Ageing brain

Age is a major risk factor for most common neurodegenerative diseases, including Mild cognitive impairment, Alzheimer's disease, cerebrovascular disease, Parkinson's disease and Lou Gehrig's disease. While much research has focused on diseases of aging, there are few informative studies on the molecular biology of the aging brain (usually spelled ageing brain in British English) in the absence of neurodegenerative disease or the neuropsychological profile of healthy older adults. However, research does suggest that the aging process is associated with several structural, chemical, and functional changes in the brain as well as a host of neurocognitive changes. This page is devoted to reviewing the changes associated with healthy aging.

Structural Changes
Aging entails many physical, biological, chemical, and psychological changes. Therefore, it is logical to assume the brain is no exception to this phenomenon. Computed Tomography (CT) studies have found that the cerebral ventricles expand as a function of age, and this process is known as ventriculomegaly. More recent MRI studies have reported age-related regional decreases in cerebral volume. Regional volume reduction is not uniform; some brain regions shrink at a rate of up to 1% per year, whereas others remain relatively stable until the end of the life-span. The brain is very complex, and is composed of many different areas and types of tissue, or matter. The different functions of different tissues in the brain may be more or less susceptible to age-induced changes. The brain matter can be broadly classified as either grey matter, or white matter. Grey matter consists of cell bodies in the cortex and subcortical nuclei, whereas white matter consists of tightly packed myelinated axons connecting the neurons of the cerebral cortex to each other and with the periphery.

Loss of Neural Circuits and Brain Plasticity
Brain plasticity refers to the brain's ability to change structure and function. This ties into that old phrase, "if you don't use it, you lose it," which is another way of saying, if you don't use it, your brain will devote less somatotopic space for it. One proposed mechanism for the observed age-related plasticity deficits in animals is the result of age-induced alterations in calcium regulation. The changes in our abilities to handle calcium will ultimately influence neuronal firing and the ability to propagate action potentials, which in turn would affect the ability of the brain to alter its structure or function (i.e. its plastic nature). Due to the complexity of the brain, with all of its structures and functions, it is logical to assume that some areas would be more vulnerable to aging than others. Two circuits worth mentioning here are the hippocampal and neocortical circuits. It has been suggested that age-related cognitive decline is due in part not to neuronal death but to synaptic alterations. Evidence in support of this idea from animal work has also suggested that this cognitive deficit is due to functional and biochemical factors such as changes in enzymatic activity, chemical messengers, or gene expression in cortical circuits.

Thinning of the Cortex
Advances in MRI technology have provided the ability to see the brain structure in great detail in an easy, non-invasive manner in vivo. Bartzokis et al., has noted that there is a decrease in grey matter volume between adulthood and old age, whereas white matter volume was found to increase from age 19-40, and decline after this age. Studies using Voxel-based morphometry have identified areas such as the insula and superior parietal gyri as being especially vulnerable to age-related losses in grey matter of older adults. Sowell et al., reported that the first 6 decades of an individual's life were correlated with the most rapid decreases in grey matter density, and this occurred over dorsal, frontal, and parietal lobes on both interhemispheric and lateral brain surfaces. It is also worth noting that areas such as the cingulate gyrus, and occipital cortex surrounding the calcarine sulcus appear exempt from this decrease in grey matter density over time. Age effects on grey matter density in the posterior temporal cortex appear more predominantly in the left versus right hemisphere, and were confined to posterior language cortices. Certain language functions such as word retrieval and production were found to be located to more anterior language cortices, and deteriorate as a function of age. Sowell et al., also reported that these anterior language cortices were found to mature and decline earlier than the more posterior language cortices. It has also been found that the width of sulcus not only increases with age, but also with cognitive decline in the elderly.

Age-Related Neuronal Morphology
There is converging evidence from cognitive neuroscientists around the world that age-induced cognitive deficits may not be due to neuronal loss or cell death, but rather may be the result of small region-specific changes to the morphology of neurons. Studies by Duan et al., have shown that dendritic arbors and dendritic spines of cortical pyramidal neurons decrease in size and/or number in specific regions and layers of human and non-human primate cortex as a result of age (Duan et al., 2003; morph). Interestingly, a 46% decrease in spine number and spine density has been reported in humans older than 50 compared with younger individuals. An electron microscopy study in monkeys reported a 50% loss in spines on the apical dendritic tufts of pyramidal cells in prefrontal cortex of old animals (27–32 years old) compared with young ones (6–9 years old).

