Longevity Expert Dr. David Sinclair: His Research and Insights Into NAD Activators, NMN and NR
In anticipation of Dr. David Sinclair’s long awaited book, Lifespan: Why We Age -- and Why We Don’t Have To, it could be helpful to get a brief perspective of the man and his promising research on lifespan extension.
For those of you who haven’t heard of him, David Andrew Sinclair is an Australian biologist and Professor of Genetics at Harvard, who is best known for his research on the biology of lifespan extension and driving research towards treating diseases of aging.
David Sinclair has made quite a splash in the longevity research world for decades, and with the release of his new book, the rest of us are going to learn about the importance of his work.
Let’s review his background, the research he’s conducted into life extension, and why his findings are significant to you.
Dr. Sinclair’s Academic and Work Background
Dr. Sinclair’s background is worthy of examination so you can get a sense of the gravity of his work and accomplishments.
He was born in Australia in 1969 and grew up in St Ives, New South Wales. His Bachelor of Science degree was earned at the University of New South Wales, Sydney. In 1995, received a Ph.D. in Molecular Genetics from the same school, focusing on gene regulation in yeast.
In 1993, Dr. Sinclair met Leonard P. Guarente, a Massachusetts Institute of Technology professor, when Dr. Guarente was on a lecture tour in Australia. Guarente had been studying the genes involved in the regulation of aging, and now is well known as the Founder of Elysium Health, the maker of Basis, which consists of NR (Nicotinamide Riboside) -- the same compound we offer in TruNiagen -- and pterostilbene, a similar compound to resveratrol.
The meeting between Guarente and Sinclair encouraged Sinclair to apply for a postdoctoral position in Dr. Guarente's lab. Earlier that year, Dr. Cynthia Kenyon's lab at UCSF had discovered that a single-gene mutation in (Daf-2) could double the lifespan of a worm species called C. elegans. Anti-aging research was beginning to take off.
In 1999, Sinclair was hired at Harvard Medical School. He began a lab, which struggled financially until he met philanthropist Paul F. Glenn in 2004 who donated $5 million to Harvard to establish the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard, of which Sinclair became the founding Director and currently serves as co-Director.
Also in 2004, Sinclair co-founded Sirtris Pharmaceuticals, which focused on developing Sinclair's research into activators of sirtuins (also referred to as “precursors”), work that began in Dr. Guarente’s lab. (You may find several articles about one of the most studied sirtuin activators, NMN, here.)
Sirtis was specifically focused on resveratrol formulations and derivatives as activators of the SIRT1 enzyme (one of seven found in mammals like us); Sirtris went public in 2007 and was subsequently purchased and made a subsidiary of GlaxoSmithKline in 2008 for $720 million.
In 2008, Dr. Sinclair was promoted to tenured professor at Harvard Medical School. He also became a professor at the University of New South Wales.
In 2011, Sinclair was a co-founder of OvaScience with Michelle Dipp (who had been involved with Sirtris), Aldrich, Westphal, and Jonathan Tilly, based on scientific work done by Tilly concerning mammalian oogonial stem cells and work on mitochondria by Sinclair.
Also in 2011, Sinclair co-founded of CohBar, along with Dr. Nir Barzila (the most prominent scientist studying the potential of a common drug to extend lifespan), and other colleagues. CoBar aimed to discover and develop novel peptides derived from mitochondria.
In 2015, Sinclair described to The Scientist his efforts to get funding for his lab, how his lab grew to around 20 people, shrunk back down to about 5, and then grew again as he brought in funding from philanthropic organizations and companies that supported his ground-breaking research, including companies that he helped to start. As of 2015, his lab had 22 people and was supported by one R01 grant and was 75% funded by non-federal funds.
In 2018, Sinclair was made an Officer of the Order of Australia (AO) for "distinguished service to medical research into the biology of ageing and lifespan extension, as a geneticist and academic, to biosecurity initiatives, and as an advocate for the study of science".
Sinclair Breaks Away From Guarente and Builds His Own Lab
While Dr. Sinclair was working in Dr. Guarente's lab, he discovered that Sirtuin 1 (called sir2 in yeast) slows aging in yeast by reducing the accumulation of extrachromosomal rDNA circles, which contribute to their aging and are found in their aged cells. Others working in the lab at the time identified NAD as an essential cofactor for sirtuin function. 
NAD, or Nicotinamide adenine dinucleotide, has several essential roles in metabolism, but unfortunately our bodies produce less and less of it as we age, This is why the NAD activators NR and NMN have become so popular among those interested in aging better.
Dr. Sinclair didn’t remain in Dr. Guarente's lab for long. In 2002, after he had left for Harvard, he clashed with Guarente at a scientific meeting at Cold Spring Harbor Laboratory, challenging Guarante's description of how sir2 might be involved in aging. Since then, these scientists have become scientific rivals, although remain friends. 
In 2003, when his lab was still small, Sinclair learned that scientists at a Pennsylvania biotech company called Biomol Research Laboratories discovered that polyphenols, including resveratrol, could activate sir2, and he collaborated with them to confirm this.  This led to publications authored in part by Sinclair in both Nature and Science in 2003. 
