Enhancing overall energy levels is particularly important during the holidays, which can be an exhausting time of year. Overall energy status in the body is dependent on several different physiological pathways and if any or all of these pathways are disrupted than fatigue can result. At the cellular level, the production of energy in the mitochondria is critical. Also, the adrenal glands can play a role as they respond to environmental stressors. In addition, neurotransmitters in the brain and the sympathetic nervous system response can impact short-term energy production.
Mitochondrial Function
Fatigue is increasingly common. In fact, 24 percent of patients report that fatigue is a major health problem.1 Evidence suggests that mitochondrial dysfunction is a major cause of fatigue. Mitochondria are cellular structures responsible for the majority of energy production in the form of adenosine tri-phosphate (ATP), the chemical energy used by the cells. The mitochondria produce ATP through three main pathways: cellular respiration including glycolysis and the citric acid cycle, oxidative phosphorylation and beta-oxidation. Mitochondria are also involved in numerous other physiological functions such as calcium signaling, cellular differentiation, apoptosis (programmed cell death), regulation of the cell cycle and cell growth. The number of mitochondria varies between cell types, depending on how much energy is required. Mitochondria are also an interesting cell structure in that they have their own DNA for replication.
Normal energy production within the mitochondria results in the formation of damaging free radicals such as the reactive oxygen species (ROS) superoxide. The body has several antioxidant enzymes to combat the production of these free radicals. However, these enzymes, as well as the enzymes required for oxidative phosphorylation, decrease with age.2 The ROS generated induce cellular oxidative stress and may contribute to age-related decline in mitochondrial function. Furthermore, the reduction in mitochondrial oxidative phosphorylation significantly impacts energy production, as this pathway provides the majority of ATP produced. Also, mitochondrial DNA mutations contribute to the decreased ATP production and increased levels of ROS seen with increasing age.3
Mitochondrial dysfunction from any cause results in decreased energy production, which may cause symptoms of fatigue. Research suggests that numerous diseases such as chronic fatigue syndrome (CFS) are associated with mitochondrial dysfunction.4 Several studies indicate that fatigue may be related to free radical-induced cellular oxidative stress causing oxidative damage to mitochondria, resulting in reduced efficiency of mitochondrial energy production.5 Optimizing mitochondrial function can support the body in long-term energy production. Research indicates that supplementation of mitochondrial nutrients and antioxidants in patients suffering with chronic fatigue reduces damage to mitochondrial membranes, restores mitochondrial energy production, protects cellular structures and enzymes from oxidative damage, and most importantly, decreases fatigue.6 A number of nutrients (all found in Mito-Boost® Caps) are important in the mitochondrial synthesis of energy as well as decrease free radical damage.
Carnitine, and the derivative acetyl-L-carnitine, is important for ATP synthesis. Acetyl-L-carnitine is the precursor to the molecule acetyl coenzyme A, which is the primary substrate for creating high-energy molecules in the citric acid cycle. In addition, N-acetyl-carnitine assists in the transportation of long-chain fatty acids into the mitochondria for beta-oxidation, the process in which fatty acids are broken down to generate the substrate acetyl coenzyme A for the citric acid cycle. Carnitines also exhibit antioxidant properties, which provide protection from free radical damage. Studies indicate that conditions such as CFS and several cardiovascular diseases have low levels of carnitines, including serum acylcarnitine, total carnitine and free carnitine. Data also suggests that higher carnitine levels correlate with better functional capacity.7-8 Similarly, research has shown that improvement in general fatigue in patients with CFS is associated with increasing concentrations of serum acylcarnitine to normal levels.9 Succinate is another citric acid cycle intermediate that has been shown to benefit patients with mitochondrial disorders.10
Antioxidant supplementation such as lipoic acid and N-acetyl-cysteine (NAC) is also important to reduce oxidative free radical damage. Lipoic acid has been shown to protect and repair age-related mitochondrial DNA damage, thus improving mitochondrial function and energy production.11 In fact, research indicates that lipoic acid decreases levels of ROS, increases the levels of antioxidants and restores the activity of key mitochondrial enzymes.12 Furthermore, research has demonstrated that lipoic acid in combination with acetyl-L-carnitine increases cellular metabolism and lowers oxidative stress better than either compound alone.13 NAC, the precursor to the potent antioxidant glutathione, has also been shown to protect mitochondrial proteins against damaging ROS and increases activity of mitochondrial complex proteins.14-15 NAC supplementation can also directly improve the efficiency of mitochondrial energy production.16
Ribose, a five-carbon sugar, is an important subunit of the molecule ATP and adding it to the above supplementation regimen can result in increased energy and stamina. The availability of ribose can impact the rate in which ATP is synthesized. D-ribose supplementation accelerates ATP synthesis by up to 4.3-fold in muscles17 and can decrease free radical formation.18 Clinical studies indicate that supplementation of D-ribose in patients with CFS and/or fibromyalgia resulted in 66 percent of patients reporting significant improvement, with an average increase in energy of 45 percent, and an average improvement in overall well-being of 30 percent. The subjects also reported significant improvement in energy, pain intensity, sleep, mental clarity and well-being.19
The Adrenal Glands
Also important for energy and stamina, the adrenal glands play a significant role in mediating the stress response. Chronic stress is increasingly common and often presents as fatigue. There are two distinct areas in the adrenal gland: the adrenal medulla, which is responsible for secreting epinephrine (adrenaline) and norepinephrine (noradrenaline); and the adrenal cortex, which secretes steroid hormones including cortisol. The stress response activates both the hypothalamus-pituitary-adrenal (HPA) axis as well as the sympathetic nervous system-adrenal response. Perceived stress causes an increase in cortisol release, which correlates to symptoms of fatigue and anxiety.20 Botanicals known as adaptogens are often used to improve the physiological resistance to stressors and balance adrenal hormone levels, thereby improving long-term energy levels and stamina.