Neurofibrillary Tangles
Age-related neuro-pathologies such as Alzheimer's disease, Parkinson's disease, diabetes, hypertension and arteriosclerosis make it difficult to distinguish the normal patterns of aging. One of the important differences between normal aging and pathological aging is the location of neurofibrillary tangles. Neurofibrillary tangles are composed of paired helical filaments (PHF). In normal, non-demented aging, the number of tangles in each affected cell body is relatively low and restricted to the olfactory nucleus, parahippocampal gyrus, amygdala and entorhinal cortex. As the non-demented individual ages, there is a general increase in the density of tangles, but no significant difference in where tangles are found. The other main neurodegenerative contributor commonly found in the brain of patients with AD is amyloid plaques. However, unlike tangles, plaques have not been found to be a consistent feature of normal aging.

Role of Oxidative Stress
Cognitive impairment has been attributed to oxidative stress, inflammatory reactions and changes in the cerebral microvasculature. The exact impact of each of these mechanisms in affecting cognitive aging is unknown. Oxidative stress is the most controllable risk factor and is the best understood. The online Merriam-Webster Medical Dictionary defines oxidative stress as, "physiological stress on the body that is caused by the cumulative damage done by free radicals inadequately neutralized by antioxidants and that is to be associated with aging." Hence oxidative stress is the damage done to the cells by free radicals that have been released from the oxidation process.

Compared to other tissues in the body, the brain is deemed unusually sensitive to oxidative damage. Increased oxidative damage has been associated with neurodegenerative diseases, mild cognitive impairment and individual differences in cognition in healthy elderly people. In 'normal aging', the brain is undergoing oxidative stress in a multitude of ways. The main contributors include protein oxidation, lipid peroxidation and oxidative modifications in nuclear and mitochondrial DNA. Oxidative stress can damage DNA replication and inhibit repair through many complex processes, including telomere shortening in DNA components. Each time a somatic cell replicates, the telomeric DNA component shortens. As telomere length is partly inheritable, there are individual differences in the age of onset of cognitive decline.

DNA Damage
At least 25 studies have demonstrated that DNA damages accumulate with age in the mammalian brain. These DNA damages include the oxidized nucleoside 8-hydroxydeoxyguanosine (8-OHdG), single- and double-strand breaks, DNA-protein crosslinks and malondialdehyde adducts (reviewed in Bernstein et al. ). Increases in DNA damages with age have been reported in the brains of mouse, rat, gerbil, rabbit, dog, and human. Young 4-day-old rats have about 3,000 single-strand breaks and 156 double-strand breaks per neuron, whereas in rats older than 2 years the level of damage increases to about 7,400 single-strand breaks and 600 double-strand breaks per neuron.

Lu et al. studied the transcriptional profiles of the human frontal cortex of individuals ranging from 26 to 106 years of age. This led to the identification of a set of genes whose expression was altered after age 40. They further found that the promoter sequences of these particular genes accumulated oxidative DNA damages, including 8-OHdG, with age (see DNA damage theory of aging). They concluded that DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a pattern of brain aging that starts early in life.

Chemical changes
In addition to the structural changes that the brain incurs with age, the aging process also entails a broad range of biochemical changes. More specifically, neurons communicate with each other via specialized chemical messengers called neurotransmitters. Several studies have identified a number of these neurotransmitters, as well as their receptors, that exhibit a marked alteration in different regions of the brain as part of the normal aging process.

