Preserving Cognitive Function with Aging
By Julius Goepp, MD* •
August 22, 2014
One of the most frightening tragedies in life is witnessing dementia rob a loved one of their memory, personality, and dignity. While there are not yet cures for these mind-destroying diseases, scientists are discovering that cognitive deterioration need not be an "inevitable" result of aging. In fact, increasing evidence suggests that cognitive decline and even dementia are preventable, and to some extent perhaps even reversible.(1)
According to a report from the Alliance for Health and the Future
, "individuals can take steps to maintain cognitive health throughout life."
(1) In this article, we will explore targeted strategies to help readers take those steps and provide updates from new studies that corroborate these findings.
The Aging Brain - The Molecular View
|What You Need to Know: Preserving Cognitive Function with Aging
- Cognitive decline and memory loss need not be considered inevitable consequences of aging - rather, they are the natural result of a lifetime of oxidative and inflammatory injury to brain tissue.
- Nutritional support for the body's natural antioxidant and anti-inflammatory systems can be found in an array of supplements that individually target those systems and provide powerful neuroprotection. These include: blueberry extract, grape seed extract, vinpocetine, phosphatidylserine, glycerophosphocholine (GPC), uridine-5'-monophosphate (UMP), ashwagandha, ginger, rosemary, hops, and the hormone pregnenolone.
- Strong evidence supports the use of all of these nutrimental agents, which together protect brain tissue from devastating attack by both external and internal oxidant stressors that lead to inflammatory injury and dysfunction.
- Both long- and short-term improvements in brain function and quality of life are seen when these nutrients form part of a responsible supplementation plan.
A remarkable review article by the Human Nutrition Research Center on Aging
at Tufts University in Boston provides a comprehensive summary of what we know about brain aging and the special significance of nutrients in slowing down or preventing this process.(2) According to scientists, many factors at the cellular and molecular levels account for the behavioral deficits so long assumed to be part of "normal" aging, especially changes in the way cells handle neurotransmitters (the molecules that nerve cells use to communicate with one another).(3-6) The resulting loss of neuron function is manifested as changes in both cognitive and motor behaviors that we associate with the aging brain.(7,8)
Critically, the scientists observe, "substantial research indicates that factors such as oxidative stress and inflammation may be major contributors to the behavioral decrements seen in aging."(2,9-11) According to growing research, there is just no question that oxidative stress is one of the most important deleterious factors for aging brain cells, resulting in decreased availability of natural antioxidants such as glutathione and increased oxidative destruction of vital lipid molecules in cell membranes(12) - all of which impair cells' ability to communicate effectively. Not only is the central nervous system especially vulnerable to oxidative stress in general, but it becomes progressively more so with advancing age,(13,14) as structural changes in cells accumulate.
Inflammation adds insult to oxidative injury in the central nervous system.(2) Even by middle age, there is an increase in the production of inflammatory proteins;(15) by the time "old age" has set in, it no longer even requires a true inflammatory stimulus to launch the process.(16) Still worse, when a genuine inflammatory stimulus arises (say, a minor infection or further oxidant stress), older brains react by producing still more inflammatory cytokines such as tumor necrosis factor-alpha
(TNF-alpha) and interleukin-6
(IL-6) than younger brains.(17,18) In fact, scientists have noted that, "up-regulation of C-reactive protein
[a ubiquitous marker of inflammation] may represent one factor in biological aging."(2)
The interactions of inflammation and free oxygen radicals perpetuate a cycle of cell damage and dysfunction.(2) Animal models of the central nervous system demonstrate that inflammation produces changes that mimic aging in the ways they influence cellular interactions, and in the ways they influence actual behavior. The Tufts review recounts a stunning series of experiments, for example, showing that injection of a potent bacterial toxin into brain tissue "can reproduce many of the behavioral, inflammatory, neurochemical, and neuropathologic changes seen in the brains of patients with Alzheimer disease... as well as producing changes in spatial learning and memory behavior."
The ability of many plant food components to reduce or block the effects of the oxidation-inflammation-oxidation cycle has captured the attention of researchers. The benefical way these plant compounds affect behavioral and neuronal aspects of aging has stimulated intense research into this area of dementia prevention.(2)
Let's take a systematic tour of the world of cognition-enhancing nutritional ingredients that show promise in protecting against some of the long-term effects of age-related oxidant/inflammatory damage on the human brain.
Berries and Grapes: Plant Polyphenols Preserve Memory
are plant molecules with a remarkable array of characteristics, notably their potent antioxidant capabilities;(19) people with a high consumption of these molecules have lower rates of neurodegenerative disorders including Alzheimer's disease.(20) Grape skins and seeds are especially rich in a group of polyphenols known as proanthocyanidins, which are proving to have astonishing anti-aging effects in the brain. Interestingly, grape seed extracts were first studied for their beneficial effects on cardiovascular function;(21) cardiovascular disease is an important risk factor in the development of dementia.(22)
Grape seed extracts
have subsequently been shown to have anti-stress and neuroprotective capabilities, preserving rats' cognitive function in the face of stressors - clearly a highly valuable benefit.(23) Interestingly, the reduction in oxidant injury to brain cells increases concentrations of the vital neurotransmitter acetylcholine in animals fed grape seed extract.(24) We have recently learned that grape seed extract induces actual neuroprotective changes in brain protein composition, suggesting in the words of one researcher that "grape seed extract may have impact on the actions of psychoactive drugs by maintaining an overall viability of the nervous system.
