Metabolic Agents and Cognitive Function

There are a number of agents which are believed to impact on metabolic functions which may ultimately impact on neuronal cell survival and cognitive function. Aging is characterized by a progressive deterioration in physiological functions and metabolic processes. Regimes that buffer intracellular energy levels may impede the progression of the neurodegenerative process. This post focuses on some of the metabolic agents that may prove to be effective in combating neurodegeneration and lead to better cognitive aging through the life span. The metabolic agents specifically focused on in this post are glucose and oxygen, pyruvate, creatine, and L-carnitine. Each of these agents is directly responsible for generating adenosine triphosphate (ATP), the molecular unit of currency of intracellular energy transfer. Their roles as cognitive agents are explored.

During normal aging neuronal cell injury and death are accelerated and lead to region-specific brain shrinkage. In brain regions particularly important for the formation of memories and decision making, for example, the hippocampus and the prefrontal white matter, shrinkage increases with age (Raz et al. 2005). Reduction in the total number of viable cells may lead to an accelerated decline in brain functioning. A likely cause of reduced neuronal cell number is impaired energy metabolism. Impeded energy metabolism may trigger pro-apoptotic signaling (programmed cell death), oxidative damage, and excitotoxicity and impede mitochondrial DNA repair (Klein and Ferrante 2007). These processes can interact and potentiate one another, which in turn results in a continuation of energy depletion. Reduced energy levels threaten cellular homeostasis and integrity. The brain is the most metabolically active organ in the body and as such is particularly vulnerable to disruption of energy resources. In addition, because of the high levels of oxygen metabolism in brain tissue, mitochondria are highly susceptible to oxidative stress (Chinnery et al. 2006). Therefore interventions that improve mitochondrial function by sustaining ATP levels may have direct and indirect importance for improving neuronal dysfunction and loss.

Regimes that buffer intracellular energy levels may significantly impede the progression of neurodegenerative diseases and disorders. Metabolic function may be improved in a variety of ways, either by improving the availability of substrates necessary for energy production or by improving the transport and effectiveness of cells involved in the metabolic process, for example, by improving mitochondrial transport and respiration. Many of these agents have multifaceted mechanisms of action and may lead to numerous cascades of biological events. It is beyond the scope of this post to review all of the possible nutritional contributors to optimal metabolic function; therefore, this post will focus on the agents which have a central action of improving availability of energy. These agents are listed next as “energy enhancers.”

The principal source of energy for brain function is derived from the oxidative breakdown of glucose. The human brain is an extremely metabolically active organ accounting for approximately 30% of the total basal energy expenditure. The brain remains metabolically active at all times, including sleep, and is thus entirely dependent on continuous and uninterrupted supply of energy in the form of the substrates glucose and oxygen. Compared to other organs in the body, the brain is particularly vulnerable to small and transient changes in its energy supply. Interrupted delivery leads within seconds to unconsciousness and within minutes may cause irreparable brain damage. Thus, the concentration of glucose in the blood plasma is tightly regulated to stay within the normal range of 60–90 mg/100 mL for humans. When blood glucose drops below 40 mg/100 mL (hypoglycemic condition) in humans, it can cause discomfort, confusion, coma, convulsions, or even death (Lehninger et al. 2005). Beyond infancy, and under normal conditions, the brain’s energy requirements are met almost exclusively by the oxidative breakdown of glucose. During times of hypoglycemia other tissues will cease to utilize glucose all together in order to increase glucose availability to the brain (Thomson 1967). Compared with other organs the brain possesses paradoxically limited stores of glycogen, which without replenishment are exhausted in up to 10 min. There is, however, no storage capacity for oxygen; thus, disruption leads to instantaneous effects. Associated measurements of oxygen and glucose levels in blood sampled upon entering and leaving the brain in humans show that almost all the oxygen utilized by the brain can be accounted for by the oxidative metabolism of glucose (McIlwain 1959). Since the brain is clearly susceptible to small changes in energy supply, metabolic activity is limited by glucose and oxygen resources.

