Oxidative Stress and Cognitive Longevity Oxidative Stress and

Oxidative Stress and Cognitive Longevity

Oxidative Stress and Cognitive Longevity “The New Brain Paradigm” § The human brain is continually remolding / rewiring itself based on “ENVIRONMENT” § DRIVEN BY: § 1) Diet, 2) Nutrition, 3) Exercise, 4) Thoughts § …. Key Nutrients Are Building Blocks for Neurotransmitter Function § …. Key Nutrients Reduce Oxidative Stress…. Slow brain aging…. Improve brain function…. § …. Nerve Growth Factor (NGF). . . depressive symptoms § …. Cholinergic Neurotransmission: Ghrelin “hunger hormone”

Oxidative Stress and Cognitive Longevity A large percentage of the United States population suffers with nutritional deficiencies and/or chronic sub-optimal nutritional intakes: § At least one-third consume below the recommended amounts of Vitamin B 3, Vitamin B 2, vitamin B 1, and vitamin C. 3, 7 § 75% of all women significantly under -consume magnesium. 4, 17 § 50 -71% of all men, and 70 -90% of all women under-consume Vitamin B 6. 2, 3, 7, 13 START WITH THE FUNDAMENTALS

Neurotransmitters: The Mental Messengers Effects of Vitamin B 6 Deficiency: 26 -36 • Fatigue • Nervousness, Anxiety • Depression, Irritability, Mood swings • Poor memory • Poor response or adaptation to stress • 50 -71% of all men, and 70 -90% of all women under-consume Vitamin B 6. 2, 3, 7, 13 • 75% of all women under-consume Magnesium. 4, 17 acetylcholine dopamine serotonin

Oxidative Stress and Cognitive Longevity ✔ Maintenance of antioxidant balance within the central nervous system - can forestall (prevent) cognitive decline and promote (advance) cognitive longevity. ✔ Certain nutrients exhibit strong neuroprotective antioxidant properties that reduce oxidative structural damage. “The brain consumes large volumes of oxygen (about 20% of whole-body O 2 consumption at rest [42– 44]) and exhibits relatively poor antioxidant defense systems [40]. Because the rate of ROS production in human tissues is proportional to the rate of local oxygen consumption [45], and the rate of oxygen consumption in the brain increases with increasing demand for cognitive functions requiring planning, inductive thinking, and flexible thought [46], the brain is a continuously operating, high-intensity oxidation/ antioxidation battleground prone to oxidative imbalance during times of high demand for complex cognitive activity. ”

Oxidative Stress and Cognitive Longevity

Oxidative Stress and Cognitive Longevity “Increasingly severe and cumulative mitochondrial decay plays a major role in the aging process [137, 138] and is a central feature of the decline in cognitive functioning abilities that is commonly associated with advancing age [8, 12, 13]. ” “The opposite of cognitive aging, cognitive longevity, requires the establishment and maintenance of systemic oxidative balance. The contribution of dietary constituents to the continuation of cognition into the twilight years cannot be overstated. ” “Dietary supplementation with specific nutrients can extend cognitive longevity in humans. ”

Oxidative Stress and Cognitive Longevity Acetyl-L-Carnitine Naturally occurs throughout the human brain, central nervous system, spinal cord, motor nerves, and skeletal muscle. A potent neuroprotector: • strong intrinsic antioxidant properties • stimulates synthesis of the natural endogenous antioxidants---- u glutathione and superoxide dismutase

Oxidative Stress and Cognitive Longevity Acetyl-L-Carnitine ATP Production Acetylcholine Cholinergic Neurotransmission Mood / Motivational Behavior Cognitive Functioning Attention / Comprehension Memory / Concentration / Problem-solving � Mental Fatigue Mental Energy

Oxidative Stress and Cognitive Longevity Acetyl-L-Carnitine and Neuroprotection Rat Brain: Relative myelin content Ramacci, et al. , Drugs Exp Clin Res 1988; 14: 593 -601

