Some people have called NAD+ an  anti-aging miracle drug. In the last post I briefly mentioned that NAD+ is considered a longevity compound. NAD+ and its precursors are key compounds that Dr. David Sinclair focuses on in his lab at Harvard and that he personally takes daily.[1] In this post, I hope to share what NAD+ is, and why you may want to consider boosting your levels.

NAD+ is a vitamin B3 derivative. It is critical to every cell and is required for energy production and cellular repair. Think high-school biology, Krebs cycle and the Electron Transport Chain. NAD+ is necessary for moving electrons around, which allows us to generate the cellular energy of ATP. It allows us to extract cellular energy from carbohydrates, proteins, and fats.

In addition to energy production, NAD+ also turns on multiple longevity genes, especially the sirtuins.  The sirtuin family of genes are regulators of epigenetics. The sirtuins create enzymes that help keep DNA organized so the DNA can function properly. Sirtuins also help in the repair of damaged DNA, reduce inflammation, and help with stress resistance. As we age, our levels of NAD+ decline, and we have a corresponding decrease in sirtuin activity.  Some researchers suspect that replacing and replenishing NAD+ levels may help stem the aging process.

Some of the studied benefits of increasing NAD+ include:

1.  Improved heart health by decreased arterial stiffness and lower blood pressure. [3,4]
2. Improvement of mitochondrial and neuronal health. In an Alzheimers mouse model, NAD supplementation through precursors slowed cognitive decline. [5,6,7]
3. Life span extension in yeast, worms and rodents. [8,9]

You may wonder why many of the longevity studies on NAD+ are in animal models.  Animals have similar genetic and molecular pathways as humans and unlike humans they do not live as long.  A study in humans on longevity could take a century, whereas in animals the study could be done in 3-5 years. 

Most of the studied benefits with NAD+ have been demonstrated using oral precursors since oral NAD+ is not easily absorbed. An alternative delivery system, IV NAD+, has not been studied as thoroughly, though there are many reported benefits, which include improvements in: 

ADHD, 
executive function, 
addiction,
anxiety, 
depression, 
chronic fatigue and 
cognitive decline.

Given the studied and reported benefits, you may wonder how to increase your NAD+.
​We can maintain youthful levels of NAD+ by either:
1. Decreasing use/destruction of NAD+
2. Increasing production or levels of NAD+

NAD+ is consumed primarily by 1. PARPs (in DNA repair) 2. Sirtuins (as discussed above) and 3. CD-38 (to be discussed below). The largest consumer of NAD as we age appears to be CD-38.  CD-38 is a signaling molecule induced by zombie cells or senescent cells from molecules they secrete. If we want to increase our pool of NAD+ by decreasing usage, the primary target should be cd-38 and zombie cells. [10]

To decrease use of NAD+:
1. Minimize cellular stressors. This includes the boring truisms of reducing or eliminating smoking, eating real foods rather than processed, lowering your intake of sugar, getting enough sleep, and stress management.
2. Lower cd-38 levels. This can be accomplished by lowering the number of zombie cells.  The best way to lower the load is through the use of senolytics. Examples of senolytics include supplements like quercetin, fiscetin and curcumin. A promising animal trial at Mayo Clinic showed a significant reduction in zombie cells using a medication called Desatinib  and quercetin. [11]

NAD+ levels can be increased by: 
1. Fasting
2. Exercise
3. IV NAD+ and oral NAD+ precursors: Animal studies have shown that taking precursors can raise blood levels of NAD by 2.7X, [12] and human studies of IV NAD+ show that NAD+ is both safe and readily taken up by tissues. [13]

To bring it all together, NAD+ is important in energy metabolism and DNA repair. With age, our NAD+ levels fall, and we are more prone to age-related diseases.  NAD+ has been shown in humans to reduce the risk of some age-related diseases and in animals to extend their lifespan.  Though I am hoping to see more research in this area, given the low risk, good safety profile, and potential upside, I personally take oral NAD+ precursors and IV NAD.  As always, talk to your doctor before starting any supplements.

Hope you have enjoyed this,

Amy

This is the last week of our four part series on how to play hard, work hard, and be fully engaged with family, friends and community for as long as possible. 

As nutrition is one of the key components of longevity, I hoped this post/email would give you compelling data on the best way to eat, but what I have found, is that the most advanced research on nutrition and longevity is not about what types of foods you should or shouldn’t eat. Instead the best research seems to be on  fasting and caloric restriction, neither of which I realize, are very sexy. But the molecular mechanisms that they turn on are pretty amazing. Both signal our cells to clean house (autophagy), stimulate stem cells, change our epigenetics (the expression of our genetic code), change metabolic pathways, turn on longevity genes like the sirtuins, and improve our stress resistance.  [1,2,3,4] Each of these  improvements should help you to play, work and engage longer.

In my practice, I focus mainly on fasting as, honestly, long term caloric restriction (CR) is not sustainable or very fun. Studies like the one conducted in Biosphere 2, which relegated human volunteers for 24 months to severe CR, resulted in cold, irritable people with no sex drive. [5] However, fasting and intermittent fasting seems to hold a lot of promise, and while not appropriate for everyone, the studies are encouraging.

Fasting has specifically been shown to lower the risk of developing cancer, cardiovascular disease, and neurodegenerative disease. [6] Fasting cycles have been shown to work as effectively as chemotherapy in some tumors, and when combined with chemotherapy it appears to enhance the benefits and lower the chemo side-effects. [7] Fasting can also be a very effective way to lower high blood pressure. [8] Fasting has even been shown to improve verbal recall. [9]

A study by de Cabo suggested that eating patterns may play a larger role than diet composition. [10] This finding is particularly interesting given all of the debate around dietary restriction.  There are so many conflicting trials and so much conflicting information in the area of dietary restriction.  Mediterranean, low carb, low fat, paleo, keto, vegan and vegetarian all seem to have studies saying they are the best.  

