Life Extension Magazine April 2005
Preventing Age-Related Cognitive Decline
By Laurie Barclay, MD
Hormones Affect Brain Function
Declining hormone levels with age affect the brain as well as other organ systems. In the brain, key hormones improve energy metabolism, protect brain cell membranes, and help maintain levels of acetylcholine, a neurochemical underlying memory.
The hormone DHEA (dehydroepiandrosterone) improves brain cell activity and facilitates changes in nerve cells, allowing them to record new memories. Remarkably, DHEA added to human brain stem cells in the laboratory dramatically increased their growth rate.18 DHEA production falls off with age in humans,19 from about 30 mg a day at age 20 to less than 6 mg a day by age 80.
In aged rodents, DHEA enhances memory20 and quadruples acetylcholine release from hippocampal cells.21 By interacting with specific nerve cell receptors, DHEA improves short-term memory for maze learning and long-term memory in mice.22
In Alzheimer’s disease, DHEA levels decrease along with hippocampal blood flow and activity.23 DHEA may help prevent the formation of a protein that accumulates in brain cells with aging and with Alzheimer’s disease.24
In the elderly, some studies suggest that DHEA may improve memory deficits and depression while enhancing physical and psychological well-being.20
For safe, long-term use, DHEA should be taken with antioxidants25 to prevent possible liver damage reported with massive doses26 that were many times higher than those used in supplements that humans take. Antioxidants that are especially effective in preventing free-radical damage in the liver include green tea, vitamin E, and N-acetylcysteine.
The hormone melatonin is a potent antioxidant that regulates the body’s internal clock and enhances cognitive function. With aging, and more so with certain types of depression and dementia, blood melatonin levels decrease and “flatten out” rather than peaking and falling at characteristic times during the 24-hour cycle.27
In a placebo-controlled study of 26 healthy elderly volunteers, melatonin taken nightly for four weeks improved verbal learning test scores and refreshing sleep.28 “Melatonin administration at a dose of 1 mg nightly may be effective in improving certain aspects of cognitive functioning and subjective reports of sleep quality in elderly subjects,” the researchers concluded. “It may prove to be a useful therapeutic agent in the treatment of age-related cognitive decline.”28
B Vitamins Boost Brain Function
The B vitamins, including folate, protect brain function by regulating energy metabolism, assisting in the production of chemicals that affect mood, and contributing to the myelin sheath surrounding and protecting nerves. B-vitamin deficiencies may therefore impair memory and increase anxiety, confusion, irritability, and depression.29 Low levels of B6, B12, and folate are associated with decreased levels of S-adenosyl-L-methionine, a nutrient with antidepressant and potential cognition-enhancing effects.30
The elderly have higher requirements for some vitamins (including vitamin B6), but poor nutrition and diminished nutrient absorption increases their risk for vitamin deficiency. Vitamins that dissolve in water, including B complex and vitamin C, are rapidly excreted and must be replenished daily. Based on large population studies, high intake of B vitamins and folate may help protect against age-related cognitive decline.31
Among 137 elderly volunteers who were studied for six years, those with higher intake of B complex and vitamins A, C, and E had better scores on tests of abstract reasoning and visual-spatial function.32 Although these effects were relatively modest, they were nonetheless striking because the volunteers were adequately nourished, well educated, and initially free of significant cognitive impairment.
In a three-year Swedish study of 370 healthy elderly adults who were at least 75 years of age, those with even slightly low levels of vitamin B12 and folate had twice the risk of developing Alzheimer’s disease as did those with normal levels of these vitamins.33
In a population study of more than 3,000 Chicago residents aged 65 and older, those with the lowest intake of vitamin B3 (niacin) were 70% more likely to develop Alzheimer’s disease than those with the highest intake, and their rate of cognitive decline was about twice as fast.29 “Dietary niacin may protect against Alzheimer’s disease and age-related cognitive decline,” the researchers concluded.
Replacement of B vitamins in deficient individuals often improves short-term memory and language skills. Elderly subjects who are low in folic acid show impairment in both word recall and object recall, suggesting a vital role for folic acid in memory function in later life.34 Memory impairment in the elderly related to vitamin B12 deficiency can be reversed by vitamin B12 injections or supplements.35
High doses of vitamin B6 and folate reduce blood levels of homocysteine, a toxic buildup product linked to heart disease and cognitive impairment.36 In dementia patients with even mild deficiencies of vitamin B12 or folate, replacement can improve cognition,37 especially in those with elevated blood homocysteine levels.38 In a study of 76 elderly males, vitamin B6 was better than placebo in improving long-term information storage and retrieval.39
Antioxidants Protect Against Free Radicals
In aging of the brain or elsewhere in the body, a chief culprit is damage by free radicals, or atoms with unpaired electrons.40 Just as exposure to oxygen eventually rusts iron, exposure to reactive oxygen species injures mitochondria, membrane lipids, proteins, and nucleic acids needed for cell structure and function.
