In aging and many disease states, the energy production capacity of the body’s cells is diminished. The mitochondria are the structures within the cell responsible for generating energy from oxygen and nutrients. If their number is reduced or their function is impaired, free radicals are produced and damaging toxins accumulate in the cells. These toxins further damage the mitochondria and impair other aspects of cellular function. Many of the most common health problems, such as obesity, diabetes, and many problems associated with aging, arise from problems in cellular energy production. As one group of researchers has put this, "[a]ging is associated with an overall loss of function at the level of the whole organism that has origins in cellular deterioration. Most cellular components, including mitochondria, require continuous recycling and regeneration throughout the lifespan."1 Another has observed, "[m]itochondrial biogenesis [the creation of new mitochondria] is a key physiological process that is required for normal growth and development and for maintenance of ongoing cellular energy requirements during aging."2 These observations link two key aspects of mitochondrial health, preventing and removing damaged mitochondria (mitophagy) and creating new mitochondria (mitogenesis).
Although the importance of the mitochondria as a central point of health has been accepted for decades, over the last few years the understanding of the mechanisms involved has changed significantly. Twenty or ten years ago, antioxidants and the free radical theory of aging largely dominated thinking. Today, the importance of mitochondrial biology linking basic aspects of aging and the pathogenesis of age-related diseases remains strong, yet the emphasis has changed. The focus has moved to mitochondrial biogenesis and turnover, energy sensing, apoptosis, senescence, and calcium dynamics.3
What Promotes Mitochondrial Biogenesis?
The body maintains a complex network of sensors and signaling functions to maintain stability despite a constantly changing environment and numerous challenges. Of special note is the concept of hormesis, meaning a state in which mild stress leads to compensation that improves the ability of the body to respond in the future to similar challenges. It turns out that many of the approaches that are associated with longevity and healthy aging promote hormesis. In terms of mitochondria biogenesis, these include caloric restriction, certain nutrient restrictions or shortages, caloric restriction mimetics, and exercise.
Many of the mechanisms that activate mitochondrial biogenesis in the face of hormesis have been elucidated. Keeping in mind that there always must be a balance between the elimination of worn-out and defective mitochondria and the generation of new ones, the activators of both actions can overlap. For instance, low energy levels (caloric restriction) and increased reactive oxygen species/free radicals can promote the activity of special cellular control points. These include activating metabolic sensors such as AMP kinase/ AMPK (adenosine monophosphate kinase) and the protein known as SIRT1 (sirtuin 1, i.e., silent mating type information regulation 2 homolog 1). Activated AMPK is an indicator that cellular energy is low and serves as a trigger to increase energy production. It inhibits insulin/IGF-1/mTOR signaling, all of which are anabolic and can lead not just to tissue production, such as muscle growth, but also to fat storage. Along with SIRT1, AMPK activates the biogenesis of new mitochondria to enable the cell to generate more energy. At the same time, activated AMPK and SIRT1 increase the activity of a tumor suppressor that induces mitophagy. The balance of the dual activations replaces defective mitochondria with newly formed functionally competent mitochondria.
A key to health and healthy aging is to regulate the catabolic processes via controlled amounts and types of stressors such that worn out mitochondria are removed without overshooting the mark and reducing overall cellular and tissue functionality. The most successful way to maintain this balance is to follow the body’s own natural metabolic signals rather than to attempt to override the body’s checkpoints. AMPK and SIRT1 ultimately are energy/nutrient sensors or control points. Hence rather than attempting to manipulate these directly, it likely is safer and ultimately more effective to address the factors in the cell that these sensors sense. The recent attention in the issue of aging to the role of NAD+ (the oxidized form of nicotinamide adenine dinucleotide) is a good example of this principle. Directions coming from the nucleus of the cell that help to regulate the normal production of NAD+ and the ratio between distinct pools found in the cytoplasm and in the mitochondria decline with age. The changes in the NAD+ from the nucleus lead to a disruption on the mitochondrial side. In terms of energy production, it is a bit like losing a link or two in the timing chain on your car engine with a resultant reduction in engine efficiency. To date, attempts to increase NAD+ in cells via supplementation with precursors have not proven particularly successful. Major benefits have been demonstrated in animal models only in the already seriously metabolically impaired or the relatively old. Recent research on oral supplementation has led to at least one extremely difficult article which, at least in this author’s opinion, delivers more smoke than heat.4,5 There is, however, an argument to the effect that supplementing together both nicotinamide riboside (a NAD+ precursor) and a sirtuin activator, such as pterostilbene, may prove to be more successful.