A few early studies demonstrated the effects of glucose on cognition around the 1950s. For example, administration of 10 g of glucose to school children every 45 min throughout a morning demonstrated improved mathematical ability and generally improved concentration (Hafermann 1955). However, a more widespread interest in glucose did not occur until the 1980s when the glucose effect was reevaluated by psychopharmacologists examining possible mechanisms of action for neuroendocrine facilitation of memory. Since then there have been increasing reports that cognitive functioning is influenced by the increased availability of glucose provision. Many reports have illustrated the robust association between changes in blood glucose levels and cognition in animals (Gold 1986; Wenk 1989; White 1991), the elderly (Gonder-Frederick et al. 1987; Craft et al. 1992, 1994), and the young (Benton and Sargent 1992; Benton and Owens 1993; Sünram-Lea et al. 2001, 2002a,b, 2004; Riby et al. 2008; Scholey et al. 2009). Thus, the cognition-enhancing action of glucose is well established. In terms of dosing the most optimal glucose dose for cognitive enhancement generally appears to follow the classic Yerkes–Dodson inverted-U dose–response profile (Sunram-Lea et al. 2011). For young adults 25 g seems to most reliably facilitate cognitive performance; however, there is some contention regarding whether the dose–response profile may be dependent upon the cognitive domain being assessed. In rats bimodal response variability was observed when different tasks were used which represented the action of glucose on two different brain substrates: the caudate nucleus and the hippocampus (Packard and White 1990). In humans the inverted-U dose–response profile has been specifically observed for tasks of verbal declarative memory, where other tasks (specifically spatial and numeric working memory) demonstrated slightly different response profiles (cubic and quartic respectively) (Sunram-Lea et al. 2011).

The clearest enhancement effects of increased glucose supply have been observed for declarative memory tasks in the form of word and paragraph recall; for a review see Hoyland et al. (2008). These findings have led to the notion that glucose facilitation may be particularly pronounced in tasks which pertain to the hippocampal formation (Sünram-Lea et al. 2001). Furthermore several studies have shown that an important mediating factor for cognitive enhancement by increased energy resources is level of task demands. That is, tasks which are more demanding appear to be more sensitive to the effect of glucose (Kennedy and Scholey 2000; Scholey et al. 2001; Sünram-Lea et al. 2002a). It has also been demonstrated that tasks which are more demanding lead to a significantly accelerated reduction in blood glucose levels compared with a semantically matched task (Scholey et al. 2001). However recent research has shown that at high dosages (60 g) implicit memory which is not regarded as either demanding nor hippocampally mediated may also be enhanced by glucose (Owen et al. 2010), adding further support to the notion that different domains of memory may follow different glucose dose–response profiles.

It is widely acknowledged that oxygen restriction and ischemic deprivation exert marked effects on cognitive function (Volpe and Hirst 1983). Furthermore restriction of oxygen supply due to altitude results in cognitive impairment on a number of cognitive parameters with these effects being instantaneously reversed by the administration of oxygen (Crowley et al. 1992). Evidence suggests that even small fluctuations in cerebral oxygen delivery within normal physiological limits may impact on cognitive performance (Walker and Sandman 1979). While cognitive deficits from oxygen restriction due to altitude (Crowley et al. 1992), carbon monoxide poisoning (Weaver et al. 2002), and isovolemic anemia (Weiskopf et al. 2002) can all be reversed by oxygen administration, impairment effects may be permanent if treatment is not administered in time. Similarly cognitive degeneration due to age is not reversed by oxygen treatment when administered either normobaric or hypobaric oxygen treatment (Raskin et al. 1978). There is very limited research of oxygen administration on cognition in normal healthy individuals. Early research examining the effects of hyperbaric oxygen supplementation demonstrated improved cognitive function (short-term memory and visual organization) in elderly outpatients com-pared to baseline performance. However this study failed to compare with a control group (Edwards and Hart 1974).

In normal healthy humans research has demonstrated that oxygen administra-tion can improve cognitive functioning compared to air-breathing control conditions. Research has shown that oxygen administration leads to improved long-term memory and reaction times compared to a control group of normal air-breathing (Moss and Scholey 1996; Moss et al. 1998; Scholey et al. 1998). Furthermore, similar to glucose facilitation, oxygen administration appears to facilitate cognition most effectively for tasks with a higher cognitive load (Moss et al. 1998; Scholey et al. 1998). In addition to this finding a further study also examined heart rate during cognitive testing with oxygen versus air-breathing controls. Compared to baseline, heart rate was significantly elevated during cognitive testing tasks in both the air and oxygen groups. In the oxygen group, significant correlations were found between changes in oxygen saturation and cognitive performance. In the air group, greater changes in heart rate were associated with improved cognitive performance (Scholey et al. 1999). These findings suggest that during times of cognitive demand avail-ability of metabolic resources impact on cognitive functioning.

