Aging brain
Encyclopedia
Age is a major risk factor for most common neurodegenerative diseases, including Alzheimer's disease
, cerebrovascular disease
, Parkinson's disease
and Lou Gehrig's disease. Other risk factors, including genetic mutations, low educational attainments and head injury contribute much less to the risk of these disorders. While a plethora of research has focused on diseases of aging, there are few informative studies on the molecular biology of brain aging in the absence of neurodegenerative disease. 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.
(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. Differing properties of different tissues in the brain may be more or less susceptible to age-induced changes. 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.
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. 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.
of old animals (27–32 years old) compared with young ones (6–9 years old).
, diabetes, hypertension
and arteriosclerosis
make it difficult to distinguish the normal patterns of aging. One of the important comparison aspects between normal aging and pathological aging are 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.
, inflammatory reactions and changes in the cerebral microvasculature. 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." 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. 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. One of these processes includes telomere
shortening in DNA components. Each time a somatic cell
replicates, the telomeric DNA component shortens. As telomere length is partly inheritable, there is individual difference in the age of an individual and the onset of cognitive decline.
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 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. 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)
. Changes in dopamine levels may also cause age-related changes in cognitive flexibility.
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.
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 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.
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, there is also data that 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). 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.
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. 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. 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.
, 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.
. These factors relate to preferred strategies employed by individuals, as well as their susceptibility to neuropathology and help determine whether a person ages gracefully or develops dementia.
The dexterity of aging is a spectrum between normal cognitive aging and outright clinical dementia. The search for genetic factors has always been an important aspect in trying to understand neuro-pathological diseases. In general, cognitive aging is related to an increased trend of developing both Alzheimer’s Disease (AD) and vascular
pathologies. Understanding the genetic component in developing AD has contributed greatly to the understanding the genetics behind normal or “non-pathological” aging.
The ability of an individual to endure this progressive pathology without demonstrating clinical cognitive symptoms is called cognitive reserve
. 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.
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:
Genes that are upregulated include:
Normal aging is distinct from Neurodegenerative disease. DNA damage due to oxidation increase as the brain ages, possibly due to impaired mitochondrial
function.
Neuroinflammation is a common feature of aging in the mammalian brain. Astrogliosis (measured by immunohistochemistry of GFAP
) increases with age in mouse, rat as well as human brain.
While there is no consensus of efficacy, the following are reported as delaying cognitive decline:
Compare with the analog in computer science: software aging
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, cerebrovascular disease
Cerebrovascular disease
Cerebrovascular disease is a group of brain dysfunctions related to disease of the blood vessels supplying the brain. Hypertension is the most important cause; it damages the blood vessel lining, endothelium, exposing the underlying collagen where platelets aggregate to initiate a repairing process...
, Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
and Lou Gehrig's disease. Other risk factors, including genetic mutations, low educational attainments and head injury contribute much less to the risk of these disorders. While a plethora of research has focused on diseases of aging, there are few informative studies on the molecular biology of brain aging in the absence of neurodegenerative disease. However, research does suggest that the aging process is associated with several structural, chemical, and functional changes in the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
as well as a host of neurocognitive changes.
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 TomographyComputed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
(CT) studies have found that the cerebral ventricles expand as a function of age, and this process is known as ventriculomegaly
Ventriculomegaly
Ventriculomegaly is a brain condition that occurs when the lateral ventricles become dilated. The most common definition uses a width of the atrium of the lateral ventricle of greater than 10 mm. This occurs in around 1% of pregnancies. When this measurement is between 10 and 15 mm, the...
. 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. Differing properties of different tissues in the brain may be more or less susceptible to age-induced changes. The brain matter can be classified as either grey matter
Grey matter
Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil , glial cells and capillaries. Grey matter contains neural cell bodies, in contrast to white matter, which does not and mostly contains myelinated axon tracts...
, or white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...
. Grey matter consists of cell bodies in the cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
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 in to 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 in fact, synaptic alterations. Evidence in support of this idea from animal work has also suggested that this cognitive deficit is due to functional and biochemical changes such as 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 manor 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 insulaInsular cortex
In each hemisphere of the mammalian brain the insular cortex is a portion of the cerebral cortex folded deep within the lateral sulcus between the temporal lobe and the frontal lobe. The cortical area overlying it towards the lateral surface of the brain is the operculum...
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. 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
Sulcus
Sulcus may refer to:* Sulcus , a groove, crevice or furrow in medicine, botany, and zoology* Sulcus , a long parallel groove on a planet or a moon-See also:...
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 are not due to neuronal loss or cell death, but is a result of small region-specific 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 cortexPrefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
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 diseaseParkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, diabetes, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
and arteriosclerosis
Arteriosclerosis
Arteriosclerosis refers to a stiffening of arteries.Arteriosclerosis is a general term describing any hardening of medium or large arteries It should not be confused with "arteriolosclerosis" or "atherosclerosis".Also known by the name "myoconditis" which is...
make it difficult to distinguish the normal patterns of aging. One of the important comparison aspects between normal aging and pathological aging are 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 impairments has been attributed to oxidative stressOxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
, inflammatory reactions and changes in the cerebral microvasculature. 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." 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. 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. One of these processes includes telomere
Telomere
A telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos "end" and merοs "part"...
shortening in DNA components. Each time a somatic cell
Somatic cell
A somatic cell is any biological cell forming the body of an organism; that is, in a multicellular organism, any cell other than a gamete, germ cell, gametocyte or undifferentiated stem cell...
replicates, the telomeric DNA component shortens. As telomere length is partly inheritable, 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 dopamineDopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
synthesis, binding sites, and number of receptors. Studies using positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
(PET) in living human subjects have shown a significant age-related decline in dopamine synthesis, notably in the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
and extrastriatal
Extrastriate cortex
The extrastriate cortex is the region of the occipital cortex of the mammalian brain located next to the primary visual cortex, which is also named striate cortex because of its appeareance in the microscope. The extrastriate cortex encompasses multiple functional areas, including V3, V4, V5/MT...
regions (excluding the midbrain
Mesencephalon
The midbrain or mesencephalon is a portion of the central nervous system associated with vision, hearing, motor control, sleep/wake, arousal , and temperature regulation....
). Significant age-related decreases in dopamine receptors D1
Dopamine receptor D1
Dopamine receptor D1, also known as DRD1, is a protein that in humans is encoded by the DRD1 gene.- Function :This gene encodes the D1 subtype of the dopamine receptor. The D1 subtype is the most abundant dopamine receptor in the central nervous system. This G-protein-coupled receptor stimulates...
, D2
Dopamine receptor D2
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene.- Function :This gene encodes the D2 subtype of the dopamine receptor. This G protein-coupled receptor inhibits adenylyl cyclase activity...
, and D3
Dopamine receptor D3
D dopamine receptor is a protein that in humans is encoded by the DRD3 gene.This gene encodes the D3 subtype of the dopamine receptor. The D3 subtype inhibits adenylyl cyclase through inhibitory G-proteins. This receptor is expressed in phylogenetically older regions of the brain, suggesting that...
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
Caudate nucleus
The caudate nucleus is a nucleus located within the basal ganglia of the brains of many animal species. The caudate nucleus is an important part of the brain's learning and memory system.-Anatomy:...
and putamen
Putamen
The putamen is a round structure located at the base of the forebrain . The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that comprises the basal ganglia. Through various pathways, the putamen is connected to the substantia nigra and globus pallidus...
. 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
Anterior cingulate cortex
The anterior cingulate cortex is the frontal part of the cingulate cortex, that resembles a "collar" form around the corpus callosum, the fibrous bundle that relays neural signals between the right and left cerebral hemispheres of the brain...
, frontal cortex, lateral temporal cortex, hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, medial temporal cortex, amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
, medial thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
, and lateral thalamus One study also indicated a significant inverse correlation between dopamine binding in the occipital cortex and age. 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. 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)
Rigidity
Rigid or rigidity may refer to:*Stiffness, the property of a solid body to resist deformation, which is sometimes referred to as rigidity*Structural rigidity, a mathematical theory of the stiffness of ensembles of rigid objects connected by hinges...
. Changes in dopamine levels may also cause age-related changes in cognitive flexibility.
Serotonin
Decreasing levels of different serotoninSerotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
receptors and the serotonin transporter
Serotonin transporter
The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
, 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 shows a trend to decrease with age. Studies have shown older subjects to have lower glutamate concentration in the motor cortexMotor cortex
Motor cortex is a term that describes regions of the cerebral cortex involved in the planning, control, and execution of voluntary motor functions.-Anatomy of the motor cortex :The motor cortex can be divided into four main parts:...
compared to younger subjects A significant age-related decline especially in the parietal gray matter, basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
, 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 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.
Changes in Orientation
OrientationOrientation (mental)
Orientation is a function of the mind involving awareness of three dimensions: time, place and person. Problems with orientation lead to disorientation, and can be due to various conditions, from delirium to intoxication...
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, there is also data that 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). 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. 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 so than 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 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. 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 imagingFunctional imaging
Functional imaging , is a method of detecting or measuring changes in metabolism, blood flow, regional chemical composition, and absorption....
, 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.
Genetic Changes
Variation in the effects of cognitive aging in different individuals is attributable 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 neuroscienceCognitive neuroscience
Cognitive neuroscience is an academic field concerned with the scientific study of biological substrates underlying cognition, with a specific focus on the neural substrates of mental processes. It addresses the questions of how psychological/cognitive functions are produced by the brain...
. These factors relate to preferred strategies employed by individuals, as well as their susceptibility to neuropathology and help determine whether a person ages gracefully or develops dementia.
The dexterity of aging is a spectrum between normal cognitive aging and outright clinical dementia. The search for genetic factors has always been an important aspect in trying to understand neuro-pathological diseases. In general, cognitive aging is related to an increased trend of developing both Alzheimer’s Disease (AD) and vascular
Vascular
Vascular in zoology and medicine means "related to blood vessels", which are part of the circulatory system. An organ or tissue that is vascularized is heavily endowed with blood vessels and thus richly supplied with blood....
pathologies. Understanding the genetic component in developing AD has contributed greatly to the understanding the genetics behind normal or “non-pathological” aging.