It turns out that there are key points in normal cellular energy generation processes that strongly influence the NAD+ pools available for the cell to draw upon and the rate at which NAD+ can be replaced in these pools. Aging has been shown to promote the decline of nuclear and mitochondrial NAD+ levels and to increase the risk of cancer along with components of the metabolic syndrome. It is significant that the risks of these conditions can be reduced in tandem. Three places to start are 1) the pyruvate dehydrogenase complex, 2) the tricarboxylic acid cycle (TCA cycle) also known as the Krebs Cycle, and 3) the malate shuttle. A fourth junction is Complex I of the electron transport system, again, in the mitochondria.6 Manipulation of steps (1) and (2) already is being used in cancer treatment.7 Readily available dietary supplements can influence all four of these metabolic bottlenecks.
Supplements for Promoting Mitochondrial Biogenesis
Medicine has started to pay a great deal of attention to effecting mitochondrial biogenesis through not just drugs, but also dietary supplements. Those interested should go online and look up "Mitochondrial Biogenesis: Pharmacological Approaches" in Current Pharmaceutical Design, 2014, Vol. 20, No. 35. Quite a few options are mentioned, including well known compounds, such as R-lipoic acid (including with L-carnitine), quercetin and resveratrol, along with still obscure supplements, including various triterpenoids and the Indian herb Bacopa monnieri.
Pomegranate, French White Oak and Walnuts
The pomegranate, with its distinctive scarlet rind (pericarp) and vibrantly colored seed cases (arils), is one of the oldest cultivated fruits in the world. This exotic fruit features prominently in religious texts and mythological tales and has been revered through the ages for its medicinal properties. An image of a pomegranate even can be found on the shield of the British Royal College of Medicine. Numerous studies have demonstrated the benefits of the fruit for cardiovascular health with other benefits suggested in areas ranging from arthritis to stability of cell replication to bone health. Now a study in Nature Medicine (July 2016) has uncovered perhaps the most important benefit of all, the ability of pomegranate compounds (ellagitannins) transformed by gut bacteria to protect the mitochondria of the muscles and perhaps other tissues against the ravages of aging. The mitochondria are the energy generators of the cells and the weakening of this energy generating function in an increasing percentage of mitochondria as we age is a primary source of physical decline over the years. Urolithin A, a byproduct of gut bacterial action on pomegranate compounds, allows the body to recycle defective mitochondria and thereby slow or even reverse for a time some of the major aspects of aging. The lifespan in a nematode model of aging was increased by more than 45 percent. Older mice in a rodent model of aging exhibited 42 percent better exercise endurance. Younger mice also realized several significant benefits.8
Beginning almost three decades ago, there were numerous speculations in the research world regarding the so-called "French Paradox" in which the French consumed quite large amounts of saturated fat in the form of butter and cheese, yet consistently experienced much lower rates of cardiovascular disease than did Americans. Not only that, the French, especially in the southwest of the country, typically led longer lives even in the areas noted for consuming large amounts of goose fat and pate de foie gras, which is to say, not just the Mediterranean diet based on olive oil, etc. One hypothesis put forth very early on was that it was the French consumption of red wine that protected them. It was thought that red wine components, including anthocyanidins, proanthocyanidins and resveratrol, are the protective compounds. Not considered until recently is that French red wines traditionally have been aged in casks made from white oak (Quercus robur). White oak contains roburin A, a dimeric ellagitannin related chemically to punicalagin. Human data show relatively good absorption and conversion of roburins into substances including urolithin A and ellagic acid—as compared with ellagitannins in general, which evidence only poor absorption. Hence, the benefits of good red wine traditionally produced and good cognac (also aged in oak barrels) involve urolithin A. Notably, the benefits of roburins, most likely derived from the conversion to urolithin A, go beyond mitophagy to include ribosomes, referring to cell components that translate DNA instructions into specific cellular proteins.9,10,11,12
Other sources of ellagitannins have been shown to lead to the production of urolithin A by bacteria in the human gut. Not surprisingly, sources of ellagitannins are foods long associated with good health longevity, including not just pomegranate and oak-aged red wine, but also walnuts (and a smattering of other nuts), strawberries, raspberries, blackberries, cloudberries and even black tea in small amounts.