A more recent study has further demonstrated the importance of metabolic resources during cognitive demand by manipulating level of cognitive demand during oxygen administration. In this study oxygen administration of 40% versus 21% was examined during completion of an addition task with three levels of difficulty. It was observed that 40% oxygen improved accuracy scores across the task compared to the 21% oxygen dose, with the difference in accuracy rate increasing between the two dosages as the task difficulty level increased (Chung et al. 2008). While cognitive demand is clearly a moderating factor for cognitive enhancement by oxygen, enhancement has been observed on several cognitive domains; for example, oxygen supplementation has been shown to improve everyday memory tasks such as memory for shopping lists and putting names to faces when participants received 100% oxygen compared with air-breathing controls (Winder and Borrill 1998). The dose–response for oxygen administration on performance appears to follow the Yerkes–Dodson inverted-U shape in a similar fashion to glucose facilitation with shorter doses of 30 s to 3 min appearing to be most beneficial while continuous oxygen breathing for longer than 10 min leading to decline in performance (Moss et al. 1998). The window for cognitive improvement through oxygen administration therefore appears to be quite brief, with research demonstrating that administration of oxygen increases blood oxygen levels for only 4–5 min (Moss et al. 1998).

Neuronal cell death resulting from hypoglycemia and hypoxia is the result of a series of events triggered by reduced energy availability, and the normalization of blood glucose and oxygen levels does not necessarily block or reverse this cell death process once it has begun. During times of low availability of glucose and oxygen the brain utilizes other, less efficient energy sources that can be produced aerobically. Pyruvate is the end product of glycolysis, which is converted into acetyl coenzyme A that enters the Krebs cycle when there is sufficient oxygen available. When the oxygen is insufficient, pyruvate is broken down anaerobically, creating lactate in humans and animals. Lactate has recently been considered as a central neuroprotective agent (Gladden 2004). The blood-brain barrier normally transports pyruvate at a rate much slower than glucose, but prior work suggests that significant pyruvate entry to the brain can be achieved by elevating plasma pyruvate concentrations (Lee et al. 2001).

During pathological insult or general aging, the main upstream event most responsible for neuronal cell death is excitotoxicity from glutamate receptor activity (Wieloch 1985). Recent research has shown that cells that would otherwise go on to die after the cascade of excitotoxic activity could be rescued by providing pyruvate (Ying et al. 2002).

However, there is remarkably little research evaluating the effects of pyruvate on cognitive function. One recent study assessed the effect of pyruvate administration in rats with hypoglycemia-induced brain injury. Insulin was used to induce hypoglycemia then hypoglycemia was terminated with either glucose alone or with glucose plus pyruvate. They found that in the four brain regions studied (CA1, subiculum, dentate gyrus of the hippocampus, and piriform cortex) the addition of pyruvate reduced neuron death by 70%–90%. Neuron survival was also observed when pyruvate delivery was delayed for up to 3 h. The improved neuron survival was accompanied by a sustained improvement in cognitive function as assessed by the Morris water maze (Suh et al. 2005).

Furthermore recent animal research has demonstrated the potential usefulness of ethyl pyruvate as a stroke therapy. Yu et al. (2005) found that ethyl pyruvate affords the strong protection of delayed cerebral ischemic injury with significant reduction in infarct volume accompanied by the suppression of the clinical manifestations associated with cerebral ischemia, including motor impairment and neurological deficits.

There are, as yet, no studies evaluating the effects of pyruvate administration on cognitive function in humans; however, pyruvate may be a good candidate for further research in those with energetic depletion and neurodegenerative diseases. Impaired energy metabolism is an early, predominant feature in Alzheimer’s disease and it is believed that impaired cerebral oxidative glucose metabolism is responsible, at least in part, for cognitive impairment in AD. Research has demonstrated that in both animals and humans increased cerebrospinal pyruvate is a biomarker for AD (Parnetti et al. 1995; Pugliese et al. 2005). Since pyruvate appears to be quite safe, aside from mild side effects, such as occasional stomach upset and diarrhea, pyruvate therapy might represent an excellent candidate for therapy in disease states accompanied by energy depletion.

Creatine (Cr) is a naturally occurring substance found in vertebrates and is essential for maintaining energy homeostasis. Cr participates in metabolic reactions within cells and eventually is catabolized in the muscles creating creatinine, which is then excreted by the kidney in urine. In the average-sized adult (70 kg) Cr store is approximately 120 g, with the daily turnover of Cr to creatinine being estimated to be about 1.6% of the body’s total Cr (Balsom et al. 1995). The daily requirement of Cr either through diet or endogenous synthesis is suggested to be approximately 2 g/day (Walker 1979).

