Key Terms Calorie Restriction (CR) A dietary regimen that reduces the caloric intake of an individual without resulting in malnutrition or a reduction in the intake of essential nutrients. NAD+/NADH Ratio A high NAD+/NADH ratio increases the stimulation of a variety of genes in the mitochondria and is associated with high energy production. CR and benaGene™ both increase the NAD+/ NADH ratio. What is Calorie Restriction? Increasing longevity (or life span) is often considered nothing more than the goal of fictional mad scientists and sorcerers. However, caloric restriction (CR) has been extensively studied over the last 70 years, with numerous
Acetyl-L-Carnitine (ALC) is the ester form of the amino acid, L-carnitine, and also the form capable of passing the blood-brain barrier to enter the central nervous system.1 It is quite a versatile nutrient as it acts on many different metabolic pathways within the body. Specifically, ALC helps to transport acetyl Coenzyme A into the cell mitochondria, a process necessary for fatty acid oxidation and cellular energy production within the Kreb’s cycle.1 It also stimulates protein and membrane phospholipid synthesis. Lastly, ALC enhances acetylcholine production, a neurotransmitter primarily used in muscle activation but also other nervous system functions such as memory.2Through these many pathways, ALC has been found useful in the treatment of Alzheimer’s Disease (AD) and other dementias. A recent 2012 study in Russia showed 3 grams of ALC to be safe and effective in the treatment of mild dementia caused by AD and vascular dementia (VD). This double-blind, placebo-controlled trial of 12-week duration, showed a 2.8 magnitude increase in cognitive function compared to placebo-treated patients, as determined by neuropsychological tests and cognitive assessment scales (such as the Mini-Mental State Exam [MMSE] ).3 It should be noted that the improvements in mild dementia were greater in those caused by AD as opposed to VD.3 A 2003 meta-analysis examined mild cognitive impairment or mild AD in a group of 21 ALC treated persons versus placebo groups. The study showed positive clinical and psychometric assessment scale results for ALC. In the majority of trials, 1.5-2 grams per day of ALC were studied and improvements were found as early as three months after supplementation began.4 One study specifically showed improvements in short-term memory, related tasks, and reaction time.5 Another study exhibited ALC’s ability to improve long-term memory performance after one full year of supplementation.6 Clearly, ALC has demonstrated a wide-range of applications on various markers of AD and cognitive impairment. ALC as a nutrient for preserving memory and cognition has also been studied in cases of hepatic encephalopathy (HE). HE is a common but serious complication in patients with liver cirrhosis that is accompanied by memory impairment, alterations in personality, poor concentration and impaired reaction times.7 A double-blind, placebo-controlled trial found that 2 grams of ALC, twice daily over three months, resulted in significant improvements in short-term memory and overall neuropsychological function.7 It seems that ALC is capable of enhancing brain function under many causative circumstances! Animal studies have supported these findings by showing that ALC increases synaptic neurotransmission in the hippocampus of the brain.8 In other words, ALC helps brain cells communicate more efficiently in the area responsible for memory and learning! Part of the mechanism responsible for this improvement was confirmed to be increased acetylcholine synthesis and nerve cell activation by this key neurotransmitter.8 These findings were supported by the direct observation that the rats exhibiting increased synaptic neurotransmission also showed improved learning capacity.8 As an added benefit to ALC’s use in memory and cognitive disorders, recent research in rat models has shown that ALC can be neuroprotective in cases of traumatic brain injury (TBI)9 (See page 18 for more information on TBI). Lastly, ALC has also been shown useful in treating depression in the elderly, peripheral nerve disorders, HIV infection, attention deficit-hyperactivity disorder, cardiovascular complications and male infertility.1 Ultimately, these applications confirm its ability to generally improve the health of the nervous system, mitochondria and overall cellular function.1