Sinclair's outspoken advocacy for resveratrol as an anti-aging compound started a scientific controversy over whether this was true, and if resveratrol even activated sirtuins.   But work in another lab, done partially funding from Sirtris, found increases in the number of mitochondria in the cells of mice given high doses of resveratrol.  Sinclair's lab continued to work on resveratrol and analogs of it, as well as on mitochondria and NAD, all directed to understanding aging and how to prevent it. 
David Sinclair’s Take On The Science on NMN and NR
A blog post written by Dr. Sinclair offers his perspective on some recent research into NMN and NR. With 25 years of experience in this field, and having read thousands of papers on this subject, he has specific, informed interpretations of the scientific literature surrounding these molecules.
Sinclair underscores that when interpreting and making conclusions about scientific studies into NMN and NR, we need to remember that:
- Cell culture results are trumped by mouse results.
- Mouse results are trumped by human results.
- Anecdotes and small human trial results, while certainly interesting and sometimes even exciting, are trumped by double-blind placebo controlled studies.
- Approved drugs trump all the rest - and even then we absolutely must push onward with more research, more research, and more research.
With that in mind, what does the science show when it comes to NMN and NR?
We know that NAD boosters, like NR and NMN have shown efficacy in many cell cultures and in mouse models of human diseases. (Mice models refer to mice that have been biologically altered to mimic a specific human disease.) Both NR and NMN have been shown to benefit the health of elderly mice, and neither of these treatments show negative health effects, even in long-term mouse experiments.
Moreover, the mice given NR or NMN experience a slightly longer life, although that’s been debated.
In humans, research into the effects of NR and NMN is underway. Ultimately, we have to test NAD precursors in people that participate in rigorous and independent scientific studies.
Most of what has been completed in humans so far has been been NR studies. For example:
- A randomized, double-blind, three-arm crossover pharmacokinetic study in 12 human subjects showed that NR raises NAD+ by as much as 2.7-fold in human blood with a single oral dose of 1,000 mg.
- Researchers at the University of Washington have completed a clinical trial with 140 participants showing that orally administered NR gives a dose dependent increase in NAD+ from 250-1,000 mg/d plateauing at a 2-fold increase in NAD+ at day nine.
- Researchers have also reported positive effects of NR on vascular endothelial function in healthy middle-aged and older adults, with further investigations of motor and cognitive changes to come.
- Most recently, a placebo-controlled study assessing 500 mg of NR, taken twice daily by 70- to 80-year olds, showed increases in NAD+ in blood (but not muscle.) NR supported healthy levels of inflammation and mitochondrial activity.
- Multiple other studies are now underway assessing the effects of NR on muscle mitochondrial function, cognition, immune function, kidney function, brown fat activity, lipid accumulation, energy metabolism, body composition, and acetylcarnitine levels.
What about human trial results for NMN? A few have been completed or are in the works now:
The first trial that tested NMN in humans was done in 2020, with a clinical study assessing the effects of a single dose of NMN in a small group of ten adults. The researchers reported that a one-time administration of NMN, in amounts ranging from 100 to 500 mg, was safe and well-tolerated, causing no adverse side effects.
Since then, one recent study found NMN to support better blood sugar sensing in the skeletal muscle of postmenopausal women, which is linked to better metabolic health. In another recent trial, healthy young adults who took NMN supplements had improved aerobic function while exercising. Overall, the research on testing NMN supplement use in humans is still in its infancy, but the available evidence thus far is encouraging.
It’s also worth noting that research and development is underway on novel NAD precursors, such as Metrobiotech’s MIB-626, which is being tested in clinical trials by an independent team at a hospital in Boston.
Right now, the bottom line is that the science is a bit further along when it comes to NR, but it is far too early to say which is better for humans, NR or NMN.
Should You Try NMN or NR?
Well, ultimately that’s up to you, but the two preeminent scientists studying how to activate NAD take either NMN or NR.
David Sinclair takes NMN daily. He says:
"It's no secret that I take NMN; I’ve been very up front about that. I would consider it to be an act of dishonesty to not disclose that fact."
Dr. Leonard Guarente has been taking NR since at least 2014, although his dosage has not been disclosed. 
His company, Elysium Health, has spearheaded human trials that indicate an increase in NAD+ levels increase by 90% over baseline after 30 days and 55% at 60 days from consuming, respectively, 250 mg of NR; 50 mg of pterostilbene and 500 mg of NR; 100 mg of pterostilbene.  It’s reasonable to presume that Dr. Guarente takes a dose within that range, if not more.
- Duncan, David Ewing (August 15, 2007). "The Enthusiast". MIT Technology Review.
- Couzin, J (27 February 2004). "Scientific community. Aging research's family feud". Science. 303 (5662): 1276–9. doi:1126/science.303.5662.1276. PMID 14988530.
- Wallace, Benjamin. "An MIT Scientist Claims That This Pill Is the Fountain of Youth". New York Magazine.