Dopamine
An overwhelming number of studies have reported age-related changes in dopamine synthesis, binding sites, and number of receptors. Studies using positron emission tomography (PET) in living human subjects have shown a significant age-related decline in dopamine synthesis, notably in the striatum and extrastriatal regions (excluding the midbrain). Significant age-related decreases in dopamine receptors D1, D2, and D3 have also been highly reported. A general decrease in D1 and D2 receptors has been shown, and more specifically a decrease of D1 and D2 receptor binding in the caudate nucleus and putamen. A general decrease in D1 receptor density has also been shown to occur with age. Significant age-related declines in dopamine receptors, D2 and D3 were detected in the anterior cingulate cortex, frontal cortex, lateral temporal cortex, hippocampus, medial temporal cortex, amygdala, medial thalamus, and lateral thalamus One study also indicated a significant inverse correlation between dopamine binding in the occipital cortex and age. Postmortem studies also show that the number of D1 and D2 receptors decline with age in both the caudate nucleus and the putamen, although the ratio of these receptors did not show age-related changes. The loss of dopamine with age is thought to be responsible for many neurological symptoms that increase in frequency with age, such as decreased arm swing and increased rigidity. Changes in dopamine levels may also cause age-related changes in cognitive flexibility.

Serotonin
Decreasing levels of different serotonin receptors and the serotonin transporter, 5-HTT, have also been shown to occur with age. Studies conducted using PET methods on humans, in vivo, show that levels of the S2 receptor in the caudate nucleus, putamen, and frontal cerebral cortex, decline with age. A decreased binding capacity of the 5-HT2 receptor in the frontal cortex was also found, as well as a decreased binding capacity of the serotonin transporter, 5-HHT, in the thalamus and the midbrain. Postmortem studies on humans have indicated decreased binding capacities of serotonin and a decrease in the number of S1 receptors in the frontal cortex and hippocampus as well as a decrease in affinity in the putamen.

Glutamate
Glutamate is another neurotransmitter that tends to decrease with age. Studies have shown older subjects to have lower glutamate concentration in the motor cortex compared to younger subjects A significant age-related decline especially in the parietal gray matter, basal ganglia, and to a lesser degree, the frontal white matter, has also been noted. Although these levels were studied in the normal human brain, the parietal and basal ganglia regions are often affected in degenerative brain diseases associated with aging and it has therefore been suggested that brain glutamate may be useful as a marker of brain diseases that are affected by aging.

Changes in Orientation
Orientation is defined as the awareness of self in relation to one's surroundings Often orientation is examined by distinguishing whether a person has a sense of time, place, and person. Deficits in orientation are one of the most common symptoms of brain disease, hence tests of orientation are included in almost all medical and neuropsychological evaluations. While research has primarily focused on levels of orientation among clinical populations, a small number of studies have examined whether there is a normal decline in orientation among healthy aging adults. Results have been somewhat inconclusive. Some studies suggest that orientation does not decline over the lifespan. For example, in one study 92% of normal elderly adults (65–84 years) presented with perfect or near perfect orientation. However some data suggest that mild changes in orientation may be a normal part of aging. For example, Sweet and colleagues concluded that "older persons with normal, healthy memory may have mild orientation difficulties. In contrast, younger people with normal memory have virtually no orientation problems" (p. 505). So although current research suggests that normal aging is not usually associated with significant declines in orientation, mild difficulties may be a part of normal aging and not necessarily a sign of pathology.

Changes in Attention
Many older adults notice a decline in their attentional abilities. Attention is a broad construct that refers to "the cognitive ability that allows us to deal with the inherent processing limitations of the human brain by selecting information for further processing" (p. 334). Since the human brain has limited resources, people use their attention to zone in on specific stimuli and block out others.

If older adults have fewer attentional resources than younger adults, we would expect that when two tasks must be carried out at the same time, older adults' performance will decline more than that of younger adults. However, a large review of studies on cognition and aging suggest that this hypothesis has not been wholly supported. While some studies have found that older adults have a more difficult time encoding and retrieving information when their attention is divided, other studies have not found meaningful differences from younger adults. Similarly, one might expect older adults to do poorly on tasks of sustained attention, which measure the ability to attend to and respond to stimuli for an extended period of time. However, studies suggest that sustained attention shows no decline with age. Results suggest that sustained attention increases in early adulthood and then remains relatively stable, at least through the seventh decade of life. More research is needed on how normal aging impacts attention after age eighty.

