Age-Related Cognitive Decline
Kira Schmid, ND
Luke Huber, ND, MBA
Lori Feldman, RD, CCRC
The following article is an abridged version of the Age-Related Cognitive Decline chapter that appears in Disease Prevention and Treatment, 5th ed., an integrative health textbook published by Life Extension®.
All aging humans will develop some degree of decline in cognitive capacity as time progresses. Data indicates that deterioration of the biological framework that underlies our ability to think and reason begins as early as the mid-20s and includes a drop in regional brain volume1–5; loss of myelin integrity6,7; cortical thinning8,9; impaired serotonin, acetylcholine, and dopamine receptor binding and signaling10–13; accumulation of neurofibrillary tangles14; and altered concentrations of various brain metabolites.15
Aging causes deterioration of neuronal and mitochondrial membranes, which leads to the loss of cellular integrity and impaired neuronal function.16–18 Steep age-related declines in neurotransmitter synthesis and signaling,19–21 coupled with reductions in synaptic density and plasticity (adaptability),22,23 and loss of as much as 50% of the length of myelinated axons,24 make the brain increasingly less efficient as we age.
However, many of these factors are modifiable to a significant extent, and proactive lifestyle changes, cognitive training, and nutritional interventions have been shown to decrease the rate of intellectual decay and to potentially reverse age-related cognitive decline.
Nutraceuticals to Support Brain Health
In the brain, omega-3 fatty acids are incorporated liberally into cellular phospholipid bilayers; docosahexaenoic acid (DHA), alone, accounts for 40% of the phospholipid content of neuronal membranes.25 Along with eicosapentaenoic acid (EPA), DHA plays a central role in neurotransmitter signaling and synthesis; together, the omega-3 fatty acids modulate numerous aspects of cognition and behavior.26–28
Evidence suggests that the typical Western diet is severely deficient in beneficial omega-3s, and supplies omega-6s in excess, which creates a fatty acid milieu that promotes inflammation and contributes to several age-related degenerative diseases.29
Slightly less than 2 grams of fish oil daily over a 24-week period was shown to significantly improve scores on a standardized assessment of cognitive function in subjects with mild cognitive impairment.30 Increases in red blood cell EPA confirmed that supplemental fish oil was biologically available and responsible for the improvement in cognition. A similar but longer-term study involving nearly 1500 subjects found that daily omega-3 supplementation was independently associated with a dramatic reduction in cognitive decline over a 1.5-year period in an aging population.31
In addition to numerous studies that have associated increased dietary omega-3 intake with better cognitive performance,32,33 a more detailed study alludes to the principle role of DHA in mediating this effect. Researchers assessed serum phospholipid levels in 280 middle-aged (35-54) healthy study volunteers, which were then correlated to cognitive function.34 It was found that subjects with the highest serum levels of DHA performed significantly better in multiple domains of cognition than their cohorts with lower DHA levels. This association remained significant even after adjustment for various confounding factors.
Multiple animal studies have provided mechanistic insights into the well-documented brain health benefits of blueberry constituents. In addition to strongly attenuating neural oxidative stress, blueberry components also inhibit acetylcholinesterase, an enzyme responsible for catabolizing the important neurotransmitter acetylcholine, thus preserving acetylcholine-related memory and learning.35 Blueberry supplementation also stimulates neurogenesis and enhances neuronal plasticity in the hippocampus, the region of the brain chiefly affected by Alzheimer’s disease.36 Other research has revealed that blueberry compounds may optimize cognitive performance through modulation of genetic expression within the brain.37
These biochemical actions translate into observable improvements in learning, memory, and overall cognitive performance from blueberry supplementation, or dietary fortification with blueberries, in both animal and human studies.38–40
Green Tea Polyphenols
Interest in studying components of tea in the context of brain health was generated by publication of epidemiological evidence that linked increased tea consumption with superior cognitive function in aged populations.41,42 Investigations led to the discovery that powerful tea constituents, including epigallocatechin-3-gallate (EGCG) and other phenolic antioxidants, possess tremendous disease-modifying potential in Alzheimer’s disease and the ability to preserve cognition during aging.43–45
In a double-blind, placebo-controlled trial, co-ingestion of green tea polyphenols and L-theanine, an amino acid found in tea, was shown to improve memory and attention in subjects with mild cognitive impairment.46 Those subjects who consumed the supplement also displayed significantly increased theta brain-wave activity, as measured by electroencephalography (EEG); theta waves are associated with learning and memory.46–48 Similar results were observed in animal models of cognitive impairment, and researchers attributed some of the benefits to the free radical-scavenging ability of green tea polyphenols.49,50 Other research has shown that daily green tea supplementation attenuates age-related cognitive dysfunction in mice, even when treatment is initiated well into adulthood.45
Tea polyphenols and L-theanine may also ameliorate the damaging effects of amyloid-beta proteins. Their accumulation in the brain is the hallmark pathology of Alzheimer’s disease, where they cause severe oxidative stress and neuronal death. Several animal studies have found that EGCG and related catechins suppress amyloid-beta-induced cognitive dysfunction and neurotoxicity.51-53
Green tea supplementation has also been shown to optimize insulin signaling54 and endothelial function,55 which may provide additional neuroprotective benefits. Additional clinical trials have established that daily green tea supplementation favorably modulates multiple other metabolic parameters related to brain health, including body weight and lipid peroxidation.56
Many researchers believe that at least some of the health benefits of red wine consumption may be due to its modest content of the well-known phenolic antioxidant, resveratrol. In addition to a multitude of evidence in experimental settings suggesting that resveratrol extends lifespan, likely by mimicking the genetic effects of calorie restriction,57 numerous publications also highlight various roles for resveratrol in optimizing brain function.
