FoundMyFitness · 2019-11-06 · Rhonda Patrick (host), David Sinclair
Dr. David Sinclair on Informational Theory of Aging, Nicotinamide Mononucleotide, Resveratrol & More
51 claims checked against research: 6 contradicted 1 overstated 3 needing context 37 supported 4 unverified
6 Contradicted by research
Deleting the SIR2 gene blocks the lifespan-extending effects of calorie restriction in yeast.
"And if you get rid of the sirtuin SIR2 gene, the real breakthrough was that now calorie restriction doesn't work anymore." (said at 0:06:05)
Although early research in Saccharomyces cerevisiae suggested that Sir2 was essential for calorie restriction (CR) to extend replicative lifespan, subsequent studies demonstrated that calorie restriction extends both replicative and chronological lifespan even in the absence of the SIR2 gene. Deleting SIR2 does not prevent CR from extending yeast lifespan; CR can extend lifespan through Sir2-independent pathways and homologous enzymes such as Hst2, as well as nutrient-sensing pathways like TOR and Sch9.
- contradicts: Sir2-independent life span extension by calorie restriction in yeast. (PLoS biology 2004) · cited 452x in the literature
"Further, calorie restriction results in a greater life span extension in cells lacking both Sir2 and Fob1 than in cells where Sir2 is present. These findings indicate that Sir2 and calorie restriction act in parallel pathways to promote longevity in yeast and, perhaps, higher eukaryotes." (abstract, results, passage verified)
pubmedfull study (doi) - contradicts: HST2 mediates SIR2-independent life-span extension by calorie restriction. (Science (New York, N.Y.) 2005) · cited 230x in the literature
"However, this hypothesis has been challenged by the observation that CR can extend yeast life span in the absence of Sir2. Here, we show that Sir2-independent life-span extension is mediated by Hst2, a Sir2 homolog that promotes the stability of repetitive ribosomal DNA, the same mechanism by which Sir2 extends life span." (abstract, results, passage verified)
pubmedfull study (doi) - contradicts: Calorie restriction extends the chronological lifespan of Saccharomyces cerevisiae indepen… (Aging cell 2007) · cited 220x in the literature
"SIR2, HST2, and HST4 were not major regulators of CLS and were not required for the lifespan extension caused by shifting the glucose concentration from 2 to 0.5% (CR). Deleting HST1 or HST3 moderately shortened CLS, but did not prevent CR from extending lifespan. CR therefore works through a Sirtuin-independent mechanism in the chronological aging system." (abstract, results, passage verified)
pubmedfull study (doi)
The circadian clock is regulated by NAD+ levels.
"What's interesting about this is that NAD isn't being driven by the clock; the clock is being driven by NAD." (said at 0:12:35)
The speaker's statement bundles two assertions: (1) that NAD+ is not driven by the circadian clock, and (2) that the clock is driven by NAD+. Biochemical and animal studies demonstrate that NAD+ biosynthesis and the molecular circadian clock exist in an interlocked, bidirectional feedback loop. Specifically, the core clock complex CLOCK:BMAL1 directly binds to the promoter of NAMPT (the rate-limiting enzyme in NAD+ biosynthesis) to drive circadian oscillations in NAD+ levels. In turn, NAD+ acts as a coenzyme for the deacetylase SIRT1 to modulate core clock proteins (such as BMAL1 and PER2). Because the core clock machinery directly drives NAD+ oscillation, the assertion that NAD+ is not driven by the clock is contradicted by published mechanistic evidence.
- contradicts: Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. (Science (New York, N.Y.) 2009) · cited 1183x in the literature
"Here we show that intracellular NAD+ levels cycle with a 24-hour rhythm, an oscillation driven by the circadian clock. CLOCK:BMAL1 regulates the circadian expression of NAMPT (nicotinamide phosphoribosyltransferase), an enzyme that provides a rate-limiting step in the NAD+ salvage pathway." (abstract, results, passage verified)
pubmedfull study (doi) - contradicts: Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. (Science (New York, N.Y.) 2009) · cited 1109x in the literature
"Here we report that both the rate-limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD+) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), and levels of NAD+ display circadian oscillations that are regulated by the core clock machinery in mice... In turn, the circadian transcription factor CLOCK binds to and up-regulates Nampt, thus completing a feedback loop involving NAMPT/NAD+ and SIRT1/CLOCK:BMAL1." (abstract, results, passage verified)
pubmedfull study (doi)
NAMPT converts NMN into NAD in a single enzymatic step, and NAMPT expression increases under cellular stress and caloric restriction.
"and the NMN is converted within one step to NAD in the cell. And now it's locked; this big molecule is locked inside the cell. And that step is carried out by an enzyme. It's got a name; it's called NAMPT. And that enzyme goes up under stress and calorie restriction" (said at 0:38:09)
The speaker misidentifies the reaction catalyzed by NAMPT. In cellular NAD biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT) converts nicotinamide into nicotinamide mononucleotide (NMN). The single-step conversion of NMN into NAD is carried out by a distinct enzyme, nicotinamide mononucleotide adenylyltransferase (NMNAT).