The most exciting and dramatic research on grape seed extract and cognition is in Alzheimer's disease, where it has long been known that moderate red wine consumption is protective.(26) Researchers in psychiatry at Mt. Sinai in New York demonstrated why: in mice fed a concentrated grape seed extract, there was significant reduction in deposits of the damaging amyloid-beta proteins associated with Alzheimer's disease, and a concomitant reduction in cognitive deterioration.(27) The observation that grape seed extract not only blocks amyloid formation but also prevents the resulting brain cell injury suggested to UCLA researchers that "[grape seed extract] is worthy of consideration as a therapeutic agent for Alzheimer's disease.
Tufts University researchers led by Dr. James Joseph have long pursued other sources of antioxidant polyphenols as a means of preventing changes associated with the aging brain.(28,29) In 1999, Dr. Joseph's group demonstrated that blueberries are potent sources of these neuroprotective polyphenols, improving rats' performance on a host of cognitive tasks, as well as enhancing the release of vital neurotransmitters from aged brain cells.(30)
Groundbreaking work in 2003 demonstrated that in a mouse model of Alzheimer's disease, blueberry supplementation prevented cognitive deficits even while brain levels of amyloid-beta remained high.(31) Since these mice have actual human genes that predispose them to this disease, scientists concluded "for the first time that it may be possible to overcome genetic predispositions to Alzheimer disease through diet.
Not content to stop there, scientists explored the mechanisms by which blueberries enhance learning and memory in a study of the hippocampus - the brain region where memories are processed, and which loses neurons with age.(32) When they supplemented aging animals with blueberries, the researchers identified improvements in the rate at which hippocampal cells form and develop receptors for neurotransmitters. They found that these structural changes correlated well with actual improvements in spatial memory. The research team also showed that blueberry polyphenol molecules can cross the vital blood-brain barrier, and hence that they exert their potent neuroprotection directly within the brain.(33)
Finally, in late 2008, neuroscientists at the University of South Florida
discovered that blueberry extracts actually prevent the final steps in formation of the dangerous amyloid-beta proteins in Alzheimer's disease.(34) They concluded that these findings could explain the recovery seen in supplemented animals and that supplementation could tip the scales away from formation of these destructive proteins in those at risk for Alzheimer's disease.(34)
Vinpocetine Manages Brain Blood Flow
To support its many vital functions, the brain receives a huge proportion of total blood flow, and has a powerful and exquisitely sensitive mechanism for regulating that flow through control of blood vessel tone.(35) One cause of cognitive decline with age is the gradual diminution of blood flow to vital areas, along with a decreased responsiveness to moment-by-moment needs, much of which results from oxidant damage to vessels.(36,37)
A little-known compound called vinpocetine, derived from the common periwinkle plant, has shown great promise in improving cerebral blood flow and restoring lost cognitive abilities. Vinpocetine appears to work by inhibiting the action of an enzyme called phosphodiesterase 1 (PDE1), resulting in relaxation of cerebral blood vessel walls and increased cerebral blood flow. This mechanism is similar to that of much better-known drugs such as sildenafil (Viagra®),(38,39) which helps restore vital blood flow by inhibiting phosphodiesterase 5 (PDE5). Additionally, vinpocetine helps support cerebral glucose metabolism by enhancing glucose supply to brain tissue.(40,41)
As early as 1987, geriatricians showed that vinpocetine could produce a significant improvement in elderly patients with chronic cerebral dysfunction.(42) The researchers gave vinpocetine supplements to 42 sufferers for 90 days, while control patients received placebo. Supplemented patients scored better on all effectiveness scales, which included measures of cognition and overall mental status. No side effects were reported.
A much larger, controlled, randomized trial followed in 1991, when another group of Britons studied 203 patients with mild-to-moderate forms of cognitive impairment, giving them vinpocetine or placebo for 16 weeks.(43) Again, no side effects were noted, and there were significant improvements in the supplemented group's performance on cognitive performance scales.
In 2003, a Bulgarian research group summarized evidence that vinpocetine can actually protect brain tissue from the effects of asymptomatic cerebrovascular disease, the silent blood vessel damage that precedes a stroke.(44) Their landmark paper cited the supplement's ability to interfere at various stages in the cascade of events leading to stroke, including its antioxidant powers, its inhibition of damage caused by overstimulation of nerve cells, and prevention of free radical release. They showed that vinpocetine passes rapidly across the blood-brain barrier, and that it is selectively accumulated in parts of the brain most closely related to cognitive function. Finally, the review cited the known beneficial effects of vinpocetine on cerebral blood flow. The paper concluded, "vinpocetine may also become a new therapeutic approach to prophylactic neuroprotection in patients at high risk of ischemic stroke.
A 2005 clinical study in Hungary clinched the effects of vinpocetine on brain blood flow.(45) In this elegant study, patients with multiple past strokes underwent ultrasound scans of brain blood vessels to examine flow, and three months later performed a battery of cognitive tests. Supplemented patients' brain blood flow was significantly improved compared with placebo recipients - and on cognitive tests, placebo patients deteriorated significantly while supplement recipients had no change at three months. This study dramatically demonstrated both the cause and the effect of neuroprotection by vinpocetine!
Most of the groundbreaking work on vinpocetine has been done in European countries, and experts there recently wrote that the supplement "improves the blood flow and the metabolism of the affected brain areas. There is increasing evidence that vinpocetine improves the quality of life in chronic cerebrovascular patients.
