The Aging Brain

Part 3: Treatment, Therapy, Preventative?

by Dan Moran

No cures or successful treatments have been developed for the family of dementias that plague the aging population. Although aging is not considered a dementia, many of the same features found in brain disease are displayed, in milder form, in the elderly. While we think of aging as a normal process, it is defined by the conditions and the molecular dysfunctions that characterize the dementias like Alzheimer’s; but to a lesser degree and with slower progression. Research has revolved around brain conditions that model age-related dysfunctions and can be studied under controlled conditions in the lab. Stroke is one such condition that can be induced in laboratory animals by cutting off oxygen and sugar to the whole brain or to slices of brain placed in culture. The calcium anomalies displayed in aged or demented brains are duplicated in very short order in such experiments.^1,2 Even brief episodes of ischemia induce the calcium dysfunction typical of that seen in aged tissues. Furthermore, many rodent studies include aged animals. These display the failing biochemistries and the sluggish behavior and poorer learning typical of aged people.

Much of our understanding of the calcium-induced dysfunction of neuronal biology has been learned through such studies. The most effective pre- and posttreatment of brains in tissue culture or in whole animals have been those that focus on managing the intracellular calcium concentration of neurons. Using agents that chelate Ca2+s, the effective concentration of calcium that would overload the tissues is reduced under the experimental conditions. By enhancing the neuronal Ca2+ buffering capacity of the tissues, neurodegenerative destruction of brain cells can be attenuated. A number of agents have been used to substitute or augment for calcium-binding proteins. The effects of strong synthetic chelators such as 1, 2 bis(2-aminophenoxy)ethane-N,N,N’,N’-tetra-acetic acid acetoxymethyl ester (BAPTA-AM) have been compared with weak organic calcium chelators like 2-aminophenol-N,N,O-triacetic acid acetoxymethyl ester. When used as a pretreatment to neuronal insults the chelators demonstrated slightly different effects on the nature of calcium activity through preconditioning of the cell, both of which resulted in neuroprotection.³ These effects benefit neurons from aged brains and not young tissues.^4–6 The effects of BAPTA-AM on the extent of recovery from induced calcium overload in brain cells were found to be concentration dependent.⁷ BAPTA-AM is a lipophilic molecule that easily penetrates the cell membrane and can localize in the cytoplasm of treated cells. This is important since the buffering capacity of this compound is dependent on its residence time inside the cell. Research has demonstrated that neuroprotection can be washed away from brain tissue when using these kinds of compounds. However, when used in collaboration with an anion transport inhibitor drug, extended neuroprotection is achieved with much smaller concentrations of BAPTA-AM.⁸

More exciting than the tissue culture research is the work of testing the calcium-hypothesis of brain aging on live animals. Using the calcium chelator BAPTA-AM and several different drugs, aged animals were tested before and after treatment with the agent and compared to young animals. Calcium-chelation was shown to improve spatial learning and synaptic plasticity in older animals. Furthermore, memory formation and retrieval was amended both by calcium chelation as a therapy and by pharmaceutical inhibition of internal calcium pumps.^9,10 When the calcium-channel blocker nimodipine was used by itself, learning was proved to take place faster in aged animals treated with the drug.¹¹

While the etiology of different brain disorders remains obscure, the single most consistently overlapping biochemical failure is calcium imbalance. The fact that this imbalance can be treated, at least temporarily, gives hope to the possibility that aging, which leads to cognitive decline, is treatable. Research must steer in the direction of development of long-term solutions to manage the Ca2+ in aging people. In this regards, a number of attempts at neuroprotection have been made, using the ischemic-stroke model of brain trauma as the principle challenge to managing brain cell death. Calbindin D-29k is abundant in brain cells, indicating its putative role in neuroprotection from calcium toxicity. Using defective neuroviral delivery systems, the gene for the protein can be delivered to cells in order to test the potential to rescue brain cells from ischemic stroke. In one effort, the delivery of the gene for calbindin D-29K resulted in raised levels of the buffering protein such that the ischemic insult to brain tissue did not result in catastrophic death of cells typical of such trauma.¹² In a second experiment, glial cells were also protected from programmed cell death by overproduction of calbindin D-29K when exposed to a calcium ionophore or the amyloid-beta peptide of Alzheimer’s disease, both of which promote cell death by calcium dysregulation.¹³ In effect, brain aging is potentially pharmacologically treatable.