Panax Ginseng (Korean ginseng) and Eleutherococcus senticosus, which are found in Ginseng Plus along with Rhodiola, have been traditionally used as adaptogenic herbs to modulate stress, fatigue and immune function. Research indicates that Panax ginseng directly influence the HPA axis.21 Evidence suggests that Panax ginseng also exhibits antioxidant and anti-inflammatory activity.22 Studies with Eleutherococcus demonstrate that this herb can improve maximal working capacity by improving oxygen metabolism reflected by an increase in maximal oxygen uptake.23 Oxygen is a required substrate for the oxidative phosphorylation pathway for ATP synthesis in the mitochondria. In addition, animal models indicate that Eleutherococcus inhibits stress-induced cortisol increase and improves overall endurance.24
Rhodiola rosea is considered to be one of the most bioactive adaptogenic herbs. In one study, Rhodiola was supplemented for 12 weeks in subjects with physical and cognitive deficiencies. The study showed a highly significant improvement in physical and cognitive deficiencies such as exhaustion, decreased motivation, daytime sleepiness, decreased libido, sleep disturbances and cognitive complaints including concentration deficiencies, forgetfulness, decreased memory, susceptibility to stress and irritability. Furthermore, 80 percent of the subjects reported the treatment as “good” or “very good.”25
Other Energy Boosters
Additional nutrients have been shown to impact energy levels. Methylcobalamin is the active, functional form of vitamin B12, which is important for nerve and blood cells. One study found that administration of vitamin B12 (methylcobalamin) to subjects complaining of tiredness or fatigue resulted in reported improvement in the subject’s general well-being.26 Another study showed that methylcobalamin supplementation improved plasma vitamin B12 levels as well as subjective reports of improved sleep quality, concentration, and feeling refreshed, while decreasing overall sleep duration.27
Short-Term Energy Support
In addition to optimizing long-term improvements in energy production, short-term support is also helpful, especially around the holidays. Many energy drinks cause a significant drop in energy once the effect of the sugar and caffeine has worn off. However, L-phenylalanine and nutrients such as pyridoxine (vitamin B6), found in Optimum Energy™, provides sustained energy support without the “crash.” L-phenylalanine is an essential amino acid that is metabolized into the amino acid tyrosine. Tyrosine is the precursor for the synthesis of norepinephrine, epinephrine and dopamine.
Norepinephrine is released into the blood from the adrenal medulla as a hormone and is released from noradrenergic neurons where it acts as a neurotransmitter in the central nervous system and sympathetic nervous system. Similarly, epinephrine acts as both a hormone secreted from the adrenal glands and as a neutrotransmitter in the brain. Both epinephrine and norepinephrine play a central role in the short-term stress reaction of the sympathetic nervous system, increasing the supply of oxygen and glucose to the brain and muscles.
Pyridoxine, or vitamin B6, is also important for short-term energy production. Supplementation with pyridoxine in pyridoxine-deficient animals normalized neurotransmitter levels including gamma-aminobutyric acid (GABA), serotonin, epinephrine and norepinephrine levels.28
Conclusion
There are several mechanisms in which energy production can be optimized. Addressing mitochondrial and adrenal function with Mito-Boost, D-Ribose, Ginseng Plus and sublingual vitamin B12 improves long-term energy and may help alleviate fatigue. Short-term support (in the form of Optimum Energy), especially around the holidays when we need extra vitality, optimizes neurotransmitters and sympathetic nervous system hormones.
References
1. Kroenke K, Wood DR, Mangelsdorff AD, et al. Chronic fatigue in primary care. Prevalence, patient characteristics, and outcome. JAMA. 1988 Aug 19;260(7):929-34.
2. Cortopassi GA, Wong A. Mitochondria in organismal aging and degeneration. Biochim Biophys Acta. 1999 Feb 9;1410(2):183-93.