Since Cr is concentrated in muscle tissue dietary sources of Cr are fish and red meat, with a much lower concentration found in some plants (Balsom et al. 1995). Unsurprisingly Cr levels of vegetarian or vegan individuals are much lower than omnivores. In a typical omnivorous diet between 0.25 and 1 g of Cr per day is obtained. It appears that Cr derived from the diet, after passing through the intestinal lumen, enters the bloodstream intact (Conway and Clark 1996).

Cr is stored in the high-energy form of phosphocreatine (PCr). PCr acts as a high-energy reserve in a coupled reaction in which energy derived from donating a phosphate group is used to regenerate the compound ATP. PCr plays a particularly

important role in tissues that have high, fluctuating energy demands such as muscle and brain. During times of brain activity, brain phospocreatine decrease rapidly in order to maintain constant ATP levels (Sappey-Marinier et al. 1992; Rango et al. 1997). Cr supplementation has pronounced effects on the body including increased muscle mass and improvements in physical performance on exercise tasks (Kreider 2003). Furthermore Cr supplementation can increase brain Cr. Studies using nuclear magnetic resonance spectroscopy have demonstrated that Cr and PCr can be increased in the brains of healthy adults by Cr supplementation (Dechent et al. 1999; Lyoo et al. 2003).

The majority of previous research examining the effects of Cr has focused on muscle mass, body mass index, and physical performance; however, more recently attention has been directed toward Cr’s effects on the brain and the metabolic changes therein.

Animal research has shown that Cr is particularly important for normal brain development and function. In its absence deleterious effects on cognition and brain development are observed, in abundance evidence for neuroprotection has been observed. For example, deletion of cytosolic brain-type creatine kinase in mice has been shown to result in slower learning of a spatial task and diminished open-field habituation as well as increased intra- and infra-pyramidal hippocampal mossy fiber area suggesting that the creatine–creatine kinase network is involved in brain plasticity in addition to metabolism (Jost et al. 2002).

Animal research has demonstrated that Cr affords significant neuroprotection against ischemic and oxidative insults (Holtzman et al. 1998; Wilken et al. 1998; Balestrino et al. 1999). One experiment investigated the possible effect of Cr dietary supplementation on brain tissue damage after experimental traumatic brain injury. Results demonstrated that chronic administration of Cr ameliorated the extent of cortical damage by as much as 36% in mice and 50% in rats. The authors suggested that protection is mediated by Cr-induced maintenance of mitochondrial bioenergetics as they observed that mitochondrial membrane potential was significantly increased, intra-mitochondrial levels of reactive oxygen species and calcium were significantly decreased, and ATP levels were maintained. Induction of mitochondrial permeability transition was significantly inhibited in animals fed Cr. The authors further suggested that Cr may be a good candidate as a neuroprotective agent against acute and delayed neurodegenerative processes (Sullivan et al. 2000).

In rodents where neurodegenerative symptoms are induced, Cr attenuated these deficits, for example, rats administered 3-nitropropionic acid (3NP) displayed neuropathological and behavioral abnormalities that are analogous to those observed in Huntington’s disease (HD). Rats fed diets containing 1% Cr over an 8 week period showed attenuation of 3NP-induced striatal lesions, striatal atrophy, ventricular enlargement, cognitive deficits, and motor abnormalities on a balance beam task compared to non-Cr supplemented rats. These findings indicate that Cr provides significant protection against neuropathological insult specifically associated with 3NP-induced behavioral and neuropathological abnormalities (Shear et al. 2000).

Clearly Cr plays a fundamental role in brain protection and development in the ani-mal model. Specifically deleterious effects were observed on cognition and brain development when Cr is absent (and/or PCr and creatine kinases), and the neuroprotective attributes of Cr in supplemented animals. These data provide a strong rationale for examination of Cr supplementation on the brain and cognition in the human model.