"(46) Such findings are leading more researchers to recommend the use of vinpocetine for the treatment of patients with mild cognitive impairment.(47)
Phosphatidylserine Maintains Cellular Integrity in the Brain
Brain cells' electrical activity and hence overall function depends critically on the status of their membranes, which are composed of a complex mix of proteins and specialized fat molecules called phospholipids, the most predominant being phosphatidylserine.(48,49) Since 1990, evidence has been growing that phosphatidylserine therapy is beneficial for preserving and even restoring brain function.(50)
In 1992, memory experts in Bethesda studied 51 people who met criteria for probable Alzheimer's disease, treating them with phosphatidylserine (300 mg/day) or placebo.(51) Phosphatidylserine recipients showed improvement on several cognitive measures compared with placebo recipients; benefits were most prominent among those who began with less severe impairment. The researchers noted that "phosphatidylserine may be a promising candidate for study in the early stages of Alzheimer's disease.
As scientists' interest grew in preventing the inflammation produced by amyloid-beta in the brain cells of patients with Alzheimer's disease, many researchers naturally turned to phosphatidylserine as a potential inhibitor of inflammation. Japanese neuropsychiatrists discovered that they could inhibit production of free oxygen radicals, and of the inflammatory cytokine TNF-alpha, if they pretreated amyloid-infested brain cells with phosphatidylserine,(52) demonstrating powerful neuroprotective properties. Those properties were demonstrated in live animals by Canadian scientists who supplemented aged beagles with phosphatidylserine along with ginkgo biloba, vitamin E, and vitamin B6.(53) The aged dogs, previously impaired on tests of visuo-spatial memory, improved their accuracy significantly after supplementation - and the improvement was long-lived.
In mid-2008, German sports physiologists demonstrated positive effects of phosphatidylserine supplements on brain activity and cognition following mental stress (stress tends to worsen any given degree of cognitive impairment).(54) They tested 16 healthy subjects on a cognitive test battery while they were connected to a brainwave scanner (EEG), enabling them to monitor actual brain activity along with cognitive performance. After baseline testing, the subjects were given phosphatidylserine or placebo for 42 days, and were then re-tested and re-scanned. Supplemented patients demonstrated brainwave activity strongly associated with a greater state of relaxation than was experienced by the placebo group. This exciting work suggests that, in addition to objective improvement in cognitive tasks, phosphatidylserine can also cut down on stress that interferes with performance of those tasks.
Evidence for phosphatidylserine has finally managed to convince the ever-skeptical FDA. In 2003, the agency gave "qualified health claim" status to phosphatidylserine, noting that "consumption of phosphatidylserine may reduce the risk of dementia in the elderly" and "consumption of phosphatidylserine may reduce the risk of cognitive dysfunction in the elderly.
GPC Reverses Cognitive Impairment
Studies suggest that GPC (glycerophosphocholine
), a compound related to phosphatidylcholine, may help prevent, halt, or even partially reverse cognitive impairment in the early stages of senile dementia.(56,57)
GPC helps boost brain function via several mechanisms. GPC helps stimulate the manufacture of new acetylcholine, a neurotransmitter involved in memory and cognition. It also stimulates release of the neurotransmitter GABA (gamma-aminobutyric acid), making more GABA available to brain cells. Dwindling levels of GABA in the elderly may partly account for early cognitive impairment, contributing to the dementia, mood disorders, and confusion seen in degenerative brain conditions such as Alzheimer's disease.(58)
The cognitive benefits of GPC have been demonstrated in numerous human studies. A multicenter study of patients with probable Alzheimer's disease showed that GPC improved cognition and was well tolerated.(59) In a review of 13 published clinical trials involving 4,054 patients with age-related memory loss or vascular dementia caused by stroke or mini-stroke (transient ischemic attack), scientists found that GPC helped improve memory and attention, and significantly improved patients' clinical conditions.(56)
A controlled, multicenter study showed that GPC improved cognitive function in 261 patients with mild-to-moderate Alzheimer's disease. Each day for six months, the patients received either GPC or placebo. At the study's end, patients who received GPC performed better on several standardized psychological tests of cognitive function. In contrast, a measure of cognitive function worsened in the placebo group. Individuals who received GPC also demonstrated behavioral improvements and improvements in physician ratings. The study findings support GPC's efficacy in treating the cognitive symptoms of dementia disorders such as Alzheimer's.(60)
Remarkably, these results resemble those achieved with Alzheimer's disease drugs such as Aricept® and Exelon®. Unlike those drugs, however, GPC is easy to tolerate, with no serious side effects.(60)
UMP's Role in Cognition Enhancement
Another approach to cognition and memory enhancement is the use of a substance known as uridine-5'-monophosphate
(UMP), which helps comprise RNA, the DNA-like structure that cells use to create proteins from blueprints in genes. UMP supplementation in animals dramatically increases the production of vital brain cell membrane structural molecules, such as CDP-choline.(61) Such structural molecules are vital for cell growth and repair, and even more importantly, for proper function of the synapses, the relay points at which brain and nerve cells communicate with each other.(62)
UMP supplementation in animals not only increases the synthesis of those vital proteins and phospholipids, but it actually helps stimulate production of neurotransmitters and of the tiny but critical cell outgrowths called neurites63 that are themselves formed and then remodeled in the process of learning(64-66) and of cell repair.(67)
Brain scientists at MIT took those observations to a higher level when they supplemented nutritionally impoverished rats with UMP and studied the effects on memory.(68) The animals were given either a control or a UMP-supplemented diet, and assessed for learning and memory skills. As expected, the impoverished animals fed a control diet did poorly on memory-dependent learning tasks, but those deficits were dramatically prevented in the UMP-supplemented group. One result of studies such as this one is the now-routine addition of UMP to infant formulas to promote healthy brain development.(69)
Declining ability to produce or respond to the neurotransmitter acetylcholine is one of the hallmarks of Alzheimer's disease and other disorders of memory. In 2007, the MIT research group found that they could increase acetylcholine concentrations in aged rats with UMP supplementation.(70) This is a stunning finding, since drugs like Aricept® that are used to treat Alzheimer's disease work by inhibiting the enzyme that breaks down acetylcholine - an approach that has had mixed success and may cause serious side effects.(71)
The same MIT researchers, partnering with Turkish neuroscientists, have recently shown that UMP, together with the omega-3 fatty acid docosahexaenoic acid (DHA), can restore function in an animal model of Parkinson's disease as well.(72) And the same team demonstrated in late 2008 that they could actually enhance the learning and memory improvements caused by DHA in gerbils by adding UMP to the supplementation.(73) They concluded, "these findings demonstrate that [UMP/DHA supplements] can enhance cognitive functions in normal animals" (emphasis added).(74) In other words, one needn't already have cognitive impairment to enjoy the potential benefits of UMP supplementation on learning and memory - and who wouldn't want better memory even at baseline?
