunction mice with a fibrosis-inducing agent, CCl4, to determine whether increasing NAD+ levels counteracts liver fibrosis in mice with telomere dysfunction.  The scientists treat mice with NMN for two weeks before CCl4 injections and continue through the CCl4 treatments (two injections per week for six weeks).  NAD+ levels decrease more in mice with telomere dysfunction compared to wild type mice, and this effect is mostly reversed with NMN treatment.  Importantly, NMN reduces damage and fibrosis of liver cells in telomere dysfunction mice. Also, NMN supplementation ameliorates fibrosis in wild type mice, indicating NMN supplementation protects cells under conditions of increased DNA damage, regardless of telomere status.

The study presents interesting data; because it demonstrates in mice, NAD+ levels fall in liver tissue with damage, especially in mice with telomere dysfunction.  NMN treatment restores NAD+ levels in these cells, and data related to mitochondrial DNA copy number indicate NMN could restore mitochondrial function in liver cells.  NMN treatment improves cellular health in liver cells treated with CCl4, a liver damage inducer.  Sirtuins may play a role in the cellular mechanism through which telomere dysfunction leads to higher incidence of liver disease.  Interestingly, sirtuins depend on the coenzyme, NAD+, to function. The scientists also point to action of NMN on DNA, specifically telomeres of DNA.  As they say in their paper, “At the DNA level, our studies demonstrate that NMN stabilize telomeres in a partially Sirt1-dependent manner under conditions of ongoing DNA damage and dampens the DNA damage response.”

STORY SOURCE
  1. Hisayuki Amano, Arindam Chaudhury, Cristian Rodriguez-Aguayo, Lan Lu, Viktor Akhanov, Andre Catic, Yury V. Popov, Eric Verdin, Hannah Johnson, Fabio Stossi, David A. Sinclair, Eiko Nakamaru-Ogiso, Gabriel Lopez-Berestein, Jeffrey T. Chang, Joel R. Neilson, Alan Meeker, Milton Finegold, Joseph A. Baur, Ergun Sahin.  Telomere dysfunction induces sirtuin repression that drives telomere-dependent diseaseCell Metab, 2019; DOI: 10.1016/j.cmet.2019.03.001.
JOURNAL REFERENCES
  1.  Hisayuki Amano, Arindam Chaudhury, Cristian Rodriguez-Aguayo, Lan Lu, Viktor Akhanov, Andre Catic, Yury V. Popov, Eric Verdin, Hannah Johnson, Fabio Stossi, David A. Sinclair, Eiko Nakamaru-Ogiso, Gabriel Lopez-Berestein, Jeffrey T. Chang, Joel R. Neilson, Alan Meeker, Milton Finegold, Joseph A. Baur, Ergun Sahin.  Telomere dysfunction induces sirtuin repression that drives telomere-dependent diseaseCell Metab, 2019; DOI: 10.1016/j.cmet.2019.03.001.
  2. Lynda Chin, Steven E. Artandi, Qiong Shen, Alice Tam, Shwu-Luan Lee, Geoffrey J. Gottlieb, Carol W. Greider, Ronald A. DePinho.  p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesisCell, 1999; DOI: 10.1016/s0092-8674(00)80762-x.
  3. Ergun Sahin, Simona Colla, marc Liesa, Javid Moslehi, Florian L. Muller, Mira Guo, Marcus Cooper, Darrell Kotton, Attila J. Fabian, Carl Walkey, Richard S. Maser, Giovanni Tonon, Friedrich Foerster, Robert Xiong, Y. Alan Wang, Schet A. Shukla, Mariela Jaskelioff, Eric S. Martin, Timothy P. Heffernan, Alexei Protopopov, Elena Ivanova, John E. Mahoney, Maria Kost-Alimova, Samule R. Perry, Roderick Bronson, Ronglih Liao, Richard Mulligan, Orian S. Shirihai, Lynda Chin, Ronald A. DePinho.  Telomere dysfunction induces metabolic and mitochondrial compromise.  Nature, 2011; DOI: 10.1038/nature09787.