Despite the obvious impact Cr has on brain development and metabolic actions in the brain, there are relatively few studies assessing the effects of Cr on cognitive performance in humans. One study assessed the effect of 20 g Cr supplementation over 7 days in sleep-deprived individuals, following 24 h sleep deprivation. Individuals who received Cr supplementation demonstrated significantly reduced decrement in performance on a number of mood, cognitive, and physical performance parameters including random movement generation, choice reaction time, balance, and mood state (McMorris et al. 2006). In a further study following 36 h sleep deprivation, Cr-supplemented individuals also demonstrated improved performance on a random number generation task (McMorris et al. 2007b). These studies appear to demonstrate benefits of Cr supplementation in young individuals who are temporarily cognitively impaired through sleep deprivation. However, these studies were considerably underpowered having no higher than 10 participants per group. Cr supplementation has also been demonstrated to improve cognition in individuals who are not cognitively impaired. One study assessed the effects of 8 g Cr per day for 5 days in healthy individuals and demonstrated reduced mental fatigue when subjects repeatedly perform a simple mathematical calculation. After Cr supplementation, task-evoked increase of cerebral oxygenated hemoglobin in the brains of subjects and reduced cerebral oxygenated hemoglobin (measured by near-infrared spectroscopy) was significantly reduced, which is compatible with increased oxygen utilization in the brain (Watanabe et al. 2002). Again, however, this study appeared to be rather underpowered with only 12 participants per group. Nonetheless, it appears that Cr supplementation may impact on cognitive function even over a relatively short period of time as these studies assessed the effects of acute supplementation over periods of 5–7 days. A more recent study assessed the impact of a new form of creatine, creatine ethyl ester, over a 2 week period (5 g/day dose compared to dextrose control group) in healthy 18–24 year old participants. The overall findings demonstrated consistent improvements for reaction time across a range of measures as well as improved accuracy on some and also improved IQ scores. The most mod-est improvements appeared to be on tasks that were less demanding, indicating that creatine supplementation may be particularly useful when performing particularly demanding or complex cognitive tasks (Ling et al. 2009).

In chronic administration conditions, one study examining Cr supplementation in young healthy adults failed to observe any effect of Cr on cognitive performance (Rawson et al. 2008). In this study 0.03 g/kg was administered daily for 6 weeks and a battery of neurocognitive tests was administered to asses cognitive processing and psychomotor performance including simple reaction time, code substitution, code substitution delayed, logical reasoning symbolic, mathematical processing, running memory, and Sternberg memory recall. No effect of Cr was observed on any of these outcome measures.

However, research examining young adults who only produce Cr endogenously (vegetarian sample), Cr supplementation was shown to improve cognitive performance following chronic administration (6 week period) (Rae et al. 2003). In this work, 5 g Cr supplementation (Cr monohydrate) was administered per day for 6 weeks

to 45 young vegetarian adults in a counterbalanced cross-over design. They observed that Cr supplementation had a significant positive effect on both working memory (backward digit span) and intelligence (Raven’s Advanced Progressive Matrices).

The pattern emerging from the present literature examining Cr and cognitive function appears to demonstrate that cognition is ameliorated specifically during times of metabolic impairment or depletion, either through low creatine availability (vegan and vegetarian samples) or by inducement (sleep deprivation or high cognitive demand). Furthermore, since there is some evidence that creatine supplementation improves cognitive function in young, non-vegetarian, healthy individuals over shorter periods of administration (5 days to 2 weeks) but not longer periods (6 weeks) it may be the case that creatine supplementation might merely have been redressing nutritional imbalances.

Since elderly populations are generally metabolically impaired and often nutritionally deficient, it seems likely that elderly and degenerative populations would most benefit from creatine interventions over time. To our knowledge only one study has assessed the impact of Cr supplementation in an elderly human population. McMorris et al. (2007a) administered 20 g of Cr per day for 7 days which resulted in improved performance of random number generation, forward and backward number and spatial recall, and long-term memory tasks but no effect on backward recall performance (McMorris et al. 2007b). In terms of neurodegeneration, there has been no research examining the effects of creatine supplementation in dementia sufferers; however, there appears to be some differences in creatine levels in those with genetic risk of developing dementia (apolipoprotein E4 carriers). Laakso et al. (2003) demonstrated that compared with the noncarriers, the levels of creatine were significantly lower in the E4 carriers. This finding may suggest increased metabolic demands in the brain of the E4 carriers. They also observed that the levels of creatine also correlated significantly with age and performance on the Mini-Mental State Examination test in the E4 carriers, but not in the noncarriers (Laakso et al. 2003). Creatine supplementation in this sample seems like a logical next step for creatine and cognitive function research.