It is worth noting that there are factors other than true attentional abilities that might relate to difficulty paying attention. For example, it is possible that sensory deficits impact older adults' attentional abilities. In other words, impaired hearing or vision may make it more difficult for older adults to do well on tasks of visual and verbal attention.

Changes in memory
There have been many different types of memory identified in humans, such as episodic, semantic, strategic, working, source spatial, and non-declarative. Studies done by Rapp et al., have found that memory functions, more specifically those associated with the medial temporal lobe are especially vulnerable to age-related decline. A number of studies utilizing a variety of methods such as histological, structural imaging, functional imaging, and receptor binding have supplied converging evidence that the frontal lobes and frontal-striatal dopaminergic pathways are especially affected by age-related processes resulting in memory changes.

Genetic changes
Variation in the effects of aging among individuals can be attributed to both genetic and environmental factors. As in so many other science disciplines, the nature versus nurture debate is an ongoing conflict in the field of cognitive neuroscience. The search for genetic factors has always been an important aspect in trying to understand neuro-pathological processes. Research focused on discovering the genetic component in developing AD has also contributed greatly to the understanding the genetics behind normal or "non-pathological" aging.

The human brain shows a decline in function and a change in gene expression. This modulation in gene expression may be due to oxidative DNA damage at promoter regions in the genome. Genes that are down-regulated over the age of 40 include:


 * GluR1 AMPA receptor subunit
 * NMDA R2A receptor subunit (involved in learning)
 * Subunits of the GABA-A receptor
 * Genes involved in long-term potentiation e.g. calmodulin 1 and CAM kinase II alpha.
 * Calcium signaling genes
 * Synaptic plasticity genes
 * Synaptic vesicle release and recycling genes

Genes that are upregulated include:


 * Genes associated with stress response and DNA repair
 * Antioxidant defence

Delaying the Effects of Aging
The process of aging may be inevitable, however one may potentially delay the effects and severity of this progression. While there is no consensus of efficacy, the following are reported as delaying cognitive decline:
 * High level of education
 * Physical exercise
 * Staying intellectually engaged, i.e. reading and mental activities (such as crossword puzzles)
 * Maintaining social and friendship networks
 * Maintaining a healthy diet, including omega-3 fatty acids, and protective antioxidants.

"Super Agers"
Longitudinal research studies have recently conducted genetic analyses of centenarians and their offspring to identify biomarkers as protective factors against the negative effects of aging. In particular, the cholesteryl ester transfer protein (CETP) gene is linked to prevention of cognitive decline and Alzheimer's disease. Specifically, valine CETP homozygotes but not heterozygotes experienced a relative 51% less decline in memory compared to a reference group after adjusting for demographic factors and APOE status.

Cognitive Reserve
The ability of an individual to demonstrate no cognitive signs of aging despite an aging brain is called cognitive reserve. This hypothesis suggests that two patients might have the same brain pathology, with one person experiencing noticeable clinical symptoms, while the other continues to function relatively normally. Studies of cognitive reserve explore the specific biological, genetic and environmental differences which make one person susceptible to cognitive decline, and allow another to age more gracefully.

Nun Study
A study funded by the National Institute of Aging followed a group of 678 Roman Catholic sisters and recorded the effects of aging. The researchers used autobiographical essays collected as the nuns joined their Sisterhood. Findings suggest that early idea density, defined by number of ideas expressed and use of complex prepositions in these essays, was a significant predictor of lower risk for developing Alzheimer's disease in old age. Lower idea density was found to be significantly associated with lower brain weight, higher brain atrophy, and more neurofibrillary tangles

Hypothalamus Inflammation and GnRH
In a very recent study (published May 1, 2013), its is suggested that the inflammation of the hypothalamus may be connected to our overall aging bodies. They focused on the activation of the protein complex NF-κB in mice test subjects, which showed increased activation as mice test subjects aged in the study. This activation not only affects aging, but affects a hormone known as GnRH, which has shown new anti-aging properties when injected into mice outside the hypothalamus, while causing the opposite effect when injected into the hypothalamus. It'll be some time before this can be applied to humans in a meaningful way, as more studies on this pathway are necessary to understand the mechanics of GnRH's anti-aging properties.