Phosphatidylserine (PS) is one of the major phospholipids found in the brain .10 Among other phospholipids, it is structurally responsible for making up the cell membrane and functionally responsible for triggering cell-to-cell communication by transfer of biochemical information into the cell.10 Overall, PS plays a crucial role in cellular function and the overall function of the central nervous system! Animal research has suggested that PS supports the growth of the brain by increasing the density of nerve growth factor receptors, normally found to decrease as we age.10 PS has also shown to positively affect specific neurotransmitters in the brain including: acetylcholine, norepinephrine, serotonin and dopamine.11 With these mechanisms in mind, it comes as no surprise that PS has shown positive clinical research in its application for improved cognitive function. In fact, more than a dozen studies have exhibited significant improvements in learning, memory, concentration, and recall .12 In one of the largest studies examining the possible role in treating Age-Associated Memory Impairment (AAMI), significant improvements were recorded. 494 elderly patients (aged 65-93) with moderate to severe cognitive decline (as measured by validated assessment tools, including the MMSE) were shown to benefit in areas of behavioral and cognitive performance with 300 mg per day of PS.13 The placebo group did not exhibit the benefits in learning and memory that the PS treatment group did after six months.13A double-blinded, placebo-controlled trial utilizing 300 mg per day of PS also showed significant enhancements in memory tests with AAMI after only three weeks of treatment.14 Specifically, improvements were seen in the treatment subjects’ abilities to remember names and faces, recall telephone numbers and remember the placement location of keys and glasses. After three months, PS improved memory by 30 percent compared to placebo.14 It should be noted that the greatest improvements in test scores were shown in those with the lowest cognitive function at baseline. In these individuals, three months of PS supplementation led to an average cognitive age score of 52 in those with an original average score of 64.14 As one would expect, PS has also shown promise in treating AD. Significant improvements in global cognitive function have been shown across the board, including activities of daily living, personal and non-personal memory, learning, motivation, socialization and information processing.15,16,17 Certain studies have shown that the greatest improvements are found in those AD patients with less severe cognitive decline.15,16,17The most effective method of supplementation is oral ingestion, as PS readily passes through the blood-brain barrier, a trait necessary for therapeutic effects on the nervous system.10 Also, there has been some controversy over the source of PS and the corresponding effectiveness of supplementation. PS can be sourced from either bovine cortex (BC-PS) or soybean (SB-PS) and some research has questioned the effectiveness of the vegetarian source.18However, a recent study confirmed that SB-PS is effective for memory and cognition, while also avoiding the theoretical risk for bovine spongiform encephalopathy from BS-PS and maintaining a sustainable source of PS.18 As a final note, PS has proven to also be beneficial for cognitive measures in cases of depression, ADHD and chronic stress10,18, and has demonstrated an extremely high safety profile.10 Most clinical studies examining the effects of PS on cognition and memory have dosed the nutrient at 200-400 mg per day. Therefore, given current evidence, 300 mg per day appears to be the best dosage for supporting memory related conditions.10
Citicoline is a known neuroprotective agent and an extremely important molecule necessary for the biosynthesis of phosphatidylcholine, a cell membrane phospholipid in the nervous system.21Levels of this crucial phospholipid can be depleted when the body needs to make more neurotransmitters (specifically acetylcholine), therefore compromising the integrity of the nerve cell membrane and overall nervous system.21 The good news is that citicoline can be taken as an oral supplement with fantastic bioavailability (almost all of the citicoline gets absorbed into the bloodstream and passes the blood-brain barrier).21 Like PS, citicoline improves the structure and functionality of nervous system cell membranes, yielding improvements in memory and other cognitive measures.Specifically, much of the clinical research on citicoline has been applied to stroke victims. Phosphatidylcholine synthesis appears to be impaired after brain ischemia,22 indicating that supplementation of citicoline may be necessary to drive this pathway. After suffering a stroke, patients are at twice the risk for developing dementia and can often be left with deficits in cognitive abilities.23 With this in