Exercise and Pyrroloquinoline Quinone (PQQ)
Peroxisome proliferator-activated receptor gamma coactivator (PGC-1á) is the master regulator of mitochondrial biogenesis.13 Exercise is perhaps the most significant activator of PGC-1á that most individuals can access. Exercise, furthermore promotes mitochondrial biogenesis through a number of other pathways, especially endurance and interval training.14
There are non-exercise options. You can’t take PGC-1á orally because it is a large protein molecule which does not survive digestion. PQQ is a small molecule that is available when ingested and that increases circulating PGC-1á. PQQ supplementation leads to more mitochondria and more functional mitochondria.15
Fasting, Ketogenic Diets and Fasting-Mimicking Supplements As already discussed, fasting promotes mitochondrial biogenesis by AMPK activation.16 AMPK senses the energy status of the cell and responds both to acute shortages, such as that induced by exercise, and to chronic shortages, such as from fasting. Probably due to an overall reduction in metabolic rate, chronic caloric restriction (as opposed to intermittent fasting) contributes to the health of mitochondria rather than biogenesis.17 The robustness of AMPK response decreases with age.18
Ketogenic diets (very low carbohydrate diets) also promote increases in mitochondria.19 Few individuals are willing or able to follow ketogenic diets chronically just as few individuals are willing to undergo routine fasts. Fasting-mimicking supplements offer an alternative approach. The dietary supplement (-)–hydroxycitric acid (HCA) is the best researched of these compounds. (Keep in mind that there is a vast difference in the efficacy of commercially available forms.20) Researchers have proposed that HCA used properly can activate mitochondrial uncoupling proteins and related effects.21
Furthermore, according to a study published in the journal Free Radical Research in 2014, HCA improves antioxidant status and mitochondrial function plus reduces inflammation in fat cells.22 Inflammation is linked to the metabolic syndrome at the cellular level by way of damage to the antioxidant enzyme system (e.g., superoxide dismutase, glutathione peroxidase, glutathione reductase) and mitochondria. This damage, in turn, propagates further production of pro-inflammatory mediators (e.g., TNF-á, MCP-1, IFN-ã, IL-10, IL-6, IL-1â). HCA protected fat cells from ER stress by improving the antioxidant status to reduce oxidative stress (i.e., reduce ROS) and improve the function of the mitochondria to short circuit an ER stress—inflammation loop in these cells. Reducing TNF-á is important in that doing so removes a major impediment to mitochondrial biogenesis.23
Other Supplements to Promote Mitochondrial Biogenesis
Scholarly reviews looking at natural compounds such as those that are found in anti-aging diets suggest yet other supplements to promote mitobiogenesis. For instance, it turns out that hydroxytyrosol, the most potent and abundant antioxidant polyphenol in olives and virgin olive oil, is a potent activator of AMPK and an effective nutrient for stimulating mitochondrial biogenesis and function via what is known as the PGC-1á pathway.24 Another herb with anti-aging effect, this time by activating the malate shuttle mechanism mentioned above, is rock lotus (Shi Lian Hua). This herb has been described in detail in this magazine in the article, "Uncovering the Longevity Secrets of the ROCK LOTUS."25
It is possible to improve the functional capacity of the mitochondria through dietary practices, exercise and supplements. Indeed, a number of compounds have been identified by researchers as mitochondrial nutrients. These compounds work together to increase the efficiency of energy production, to reduce the generation of free radicals, and so forth and so on. Likewise, these nutrients have been shown to improve the age-associated decline of memory, improve mitochondrial structure and function, inhibit the ageassociated increase of oxidative damage, elevate the levels of antioxidants, and restore the activity of key enzymes. Perhaps best of all, the body can be encouraged both to remove damaged mitochondria (mitophagy) and to create new ones, which is to say, mitochondrial biogenesis.
- López-Lluch G, Irusta PM, Navas P, de Cabo R. Mitochondrial biogenesis and healthy aging. Exp Gerontol. 2008 Sep;43(9):813–9.
- Stefano GB, Kim C, Mantione K, Casares F, Kream RM. Targeting mitochondrial biogenesis for promoting health. Med Sci Monit. 2012 Mar;18(3):SC1-
- Gonzalez-Freire M, de Cabo R, Bernier M, Sollott SJ, Fabbri E, Navas P, Ferrucci L. Reconsidering the Role of Mitochondria in Aging. J Gerontol A Biol Sci Med Sci. 2015 Nov;70(11):1334-42.
- Trammell SA, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, Li Z, Abel ED, Migaud ME, Brenner C. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016 Oct 10;7:12948.
- Mitteldorf J. Nicotinamide Riboside —Where’s the Beef? http://joshmitteldorf.scienceblog.com/2014/11/17/nicotinamide-riboside-wheres-thebeef/.
- Yang Y, Sauve AA. NAD+ metabolism: Bioenergetics, signaling and manipulation for therapy. Biochim Biophys Acta. 2016 Dec;1864(12):1787– 1800.
- Schwartz L, Buhler L, Icard P, Lincet H, Steyaert JM. Metabolic treatment of cancer: intermediate results of a prospective case series. Anticancer Res. 2014 Feb;34(2):973–80.
- Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-Félix AA, Williams EG, Jha P, Lo Sasso G, Huzard D, Aebischer P, Sandi C, Rinsch C, Auwerx J. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med. 2016 Aug;22(8):879-88.
- Pellegrini L, Belcaro G, Dugall M, Corsi M, Luzzi R, Hosoi M. Supplementary management of functional, temporary alcoholic hepatic damage with Robuvit® (French oak wood extract). Minerva Gastroenterol Dietol. 2016 Sep;62(3):245–52.
- Vinciguerra MG, Belcaro G, Cacchio M. Robuvit® and endurance in triathlon: improvements in training performance, recovery and oxidative stress. Minerva Cardioangiol. 2015 Oct;63(5):403–9.
- Országhová Z, Waczulíková I, Burki C, Rohdewald P, Ïuraèková Z. An Effect of Oak-Wood Extract (Robuvit®) on Energy State of Healthy Adults-A Pilot Study. Phytother Res. 2015 Aug;29(8):1219–24.
- Natella F, Leoni G, Maldini M, Natarelli L, Comitato R, Schonlau F, Virgili F, Canali R. Absorption, metabolism, and effects at transcriptome level of a standardized French oak wood extract, Robuvit, in healthy volunteers: pilot study. J Agric Food Chem. 2014 Jan 15;62(2):443–53.
- Ventura-Clapier R, Garnier A, Veksler V. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res. 2008 Jul 15;79(2):208–17.
- Wright DC, Han DH, Garcia-Roves PM, Geiger PC, Jones TE, Holloszy JO. Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1alpha expression. J Biol Chem. 2007 Jan 5;282(1):194–9.
- Bauerly K, Harris C, Chowanadisai W, Graham J, Havel PJ, Tchaparian E, Satre M, Karliner JS, Rucker RB. Altering pyrroloquinoline quinone nutritional status modulates mitochondrial, lipid, and energy metabolism in rats. PLoS One. 2011;6(7):e21779.
- Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):15983–7.
- Lee CM, Aspnes LE, Chung SS, Weindruch R, Aiken JM. Influences of caloric restriction on age-associated skeletal muscle fiber characteristics and mitochondrial changes in rats and mice. Ann N Y Acad Sci. 1998 Nov 20;854:182–91.
- Jornayvaz FR, Shulman GI. Regulation of mitochondrial biogenesis. Essays Biochem. 2010;47:69–84.
- Bough KJ, Rho JM. Anticonvulsant mechanisms of the ketogenic diet. Epilepsia. 2007 Jan;48(1):43–58.
- Louter-van de Haar J, Wielinga PY, Scheurink AJ, Nieuwenhuizen AG. Comparison of the effects of three different (-)-hydroxycitric acid preparations on food intake in rats. Nutr Metab (Lond). 2005 Sep 13;2:23.
- McCarty MF. High mitochondrial redox potential may promote induction and activation of UCP2 in hepatocytes during hepatothermic therapy. Med Hypotheses. 2005;64(6):1216–9.
- Nisha VM, Priyanka A, Anusree SS, Raghu KG. (-)–Hydroxycitric acid attenuates endoplasmic reticulum stress-mediated alterations in 3T3-L1 adipocytes by protecting mitochondria and downregulating inflammatory markers. Free Radic Res. 2014 Nov;48(11):1386-96.
- Valerio A, Cardile A, Cozzi V, Bracale R, Tedesco L, Pisconti A, Palomba L, Cantoni O, Clementi E, Moncada S, Carruba MO, Nisoli E. TNFalpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents. J Clin Invest. 2006 Oct;116(10):2791–8.
- Liu J, Shen W, Zhao B, Wang Y, Wertz K, Weber P, Zhang P. Targeting mitochondrial biogenesis for preventing and treating insulin resistance in diabetes and obesity: Hope from natural mitochondrial nutrients. Adv Drug Deliv Rev. 2009 Nov 30;61(14):1343–52.
Dallas Clouatre, PhD
Dallas Clouatre, Ph.D. earned his A.B. from Stanford and his Ph.D. from the University of California at Berkeley. A Fellow of the American College of Nutrition, he is a prominent industry consultant in the US, Europe, and Asia, and is a sought-after speaker and spokesperson. He is the author of numerous books. Recent publications include "Tocotrienols in Vitamin E: Hype or Science?" and "Vitamin E – Natural vs. Synthetic" in Tocotrienols: Vitamin E Beyond Tocopherols (2008), "Grape Seed Extract" in the Encyclopedia Of Dietary Supplements (2005), "Kava Kava: Examining New Reports of Toxicity" in Toxicology Letters (2004) and Anti-Fat Nutrients (4th edition).