Ashwagandha Relieves Stress, Enhances Cognition
|Promoting Youthful Cognitive Function with Pregnenolone
Ensuring optimal levels of pregnenolone is another crucial aspect of supporting nervous system health with aging. Derived from cholesterol, pregnenolone acts as a precursor for numerous key hormones in the body including dehydroepiandrosterone (DHEA), estrogen, progesterone, and testosterone.(94)
With aging, individuals experience a dramatic decline in pregnenolone production, as well as in the hormones for which pregnenolone is a precursor.(95-97) Decreasing levels of these essential hormones have been linked with many disorders that commonly accompany aging.
Scientists believe that pregnenolone is intimately connected with cognitive performance. In fact, pregnenolone directly influences release of the crucial neurotransmitter acetylcholine in regions of the brain linked with memory, learning, cognition, and sleep-wake cycles. Furthermore, administration of pregnenolone reverses the decline in new nerve growth (neurogenesis) that commonly occurs in disorders like Alzheimer's disease. Pregnenolone particularly enhances nerve cell growth in the hippocampus, the brain region responsible for memory, which undergoes marked deterioration in Alzheimer's patients.(98,99)
Supplemental pregnenolone may thus support youthful cognition and health by contributing to optimal hormone levels, supporting acetylcholine activity, and promoting nerve cell growth in the brain's memory center.
Because pregnenolone may affect hormone levels, those with hormonally related cancers such as prostate or breast cancer should avoid using pregnenolone.
Numerous herbs from ancient India are reputed to promote physical and mental health, improve defense mechanisms of the body, and enhance longevity. Among the most promising of these for promoting cognitive health is a plant known as ashwagandha.
Indian researchers characterized the powerful antioxidant capabilities of ashwagandha extracts in 1997, showing that they increased concentrations of natural antioxidants in animal brains after supplementation.(75) These researchers concluded that their findings explained the anti-stress, immunomodulatory, cognition-facilitating, anti-inflammatory, and anti-aging effects reported by other researchers in animal and clinical studies.
The same group later found that they could reduce the chronic stress effects of a mild, unpredictable foot shock in rats if they first supplemented them with ashwagandha extracts.(76) Untreated animals experienced elevated blood sugar, glucose intolerance, increased stress steroid levels, gastric ulcers, male sexual dysfunction, cognitive deficits, and depression - common findings in humans exposed to chronic stress - but administration of ashwagandha extracts an hour before shocks dramatically attenuated all of these outcomes. As we noted with phosphatidylserine above, reduced stress allows increased focus on tasks and therefore better cognitive performance, in addition to simply improving quality of life.
A different Indian scientific group studied ashwagandha in diabetic rats, reasoning that the memory impairment seen in diabetes is in part related to oxidative damage in brain regions that are pivotal in memory and the ability to detect and process new information.(77) They found a significant increase in production of oxidation end products in those brain regions, and a decrease in cognitive function, after the rats became diabetic. But following supplementation, the oxidative damage in the relevant brain regions was significantly reduced, as were blood glucose levels. Dramatically, memory impairment and motor dysfunction were also improved in the supplemented animals.
In 2007, further support for the use of ashwagandha extracts in Alzheimer's disease was provided by the discovery that the extracts are among the most potent inhibitors of acetylcholinesterase, an enzyme that breaks down the vital memory-related neurotransmitter acetylcholine.(78) Drugs that block acetylcholine breakdown (such as Aricept®) are utilized in the management of Alzheimer's disease. The researchers correctly observed that "these results partly substantiate the traditional use of these herbs for improvement of cognition.
" Western research into the benefits of ashwagandha is very recent, so stay tuned for additional exciting news on this extract's memory- and cognition-enhancing properties.
Herbal Extracts Spice up Memory
It is now apparent that many traditional spices, in addition to adding interest to our food, can provide vital anti-inflammatory and antioxidant function that is having an impact on how we think about chronic illness and aging.(79) Three of these in particular deserve special mention for their powerful effects on learning and memory.
Ginger is an age-old part of Asian kitchens and pharmacopeias,(80) and we focus on it here especially for its ability to regulate platelet aggregation, which contributes not only to cardiovascular disease but also to cerebrovascular disease risk.(81-84) Experimental studies demonstrated early in the millennium that ginger extracts could protect cells from the inflammatory action of the Alzheimer's disease-related protein amyloid-beta.(85-87) By its blood pressure-lowering effects, ginger can protect against the chronic brain injury caused by hypertension.(82)
Rosemary is an herb more familiar in Western kitchens, but has an equally distinguished record as a neuroprotectant through its antioxidant constituent, carnosic acid.(88) Rosemary extracts block damaging lipid peroxidation, the destruction of brain cells' fatty membranes that impairs cognitive performance.(89) Rosemary also protects cell nuclei from DNA damage that results from both oxidant stress and ultraviolet light(90) - such damage is at the root of many cancers, but short of cancer it can impair a cell's ability to function normally.
