Matt and City of Hope Alfred E. Mann Family Foundation Chair of Diabetes and Cancer Metabolism Charles Brenner have had several public disagreements on social media. We love a good conversation between two distinguished scientists whose views may not entirely align, so we were pleased to host Charles on the Optispan Podcast for a discussion of topics in geroscience ranging from whether sirtuins are actually longevity regulators to the clinical utility of epigenetic age tests to the incentive structures around clinical trials. We also spent a chunk of time on NAD+ boosters, one of Charles' areas of expertise, and their relevance to aging and other conditions such as COVID-19.

Prior to his City of Hope appointment, Charles served on the faculties of Thomas Jefferson University, Dartmouth College and University of Iowa, where he was Roy J. Carver Head of Biochemistry for 11 years. He currently serves as the Chief Scientific Advisor of the biotechnology company ChromaDex, which uses his nicotinamide riboside (NR) intellectual property. He is also a cofounder of Alphina and Juvenis, companies in the NAD+ booster space. Charles conducted postdoctoral research at Brandeis University and received a PhD and a B.A. from Stanford University and Wesleyan University respectively.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans

This 2004 paper, which Charles coauthored, is a foundational paper in the NAD+ literature that describes the NR pathway in yeast and humans.

Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+

Charles coauthored this paper describing two NR pathways that boost NAD+ and demonstrating that NR increases yeast sir2 activity and lifespan without caloric restriction.

Targeted, LCMS-based Metabolomics for Quantitative Measurement of NAD(+) Metabolites

This paper describes methods that Charles' group developed as well as technical challenges for quantifying targeted NAD+ metabolites.

Sirtuins are Not Conserved Longevity Genes

Matt and Charles spend some time on a nuanced discussion of sirtuins in this episode, and Charles expresses his grave doubts about claims in the sirtuin literature outside of yeast replicative aging. In 2022, Charles published this paper documenting issues in the animal sirtuin literature as well as providing a working definition of conserved gene function.

RAPAMUNE labeling document

In discussing his concerns with human off-label rapamycin use, Charles cites this RAPAMUNE labeling document along with Blake Rasmussen's randomized clinical trial showing that rapamycin inhibits skeletal muscle protein synthesis after exercise. Charles does consider the premise of the geroscience hypothesis—the idea that the biological processes underlying aging are the root cause of many chronic diseases and conditions commonly associated with aging such as cardiovascular disease, diabetes, Alzheimer's disease, and cancer—to be proven in mice based on the activity of rapamycin.

The papers below discuss the effects of dysregulated NAD+ metabolism on various conditions:

Type II diabetes: Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice

Alcohol-Related Liver Disease: Nicotinamide Adenine Dinucleotide Metabolome Is Functionally Depressed in Patients Undergoing Liver Transplantation for Alcohol-Related Liver Disease

Postpartum conditions: Maternal Nicotinamide Riboside Enhances Postpartum Weight Loss, Juvenile Offspring Development, and Neurogenesis of Adult Offspring

Heart failure: Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy

Mitochondrial Myopathy: Niacin Cures Systemic NAD + Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy

Coronavirus infection: Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity

Charles cites a number of positive NR human trials that, in his view, strongly support the use case of NR in healthy aging. We list some of those trials below:

Trials showing anti-inflammatory effects of NR: A Milestone Clinical Study Reveals that Elevating Nicotinamide Adenine Dinucleotide (NAD+) with Nicotinamide Riboside (NR) Supplementation Effectively Reduces Inflammation in Both Healthy Subjects and Immune Cells Derived from Psoriasis Patients (Charles serves as Chief Scientific Advisor of Chromadex)

The NICE trial for peripheral artery disease: Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial

The NADPARK trial for Parkinson’s disease: The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease