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The aging brain.

Introduction By 2030, 72 million Americans, or 20% of the population will be over 65 years of age (from AgingStats. gov). Improvements in hygiene and health care have created the largest and healthiest aged population ever recorded. However, with age comes chronic illnesses and increasing risks of cognitive dysfunction and brain dementias such as Alzheimer's disease. In 2013, an estimated 5 million Americans aged 65 and older had Alzheimer's disease.' By 2050, this number may rise to 13.5 million (CDC Healthy Brain Initiative, 2013). (2) Approximately 10,000 persons reach age 65 every day in the US (www.pewresearch.org/daily-number/baby-boomers-retire). This is due to the Baby Boom generation, but the decline in birth rates assures that this change in demographics will continue long after this generation expires (ibid.). The aging population is an economic and general health concern; little has been done to educate the population on how to age successfully.

Aging has both physical and cognitive components. In terms of cognitive abilities, aging causes reaction times to slow down. From perception to conceptualization, and to decision-making and response, the processes involved in reaction time are reduced in aging. The level of complexity that requires a response adds to the reaction time. Cognition in normal aging might also be said to impinge on executive control. This concept includes the range of processes that involve planning, organizing, coordinating, implementing, and assessing many normal but non-routine activities of daily life. Older people may not show a drop in intelligence or in the ability to learn, but short-term memory is impaired and a different approach to problem-solving is used as the brain circuitry compensates for age-related changes at the cellular level. While the ability to learn is not damaged, the time needed to learn is extended in aged persons. Although attention skills are not affected in the aged, multitasking is reduced. Language skills work well, though processing time can be slower than in younger adults. Older people have conversational skills that are robust and are better than the conversation skills of younger adults. (3) However, loss in hearing and vision may be ascribed to cognitive deficits in persons misdiagnosed as cognitively impaired. While over 94% of seniors continue to live independently until their death, age-related changes in cognition are a reality that older people say they do not want. (4)

From birth to old age, the human brain undergoes extensive but subtle changes in shape, size, and neuronal wiring. Through young adulthood, the brain increases its connectivity. The maximum brain size is achieved around age 20 and shrinkage occurs at a rate of about 1 gram per year afterwards. (5) Throughout life, the brain's wiring will change as learning and memories continue to form. The branching and connectivity of the brain form memory, recall, and cognitive power. This is particularly true for regions dedicated to cognition including the hippocampus, frontal cortex, amygdala, and parietal lobes. A single neocortical neuron has 2500 connections at birth, but by age 2, it may have up to 15,000 synaptic connections.(5), (6) The brain's 100 billion cells will make 150 trillion connections in a lifetime.

After age 20 or so, as the brain begins to shrink, the number of neuronal cells drops by 10% but the glial cells, which support the neurons, are fully formed in youth and do not drop significantly in old age. The neocortex shrinks an average of 10% by age 80. (5) However, the white matter accounts for 24% of this shrinkage, while the gray matter does not shrink or lose thickness much. (7) A nearly 50% loss in myelinated fibers occurs from age 20 to age 80. (7) This is the equivalent of a 180,000-kilometer highway system being cut in half (the US has around 80,000 km of highway). The ventricles of the middle brain enlarge in response to this loss of white matter. An average of 85,000 brain cells dies every day; this is 1 cell per second, or 31 million a year. (5) There is a reduction in dendritic spines and blood vasculature, and dead cells begin to accumulate, which indicates the processes of brain maintenance slowdown. (8) As the connections between neurons (the neuropil) are progressively lost in the aging brain, so are memory, sensory learning, and neuroplasticity. (9) Cells that do not die, eliminating their connectivity, undergo a reduction in the size and the stability of their connections, resulting in weaker synapses less capable of short-term plasticity. (10) This activity is fundamental to dynamic responses in cognition.

Aging is the greatest risk factor for neurodegenerative diseases of the brain. This is true for Alzheimer's disease, Parkinson's, ALS, and other dementias and disorders. (5) When age-related changes are compared with pathological brains such as those of Alzheimer's victims, the results are exponentially worse. Areas of the brain involved in learning and memory are not diminished, they are devastated. At death, the heart of memory, the hippocampus, is obliterated of cells. Strangely, the reported changes in the normal aging of individuals are confounded when measures of cognitive performance are used to test the elderly. The results show a continuum of values between demented and nondemented persons. (11) This is disconcerting, since no clear demarcation between diseased and normal-aged persons can be drawn, and it suggests that the future for many normal individuals is impairment, memory loss, and some degree of behavioral change as they age. (5)

Neurology 101

The brain contains several major cell types, the neuron that transmits electrical impulses and glial cells that support the health and function of neurons. Neurons can transmit electrical signals down the length of their axons by generating an action potential. Action potentials are generated by voltage-gated ion channels embedded in the plasma membrane. Innervation causes these channels to open, allowing sodium ions to pass to the inside of the cell. The cascade of the electrochemical signals runs down the length of the cell's axon, creating a traveling spike of electrical activity. As the sodium channels close, potassium channels open, allowing potassium ions to exit the cell, repolarizing the neuronal membrane. A slight hyperpolarization occurs due to the charge difference between potassium and sodium ions across the membrane. This afterhyperpolarization varies in duration for different signals due to the length of time for potassium channels to shut. The afterhyperpolarization forces the depolarization in one direction and plays a role in the response time of neurons to reach resting potential. When this signal reaches the synapse, the junction between two neurons, a second set of voltage-gated channels allow calcium into the axon terminals. Calcium ions (Ca2 + s) activate the release of neurotransmitters across the gap. Receptors on the postsynaptic neuron located on the dendritic spine of the synapse bind the neurotransmitters, causing local depolarization of the membrane at these junctions. Sufficient depolarization of the postsynaptic membrane reaches a threshold at which a second action potential is induced and the impulse is successfully transmitted to the next neuron. In aging neurons, nerve cell excitability is altered in several ways that is reflected in changes in reaction time and hence cognition.

Brain Function at the Molecular Level Aging is a multifactorial process of change, with the Ca2 + as a common denominator. In fact, aging is highly correlated to the ability of brain cells to regulate the Ca2 +. Ca2 + s are used to mediate the biology of muscle contraction, protein secretion, respiration of sugars, cell division, chemical transport, gene activity, memory consolidation, neuronal plasticity, and even thought through a network of intracellular messaging systems. (12) In neurons, proteins form the channels, pores, messenger signals, sensors, buffers, and pumps that manage the calcium concentration across internal and external membranes of the cell.

Three major regions of high calcium concentration exist with respect to the inside of the cell. These are the external membrane, the internal membrane (endoplasmic reticulum, or ER) and the mitochondria. Calcium concentrations are kept some 10,000 times higher outside the cell than inside the cell. Internal stores of calcium are sequestered to the ER (internal membranes) and the mitochondria. Channels, pumps, pores, and ion transporters control the entry and exit of calcium from across the cell membrane. Internal stores of calcium release the Ca2 + into the cytosol upon activation by signals received across the cell membrane. The Ca2 + activates Ca2 + release inside the cell through signal transduction mechanisms found at the cell membrane. The ER extends throughout the neuron as a complex system of endomembranes. Calcium activation of Ca2 + release from the ER initiates waves of internal ion release, creating an internal depolarization. The type of wave communicates the changes in synapse morphology and by this the nature of synaptic plasticity, short-term versus long-term memory formation. (13) Mitochondria most often act as emergency sinks for excess calcium, adding to the fine-tuning of calcium concentration in the cytosol of the ce11. (14) The mitochondria hold the Ca2 + until safe concentrations of the ion are obtained by membrane pumps and transporters. Even the location of these cellular organelles is controlled by the neuron to optimize the local homeostasis of the Ca2 + .(14), (15)

A good example of calcium-activated release of ER stores of calcium is found in muscle cells. Innervation by the brain transmits electrical signals to the membrane of the muscle cell. This innervation of muscle cells causes a massive release of internal calcium from stores of the ER. The calcium is bound by the muscle protein troponin, which changes conformation to expose an ATPase domain on its protein partner the myosin chain. ATP then drives the contraction of these intertwined proteins, causing them to slide past one another, creating contraction. The burst of calcium release from the ER of muscle cells is buffered by the presence of calcium-binding proteins such as calbindin-D9k and parvalbumin. This allows contraction of the muscle cell while holding the overall calcium concentration at nontoxic concentrations until the Ca2 + s are sequestered by the ER once again. This sequestering of calcium is done by energy-dependent ATP-driven pumps in preparing for the next contraction event. These pumps are abundant, comprising 80% of the membrane proteins of the muscle ER and occupying 30010 of the membrane surface. (16)

Much has been gained in model species such as rodents, fruit flies, nematodes, and the microscopic rotifer, a multicellular animal with complete digestive, nervous, and sexual reproductive systems. Early studies on aging revealed that as animals age their intracellular calcium concentration rises above the basal concentration of younger cells. It was noted that as rotifers age, they stop sexual reproduction, locomotion slows down, and feeding and reaction times become sluggish until the animal dies in about 10 days. (17) The internal calcium concentration increased in rotifers as senescence set in. With the calcium--channel blocking drug nifedipine, age-related decline and a longer life span (15%) were demonstrated in the rotifer. (18), (19) Rotifers grown in a low-calcium environment lived up to 50% longer than those grown in higher-calcium solutions. (20) Aging not only slowed but was reversed in these studies.

Calcium plays a multitude of roles in brain cell physiology, including such events as the generation of the action potential that innervates neurons, the calcium-induced release of neurotransmitters at the synaptic junction that transmits the electrical activity of one neuron to another, and the calcium activation of genetic events leading to the formation and the modification of synaptic junctions. (12) This latter event mediates neuronal plasticity, the dynamic formation or modification of neuronal wiring. In contrast to a former hypothesis that the brain was a static organ, neural plasticity is known to modify the fundamental architecture of the brain throughout life. It is now understood that memory formation is a product of neural plasticity and the brain's cellular connections are the foundation to creating hardwired networks for memory, learning, recall, and ultimately cognition. Cognition, of course, is defined as the existence of mental processing. This must include accessing a working memory, reasoning, comprehension, deliberation, communicating, and decision-making. Calcium is thus the mediator of our awareness and ultimately the toxin that disturbs and dims our consciousness as we age.