Resveratrol may benefit the brain via mechanisms including increased synthesis of the growth factors IGF-158 and BDNF59 in the hippocampus, suppressing formation of inflammatory metabolic products within the brain,60,61 reinforcing the integrity of the blood-brain barrier,62 and optimizing overall brain metabolism.64,63 Other studies have shown that resveratrol supplementation preserves cerebrovascular integrity during aging64 and also protects the brain after traumatic brain injury.65
In a double-blind, randomized, placebo-controlled human clinical trial, doses of resveratrol ranging from 250-500 mg were shown to dose-dependently enhance cerebral circulation and brain oxygenation.66 In a trial involving non-human primates, resveratrol supplementation was shown to increase physical activity levels and enhance both working and spatial memory. According to the investigators, “these results suggest that resveratrol could be a good candidate to mimic long-term CR [caloric restriction] effects and support the growing evidences that nutritional interventions can have beneficial effects on brain functions even in adults.”67
Inside the central nervous system, B-vitamin-dependent reactions are responsible for ensuring the proper function of a vast array of neurochemical processes. When levels of B vitamins – especially B6, B12, and folic acid – are insufficient to optimally support these reactions, consequences such as impaired neurotransmitter synthesis and neurocapillary-damaging hyperhomocysteinemia can result.68
Multiple human studies have associated low plasma levels of B vitamins, and even subclinical deficiencies, with cognitive decline and dementia.69-71 One study showed that in elderly patients, levels of folate correlate positively with the volume of the hippocampus and amygdala, and inversely with white matter hyperintensities, a marker of neuropathology observable upon MRI brain imaging.72
The brain may be the first organ affected by insufficient intake of various other B vitamins, including pantothenic acid, riboflavin, and nicotinamide, since these nutrients are important intermediaries in the mitochondrial oxidative phosphorylation (OXPHOS) pathway – a series of reactions by which chemical energy in the form of adenosine triphosphate (ATP) is produced. The brain produces more energy per volume than any other organ in the body, thus reflecting the sheer number of OXPHOS reactions taking place therein.73-75
A critical component of the OXPHOS reaction pathway, CoQ10 serves to shuttle electrons between 2 “stations” along the mitochondrial inner membrane on the pathway to ATP formation. Without adequate CoQ10, electron transport may slow, resulting in fewer ATP molecules being produced, and ultimately less available cellular energy.76
CoQ10 supplementation has been shown to improve outcomes in several neurodegenerative disorders involving loss of mitochondrial function, such as Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.77,78 Some animal data provides evidence for CoQ10’s potential for preserving cognitive function in conditions such as experimental Alzheimer’s disease.79
Inhibition of HMG-CoA by widely-prescribed cholesterol-lowering statin drugs is known to deplete levels of CoQ10 in the body. Indeed, studies have shown that co-administration of CoQ10 with statins may ameliorate some of the side effects of the drugs,80-82 and individuals with memory complaints who are also taking statin drugs may benefit from supplementation.