Neuroscientists in England recently showed a remarkable capacity of rosemary: humans exposed just to the aroma of its essential oil performed significantly better on overall memory quality compared with controls.(91) Subjects also had increased states of alertness compared with controls or those exposed to lavender aroma.
Completing the culinary triad of memory-enhancing herbs is hops, the bitter ingredient of beer. Hops' value may be primarily in its ability to promote relaxation and sleep - in one study, the combination of hops with valerian compared equally with a Valium®-like, sleep-inducing drug, and had none of the "hangover" effects seen with the drug.(92) Similar results were found in another study comparing a Valium®-like drug with a hops/valerian combination: both groups did equally well on sleep, relaxation, and quality of life improvement, but patients experienced withdrawal symptoms when they stopped taking the drug.(93)
Far from being an "inevitable" consequence of aging, we now understand that cognitive decline and memory deficits are the predictable results of a lifetime of oxidative and inflammatory injury that damages brain cells' ability to communicate with one another. A vast array of valuable nutrients are available to help block that damage - and in some cases to actually reverse it. Strong evidence abounds that the nutrients described in this review have important roles in improving the quality of life of older adults, keeping their wits sharp and their experiences vivid. These nutrients together, therefore, make up a vital part of any long-term brain health regimen.
* This article is excerpted with kind permission from the March 2009 issue of Life Extension Magazine (www.LEF.org/magazine). ©1995-2013 Life Extension® All rights reserved.
1. Butler RN, Forette F, Greengross BS. Maintaining cognitive health in an ageing society. J R Soc Health. 2004 May;124(3):119-21.
2. Joseph JA, Shukitt-Hale B, Casadesus G. Reversing the deleterious effects of aging on neuronal communication and behavior: beneficial properties of fruit polyphenolic compounds. Am J Clin Nutr. 2005 Jan;81(1 Suppl):313S-6S.
3. Egashira T, Takayama F, Yamanaka Y. Effects of bifemelane on muscarinic receptors and choline acetyltransferase in the brains of aged rats following chronic cerebral hypoperfusion induced by permanent occlusion of bilateral carotid arteries. Jpn J Pharmacol. 1996 Sep;72(1):57-65.
4. Joseph JA, Berger RE, Engel BT, Roth GS. Age-related changes in the nigrostriatum: a behavioral and biochemical analysis. J Gerontol. 1978 Sep;33(5):643-9.
5. Joseph JA, Kowatch MA, Maki T, Roth GS. Selective cross-activation/inhibition of second messenger systems and the reduction of age-related deficits in the muscarinic control of dopamine release from perifused rat striata. Brain Res. 1990 Dec 24;537(1-2):40-8.
6. Landfield PW, Eldridge JC. The glucocorticoid hypothesis of age-related hippocampal neurodegeneration: role of dysregulated intraneuronal calcium. Ann NY Acad Sci. 1994 Nov 30;746:308-21.
7. Bartus RT. Drugs to treat age-related neurodegenerative problems. The final frontier of medical science? J Am Geriatr Soc. 1990 Jun;38(6):680-95.
8. Joseph JA, Bartus RT, Clody D, et al. Psychomotor performance in the senescent rodent: reduction of deficits via striatal dopamine receptor up-regulation. Neurobiol Aging. 1983;4(4):313-9.
9. Hauss-Wegrzyniak B, Vannucchi MG, Wenk GL. Behavioral and ultrastructural changes induced by chronic neuroinflammation in young rats. Brain Res. 2000 Mar 17;859(1):157-66.
10. Hauss-Wegrzyniak B, Willard LB, Del SP, Pepeu G, Wenk GL. Peripheral administration of novel anti-inflammatories can attenuate the effects of chronic inflammation within the CNS. Brain Res. 1999 Jan 2;815(1):36-43.
11. Shukitt-Hale B, McEwen JJ, Szprengiel A, Joseph JA. Effect of age on the radial arm water maze-a test of spatial learning and memory. Neurobiol Aging. 2004 Feb;25(2):223-9.
12. Denisova NA, Erat SA, Kelly JF, Roth GS. Differential effect of aging on cholesterol modulation of carbachol-stimulated low-K(m) GTPase in striatal synaptosomes. Exp Gerontol. 1998 May;33(3):249-65.
13. Joseph JA, Erat S, Rabin BM. CNS effects of heavy particle irradiation in space: behavioral implications. Adv Space Res. 1998;22(2):209-16.
14. Joseph JA, Denisova N, Fisher D, et al. Membrane and receptor modifications of oxidative stress vulnerability in aging. Nutritional considerations. Ann NY Acad Sci. 1998 Nov 20;854:268-76.
15. Rozovsky I, Finch CE, Morgan TE. Age-related activation of microglia and astrocytes: in vitro studies show persistent phenotypes of aging, increased proliferation, and resistance to down-regulation. Neurobiol Aging. 1998 Jan;19(1):97-103.
16. McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev. 1995 Sep;21(2):195-218.
17. Chang RC, Chen W, Hudson P, et al. Neurons reduce glial responses to lipopolysaccharide (LPS) and prevent injury of microglial cells from over-activation by LPS. J Neurochem. 2001 Feb;76(4):1042-9.
18. Spaulding CC, Walford RL, Effros RB. Calorie restriction inhibits the age-related dysregulation of the cytokines TNF-alpha and IL-6 in C3B10RF1 mice. Mech Ageing Dev. 1997 Feb;93(1-3):87-94.
19. Barros D, Amaral OB, Izquierdo I, et al. Behavioral and genoprotective effects of Vaccinium berries intake in mice. Pharmacol Biochem Behav. 2006 Jun;84(2):229-34.