The ability of an individual to endure this progressive pathology without demonstrating clinical cognitive symptoms is called cognitive reserve
Cognitive reserve
The term cognitive reserve describes the mind's resilience to neuropathological damage of the brain. The mind's resilience is evaluated behaviorally, whereas the neuropathological damage is evaluated histologically, although damage may be estimated using blood-based markers and imaging methods...
. 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.
The human brain shows a decline in function and a change in gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
. 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 receptorAMPA receptorThe α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog AMPA...
subunitProtein subunitIn structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric... - NMDANMDA receptorThe NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
R2A receptor subunit (involved in learningMemoryIn psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
) - Subunits of the GABA-A receptorGABA A receptorThe GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid , the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in...
- Genes involved in long-term potentiationLong-term potentiationIn neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
e.g. calmodulinCalmodulinCalmodulin is a calcium-binding protein expressed in all eukaryotic cells...
1 and CAM kinase II alpha. - Calcium signaling genes
- Synaptic plasticity genes
- Synaptic vesicle release & recycling genes
Genes that are upregulated include:
- Genes associated with stress response and DNA repairDNA repairDNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
- AntioxidantAntioxidantAn antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
defence
Normal aging is distinct from Neurodegenerative disease. DNA damage due to oxidation increase as the brain ages, possibly due to impaired mitochondrial
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
function.
Neuroinflammation is a common feature of aging in the mammalian brain. Astrogliosis (measured by immunohistochemistry of GFAP
Glial fibrillary acidic protein
Glial fibrillary acidic protein is an intermediate filament protein that was thought to be specific for astrocytes in the central nervous system . Later, it was shown that GFAP is also expressed by other cell types in CNS, including ependymal cells...
) increases with age in mouse, rat as well as human brain.
Environmental Influences
The anonymous division between genetic and environmental factors has been explored using twin studies. It’s unknown how much credit should be given to either genetics or environmental influences, but it is known that both play a significant part in cognitive aging and both areas should be studied thoroughly. Research by Anderton has clearly shown one important environmental power as being an individual’s level of education. It has been made known that poor educational achievement quickens memory decline and increases the likelihood of dementia. Not only this, research has shown that individuals with high levels of education, intellectual ability and social economic status are in general, more likely to engage in lifestyles that promote graceful cognitive aging.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:
- Physical Exercise
- Staying intellectually engaged i.e. Reading and mental activities (such as crossword puzzles)
- Maintaining social and friendship networks
- Minimizing the stressful events in your life
- Maintaining a healthy diet i.e. 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.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 tanglesSee also
- Aging
- Aging movement controlAging movement controlNormal aging movement control in human is about the changes on the muscles, motor neurons, nerves, sensory functions, gait, fatigue, visual and manual responses, in men and women as they get older but who do not have neurological, muscular or neuromuscular disorder...
- Alzheimer's diseaseAlzheimer's diseaseAlzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
- DementiaDementiaDementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
- DNA damage theory of agingDNA damage theory of agingThe DNA damage theory of aging proposes that aging is a consequence of unrepaired DNA damage accumulation. Damage in this context includes chemical reactions that mutate DNA and/or interfere with DNA replication. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear...
- Life extensionLife extensionLife extension science, also known as anti-aging medicine, experimental gerontology, and biomedical gerontology, is the study of slowing down or reversing the processes of aging to extend both the maximum and average lifespan...
- List of life extension related topics
- Memory and agingMemory and agingOne of the key concerns of older adults is the experience of memory loss, especially as it is one of the hallmark symptoms of Alzheimer's disease. However, memory loss is qualitatively different in normal aging from the kind of memory loss associated with a diagnosis of Alzheimer's...
- Neuropsychological testNeuropsychological testNeuropsychological tests are specifically designed tasks used to measure a psychological function known to be linked to a particular brain structure or pathway. Tests are used for research into brain function and in a clinical setting for the diagnosis of deficits. They usually involve the...
- Nun StudyNun StudyThe Nun Study of Aging and Alzheimer's Disease is a still-running longitudinal study, begun in 1986, to examine the onset of Alzheimer's Disease. David Snowdon, the founding Nun Study investigator, originally began his research at the University of Minnesota, but moved it to the University of...
- SenescenceSenescenceSenescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
- Reliability theory of aging and longevityReliability theory of aging and longevityReliability theory of aging and longevity is a scientific approach aimed to gain theoretical insights into mechanisms of biological aging and species survival patterns by applying a general theory of systems failure, known as reliability theory.-Overview:...
Compare with the analog in computer science: software aging
Software aging
In software engineering, software aging refers to progressive performance degradation or a sudden hang/crash of a software system due to exhaustion of operating system resources, fragmentation and accumulation of errors. A proactive fault management method to deal with the software aging...