mind, preventative measures to reduce this risk are extremely valuable. Alvarez-Sabin et al. found that 1000mg per day improved cognitive function at six and 12 months post-stroke (specifically in areas of attention, executive function and temporal orientation).23 Another analysis stated that initiating citicoline within 24 hours after the occurrence of a stroke “increases the probability of complete recovery at three months.”24 Most recently, researchers in Italy examined the effects of citicoline in those with mild vascular cognitive impairment and no diagnosis of AD. After nine months of taking 500mg per day, the treatment group (mean age of 79) did not show deterioration in mental function based on MMSE scores, whereas the control group showed significant declines.25These findings are quite significant because much of the research examining citicoline has not looked at its effects for such a long duration of time. Researchers in the Italian study concluded that the most pronounced benefits of citicoline on vascular cognitive impairment might be seen over an even greater duration of use.25Citicoline has also shown application as a memory aid without vascular causes, most likely through the enhancement of neurotransmitter synthesis in these circumstances. Animal studies in aging rats and young dogs have clearly shown its usefulness in enhancing memory and learning,26,27,28 while human clinical trials have supported these findings. A double-blind, randomized control trial found that 1000-2000mg of citicoline for up to 5 months duration led to improved verbal memory in individuals with “poorer-than-average memory.”29 This study built on the previous research showing that taking one gram per day of citicoline for six weeks enhanced global memory and, specifically, acquisition efficiency (the ability to acquire new memories) in those with mild-to-moderate memory loss.21 Finally, citicoline has also shown promising application in treating other conditions including Parkinson’s (due to its dopaminergic action),21 amnestic mild cognitive impairment,30 early-onset AD,31,32 spinal cord or brain injury33 and glaucoma.21 Please see the article titled “Traumatic Brain Injury” for more information on citicoline’s use in preserving cognitive function after physical trauma to the head.Overall, citicoline shows promise in treating memory deficits and cognitive decline due to a variety of causative factors, and also through a variety of mechanisms. A 2005 Cochrane Review looked at all of the data from published, double-blind, randomized human trials on citicoline and cognitive impairment at the time. It concluded that there was clear evidence of the benefits of citicoline on memory function and behavior.34 It is clear that anyone looking to support their brain and nervous system function should consider the benefits of citicoline supplementation quite seriously.
1. Acetyl-L-Carnitine Monograph. Alternative Medicine Review 2010; 15(1):76-83
2. Michael E Hasselmo. The role of acetylcholine in learning and memory. Curr Opin Neurobiol. 2006 December; 16(6): 710–715.
3. Gavrilova SI, Kalyn IaB, Kolykhalov IV et al. Acetyl-L-carnitine (carnicetine) in the treatment of early stages of Alzheimer’s disease and vascular dementia. Zh Nevrol Psikhiatr Im S S Korsakova. 2011;111(9):16-22.
4. Montgomery SA, Thal LJ, Amreim R. Meta-analysis of double blind randomized controlled clinical trials of acteyl-l-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol 2003; 18:61-71
5. Rai G, Wright G, Scott L, et al. Double-blind, placebo controlled study of acetyl-L-carnitine in patient’s with Alzheimer’s dementia. Curr Med Res Opin 1990; 11:638-647
6. Spagnoli A, Lucca U, Menasce G, et al. Long-term acetyl-L-carnitine treatment in Alzheimer’s disease. Neurology. 1991; 41:1726-1732
7. Malaguarnera M, Gargante MP, Cristaldi E, et al. Acetyl-L-Carnitine treatment in minimal hepatic encephalopathy. Dig Dis Sci 2008; 53:3018-3025
8. Kobayashi S, Iwamoto M, Kon K, et al. Acetyl-L-carnitine improves aged brain function. Geriatr Gerontol Int. 2010 Jul;10 Suppl 1:S99-106
9. Scafidi S, Racz J, Hazelton J, et al. Neuroprotection by acetyl-L-carnitine after traumatic injury to the immature rat brain. Dev Neurosci. 2010;32(5-6):480-7.
10. Phosphatidylserine Monograph. Alt Med Review 2008; 13(3):245-247
11. Richter Y, Herzog Y, Cohen T, et al. The effect of phosphatidylserine-containing omega-3 fatty acids on memory abilities in subjects with subjective memory complaints: a pilot study. Clinical Interventions in Aging 2010; 5:313-316
12. Kidd PM. Phosphatidylserine; membrane nutrient for memory. A clinical and mechanistic assessment. Altern Med Rev 1996;1:70-84.