The amino acids lysine and methionine are biochemically conjoined in vivo to form the compound carnitine. Carnitine is essential for ensuring that fatty acids are transported into the mitochondrial matrix where they fuel aspects of OXPHOS; however, under certain conditions, including age-related cognitive decline, endogenous synthesis may be insufficient to support optimal fatty acid transport. Subsequent to delineation of the role of carnitine in energy production, many researchers began to study the effects of supplementation with carnitine, and its more brain-permeable derivative, acetyl-L-carnitine, upon various energy-demanding systems and reactions in the body.83
Supplementation with carnitine and acetyl-L-carnitine has been well-documented to ameliorate consequences of disease states with widespread implications for health, including type 2 diabetes and stroke.84,85 However, more impressive is the efficacy of acetyl-L-carnitine in supporting brain health and cognition during normal age-related cognitive decline and Alzheimer’s disease. Acetyl-L-carnitine optimizes cognition by acting upon multiple facets of neuronal function, including enhancing efficiency of cholinergic neurotransmission,86 stabilizing neuronal mitochondrial membranes,87 increasing neural antioxidant defenses,88 and enhancing neuron growth through sensitization to neurotrophic factors.89,90
A meta-analysis of randomized, controlled human clinical trials involving data from 21 studies and data for over 1200 subjects with mild cognitive impairment or mild-to-moderate Alzheimer’s disease provides unequivocal evidence that supplementation with acetyl-L-carnitine ameliorates cognitive deficits observed during aging and during pathological brain deterioration.91 The reviewers found that daily doses of acetyl-L-carnitine ranging from 1.5-3.0 g consistently provided a statistically significant benefit over placebo for preserving cognition, as assessed by multiple standardized tests. Moreover, there was a clear trend for a cumulative effect of acetyl-L-carnitine supplementation over time, suggesting that long-term use of acetyl-L-carnitine may provide the greatest benefit.
Like the omega-3s EPA and DHA, phosphatidylserine is an especially important component of cellular membranes. In the brain, phosphatidylserine conjugates with DHA and helps maintain the proper electrical gradient along neuronal membranes, thus facilitating proper neural communication.92 Human clinical trials have found that orally administered phosphatidylserine in doses ranging from 200-600 mg daily improves cognitive function in aging subjects with cognitive impairment.93-95
The leaves of the Ginkgo biloba tree have been highly regarded throughout human history and used as a food additive and as a traditional medicine. Though widely regarded as a nootropic, or cognitive enhancer, human clinical data suggest that supplementation with Ginkgo biloba extract alone, ie, not in combination with other cognitive support ingredients, is minimally effective for improving cognitive function in those with Alzheimer’s disease or cognitive impairment.96 Nonetheless, because studies have shown that supplementation with ginkgo improves cerebral blood flow97 and other cerebrovascular-related aspects of cognition,97 its use in combination with other brain-supporting nutrients may provide synergistic benefits for cognition. Indeed, results from both animal and human studies suggest that when ginkgo is combined with nutrients such as phosphatidylserine, B vitamins, or vitamin E, the combination of ingredients confer cognitive benefits.98,99 In fact, in a study comparing the effects of supplementation with Ginkgo biloba extract alone to Ginkgo biloba extract together with phosphatidylserine, the combination of the 2 ingredients resulted in improvements in at least 2 aspects of memory performance, while ginkgo alone did not.99
Bacopa monnieri is rich in free radical-scavenging compounds, including polyphenols and sulfur-based molecules, and so may ameliorate the oxidative stress generated by the brain’s intense metabolic rate.100 It also contains various phytochemicals with known anti-inflammatory properties, such as luteolin and apigenin.101,102
Several human clinical trials have revealed cognitive-enhancing and memory-improving effects of supplementation with Bacopa extract. In one double-blind, placebo-controlled trial, daily doses of 300 mg of Bacopa extract significantly improved visual information-processing speed and memory consolidation, and lessened anxiety in healthy individuals after 12 weeks of supplementation.103 Another double-blind, placebo-controlled study of the same duration and using the same dose of Bacopa extract, found that the benefits extend to elderly subjects as well. In this study, the group receiving Bacopa also fared better on an auditory verbal learning test, and scored lower on anxiety and depression scales than those taking placebo.104 Additional promising results were achieved in a similar study in which healthy adults received either 300 mg of Bacopa extract or placebo daily for 90 days. Improvements in working memory were noted in the Bacopa group, but not in the placebo group.105
A compound derived from the plant Huperzia serrata, commonly known as clubmoss or firmoss, huperzine A is a well-established inhibitor of the acetylcholinesterase enzyme, a mechanism it shares with many commonly-prescribed pharmaceutical treatments for Alzheimer’s disease.106,107