Consuming resveratrol with fat increases its absorption and bloodstream levels 5- to 10-fold compared to taking dry powder alone.
"Include it with a bit of fat, it'll go up 5- to 10-fold in the bloodstream." (said at 0:44:14)
Clinical pharmacokinetic data contradict the claim that co-ingesting resveratrol with dietary fat increases its absorption or blood concentrations 5- to 10-fold. In a randomized crossover trial evaluating a 400 mg dose of trans-resveratrol taken either after fasting or with a standard high-fat meal in 24 healthy adults, overall systemic exposure (AUC) was virtually unchanged (geometric mean ratio fed/fasting of 106%), while peak plasma concentration (Cmax) was slightly reduced and delayed (tmax increased from 0.5 to 2.0 hours).
- contradicts: Effect of food on the pharmacokinetic profile of trans-resveratrol. (International journal of clinical pharmacology and therapeutics 2008) · cited 102x in the literature
"Mean +/- SD maximum plasma concentration (Cmax) was 42.2 +/- 36.6 ng/ml in fed and 47.3 +/- 30.0 ng/ml in fasting conditions. Median time to Cmax (tmax) was 2.0 h in fed and 0.5 h in fasting (p < 0.0001). The fed/fasting geometric mean ratio (GMR) and 90% confidence interval (90% CI) were 79.4 and 53.8, 117.0% for Cmax, and 106.0 and 86.8, 128.0% for the area under the plasma concentration-time curve (AUC0- yen)... The rate of absorption of trans-resveratrol following an oral 400 mg single-dose was significantly delayed by the presence of food, as reflected by Cmax and tmax. However, the extent of absorption, as reflected by AUC- yen, was not affected in a relevant way." (abstract, results and conclusions, passage verified)
pubmedfull study (doi)
Phase 1 and Phase 2 clinical trials in Alzheimer's disease showed that resveratrol at doses of 500 mg or 1,000 mg daily reduced cerebrospinal fluid amyloid-beta 42 and improved cognitive function.
"There's a couple of studies, as you know, there was Phase 1 and 2 clinical studies on Alzheimer's disease where they were given 500 milligrams or 1,000 milligrams of resveratrol a day, and both these studies found that there was a reduction in amyloid-beta 42 in cerebrospinal fluid, there was an improvement in cognitive function and a couple of other parameters." (said at 0:48:25)
In the Phase 2 multicenter randomized controlled trial of resveratrol in mild-to-moderate Alzheimer's disease (500 mg daily escalated up to 1,000 mg twice daily; Turner et al., 2015), resveratrol did not improve cognitive function, and brain volume loss was actually greater in the resveratrol group than placebo. Furthermore, the claim inverts the biomarker findings: in Alzheimer's disease, CSF Aβ42 levels characteristically decline as amyloid is sequestered into brain plaques. Rather than reducing CSF Aβ42, resveratrol treatment was associated with an attenuation of the normal decline in CSF amyloid levels (Aβ40 in the primary study, and Aβ42 in a retrospective subset analysis of biomarker-confirmed cases; Moussa et al., 2017). Resveratrol also merely attenuated declines in MMSE and ADL scores in that subgroup, rather than producing cognitive improvement.
- contradicts: A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. (Neurology 2015) · cited 724x in the literature
"CSF Aβ40 and plasma Aβ40 levels declined more in the placebo group than the resveratrol-treated group, resulting in a significant difference at week 52. Brain volume loss was increased by resveratrol treatment compared to placebo." (abstract, results, passage verified)
pubmedfull study (doi) - contradicts: Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's dise… (Journal of neuroinflammation 2017) · cited 707x in the literature
"In this subset analysis, resveratrol treatment attenuated declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aβ42 levels during the 52-week trial, but did not alter tau levels." (abstract, results, passage verified)
pubmedfull study (doi)
A clinical study administering a 1,000 mg dose of nicotinamide riboside reported participant dropouts due to side effects including flushing and skin rashes.
"if you read the most recent clinical study where the dose of nicotinamide riboside was like a thousand milligrams, there were a lot of people that dropped out because they had rashes and flushing." (said at 1:00:47)
The claim is contradicted by clinical trial evidence. Unlike nicotinic acid (niacin), which is well known to induce cutaneous flushing and rash, nicotinamide riboside (NR) does not activate the flushing receptor and is well tolerated without causing flushing-related dropouts. In randomized, double-blind, placebo-controlled clinical trials administering 1,000 mg daily (PMID: 31278280) and up to 2,000 mg daily (PMID: 29992272), there were no reports of flushing or high rates of participant dropouts from rashes and flushing compared to placebo.
Unverified means no publication matching the claim was located; it does not prove the claim false. Spotted an error? See the corrections policy - disputes from the people quoted are prioritized.