What is right answer? Evidence suggests that when people stop eating the processed Standard American Diet (SAD) and move to a real foods plan (eating foods devoid of processed and sugary foods), any of these diet styles are an improvement. If we look at the top ten sources of American calories, grain-based desserts like cakes and cookies top the list followed closely by sugary drinks, alcoholic beverages and dairy desserts. [Source: Report of the 2010 Dietary Guidelines Advisory Committee]

Many patients have asked me about the Netflix show, “The Game Changers.” I propose that when we eliminate the processed and sugary foods and move to a real foods plan whether it’s keto, vegetarian, paleo, low fat or otherwise, we will begin to feel and perform better. If you want a balanced, well-considered perspective on “Game Changers” please see the Peter Attia article.

Getting back to longevity, we know there is a link between sugar and inflammation. You already know the painful consequences of inflammation when you overdo it at the gym, but what you may not be aware of is how inflammation impacts your system when you indulge in too much sugar. I generally suggest avoiding sugary foods such as sodas as well as most processed foods, which can be loaded with hidden sugars. Reducing your sugar intake reduces inflammation, which in turn may slow the aging process.

So how can you eat to live your best life? 

1. Eat “real” foods instead of processed. If you are buying things in box or a can, read labels for grams of sugar and check ingredients.  If you want to get deep in the weeds, I have found Rhonda Patrick's SNP analysis helpful in beginning to understand how different dietary and supplement approaches may affect you based on your genetic profile.

2. Intermittent fasting or time restricted eating may be part of a healthy longevity plan. A Stanford oncology trained friend of mine suggests everyone allow at least 12 hours every night between their last food of the night and breakfast. This allows for autophagy or cell cleaning to occur.

3. A good resource for learning more about how to fast is: “The Complete Guide to Fasting.” I also like the documentary “Eat, Fast, Live Longer.”

4. There are also fasting mimicking diets (FMD's). These are often 3-5 day plans that allow you to consume some food but make your body think it is fasting. Valter Longo a prominent researcher in this field has a commercially available plan called Prolon.  In humans, this FMD lowers inflammation markers, improves blood pressure, enhances cognitive performance, increases circulating stem cells by 800% and lowers biomarkers/risk factors for aging, diabetes, cardiovascular disease, and cancer. [11] Each of these improvements should lead to a longer, healthier life.

I personally like the 5 day FMD, Prolon as it has solid research supporting it. I think a five day plan is easy to finish and the perfect amount of time for a re-set.

-Amy

1.Fontana L, Partridge L, Longo V.D. Extending healthy life span—from yeast to humans. Science. 2010; 328: 321-326 
 2 Mattson, W, et al. Flipping the Metabolic Switch: Understanding and Applying Health Benefits of Fasting. Obesity (Silver Spring). 2018 Feb; 26(2): 254–268. doi: 10.1002/oby.22065
3. Haigis MC, Guarente LP. Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. Genes Dev. 2006 Nov 1;20(21):2913-21.
 4. Madeo F, De Cabo R. Et al. The search for antiaging interventions: from elixirs to fasting regimens. Cell. 2014; 157: 1515-1526.
 5. Walford R.L. Mock D. Verdery R. MacCallum T. Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. J. Gerontol. A Biol. Sci. Med. Sci. 2002; 57: B211-B224.
 6. Longo V.D. Mattson M.P. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014; 19: 181-192. 
 7. Raffaghello L. Lee C. Safdie F.M. Wei M. Madia F. Bianchi G. Longo V.D. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc. Natl. Acad. Sci. USA. 2008; 105: 8215-8220.
 8. Goldhamer A.C. Lisle D.J. Sultana P. Anderson S.V. Parpia B. Hughes B. Campbell T.C.Medically supervised water-only fasting in the treatment of borderline hypertension. J. Altern. Complement. Med. 2002; 8: 643-650.

9. Madeo F. Et al. Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans. Cell Metabolism. 2019; 30: 3: 462-476.E5.
 10. de Cabo et al. Daily Fasting Improves Health and Survival in Male Mice Independent of Diet Composition and Calories. Cell Metabolism, 2018; DOI: 10.1016/j.cmet.2018.08.011

11. Wei M, Brandhorst S, Shelehchi M, Mirzaei H, Cheng CW, Budniak J, Groshen S, Mack WJ, Guen E, Di Biase S, Cohen P, Morgan TE, Dorff T, Hong K, Michalsen A, Laviano A, Longo VD. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017 Feb 15;9(377). doi: 10.1126/scitranslmed.aai8700.

Other related studies:

Mattson M.P. et al. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proc. Natl. Acad. Sci. USA. 2003; 100: 6216-6220

Panda S. et al. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab. 2014; 20: 991-1005

Longo, V.D., Panda S. Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan. Cell Metab. 2016; 23: 1048-1059

Minor R.K. Allard J.S. Younts C.M. Ward T.M., de Cabo R. Dietary interventions to extend life span and health span based on calorie restriction. J. Gerontol. A. Biol. Sci. Med. Sci. 2010; 65: 695-703

Longo et al.  A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan.
Cell Metab. 2015 Jul 7;22(1):86-99. doi: 10.1016/j.cmet.2015.05.012. Epub 2015 Jun