Metabolic Agents that Enhance ATP can Improve Cognitive Functioning: A Review of the Evidence for Glucose, Oxygen, Pyruvate, Creatine, and l-Carnitine

Abstract

Over the past four or five decades, there has been increasing interest in the neurochemical regulation of cognition. This field received considerable attention in the 1980s, with the identification of possible cognition enhancing agents or “smart drugs”. Even though many of the optimistic claims for some agents have proven premature, evidence suggests that several metabolic agents may prove to be effective in improving and preserving cognitive performance and may lead to better cognitive aging through the lifespan. Aging is characterized by a progressive deterioration in physiological functions and metabolic processes. There are a number of agents with the potential to improve metabolic activity. Research is now beginning to identify these various agents and delineate their potential usefulness for improving cognition in health and disease. This review provides a brief overview of the metabolic agents glucose, oxygen, pyruvate, creatine, and L-carnitine and their beneficial effects on cognitive function. These agents are directly responsible for generating ATP (adenosine triphosphate) the main cellular currency of energy. The brain is the most metabolically active organ in the body and as such is particularly vulnerable to disruption of energy resources. Therefore interventions that sustain adenosine triphosphate (ATP) levels may have importance for improving neuronal dysfunction and loss. Moreover, recently, it has been observed that environmental conditions and diet can affect transgenerational gene expression via epigenetic mechanisms. Metabolic agents might play a role in regulation of nutritional epigenetic effects. In summary, the reviewed metabolic agents represent a promising strategy for improving cognitive function and possibly slowing or preventing cognitive decline.

Effect of L-carnitine Supplementation on Nutritional Status and Physical Performance Under Calorie Restriction

“…It is also a glycogen sensor and may be inhibited by glycogen [44]. L-carnitine is responsible for generating ATP and glycogen [45]. In agreement with this, lowered AMPK activity of CR ?…”

Elevated [Ca2+]i Levels Occur with Decreased Calpain Activity in Aged Fibroblasts and Their Reversal by Energy-Rich Compounds: New Paradigm for Alzheimer's Disease Prevention

“…In this context, the energy and Ca 2+ -signal activating effects of the energy-rich compounds, together with their neuroprotective roles reported by us [29] and by other investigators [32,33,54,64], raise the possibility that these compounds, and many other asyet-unidentified bioenergy-boosting substances, may strengthen and protect the aging brain cells. This strategy, if combined with other neuroprotective agents (such as antioxidants and metabolic stimulators), especially enhanced by targeting the modifiable risk factors in late life, will extend the lifespan of the aging brain cells to catch up with the demographic changes, the ultimate cause for rapid increase of sporadic AD today.…”

“…5) is the common driving force for the observed effects [54]. Furthermore, the intimate relationship between bioenergetics and Ca 2+ signaling may help explain why Ca 2+ and calpain both play vital roles in cognition [21,22], a highly energy-dependent process [54,55].…”

Functional Expression of Organic Cation/carnitine Transporter 2 (OCTN2/SLC22A5) in Human Brain Capillary Endothelial Cell Line hCMEC/D3, a Human Blood-brain Barrier Model

“…11,12) Because of the physiological roles of these compounds in the cholinergic neurons, the effects of Lcarnitine and its metabolites on the central nervous system (CNS) have attracted increasing attention. 13) Indeed, it has also been shown that L-carnitine and acetyl-L-carnitine are relevant to the pathology of Alzheimer's disease. Although OCTN2 in the rodent BBB has been reported to transport L-carnitine and acetyl-Lcarnitine, 14) our knowledge of OCTN2 function at the human BBB remains incomplete.…”