13. Cenacchi T, Bertoldin T, Farina C, et al. Cognitive decline in the elderly: a double-blind, placebo-controlled multicenter study on efficacy of phosphatidylserine administration. Aging (Milano) 1993;5:123-133
14. Crook TH, Tinklenberg J, Yesavage J, et al. Effects of phosphatidylserine in age-associated memory impairment. Neurology 1991;41:644-649
15. Crook T, Petrie W, Wells C, et al. Effects of phosphatidylserine in Alzheimer’s disease. Psychopharmacol Bull 1992;28:61-66.
16. Amaducci L. Phosphatidylserine in the treatment of Alzheimer’s disease: results of a multicenter study. Psychopharmacol Bull 1988;24:130-134.
17. Klinkhammer P, Szelies B, Heiss WD. Effect of phosphatidylserine on cerebral glucose metabolism in Alzheimer’s disease. Dementia 1990;1:197-201.
18. Kato-Kataoka A, Sakai M, Ebina R, et al. Soybean Derived Phosphatidylserine Improves Memory Function of the Elderly Japanese Subjects with Memory Complaints. J. Clin. Biochem. Nutr. 2010; 47:246–255
19. Baumeister J, Barthel T, Geiss KR, et al. Influence of phosphatidylserine on cognitive performance and cortical activity after induced stress. Nutritional Neuroscience. 2008; 11(3):103-110
20. Vakhapova V, Richter Y, Cohen T, et al. Safety of phosphatidylserine containing omega-3 fatty acids in non-demented elderly: a doubleblind placebo-controlled trial followed by an open-label extension. BMC Neurology 2011, 11:79-80
21. Citicoline Monograph. Alt Med Review 2008; 13(1):50-57
22. Adibhatla RM, Hatcher JF, Dempsey RJ. Cytidine-5’-disphosphocholine affects CTP-phosphocholine cytidylyltransferase and lyso-phosphatidylcholine after transient brain ischemia. J Neurosci Res 2004;76:390-396
23. Alvarez-Sabín J, Ortega G, Jacas C, et al. Long-term treatment with citicoline may improve poststroke vascular cognitive impairment. Cerebrovasc Dis. 2013;35(2):146-54.
24. Davalos A, Castillo J, Alvarez-Sabin J, et al. Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials. Stroke 2002;33:2850-2857.
25. Cotroneo AM, Catsagna A, Putignano S, et al. Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study. Clinical Investigation in Aging 2013; 8:131-137
26. Bruhwyler J, Liegeois JF, Geczy J. Facilitatory effects of chronically administered citicoline on learning and memory processes in the dog. Prog Neuropsychopharmacol Biol Psychiatry 1998;22:115-128.
27. Drago F, Mauceri F, Nardo L, et al. Effects of cytidine-diphosphocholine on acetylcholine-mediated behaviors in the rat. Brain Res Bull 1993;31:485-489.
28. Petkov VD, Kehayov RA, Mosharrof AH, et al. Effects of cytidine diphosphate choline on rats with memory deficits. Arzneimittelforschung 1993;43:822- 828.
29. Spiers PA, Myers M, Hochanadel GS, et al. Citicoline improves verbal memory in aging. Arch Neurol 1996; 53:441-448
30. Gavrilova SI, Fedorova IaB, Gantman, Kalyn IaB et al. [Ceraxon (citicoline) in the treatment of the mild cognitive impairment syndrome]. [Article in Russian] Zh Nevrol Psikhiatr Im S S Korsakova. 2011;111 (12):16-20.
31. Caamano J and Gomez MJ. Effects of CDP-choline on cognition and cerebral hemodynamics in patients with Alzheimer’s disease. Methods Find Exp Clin Pharmacol 1994;16:211-218.
32. Alvarez XA, Sampedro C, Lozano R, et al.Citicoline protects hippocampal neurons against apoptosis induced by brain beta-amyloid deposits plus cerebral hypoperfusion in rats. Methods Find Exp Clin Pharmacol 1999;21:535-540.
33. Leon-Carrion J, Dominguez-Roldan JM, Murillo-Cabezas F, et al. The role of citicoline in neuropsychological training after traumatic brain injury. NeuroRehabilitation 2000;14:33-40
34. Fioravanti M and Yanagi M. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD000269