20. Ramirez MR, Izquierdo I, do Carmo Bassols RM, et al. Effect of lyophilised Vaccinium berries on memory, anxiety and locomotion in adult rats. Pharmacol Res. 2005 Dec;52(6):457-62.
21. Sato M, Bagchi D, Tosaki A, Das DK. Grape seed proanthocyanidin reduces cardiomyocyte apoptosis by inhibiting ischemia/reperfusion-induced activation of JNK-1 and C-JUN. Free Radic Biol Med. 2001 Sep 15;31(6):729-37.
22. Fillit H, Nash DT, Rundek T, Zuckerman A. Cardiovascular risk factors and dementia. Am J Geriatr Pharmacother. 2008 Jun;6(2):100-18.
23. Sreemantula S, Nammi S, Kolanukonda R, Koppula S, Boini KM. Adaptogenic and nootropic activities of aqueous extract of Vitis vinifera (grape seed): an experimental study in rat model. BMC Complement Altern Med. 2005 Jan 19;51.
24. Devi A, Jolitha AB, Ishii N. Grape seed proanthocyanidin extract (GSPE) and antioxidant defense in the brain of adult rats. Med Sci Monit. 2006 Apr;12(4):BR124-9.
25. Kim H, Deshane J, Barnes S, Meleth S. Proteomics analysis of the actions of grape seed extract in rat brain: technological and biological implications for the study of the actions of psychoactive compounds. Life Sci. 2006 Mar 27;78(18):2060-5.
26. Ono K, Condron MM, Ho L, et al. Effects of grape seed-derived polyphenols on amyloid beta-protein self-assembly and cytotoxicity. J Biol Chem. 2008 Nov 21;283(47):32176-87.
27. Wang J, Ho L, Zhao W, et al. Grape-derived polyphenolics prevent Abeta oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimer's disease. J Neurosci. 2008 Jun 18;28(25):6388-92.
28. Joseph JA. The putative role of free radicals in the loss of neuronal functioning in senescence. Integr Physiol Behav Sci. 1992 Jul;27(3):216-27.
29. Joseph JA, Denisova N, Fisher D, et al. Age-related neurodegeneration and oxidative stress: putative nutritional intervention. Neurol Clin. 1998 Aug;16(3):747-55.
30. Joseph JA, Shukitt-Hale B, Denisova NA, et al. Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J Neurosci. 1999 Sep 15;19(18):8114-21.
31. Joseph JA, Denisova NA, Arendash G, et al. Blueberry supplementation enhances signaling and prevents behavioral deficits in an Alzheimer disease model. Nutr Neurosci. 2003 Jun;6(3):153-62.
32. Casadesus G, Shukitt-Hale B, Stellwagen HM, et al. Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supplementation in aged rats. Nutr Neurosci. 2004 Oct;7(5-6):309-16.
33. Andres-Lacueva C, Shukitt-Hale B, Galli RL, et al. Anthocyanins in aged blueberry-fed rats are found centrally and may enhance memory. Nutr Neurosci. 2005 Apr;8(2):111-20.
34. Zhu Y, Bickford PC, Sanberg P, Giunta B, Tan J. Blueberry opposes beta-amyloid peptide-induced microglial activation via inhibition of p44/42 mitogen-activation protein kinase. Rejuvenation Res. 2008 Oct;11(5):891-901.
35. Bailey DM, Evans KA, James PE, et al. Altered free radical metabolism in acute mountain sickness: implications for dynamic cerebral autoregulation and blood-brain barrier function. J Physiol. 2008 Oct 27.
36. Lacombe P, Oligo C, Domenga V, Tournier-Lasserve E, Joutel A. Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy arteriopathy. Stroke. 2005 May;36(5):1053-8.
37. Ogunniyi A, Talabi O. Cerebrovascular complications of hypertension. Niger J Med. 2001 Oct;10(4):158-61.
38. Blokland A, Schreiber R, Prickaerts J. Improving memory: a role for phosphodiesterases. Curr Pharm Des. 2006;12(20):2511-23.
39. Mostafa T. Oral phosphodiesterase type 5 inhibitors: nonerectogenic beneficial uses. J Sex Med. 2008 Nov;5(11):2502-18.
40. Vas A, Gulyas B. Eburnamine derivatives and the brain. Med Res Rev. 2005 Nov;25(6):737-57.
41. Vas A, Gulyas B, Szabo Z, et al. Clinical and non-clinical investigations using positron emission tomography, near infrared spectroscopy and transcranial Doppler methods on the neuroprotective drug vinpocetine: a summary of evidences. J Neurol Sci. 2002 Nov 15;203-204:259-62.
42. Balestreri R, Fontana L, Astengo F. A double-blind placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction. J Am Geriatr Soc. 1987 May;35(5):425-30.
43. Hindmarch I, Fuchs HH, Erzigkeit H. Efficacy and tolerance of vinpocetine in ambulant patients suffering from mild to moderate organic psychosyndromes. Int Clin Psychopharmacol. 1991;6(1):31-43.
44. Hadjiev D. Asymptomatic ischemic cerebrovascular disorders and neuroprotection with vinpocetine. Ideggyogy Sz. 2003 May 20;56(5-6):166-72.
45. Kemeny V, Molnar S, Andrejkovics M, Makai A, Csiba L. Acute and chronic effects of vinpocetine on cerebral hemodynamics and neuropsychological performance in multi-infarct patients. J Clin Pharmacol. 2005 Sep;45(9):1048-54.
46. Bagoly E, Feher G, Szapary L. The role of vinpocetine in the treatment of cerebrovascular diseases based in human studies. Orv Hetil. 2007 Jul 22;148(29):1353-8.