Oxidative Stress and Cognitive Longevity Animal Models and Acetyl-L-Carnitine Young, middle-aged and elderly rats and mice fed supplemental acetyl-L-carnitine exhibit enhanced performance on multiple tests: • short-term memory • long-term memory • learning ability + significantly increased amounts of spontaneous voluntary exploratory locomotor activity Bossoni G, et al. , Drugs Exp Clin Res 1986; 12: 911 -916 Hagen TM, et al. , Proc Natl Acad Sci U S A 1998; 95: 9562 -9566 Kohjimoto Y, et al. , Jpn J Pharmacol 1988; 48: 365 -371 Sharman, et al. , Brain Res 2002; 957: 223 -230 Sasaki K, et al. , Int Congr Ser 2004; 1260: 123 -128

Oxidative Stress and Cognitive Longevity Animal Models and Acetyl-L-Carnitine (Acetyl-L-Carnitine facilitates the secretion of dopamine and serotonin) Distance traveled by rats Hagen TM, et al. , Proc Natl Acad Sci U S A 1998; 95: 9562 -9566 Tolu P, et al. , Neuropsychopharmacology 2002; 27: 410 -420 Masi F, et al. , Neuropsychopharmacology 2003; 28: 683 -693

Oxidative Stress and Cognitive Longevity ALCAR : Acetyl-L-Carnitine Double-blind, randomized, placebo-controlled clinical trial Subjects: Over 65 years of age with mild cognitive decline Duration - 3 Months – Placebo No effect Daily administration of 2, 000 mg Acetyl-L-Carnitine resulted in significant improvements in: � Short-term learning ability ÇLong term memory recall Ç Verbal skills Passeri, et al. , Int J Clin Pharmacol Res 1990; 10: 75 -79

Oxidative Stress and Cognitive Longevity ALCAR : Acetyl-L-Carnitine Double-blind, randomized, placebo-controlled clinical trial Subjects over 65 years of age with mild cognitive decline Duration - 6 months – Placebo No effect Daily administration of 2, 500 mg Acetyl-L-Carnitine resulted in significant improvements: � Short-term learning ability � Long-term memory recall � Verbal skills Ç The accuracy of reactions Ç The ability to recall number sequences Sano, et al. , Arch Neurol 1992; 49: 1137 -1141

Oxidative Stress and Cognitive Longevity Subjects with Diabetic Neuropathy: Two randomized, placebo-controlled human studies Duration - 1 Year – Placebo No effect Daily administration of 1, 500 mg or 3, 000 mg ALCAR “These studies demonstrate that ALCAR treatment is efficacious in alleviating symptoms, particularly pain, and improves nerve fiber regeneration and vibration perception in patients with established diabetic neuropathy. ” Sima, et al. , Diabetes Care 2005; 28: 89 -94

Oxidative Stress and Cognitive Longevity ALCAR Treatment in elderly patients with fatigue: Increases in: Ç Overall functional status Ç Cognitive functions Ç Mini Mental State Examination (MMSE) Decreases in: È Physical fatigue � Severity fatigue È Fatigue after exercise � Mental fatigue � Muscle pain � Sleep disorders Arch Gerontol Geriatr. 2008 Mar-Apr; 46(2): 181 -90.

Oxidative Stress and Cognitive Longevity Acetyl-L-Carnitine for Alcohol Craving and Relapse Prevention in Alcoholics: A Randomized, Double -Blind, Placebo-Controlled Trial 64 alcohol-dependent patients: 23 received ALCAR at a dose of 3 g/day, 21 received ALCAR at a dosage of 1 g/day and 20 were given placebo. Results: Patients treated with ALCAR remained completely abstinent for longer than those treated with placebo. Conclusions: The results of this study suggest that ALCAR can reduce craving and the time to first drink. Alcohol and Alcoholism Vol. 45, No. 5, pp. 449– 455, 2010

Oxidative Stress and Cognitive Longevity Acetyl-L-Carnitine Supplementation: Results of parallel-group, double-blind, randomized, placebo-controlled clinical trials show: Significant improvements in: • • • short-term learning ability long-term memory recall verbal skills the accuracy of reactions and the ability to recall number sequences After six-months of daily dietary supplementation.