As we age, molecular changes in calcium regulation impinge on neuronal physiology. Changes in brain cell biology have ramifications for the health of the brain and may compromise cognitive function, reducing the quality of life and potentially staging older people for serious cognitive impairment or conditions such as Alzheimer's disease. Understanding the fundamentals of brain cell biology can help in designing research programs to aid in the prevention and treatment of age-related cognitive decline. A number of promising technologies and health initiatives are in place to support successful aging. In the next article, the details of molecular and cellular biology of aging brain cells will explain the basis for changes in cognition. Although aging is not yet defined as disease, there are known preventive measures to retaining brain health and hopeful strategies to support cognitive function in old age.

Health Road Map for State and National Partnerships, 2013-2018. Chicago: Alzheimer's Association; 2013. Available at http://www.cdc.goviaging/pd1/2013-healthybrain-initiative.pdf.

Notes

(1.) Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (20102050) estimated using the 2010 census. Neurology. 2013; 80(19): 1778-1783.

(2.) Alzheimer's Association and Centers for Disease Control. The Healthy Brain Initiative: The Public

(3.) Glisky EL. Changes in cognitive function in human aging. Chapter 1 in: Riddle EB. Brain Aging - Models, Methods, and Mechanisms. Boca Raton, FL: CRC Press; 2007.

(4.) The aging process: psychological changes [Web page]. Transgenerational Design. http://transgenerational.org/aging/aging-process.htm#PsychologicalChanges.

(5.) Pakkenberg B, Pelvig D, Marner L, et al. Aging and the human neocortex. Exper Gerontol. 2003; 38: 9599.

(6.) Graham J. Children and brain development: what we know about how children learn. Bulletin #4356, University of Maine Cooperative Extension Publication; 2011. Available at http://umaine.edu/publications/4356e.

(7.) Sherwood CG. Aging of the cerebral cortex differs between humans and chimpanzees. PNAS. 2011; 108(32): 13029-13034.

(8.) Raz N, Rodrigue KM. Differential aging of the brain: Patterns, cognitive correlates and modifiers. Neurosci Biobehav Rev. 2006; 30: 730-748.

(9.) Moran RI, Symmonds M2, Dolan R13, Friston KJ. The brain ages optimally to model its environment: evidence from sensory learning over the adult lifespan. PLoS Comput Biol. 2014; 10W: el 003422.

(10.) Mostany R, Anstey JE, Crump KL, Maco B, Knott G, Portera-Cailliau C. Altered synaptic dynamics during normal brain aging. / Neurosci. 2013; 33(9): 40944104.

(11.) Whalley L. Brain ageing and dementia: what makes the difference? Br Psychol. 2002; 181: 369-371.

(12.) Burgoyne RD, Haynes LP. Understanding the physiological roles of the neuronal calcium sensor proteins. Mol Brain. 2012; 5: 2-11.

(13.) Nikoletopoulou V, Tavernarakis N. Calcium homeostasis in aging neurons. Front Genet. 2012; 3: 200.

(14.) Kawamata H, Manfredi G. Mitochondrial dysfunction and intracellular calcium dysregulation in ALS. Mech Ageing Dev. 2010; 131(7-8): 517-526.

(15.) Vi M, Weaver D, HajnOczky G. Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit. Cell Biol. 2004; 167(4): 661-672.

(16.) Forsen S. Kordel J. Calcium in biological systems. In: Bertini HBI. Bioinorganic Chemistry. Mill Valley, CA: Science Books; 1994: 107-166.

(17.) Korstad J, Olsen 1, Vadstein 0. Life history characteristics of Brachionus plicatilis (rotifera) fed different algae. Hydrobiologia. 1989; 186/187: 43-50.

(18.) Mctavish MS. Nifedipine influences rotifer lifespan studies on the calcium theory of aging. Age. 1990; 13(3): 65-71.

(19.) Enesco HE. Rotifers in aging research: use of rotifer to test various theories of aging. Hydrobiologia. 1993; 255/256: 59-70.

(20.) Sincock AM. Calcium and aging in the rotifer Mytilina brevispina var redunca. / Gerontol. 1974; 29(5): 514517.

Dr. Moran is the director of manufacturing science for Quincy Bioscience and has over 25 years of practical recombinant fermentation experience. He is responsible for the development of practical and efficient manufacturing techniques for apoaequorin and also for accomplishing scaleup capabilities to include continuous batch manufacturing. Dr. Moran holds a PhD in genetic engineering and a master's degree in microbiology from Ohio University.
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Author:Moran, Dan
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Geographic Code:1USA
Date:Oct 1, 2014
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