Dr. David Sinclair on Informational Theory of Aging, Nicotinamide Mononucleotide, Resveratrol & More
David A. Sinclair, PhD, is a professor in the Department of Genetics at Harvard Medical School and co-director of the Paul F. Glenn Center for the Biological Mechanisms of Aging.
Dr. Sinclair’s work focuses on understanding the mechanisms that drive human aging and identifying ways to slow or reverse aging’s effects. In particular, he has examined the role of sirtuins in disease and aging, with special emphasis on how sirtuin activity is modulated by compounds produced by the body as well as those consumed in the diet, such as resveratrol. His work has implications for human metabolism, mitochondrial and neurological health, and cancer.
00:00:36 - Landmark moments in longevity research with the discovery of genes that control the aging process and how these genes can be activated by lifestyle factors such as fasting and exercise.
00:01:06 - Altering the insulin/IGF-1 signaling pathway in earthworms can extend their lifespan by 100%.
00:01:45 - Slowly ageing by design: the rise of NAD+ and sirtuin-activating compounds.
00:05:02 - How resveratrol may delay aging by activating a class of enzymes called sirtuins.
00:06:15 - How the addition of an extra copy of the SIR2 gene in S. cerevisiae (yeast) can extend yeast lifespan by 30%.
00:06:40 - How having high levels of sirtuins may give organisms the benefit of caloric restriction or other stressors such as heat stress or amino acid restriction without actually engaging in those activities.
00:07:50 - How fasting for one or two days per week, a type of intermittent fasting, may activate sirtuins sufficiently to recapitulate the benefits of long-term caloric restriction. Review on caloric restriction and sirtuin biology.
00:08:15 - How the metabolic switch into ketosis may be an important differentiator between ongoing caloric restriction and finite periodic fasts.
00:08:50 - How caloric restriction potently increases sirtuins, as measured by SIRT1 levels, by as much as 5- to 10-fold in the liver and muscle of rats, but this beneficial activity is immediately dampened by the introduction of IGF-1 and insulin.
00:10:13 - How several pathways, including those involving sirtuins, insulin/IGF-1, and mTOR, all interact as components of a highly conserved holistic network to create the benefits of caloric restriction.
00:10:56 - Caloric restriction, fasting, and exercise increase levels of NAD+, and this activates sirtuins.
00:12:20 - NAD+ may regulate circadian rhythm though its control of sirtuins, which in turn regulate both the circadian clock in the brain as well as peripheral clocks, such as the liver.
00:13:00 - In addition to activating sirtuins, NAD+ is essential for mitochondrial metabolism and function but it is also required for repairing damage to DNA by activating an enzyme called PARP.
00:13:30 - How organisms have developed nutrient-sensing genetic pathways such as sirtuins, AMPK, and mTOR in order to understand what is going on in the environment.
00:14:44 - Although NAD+ levels and sirtuin activities decrease with age, animal studies suggest that raising cellular NAD+ levels can trick the body into thinking it is younger.
00:16:00 - Resveratrol enhances the binding of sirtuins to NAD+ thus making sirtuins more easily activated for a longer period.
00:17:28 - How DNA damage consumes NAD+ through the activation of PARP, a major DNA repair protein, leaving less NAD+ available to activate sirtuins and distracting sirtuins from fulfilling their other roles.
00:20:00 - Dr. Sinclair’s informational theory of aging posits that aging is due to a loss of cellular identity, a type of epigenetic signal noise, that has parallels in biology with the signal correction capabilities of the TCP/IP protocol.
00:20:33 - Steve Horvath’s epigenetic aging clock, which measures DNA methylation groups, may play a role in widespread gene regulation, including sirtuin genes, and how NAD+ may participate in resetting the clock.
00:22:56 - How the epigenetic clock can predict your chronological age and how long you have to live.
00:23:47 - How epigenetic reprogramming in old mice can restore youthful gene activity patterns, reverse the DNA methylation aging clock, and restore the function and regenerative capacity of the aging retina.
00:24:51 - The signal that resets the epigenetic clock in mice involves Yamanaka factors – a group of four transcription factors that can reprogram an adult cell to become a pluripotent stem cell that can form any cell type.
00:26:24 - How short term treatment with the Yamanaka factors can reverse cellular and physiological hallmarks of aging and prolong lifespan in mice with a premature aging phenotype.
00:27:45 - Dr. Sinclair’s hope that we may eventually find a way to induce Yamanaka factors in a way that is more safe and applicable to humans than current genetic engineering and viral techniques used in animal research.
00:28:25 - How fasting, exercise, and other lifestyle factors may slow the rate of epigenetic aging but may not be sufficient to reverse it like some of the powerful Yamanka factors may be able to.
00:29:51 - How Dr. Sinclair’s lab and others are trying to find safe ways to reset the epigenetic aging clock with Yamanaka factors without causing tumors and other safety issues.
00:32:46 - How Dr. Sinclair thinks Claude Shannon’s theory on mathematical theory communication may also explain the aging process.