Oxidative Stress and Cognitive Longevity Acetyl-L-carnitine enhances the formation of short-term memory. (23 peer-reviewed references) Acetyl-L-carnitine enhances the consolidation of long-term memory. (22 peer-reviewed references) Acetyl-L-carnitine enhances the ability to create new memories. (22 peer-reviewed references) Acetyl-L-carnitine enhances the ability to retrieve memories. (22 peer-reviewed references) Acetyl-L-carnitine enhances the ability to learn. (22 peer-reviewed references) Acetyl-L-carnitine enhances the ability to recall information. (22 peer-reviewed references) Acetyl-L-carnitine enhances the ability to reason and solve problems. (22 peer-reviewed references)

Oxidative Stress and Cognitive Longevity “Maintenance of optimal long-term health conditions is accomplished by a complex network of longevity assurance processes that are controlled by vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. “Dietary antioxidants, such as polyphenols and Lcarnitine/acetyl-l-carnitine, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. ” “In this review we discuss the most current and up-to-date understanding of the possible signaling mechanisms by which acety-l-carnitine by activating vitagenes can differentially modulate signal transduction cascades inducing apoptosis/cell death in abnormal cancer cells but at the same time enhancing defensive enzymes to protect against carcinogenesis and neurodegeneration in normal cells. ”

Oxidative Stress and Cognitive Longevity “Acetyl-L-carnitine has been proposed to have beneficial effects in preventing the loss of brain plasticity which typically occurs during aging and neurodegenerative disorders [143]. ” “The main mechanism of action of ALC is the improvement of mitochondrial bioenergetics that allows the neuron to produce ATP necessary to maintain the normal membrane potential and restore altered redox balance [22, 143]. ” “ “However, ALC has been shown to be neuroprotective through a variety of other effects such as the increase in PKC activity [144]. Interestingly ALC counteracted the loss of NMDA receptors in neuronal membrane and increased the production of neurotrophins, two effects strictly related to synaptic plasticity [144]. ”

Oxidative Stress and Cognitive Longevity “Acetylcarnitine is proposed as a therapeutic agent for several neurodegenerative disorders, and there is now evidence that it may play a critical role as modulator of cellular stress response in health and disease states. ” “In the present review, we first discuss the role of nutrition in carnitine metabolism, followed by a discussion of carnitine and acetyl-l-carnitine in mitochondrial dysfunction, in aging, and in age-related disorders. ” “We then review the evidence for the role of acetylcarnitine in modulating redox-dependent mechanisms leading to upregulation of vitagenes in brain, and we also discuss new approaches for investigating the mechanisms of lifetime survival and longevity. ”

Oxidative Stress and Cognitive Longevity “Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and cognition and by senile plaques and neurofibrillary tangles in brain. ” “Amyloid-beta peptide, particularly the 42 - amino-acid peptide (Ab 1– 42), is a principal component of senile plaques and is thought to be central to the pathogenesis of the disease. ” “The AD brain is under significant oxidative stress, and Ab 1– 42 peptide is known to cause oxidative stress in vitro and in vivo. Acetyl-L-carnitine (ALCAR) is an endogenous mitochondrial membrane compound that helps to maintain mitochondrial bioenergetics and lowers the increased oxidative stress associated with aging. Glutathione (GSH) is an important endogenous antioxidant, and its levels have been shown to decrease with aging. Administration of ALCAR increases cellular levels of GSH in rat astrocytes. ”

