In this episode, Matt and Nick react to investigative journalist and author Scott Carney's video describing what he calls "David Sinclair's longevity lie" in the context of David's longevity-focused entrepreneurial ventures. Matt shares his professional history with David, including his early interactions with David in Leonard Guarente's lab at the Massachusetts Institute of Technology (MIT) and scientific differences that emerged after Matt and colleagues were unable to reproduce a key result from David's work pertaining to resveratrol. Their discussion touches on some of David's scientific claims about age reversal, the role of institutions such as Harvard University in regulating scientific integrity, the potential for future interventions in healthspan and longevity, and the importance of separating personal feelings from scientific evaluation.

David, currently a professor in Harvard Medical School's Department of Genetics at the Paul F. Glenn Center for Biology of Aging Research, is a prominent aging researcher whose lab focuses on age-related epigenetic change, cellular reprograming, longevity drug discovery, mitochondrial fitness, reproductive aging, neurodegenerative disease,, and the human secretome. He has received awards including the National Institutes of Health Nathan Shock Award, the Merck Prize, and the Australian Medical Research Medal, and was elected to TIME's 2014 “100 Most Influential People in the World" list. David conducted postdoctoral research at MIT and obtained a PhD in Molecular Genetics at the University of New South Wales.

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!

The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms

Matt and colleagues coauthored this paper in 1999 demonstrating that the SIR2 gene regulates yeast lifespan. Upregulating SIR2 extended yeast lifespan by about 30 percent.

Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

This paper really kicked off David's sirtuin story. The paper's authors, which included David, developed an assay—a test or an analysis done to figure out the amount or presence of a specific substance or component in a sample—to identify drugs to activate the SIR2 gene and/or sirtuins, a family of proteins that help regulate important processes like metabolism, DNA repair, and stress response in the body. They found that resveratrol and several other compounds activated sirtuins and made yeast live longer.

Substrate-specific Activation of Sirtuins by Resveratrol

Matt and colleagues examined the effects of resveratrol on yeast SIR2 and found that the resveratrol-induced activation of yeast SIR2 was entirely dependent upon the presence of a particular fluorescent group. Without that group, resveratrol no longer had a significant effect on yeast SIR2 activity.

Mechanism of Human SIRT1 Activation by Resveratrol

This paper independently reproduced the findings of Matt and colleagues that resveratrol did not, in fact, affect sirtuin activation. Researchers tested the effects of resveratrol on three enzymes—yeast SIR2, human SIRT1, and human SIRT2—using the same assay that the authors of the original yeast life-extension-by-resveratrol paper developed and presented. They found that resveratrol activated only one of the enzymes, SIRT1. Crucially, it seemed that removing a particular fluorescent group removed the effect of resveratrol on SIRT1, suggesting that the finding was an artifact. The rather mild title of both this paper and Matt's may have contributed to the resveratrol story's persistence in the public consciousness for many years after these findings should have called the molecule's effectiveness as a lifespan extension tool into question.

A randomized, controlled clinical trial demonstrates improved owner‑assessed cognitive function in senior dogs receiving a senolytic and NAD+ precursor combination

This study describes the results of a clinical trial that Animal Biosciences, a company that David founded, funded. The clinical trial examined the effects of a therapeutic consisting of an NAD+ precursor and senolytic on dogs with mild to moderate cognitive impairment and reported a significant difference in cognitive impairment as measured by the owner-reported Canine Cognitive Dysfunction Rating (CCDR) scale. In a press release, David made claims about the findings of this study that Matt criticized as dishonest.