Prevention

Research studies reveal that the development of the aging brain can be postponed or lessened through deliberate steps taken in younger years. Diet, exercise, socialization, and mental activity are correlated to brain aging.^14,15 Calorie restriction and a diet high in antioxidants, fruits, berries, and vegetables are believed to prolong life and reduce oxidative damage in the brain, potentially protecting it from age-related decline.^15,16 Other foods rich in plant polyphenols and saponins, chemically unique compounds that aid the body in homeostasis, maintain cognitive health well into old age.^17,18 Such plants as the ginseng root and chocolate, coffee, green tea, olive oil, and red wine are rich in such substances. Good evidence supports the use of dietary supplements and vitamins, E, C, D, A and the B vitamins.^19–25 These aid cognitive function by quenching free radical formation, promoting healthy gene expression in the hippocampus and improving waste clearance in the brain.^{15,16,26–28} Omega-3 fatty acids obtained through supplement and a diet of fish, at least once a month, is protective of the brain and may reduce risks of stroke.^15,29 Aerobic exercise promotes brain health by increasing blood flow to the brain, having the effect of stimulating neurogenesis, promoting gene expression in the memory center of the brain, the hippocampus, and reducing shrinkage of brain volume.^15,16,30,31 Another factor is the effect of cognitive reserve on cognitive decline. This is the role that mental stimulation from occupations and education has on neural wiring, creating an expanded circuitry in the brain on which to rely even despite neuropathological conditions.^15,16,32 Moderate alcohol consumption was found to benefit brain health over abstinence. Alcohol improves cardiovascular risks and stimulates gene expression in the hippocampus.¹⁵

Increasing evidence for the consumption of proteins and peptides has shown positive correlations with cognitive health. Whey, soy, milk, egg, probiotic peptides, and proteins rich in certain amino acids are among the proteins now recognized as having bioactivity on brain function and health.^33,34 Such bioactivity reduces brain inflammation, supports the production of neurotransmitters, enhances gene expression in the hippocampus, and has immunomodulatory roles in protecting the brain from age-related damage.

Diabetes, hypertension, smoking, drug use, heart failure, concussions, and other brain insults have been associated with early brain aging as well as Alzheimer’s disease.^35–38 While many disease conditions and accidents cannot be prevented, many of these conditions correspond to poor diet, hard living, lack of safety measures in sports or hobbies, bad habits and dependencies.

No one really knows why we age, and we are only beginning to know how we age. In effect, aging of the brain can be characterized as oxidative damage to proteins, genes, internal membranes and the mitochondria through a lifetime of high-energy respiration of the organ of the brain, all of which impinge on the fine balance of the Ca2+ network. Balanced with a lifetime of good diet, proper exercise, socialization, stimulating experiences, combined with supplements that support brain health, old age may be a fulfilling experience. Nothing is going to stop the aging process soon. Nevertheless, it is never too late to be informed and to supplement your diet with the recommendations from good science.

Notes

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2. Bickler PE, Fahlman CS, Gray JJ. Hypoxic preconditioning failure in aging hippocampal neurons: impaired gene expression and rescue with intracellular calcium chelation. J Neurosci Res. 2010;88(16):3520–3529.

3. Abdel-Hamid KM1, Tymianski M. Mechanisms and effects of intracellular calcium buffering on neuronal survival in organotypic hippocampal cultures exposed to anoxia/aglycemia or to excitotoxins. J Neurosci. 1997;17(10):3538–3553.

4. Ouanounou A, Zhang L, Charlton MP, Carlen PL. Differential modulation of synaptic transmission by calcium chelators in young and aged hippocampal CA1 neurons: evidence for altered calcium homeostasis in aging. J Neurosci. 1999;19(3):906–915.

5. Bickler PE, Fahlman CS, Gray JJ. Hypoxic preconditioning failure in aging hippocampal neurons: impaired gene expression and rescue with intracellular calcium chelation. J Neurosci Res. 2010;88(16):3520–3529.

6. Tonkikh A, Janus C, El-Beheiry H, et al. Calcium chelation improves spatial learning and synaptic plasticity in aged rats. Exp Neurol. 2006;197(2):291–300.

7. Ouanounou A, Zhang L, Tymianski M, Charlton MP, Wallace MC, Carlen PL. Accumulation and extrusion of permeant Ca2+ chelators in attenuation of synaptic transmission at hippocampal CA1 neurons. Neuroscience. 1996;75(1):99–109.

8. Ouanounou A, Zhang L, Tymianski M, Charlton MP, Wallace MC, Carlen PL. Accumulation and extrusion of permeant Ca2+ chelators in attenuation of synaptic transmission at hippocampal CA1 neurons. Neuroscience. 1996;75(1):99–109.

9. Tonkikh A, Janus C, El-Beheiry H, Pennefather PS, et al. Calcium chelation improves spatial learning and synaptic plasticity in aged rats. Exp Neurol. 2006;197(2):291–300.

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