Huperzine A has been shown to enhance memory in healthy young humans,108 and in a comprehensive literature review it was found that high doses of huperzine A significantly improved scores on standardized cognitive tests in patients with Alzheimer’s disease in a time-dependent manner, with longer duration of supplementation leading to better results.109
Glyceryl Phosphoryl Choline
Glyceryl phosphoryl choline (GPC) is a form of choline naturally present in cells. Among aging adults, the rationale for GPC therapy goes back to the hypothesis, developed more than 30 years ago, that declining levels of acetylcholine – and a concurrent decrease in the number of neurons that are its intended target – are responsible for a range of cognitive deficits.110 Acetylcholine is an essential neurotransmitter involved in muscle control, sleep, and cognition. Research has shown that GPC is a precursor of acetylcholine that is safe and well-tolerated.111 A review of 13 published studies, involving more than 4000 participants, found that patients taking GPC exhibited neurological improvement that was superior to placebo and “superior or equivalent” to that obtained with prescription drugs. The same authors found that GPC was superior to choline and lecithin and that it deserved wider study as a therapy for stroke patients seeking to regain cognitive function.112
A semisynthetic derivative of the lesser periwinkle plant (Vinca minor), vinpocetine has been shown to exert a variety of biological effects that may benefit brain health. It has been shown in an animal model to regulate the action of sodium in neurons, lessen the damaging effects of hypoxia, and mitigate oxidative stress.113 In another animal study, vinpocetine was shown to blunt the activity of the enzyme phosphodiesterase-1, an effect which may increase neuronal energy by upregulating the energy “throttle” cyclic AMP.114 Also, vinpocetine itself has demonstrated the ability to neutralize particularly damaging hydroxyl radicals.115 Moreover, vinpocetine supports healthy blood flow by enhancing vasodilation and blunting platelet aggregation – effects that may enhance cerebral circulation.116,117 Indeed, human clinical trials show that large doses of IV vinpocetine, followed by 3 months of oral supplementation with 30 mg vinpocetine, improves blood flow in patients with chronic cardiovascular disease.118
In a randomized, controlled trial involving over 200 healthy middle-aged individuals, subjects were given either a multi-vitamin or placebo for more than 2 months, and both groups were then assessed for cognitive function.119 It was shown that those taking the multi-vitamin displayed less fatigue during extended cognitive challenges, and were also more accurate. Also, those taking multi-vitamins were able to more quickly complete mathematical processing tests than subjects receiving placebo.119
Based on clinical research to-date, the following dose ranges appear to offer the most benefit in the prevention of age-related cognitive decline:
- Fish oil: 2-6 g daily (minimum of 1400 mg EPA and 1000 mg of DHA)
- Glyceryl phosphoryl choline: 600 mg daily
- Phosphatidylserine: 100-200 mg daily
- Vinpocetine: 15-30 mg daily
- Acetyl-L-carnitine: 1500-3000 mg daily
- Trans-Resveratrol: 250-500 mg daily
- Blueberry; standardized extract: 500-1000 mg daily
- Green tea; standardized extract: 725-1450 mg daily
- Huperzine A: 50-100 µg daily
- B-vitamin complex: Per label instructions
- Complete multi-vitamin: Per label instructions
- CoQ10 (as ubiquinol): 100-300 mg daily
- Bacopa; standardized extract: 450-900 mg daily
- Ginkgo biloba; standardized extract: 120 mg daily
In addition, the following blood testing resources may be helpful:
- CoQ10 (Coenzyme Q10)
- Complete Blood Count (CBC)
- C-Reactive Protein
- Vitamin D
More information on the integrative interventions and lab tests mentioned in this article is available from Life Extension®, an organization dedicated to scientific innovation. To receive a FREE copy of Life Extension magazine visit www.lifeextension.com/Book7 or call toll-free (1-866-606-9803) and mention discount code DPT507A.
Mr Gossard, Ms Feldman, Dr Schmid, and Dr Huber contribute to the development of evidence-based chapters for the integrative health textbook, Disease Prevention and Treatment.
Blake Gossard is the chief editor of Life Extension’s Disease Prevention and Treatment textbook. He was born and raised in Ohio, and now lives in Fort Lauderdale, FL, with his wife and daughter.
Lori Feldman, RD, CCRC, is the managing editor of Life Extension’s Disease Prevention and Treatment textbook. She graduated magna cum laude from Florida International University in Miami, FL, and currently resides in Fort Lauderdale.
Kira Schmid, ND, received her doctorate in naturopathic medicine from Bastyr University in Seattle, WA. Dr Schmid is Scientific Director for Life Extension, and she is often heard on national and regional health programs, as well as being a frequent contributor to widely-read health and wellness publications.
Luke Huber, ND, MBA, is Vice-President of Product Innovation and Scientific Development at Life Extension. He received his doctorate from Bastyr University, completed hospital-based residency at Cancer Treatment Centers of America’s flagship hospital near Chicago, IL, and received his Master of Business Administration from the University of Massachusetts – Amherst with high honors.
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