Oxidative Stress and Cognitive Longevity “In the current study, we investigated whether ALCAR plays a protective role in cortical neuronal cells against Ab 1– 42 mediated oxidative stress and neurotoxicity. ” “Pretreatment of primary cortical neuronal cultures with ALCAR significantly attenuated Ab 1– 42 -induced cytotoxicity, protein oxidation, lipid peroxidation, and apoptosis in a dose-dependent manner. Addition of ALCAR to neurons also led to an elevated cellular GSH and heat shock proteins (HSPs) levels compared with untreated control cells. ” “Our results suggest that ALCAR exerts protective effects against Ab 1– 42 toxicity and oxidative stress in part by upregulating the levels of GSH and HSPs. This evidence supports the pharmacological potential of acetyl-l-carnitine in the management of Ab 1– 42 -induced oxidative stress and neurotoxicity. Therefore, ALCAR may be useful as a possible therapeutic strategy for patients with AD. ”

Oxidative Stress and Cognitive Longevity Acetyl-L-Carnitine Is…. Mitochondrial targeted antioxidant Increases (GSH) Increases ATP Increases the number of mitochondria Protects existing mitochondria from oxidative damage Increases the brains production of healthy phospholipids

Oxidative Stress and Cognitive Longevity Acetyl-L-Carnitine: Substantiated Benefits In Clinical Practice 2, 000 mg/day over 3 -months resulted in significant improvements in: Short-term learning ability; Long term memory recall; Verbal skills. 2, 500 mg/day over 6 -months resulted in significant improvements in: Short-term learning ability; Long term memory recall; Verbal skills; Accuracy of reactions; Ability to recall number sequences. 1, 500 – 3, 000 mg/day over 1 year in patients with Diabetic neuropathy – efficacious in alleviating symptoms, particularly pain; improves nerve fiber regeneration and vibration perception. 4, 000 mg/day over 6 -months in elderly patients with fatigue improved: Overall functional status; Cognitive functions; Mini Mental State Examination (MMSE); And decreased: Physical fatigue; Mental fatigue; Severity of fatigue; Muscle pain; Fatigue after exercise; Sleep disorders.

Oxidative Stress and Cognitive Longevity Phosphatidylserine ü Key cell membrane phospholipid ü Major structural support for healthy mitochondria ü Facilitates membrane environment for at least 9 nerve transmitter receptors ü Increases %-of-hippocampal-tissue with NGF receptors in animal model ü Adequate intramembrane PS content is required for the fusion of intraneuronal secretory granules with the presynaptic membrane and the subsequent release of neurotransmitter molecules into the synaptic cleft

Oxidative Stress and Cognitive Longevity “A large body of scientific evidence describes the interactions among PS, cognitive activity, cognitive aging, and retention of cognitive functioning ability. ” “Phosphatidylserine is required for healthy nerve cell membranes and myelin. ” “Aging of the human brain is associated with biochemical alterations and structural deterioration that impair neurotransmission. ” “Exogenous PS (300– 800 mg/d) is absorbed efficiently in humans, crosses the blood–brain barrier, and safely slows, halts, or reverses biochemical alterations and structural deterioration in nerve cells. ”

Oxidative Stress and Cognitive Longevity “The effectiveness of oral PS supplementation also has been studied in double-blind placebo-controlled randomized clinical trials. Men and women age >60 y exhibiting mild memory loss were given placebo or oral PS (100 mg three times daily) for 90 d [106]. Compared with the effects of placebo, which was ineffective, PS supplementation produced significant improvements in short-term recall, immediate memory, vocabulary skills and ability to recall words, attention, and vigilance. More severe deterioration of cognitive functions (such as attention, concentration, learning ability, and ability to perform daily activities), but without dementia or pseudo-dementia, also has responded to supplementation with oral PS (100 mg three times daily for 2 mo), with significantly greater improvements in verbal recall, initiation, withdrawal, apathy, and overall cognitive functioning than those produced by placebo [107]. Similar results were obtained when older adults with moderately severe cognitive impairment were supplemented with oral PS (100 mg three times daily) for 6 mo [63]. Additionally, long-term memory and ability to perform activities of daily living (ADLs) improved significantly. ”