47. Valikovics A. Investigation of the effect of vinpocetine on cerebral blood flow and cognitive functions. Ideggyogy Sz. 2007 Jul 30;60(7-8):301-10.
48. Anon. Phosphatidylserine. Monograph. Altern Med Rev. 2008 Sep;13(3):245-7.
49. Araki W, Wurtman RJ. How is membrane phospholipid biosynthesis controlled in neural tissues? J Neurosci Res. 1998 Mar 15;51(6):667-74.
50. Maggioni M, Picotti GB, Bondiolotti GP, et al. Effects of phosphatidylserine therapy in geriatric patients with depressive disorders. Acta Psychiatr Scand. 1990 Mar;81(3):265-70.
51. Crook T, Petrie W, Wells C, Massari DC. Effects of phosphatidylserine in Alzheimer's disease. Psychopharmacol Bull. 1992;28(1):61-6.
52. Hashioka S, Han YH, Fujii S, et al. Phosphatidylserine and phosphatidylcholine-containing liposomes inhibit amyloid beta and interferon-gamma-induced microglial activation. Free Radic Biol Med. 2007 Apr 1;42(7):945-54.
53. Araujo JA, Landsberg GM, Milgram NW, Miolo A. Improvement of short-term memory performance in aged beagles by a nutraceutical supplement containing phosphatidylserine, Ginkgo biloba, vitamin E, and pyridoxine. Can Vet J. 2008 Apr;49(4):379-85.
54. Baumeister J, Barthel T, Geiss KR, Weiss M. Influence of phosphatidylserine on cognitive performance and cortical activity after induced stress. Nutr Neurosci. 2008 Jun;11(3):103-10.
55. Available at: http://vm.cfsan.fda.gov/~dms/ds-ltr36.html. Accessed December 16, 2008.
56. Parnetti L, Amenta F, Gallai V. Choline alphoscerate in cognitive decline and in acute cerebrovascular disease: an analysis of published clinical data. Mech Ageing Dev. 2001 Nov;122(16):2041-55.
57. Manev H, Uz T, Sugaya K, Qu T. Putative role of neuronal 5-lipoxygenase in an aging brain. FASEB J. 2000 Jul;14(10):1464-9.
58. Cummings JL, et al. Neurobiological basis of behavior. In: Coffey CE, Cummings JL, eds. Textbook of Geriatric Neuropsychiatry. American Psychiatric Press; 1994:72-96.
59. Parnetti L, Abate G, Bartorelli L, et al. Multicentre study of l-alpha-glyceryl-phosphorylcholine vs ST200 among patients with probable senile dementia of Alzheimer's type. Drugs Aging. 1993 Mar;3(2):159-64.
60. De Jesus Moreno MM. Cognitive improvement in mild to moderate Alzheimer's dementia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, double-blind, randomized, placebo-controlled trial. Clin Ther. 2003 Jan;25(1):178-93.
61. Cansev M, Watkins CJ, van der Beek EM, Wurtman RJ. Oral uridine-5'-monophosphate (UMP) increases brain CDP-choline levels in gerbils. Brain Res. 2005 Oct 5;1058(1-2):101-8.
62. Wang L, Pooler AM, Albrecht MA, Wurtman RJ. Dietary uridine-5'-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats. J Mol Neurosci. 2005;27(1):137-45.
63. Sakamoto T, Cansev M, Wurtman RJ. Oral supplementation with docosahexaenoic acid and uridine-5'-monophosphate increases dendritic spine density in adult gerbil hippocampus. Brain Res. 2007 Nov 28;1182:50-9.
64. Drees F, Gertler FB. Ena/VASP: proteins at the tip of the nervous system. Curr Opin Neurobiol. 2008 Feb;18(1):53-9.
65. Yamauchi T. Molecular mechanism of learning and memory based on the research for Ca2+/calmodulin-dependent protein kinase II. Yakugaku Zasshi. 2007 Aug;127(8):1173-97.
66. Skaper SD. Neuronal growth-promoting and inhibitory cues in neuroprotection and neuroregeneration. Ann NY Acad Sci. 2005 Aug;1053:376-85.
67. Carulli D, Buffo A, Strata P. Reparative mechanisms in the cerebellar cortex. Prog Neurobiol. 2004 Apr;72(6):373-98.
68. Teather LA, Wurtman RJ. Chronic administration of UMP ameliorates the impairment of hippocampal-dependent memory in impoverished rats. J Nutr. 2006 Nov;136(11):2834-7.
69. Wurtman RJ. Synapse formation and cognitive brain development: effect of docosahexaenoic acid and other dietary constituents. Metabolism. 2008 Oct;57(Suppl 2):S6-10.
70. Wang L, Albrecht MA, Wurtman RJ. Dietary supplementation with uridine-5'-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat. Brain Res. 2007 Feb 16;1133(1):42-8.
71. Hansen RA, Gartlehner G, Webb AP, et al. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer's disease: a systematic review and meta-analysis. Clin Interv Aging. 2008;3(2):211-25.
72. Cansev M, Ulus IH, Wang L, Maher TJ, Wurtman RJ. Restorative effects of uridine plus docosahexaenoic acid in a rat model of Parkinson's disease. Neurosci Res. 2008 Nov;62(3):206-9.
73. Holguin S, Huang Y, Liu J, Wurtman R. Chronic administration of DHA and UMP improves the impaired memory of environmentally impoverished rats. Behav Brain Res. 2008 Aug 5;191(1):11-6.
74. Holguin S, Martinez J, Chow C, Wurtman R. Dietary uridine enhances the improvement in learning and memory produced by administering DHA to gerbils. FASEB J. 2008 Nov;22(11):3938-46.