00:34:02 - Dr. Sinclair’s take on who some of the top scientists to follow in the field of aging epigenetics are, which includes Drs. Juan Carlos Izpisua Belmonte, Steve Horvath, Manuel Serrano, Anne Brunet, Shelley Berger, and Jessica Tyler.
00:36:00 - How nobel-prize winning biologist John Gurdon put an adult cell nucleus from a tadpole into a frog’s egg, producing a new tadpole, suggesting that the genome can be reset to a very early stage in an organism’s lifespan. Review on nuclear reprogramming.
00:36:22 - How cellular NAD+ is made from a variety of precursors including tryptophan, nicotinic acid, nicotinamide riboside, nicotinamide mononucleotide, and nicotinamide. Nicotinamide riboside gets converted into nicotinamide mononucleotide, which is then converted to NAD+.
00:37:33 - How NAD+ is a large molecule that does not get taken up in animals as efficiently as the NAD+ boosters nicotinamide riboside and nicotinamide mononucleotide, the latter of which is transported by a recently discovered transporter.
00:38:18 - How NAMPT, an enzyme in yeast that is activated by exercise and calorie restriction, is key for NAD+ production and longevity benefits.
00:39:45 - Plants produce compounds that activate sirtuin pathways in plants in response to stress and, in turn, the compounds activate beneficial pathways like the sirtuin pathway in humans, a phenomenon called xenohormesis. Resveratrol is one such compound and is produced when grape plants are stressed either in response to fungus or a lack of water.
00:41:11 - How small stressors such as exercise, calorie restriction, and ingestion of plant polyphenol compounds activate various stress response pathways in the body that help slow aging, but calorie excess and a sedentary lifestyle have the opposite effect, signaling the body to reproduce and continue aging, a concept known as the disposable soma theory of aging.
00:41:56 - When rhesus monkeys were fed a diet high in refined sugar (sucrose) and fat for two years, they experienced a 40% increase in arterial stiffness and inflammation but this was completely reversed if they were given 80 mg of resveratrol per day for one year then 480 mg/day for a second year.
00:44:26 - How resveratrol is a very insoluble molecule but its bioavailability can be increased if it is taken with food that contains a moderate amount of fat.
00:45:38 - Mice that were fed an obesogenic diet but were also given a low dose of resveratrol lived longer and had organs that were healthier and younger looking compared to mice fed the obesogenic diet alone.
00:48:32 - How a phase 2 clinical trial involving people with Alzheimer’s disease showed resveratrol improved mental examination status scores, induced marker changes that might suggest reduced accumulation of amyloid-beta in the brain, lowered markers of activated microglia, and more.
00:49:28 - How resveratrol has been shown to induce autophagy by directly inhibiting mTOR through ATP competition in mice.
00:51:00 - How both nicotinamide riboside and nicotinamide mononucleotide have been shown to improve cognitive function and brain pathology in mice that have been engineered to get a disease similar to Alzheimer’s disease.
0:51:29 - How treating mice with nicotinamide mononucleotide can prevent age-related endurance losses by promoting new blood vessel growth.
00:52:30 - How an NAD+ isotope tracer study revealed that orally administered precursors of NAD+ such as nicotinamide riboside and nicotinamide mononucleotide do not form NAD+ in any other tissues other than the liver, but that dose was half the amount used in animal studies that showed benefits in the brain and muscle.
00:53:37 - How there may be a threshold dose of nicotinamide riboside and nicotinamide mononucleotide that needs to be crossed in order to override the liver’s first pass clearance mechanisms so that nicotinamide riboside and nicotinamide mononucleotide NAD+ levels rise in other tissues like skeletal muscle, and this is why almost all animal studies use very high doses.
00:54:13 - How there may be challenges in translating animal studies on nicotinamide riboside and nicotinamide mononucleotide to humans particularly due to the need to determine the dose required to promote health benefits.
00:56:33 - How a couple of clinical trials are underway to test safety with a molecule called MIB-626, which is a potential strong NAD+ booster.
00:57:55 - How nicotinamide riboside and nicotinamide mononucleotide should be kept in the refrigerator because they are both unstable and quickly degrade to nicotinamide, which can inhibit sirtuin activity at high concentrations.
00:59:16 - Older mice that were given NMN (300 mg/kg/day) experienced delayed aging in the liver, muscle, immune cells, eyes, and bones, but those that took a lower dose of NMN (100mg/kg/day or human equivalent of 8mg/kg/day) had improved mitochondrial function and enhanced physical performance.
01:00:05 - How fragmented sleep consistently leads to higher fasting and postprandial blood glucose levels.
To touch on the fact that NMN needs to be kept cool, our NMN when stored correctly, reliably tests at over 99% purity at up to 2 years - our use-by date.
Our recommendations are to reseal the packet after use, and to store NMN in a cool dry place:
To expand on that slightly, if your room temperature exceeds 24 degrees Celsius, it wouldn’t be considered cool, and storage in the fridge would be fine then.