Oxidative Stress and Cognitive Longevity PS Benefits: • • Human cognitive functions The formation of short-term memory The consolidation of long-term memory The ability to create new memories The ability to retrieve memories The ability to learn and recall information The ability to focus attention and concentrate The ability to reason and solve problems, language skills, and the ability to communicate • PS also supports locomotor functions, especially rapid reactions and reflexes

Oxidative Stress and Cognitive Longevity “The biochemistry of testosterone synthesis within the Leydig cells of the human testes is well characterized. Reliance on the mitochondrial electron transfer system for the energy to drive testosterone synthesis exposes Leydig cell mitochondria to oxidative stress. ” “Leydig cells experiencing oxidative stress exhibit reduced activities of antioxidant enzymes, increased lipid peroxidation, reductions in mitochondrial membrane potential required for testosterone synthesis, and reduced expression of the St. AR steroidogenic acute regulatory (St. AR) protein, culminating in inhibition of the synthesis and secretion of testosterone. ”

Oxidative Stress and Cognitive Longevity “Evidence obtained from in vitro, laboratory, and animal experiments, and from human trials, provides strong support for the hypothesis that reducing oxidative stress releases Leydig cells from oxidative inhibition of testosterone synthesis and can improve testosterone status. ” “Selected dietary antioxidants (e. g. , the phytonutrients in pomegranates, phosphatidylserine, vitamin C, vitamin E, α-lipoic acid, zinc, and selenium) can contribute safely to oxidative stress reduction and enhanced androgenic status in otherwise healthy adult males. In this era of science-based medical decision-making, addressing oxidative stress and its potential role in undermining testosterone status deserves closer scrutiny. ”

Oxidative Stress and Cognitive Longevity “An increase in physical activity or exertional exercise is a common recommendation for individuals with impaired glucoregulation. ” “For example, in 2010, the American College of Sports Medicine and the American Diabetes Association jointly concluded that “The inclusion of an exercise program or other means of increasing overall physical activity is critical for optimal health in individuals with type 2 diabetes” [1]. ”

Oxidative Stress and Cognitive Longevity Exercise Improves Insulin Sensitivity A single bout of high intensity exercise (cycling, 274279 running 279, 280) to exhaustion or near-exhaustion increases whole-body insulin sensitivity. Regimens as short as 7 days are as effective in increasing insulin sensitivity as are regimens lasting several months. 290, 291 **** However make a note: The exercise-induced increase in insulin sensitivity is negated or abolished in those who continue to consume high GI diets. 280, 292

Oxidative Stress and Cognitive Longevity Exercise Improves Insulin Sensitivity… And So Much More: 317 -323 · Significantly improves cholinergic / brain function · Improves sleep quality · Elevates mood (decreases depression) · Reduces stress (resets stress-response) · Improves focus, concentration, memory · Improves self-esteem and self-confidence · Exercise powerfully induces the expression of neurotrophins: Nerve growth factor (NGF) and Brainderived neurotrophic factor (BDNF)

Oxidative Stress and Cognitive Longevity Brain-derived neurotrophic factor (BDNF) in the dentate gyrus of rats exercised daily for just 6 days. Brain-derived neurotrophic factor (BDNF) in the dentate gyrus of sedentary rats. Cotman and Engesser-Cesar, Exerc Sports Sci Rev 2002; 30: 75 -79

Oxidative Stress and Cognitive Longevity Low-Glycemic Antioxidant- Rich: Paleo-Diet Daily, Brief Progressive Exercise 3 Keys To Cognitiv e Longevit y Nutrients To Reduce Oxidative Stress

Oxidative Stress and Cognitive Longevity drkyl@progressivelabs. com