75. Bhattacharya SK, Satyan KS, Ghosal S. Antioxidant activity of glycowithanolides from Withania somnifera. Indian J Exp Biol. 1997 Mar;35(3):236-9.
76. Bhattacharya SK, Muruganandam AV. Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress. Pharmacol Biochem Behav. 2003 Jun;75(3):547-55.
77. Parihar MS, Chaudhary M, Shetty R, Hemnani T. Susceptibility of hippocampus and cerebral cortex to oxidative damage in streptozotocin treated mice: prevention by extracts of Withania somnifera and Aloe vera. J Clin Neurosci. 2004 May;11(4):397-402.
78. Vinutha B, Prashanth D, Salma K, et al. Screening of selected Indian medicinal plants for acetylcholinesterase inhibitory activity. J Ethnopharmacol. 2007 Jan 19;109(2):359-63.
79. Aggarwal BB, Shishodia S. Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning. Ann NY Acad Sci. 2004 Dec;1030:434-41.
80. Hoffman T. Ginger: an ancient remedy and modern miracle drug. Hawaii Med J. 2007 Dec;66(12):326-7.
81. Bordia A, Verma SK, Srivastava KC. Effect of ginger (Zingiber officinale Rosc.) and fenugreek (Trigonella foenumgraecum L.) on blood lipids, blood sugar and platelet aggregation in patients with coronary artery disease. Prostaglandins Leukot Essent Fatty Acids. 1997 May;56(5):379-84.
82. Ghayur MN, Gilani AH, Afridi MB, Houghton PJ. Cardiovascular effects of ginger aqueous extract and its phenolic constituents are mediated through multiple pathways. Vascul Pharmacol. 2005 Oct;43(4):234-41.
83. Koo KL, Ammit AJ, Tran VH, Duke CC, Roufogalis BD. Gingerols and related analogues inhibit arachidonic acid-induced human platelet serotonin release and aggregation. Thromb Res. 2001 Sep 1;103(5):387-97.
84. Young HY, Liao JC, Chang YS, et al. Synergistic effect of ginger and nifedipine on human platelet aggregation: a study in hypertensive patients and normal volunteers. Am J Chin Med. 2006;34(4):545-51.
85. Kim DS, Kim DS, Oppel MN. Shogaols from Zingiber officinale protect IMR32 human neuroblastoma and normal human umbilical vein endothelial cells from beta-amyloid(25-35) insult. Planta Med. 2002 Apr;68(4):375-6.
86. Grzanna R, Phan P, Polotsky A, Lindmark L, Frondoza CG. Ginger extract inhibits beta-amyloid peptide-induced cytokine and chemokine expression in cultured THP-1 monocytes. J Altern Complement Med. 2004 Dec;10(6):1009-13.
87. Kim DS, Kim JY, Han YS. Alzheimer's disease drug discovery from herbs: neuroprotectivity from beta-amyloid (1-42) insult. J Altern Complement Med. 2007 Apr;13(3):333-40.
88. Aruoma OI, Halliwell B, Aeschbach R, Loligers J. Antioxidant and pro-oxidant properties of active rosemary constituents: carnosol and carnosic acid. Xenobiotica. 1992 Feb;22(2):257-68.
89. Haraguchi H, Saito T, Okamura N, Yagi A. Inhibition of lipid peroxidation and superoxide generation by diterpenoids from Rosmarinus officinalis. Planta Med. 1995 Aug;61(4):333-6.
90. Slamenova D, Kuboskova K, Horvathova E, Robichova S. Rosemary-stimulated reduction of DNA strand breaks and FPG-sensitive sites in mammalian cells treated with H2O2 or visible light-excited Methylene Blue. Cancer Lett. 2002 Mar 28;177(2):145-53.
91. Moss M, Cook J, Wesnes K, Duckett P. Aromas of rosemary and lavender essential oils differentially affect cognition and mood in healthy adults. Int J Neurosci. 2003 Jan;113(1):15-38.
92. Gerhard U, Linnenbrink N, Georghiadou C, Hobi V. Vigilance-decreasing effects of 2 plant-derived sedatives. Praxis Bern. 1994;85:473-81.
93. Schmitz M, Jackel M. Comparative study for assessing quality of life of patients with exogenous sleep disorders (temporary sleep onset and sleep interruption disorders) treated with a hops-valarian preparation and a benzodiazepine drug. Wien Med Wochenschr. 1998;148(13):291-8.
94. Meieran SE, Reus VI, Webster R, Shafton R, Wolkowitz OM. Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation. Psychoneuroendocrinology. 2004 May;29(4):486-500.
95. Karishma KK, Herbert J. Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosterone-induced suppression. Eur J Neurosci. 2002 Aug;16(3):445-53.
96. Goncharova ND, Lapin BA. Effects of aging on hypothalamic-pituitary-adrenal system function in non-human primates. Mech Ageing Dev. 2002 Apr 30;123(8):1191-201.
97. Zietz B, Hrach S, Scholmerich J, Straub RH. Differential age-related changes of hypothalamus - pituitary - adrenal axis hormones in healthy women and men - role of interleukin 6. Exp Clin Endocrinol Diabetes. 2001;109(2):93-101.
98. Mayo W, Lemaire V, Malaterre J, et al. Pregnenolone sulfate enhances neurogenesis and PSA-NCAM in young and aged hippocampus. Neurobiol Aging. 2005 Jan;26(1):103-14.
99. Mayo W, George O, Darbra S, et al. Individual differences in cognitive aging: implication of pregnenolone sulfate. Prog Neurobiol. 2003 Sep;71(1):43-8.