3. Wei YH, Lee HC. Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med (Maywood). 2002 Oct;227(9):671-82.
4. Pieczenik SR, Neustadt J. Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol. 2007 Aug;83(1):84-92.
5. Nicolson GL. Metabolic syndrome and mitochondrial function: molecular replacement and antioxidant supplements to prevent membrane peroxidation and restore mitochondrial function. J Cell Biochem. 2007 Apr 15;100(6):1352-69.
6. Nicolson GL, Conklin KA. Reversing mitochondrial dysfunction, fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy. Clin Exp Metastasis. 2008;25(2):161-9.
7. Plioplys AV, Plioplys S. Serum levels of carnitine in chronic fatigue syndrome: clinical correlates. Neuropsychobiology. 1995;32(3):132-8.
8. Carvajal K, Moreno-Sanchez R. Heart metabolic disturbances in cardiovascular diseases. Arch Med Res. 2003;34:89-99.
9. Kuratsune H, Yamaguti K, Takahashi M, et al. Acylcarnitine deficiency in chronic fatigue syndrome. Clin Infect Dis. 1994 Jan;18 Suppl 1:S62-7.
10. Shoffner JM, Lott MT, Voljavec AS, et al. Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. Proc Natl Acad Sci USA. 1989 Oct;86(20):7952-6.
11. McCarty MF, Barroso-Aranda J, Contreras F. The “rejuvenatory” impact of lipoic acid on mitochondrial function in aging rats may reflect induction and activation of PPAR-gamma coactivator-1alpha. Med Hypotheses. 2009 Jan;72(1):29-33.
12. Hagen TM, Ingersoll RT, Lykkesfeldt J, et al. (R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J. 1999 Feb;13(2):411-8.
13. Liu J. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem Res. 2008 Jan;33(1):194-203.
14. Banaclocha MM. Therapeutic potential of N-acetylcysteine in age-related mitochondrial neurodegenerative diseases. Med Hypotheses. 2001 Apr;56(4):472-7.
15. Nicoletti VG, Marino VM, Cuppari C, et al. Effect of antioxidant diets on mitochondrial gene expression in rat brain during aging. Neurochem Res. 2005 Jun-Jul;30(6-7):737-52.
16. Cocco T, Sgobbo P, Clemente M, et al. Tissue-specific changes of mitochondrial functions in aged rats: effect of a long-term dietary treatment with N-acetylcysteine. Free Radic Biol Med. 2005 Mar 15;38(6):796-805.
17. Hellsten Y, Skadhauge L, Bangsbo J. Effect of Ribose Supplementation on Resynthesis of Adenine Nucleotides after Intermittent Training in Humans. AM J Physiol, Regul Intergr Comp Physiol. 2004;286:R182-R188.
18. Seifert JG, Subhudi A, Fu M-X, et al. The Effects of Ribose Ingestion on Indicies or Free Radical Production During Hypoxic Exercise. Free Rad Biol Med. 2002;33(Suppl 1):S269.
19. Teitelbaum JE, Johnson C, St Cyr J. The use of D-ribose in chronic fatigue syndrome and fibromyalgia: a pilot study. J Altern Complement Med. 2006;12(9):857-62.
20. Izawa S, Sugaya N, Ogawa N, et al. Episodic stress associated with writing a graduation thesis and free cortisol secretion after awakening. Int J Psychophysiol.2007 May;64(2):141-5.
21. Hiai S, Yokoyama H, Oura H, et al. Stimulation of pituitary-adrenocortical system by ginseng saponin. Endocrinol Jpn. 1979 Dec;26(6):661-5.
22. Radad K, Gille G, Liu L, et al. Use of ginseng in medicine with emphasis on neurodegenerative disorders. J Pharmacol Sci. 2006 Mar;100(3):175-86.
23. Asano K, Takahashi T, Miyashita M, et al. Effect of Eleutheroccocus senticosus Extract on Human Physical Working Capacity. Planta Med. 1986 Jun;52(3):175-7.
24. Kimura Y, Sumiyoshi M. Effects of various Eleutherococcus senticosus cortex on swimming time, natural killer activity and corticosterone level in forced swimming stressed mice. J Ethnopharmacol. 2004 Dec;95(2-3):447-53.
25. Fintelmann V, Gruenwald J. Efficacy and tolerability of a Rhodiola rosea extract in adults with physical and cognitive deficiencies. Adv Ther. 2007 Jul-Aug;24(4):929-39.
26. Ellis FR, Nasser S. A pilot study of vitamin B12 in the treatment of tiredness. Br J Nutr. 1973;30:277-83.
27. Mayer G, Kröger M, Meier-Ewert K. Effects of vitamin B12 on performance and circadian rhythm in normal subjects. Neuropsychopharmacology. 1996 Nov;15(5):456-64.
28. Paulose CS, Dakshinamurti K, Packer S, et al. Sympathetic stimulation and hypertension in the pyridoxine-deficient adult rat. Hypertension. 1988 Apr;11(4):387-91.