Structural Changes
As people age, there are a number of changes that take place, whether physical, chemical or biological. 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.[1][2] 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.[3] The brain is very complex, and is composed of many different areas and types of tissue, or matter. Differing properties of different tissues in the brain may be more or less susceptible to age-induced changes.[1] The brain matter can be 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.[1]Loss of Neural Circuits and Brain Plasticity
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 manor in vivo.[7] 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.[7] 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.[7] 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. 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.[7] 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.[7] It has also been found that the width of sulcus not only increases with age,[8] but also with cognitive decline in the elderly.[9]Age-Related Neuronal Morphology
There is converging evidence from cognitive neuroscientists around the world that age-induced cognitive deficits may not due to neuronal loss or cell death, but rather may be the result of small region-specific morphology of neurons.[5] 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.[6] 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).[6]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.[10] One of the important comparison aspects between normal aging and pathological aging are neurofibrillary tangles. Neurofibrillary tangles are composed of paired helical filaments (PHF).[11] In normal, non-demented aging, the number of tangles in each affected cell body is relatively low[11] and restricted to the olfactory nucleus, parahippocampal gyrus, amygdala and entorhinal cortex.[12] 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.[12] 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.[12]Role of Oxidative Stress
Cognitive impairments has been attributed to oxidative stress, inflammatory reactions and changes in the cerebral microvasculature.[13] The exact intensity 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."[14] Hence, simply put, 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 abnormally sensitive to oxidative damage.[15] 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.[15] Oxidative stress can damage DNA replication and inhibit repair through many complex processes. One of these processes includes telomere shortening in DNA components.[16] Each time a somatic cell replicates, the telomeric DNA component shortens. As telomere length is partly inheritable,[16] there is individual difference in the age of an individual and the onset of cognitive decline.
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,[17] notably in the striatum and extrastriatal regions (excluding the midbrain).[18] Significant age-related decreases in dopamine receptors D1, D2, and D3 have also been highly reported.[19][20][21][22][23] A general decrease in D1 and D2 receptors has been shown,[21] and more specifically a decrease of D1 and D2 receptor binding in the caudate nucleus and putamen.[20][23] 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[19] One study also indicated a significant inverse correlation between dopamine binding in the occipital cortex and age.[20] Postmortem studies as well 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.[22] 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 (neurology).[24] Changes in dopamine levels may also cause age-related changes in cognitive flexibility.[24]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.[23] A decreased binding capacity of the 5-HT2 receptor in the frontal cortex was also found,[21] as well as a decreased binding capacity of the serotonin transporter, 5-HHT, in the thalamus and the midbrain.[25] 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.[26]Glutamate
Glutamate is another neurotransmitter that shows a trend to decrease with age.[27][28][29] Studies have shown older subjects to have lower glutamate concentration in the motor cortex compared to younger subjects[29] 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.[27][28] Although these levels were studied in the normal human brain, the parietal and basal ganglia regions are often affected in degenerating brian 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.[27]Neuropsychological Changes
Changes in Orientation
Orientation is defined as the awareness of self in relation to one’s surroundings [30] 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.[31] 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. [32][33] For example, in one study 92% of normal elderly adults (65–84 years) presented with perfect or near perfect orientation. [34] However, there is also data that suggest that mild changes in orientation may be a normal part of aging. [35][36] 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” [36] (p. 505). Hence, research up to this point suggests that normal aging is not associated with significant declines in orientation to person, place, or time. But, mild difficulties may be a part of the aging process and are not necessarily a sign of pathology.Changes in Attention
Many older adults notice a decline in their attentional abilities.[37] 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).[38] 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 so than younger adults. However, a large review of studies on cognition and aging suggest that this hypothesis has not been wholly supported.[39] While some studies have found that older adults have a more difficult time encoding and retrieving information in a divided attention situations than do younger adults, other studies have not found meaningful differences.Similarly, one might expect older adults to do poorer 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. [40] 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. [37]
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.[1] 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.[6] A number of studies utilizing a variety of methods such as histological, structural imaging, functional imaging, and receptor binding have converging evidence that the frontal lobes and frontal-striatal dopaminergic pathways are especially affected by age-related processes resulting in memory.[1]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. [10] [11] The search for genetic factors has always been an important aspect in trying to understand neuro-pathological diseases. 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.[11]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 & recycling genes
- 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 [11] [41]
- Physical Exercise [42]
- Staying intellectually engaged i.e. Reading and mental activities (such as crossword puzzles) [43]
- Maintaining social and friendship networks [44]
- Maintaining a healthy diet i.e. Omega-3 fatty acids, and protective antioxidants [10]
"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[45]. 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 within the context of an aging brain is called cognitive reserve.[41] [13] This hypothesis comes into play when two patients have the same brain pathology, one leading to noticeable clinical symptoms, while the other continues to function relatively normally. Cognitive reserve explores the specific differences between these two individuals, biologically, genetically and environmentally which makes one more susceptible to an increased decline in cognitive functioning, and allows the other to age more gracefully.Nun Study
A study funded by the National Institute of Aging, studied a group of 678 Roman Catholic sisters and the effects of aging. The researchers used autobiographical essays that were collected as the nuns joined Sisterhood. Findings suggest that essays that early idea density, defined by number of ideas expressed per ten words and the use of complex prepositions, was a significant predictor of its author’s 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 [46]See also
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