Despite the obvious potential benefits of Cr supplementation, there is considerable lack of research examining the cognitively enhancing capabilities of Cr and a number of questions remain to be answered. Firstly there has been no research examining whether an acute administration of one single dose of Cr can affect cognitive performance. Secondly the only study to examine the effects of Cr on cognition in the elderly was only over a period of 7 days. Further to this there has been no examination of the usefulness of creatine in dementia research where there appears to be some evidence that creatine may be of particular therapeutic value. Since the evidence seems to suggest that Cr acts to buffer intracellular energy levels and potentially impede the progression of neurodegenerative processes a more systematic evaluation of Cr mapping cognitive performance over a more substantial timeframe is required.

CARNITINE/ACETYL-L-CARNITINE

In animals and humans, carnitine is biosynthesized primarily in the liver and kid-neys from the amino acids lysine or methionine (Steiber et al. 2004) with Vitamin C (ascorbic acid) being essential to the synthesis of carnitine. In food, the highest concentrations of carnitine are found in red meat and dairy products. Other natural sources of carnitine include nuts and seeds, legumes or pulses, vegetables, and cereals. Carnitine is a quaternary ammonium compound that, in living cells, is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids (or fats) for the generation of metabolic energy. Carnitine exists in two stereoisomers: its biologically active form is L-carnitine, while its enantiomer, D-carnitine, is biologically inactive (Liedtke et al. 1982). Carnitine transports long-chain acyl groups from fatty acids into the mitochondrial matrix, so that they can be broken down through 0-oxidation to acetate to obtain usable energy via the citric acid cycle. Under normal nutritional conditions and in healthy persons, L-carnitine availability is not a limiting step in 0-oxidation; however, L-carnitine is required for mitochondrial long-chain fatty acid oxidation (Simon 2005), which is a main source of energy during exercise (Wasserman and Whipp 1975). Furthermore increase in L-carnitine content might increase the rate of fatty acid oxidation, permitting a reduction of glucose utilization, preserving muscle glycogen content, and ensuring maximal rates of oxidative ATP production. In one study L-carnitine improved glucose disposal among 15 patients with type II diabetes and 20 healthy volunteers (Mingrone et al. 1999). Glucose storage increased between both groups and glucose oxidation increased in the diabetic group. Furthermore glucose uptake increased by approximately 8% for both diabetic and non-diabetic groups.

In neuronal cells, the L-carnitine shuttle mediates translocation of the acetyl moiety from mitochondria into the cytosol and contributes to the synthesis of acetylcholine and of acetylcarnitine (Imperato et al. 1989; Nalecz and Nalecz). The neurobiological effects of acetyl carnitine include modulation of brain energy and phospholipids metabolism, cellular macromolecules (such as neurotrophic factors and neurohormones), synaptic morphology, and synaptic transmission of multiple neurotransmitters (see review [Furlong 1996]).

The majority of research assessing the effects of L-carnitine or acetyl-L-carnitine (acetylated derivative of L-carnitine with improved bioavailability) has focused on its benefits to elderly and demented populations. It has been established that acetyl L-carnitine transverses the blood brain-barrier efficiently. With CSF concentrations increasing sufficiently via both intravenous and oral rout in patients with severe dementia (Parnetti et al. 1992). In terms of efficacy, a meta-analysis examining the effects of acetyl-L-carnitine in mild cognitive impairment and mild (early) Alzheimer’s disease was conducted (Montgomery et al. 2003). Studies included in the analysis were at least 3 months in duration, with a dosage of 1.5–3.0 g/day. The results showed beneficial effects on both clinical scales and psychometric tests with improvements being observed at the first assessment (3 months) and increasing over time.

In a more recent study, the effects of 2 g of L-carnitine per day for 6 weeks were assessed in centenarians aged between 100 and 106 (Malaguarnera et al. 2007). Those treated with L-carnitine demonstrated significant physiological improvements in fat mass, muscle mass, plasma total carnitine, and plasma long- and short-chain acetylcarnitine. They also showed significantly improved mental fatigue and cognitive function assessed by the Mini-Mental State Examination (MMSE).

There are, as yet, no studies examining the effect of L-carnitine or acetyl-L-carnitine on cognitive function in young human populations. Since the action of L-carnitine avail-ability is not a limiting step in 0-oxidation, any beneficial effects are most likely to be observed in populations with depleted energy resources or under physically fatigued conditions. Therefore, the utility of L-carnitine/acetyl-L-carnitine may be more pronounced in age and degenerative disease.