Lipoic acid, green tea, and other antioxidants are free-radical scavengers that protect the brain. They may help to stave off age-related cognitive decline by protecting the heart and blood vessels, thereby improving circulation to the brain and reducing stroke risk.
Laboratory studies also support the role of antioxidants in protecting the brain. Rats subjected to oxidative stress affecting the hippocampus demonstrate impaired learning and memory deficits. Vitamin E supplementation accelerated learning and prevented the memory deficits associated with oxidative stress.41 Nerve cells grown in the laboratory and damaged chemically were protected by antioxidants, including vitamin E and glutathione,42 suggesting that antioxidants may reduce neuronal damage in pathological conditions associated with oxidative stress.
Many population studies have investigated the link between antioxidant intake and age-related cognitive decline. In a Swiss study that followed 442 elderly people for 22 years, higher blood levels of vitamin C (ascorbic acid) and beta-carotene predicted better test scores for free recall, recognition, and vocabulary.43 Additionally, plasma antioxidant levels remained significantly stable over the 22-year study period. “Among people aged 65 and older, higher ascorbic acid and beta-carotene plasma levels are associated with better memory performance,” the researchers concluded. “These results indicate the important role played by antioxidants in brain aging and may have implications for prevention of progressive cognitive impairments.”
In another study, blood levels of vitamin C were lower in 43 institutionalized patients with dementia than in 50 institutionalized patients without cognitive impairment, and vitamin C levels were associated with higher scores of mental functioning.44 Based on these findings, the researchers recommended studying whether vitamin C supplementation would prevent or delay cognitive decline in patients with dementia and Alzheimer’s disease.
In a random sample of 815 community-dwelling residents aged 65 and older, higher dietary intake of vitamin E was associated with up to a 70% decreased risk of developing Alzheimer’s disease over a four-year period. This was true only for individuals not carrying a specific gene (apolipoprotein E4) related to Alzheimer’s risk.45 Patients with Alzheimer’s disease have lower levels of vitamin E in the cerebrospinal fluid bathing the brain than do healthy elderly people, providing further support for the theory that vitamin E supplementation may help to delay or protect against age-related cognitive decline or Alzheimer’s.46
Over a six-year period, the Rotterdam Study followed more than 5,000 Dutch community residents without dementia who were at least 55 years old.47 High intake of vitamins C and E from foods, but not from supplements, was associated with up to a 42% reduction in risk for Alzheimer’s disease, especially in smokers. This type of study reveals the importance of consuming plant-derived antioxidants.
More evidence supporting the protective role of vitamin E comes from a study of nearly 3,000 community-dwelling elderly who completed a survey about their diet and performed four different cognitive tests three years later. After accounting for age, sex, smoking, alcohol consumption, and intake of other vitamins, subjects in the highest 20% of total vitamin E intake had a 36% reduction in their rate of cognitive decline compared with those in the lowest 20%.48 “Vitamin E intake, from foods or supplements, is associated with less cognitive decline with age,” the researchers concluded.
On the other hand, a large study of supplement use and cognitive decline in elderly residents of southwestern Pennsylvania did not confirm protection against age-related cognitive decline by supplements containing vitamins A, C, or E, beta-carotene, zinc, or selenium.49
What accounts for this discrepancy? Scientists from the University of Valencia in Spain suggest that antioxidant supplements may protect only individuals under oxidative stress.50 When these researchers gave vitamin E to patients with Alzheimer’s disease, they found cognitive improvement only in patients with blood tests indicating oxidative stress. “The effect of vitamin E on Alzheimer’s disease patients showed considerable variations both in its antioxidant function and in its capacity to improve cognitive functions,” they concluded. Further large-scale studies may help to determine which individuals are most likely to benefit from vitamin supplements.
Selenium, a trace mineral known for its antioxidant and immune-boosting effects, appears to also play a role in cognitive function. In a population study of more than 1,000 French subjects aged 60 to 70, low blood levels of selenium and other antioxidants predicted a higher rate of cognitive decline.51 “These results suggest that increased levels of oxidative stress and/or antioxidant deficiencies may pose risk factors for cognitive decline,” the researchers concluded. “The direct implication of oxidative stress in vascular and neurodegenerative mechanisms that lead to cognitive impairment should be further explored.”
Zinc, another antioxidant mineral that is involved in many enzymatic reactions in the body, may also play a role in protecting brain function and health. Zinc is crucial during times of rapid brain growth, and zinc deficiency in juveniles or adolescents causes cognitive impairment.52 Zinc’s role in protecting brain health in adults is less clear, and further studies are warranted.