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| Year : 2010 | Volume
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| Issue : 4 | Page : 595-604 |
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| Biology of aging brain |
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SK Shankar
Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore - 560 029, Karnataka, India
Click here for correspondence address and email
| Date of Web Publication | 27-Oct-2010 |
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 Abstract | | |
Normal aging of the nervous system is associated with some degree of decline in a number of cognitive functions. With the present day attempts to increase the life span, understanding the metabolic interactions and various mechanisms involved in normal neuronal aging continues to be a challenge. Loss of neurons is now recognized to be more modest than the initial estimates suggested and the loss only affected some of the specific neuroanatomical areas like hippocampus and prefrontal cortex. Individual neurons in addition show reduced size of dendritic and axonal arborization. Neurons have significant homeostatic control of the essential physiological functions like synaptic excitability, gene expression and metabolic regulation. Deviation in these normal events can have severe consequences as observed in aging and neurodegeneration. Based on experimental evidence, the evolution of aging is probably the result of altered metabolic triad: the mitochondria, reactive oxygen species and intracellular calcium homeostasis. Perturbations in the metabolic and functional state of this triad lead to a state of decreased homeostatic reserve, where the aged neurons still could maintain adequate function during normal activity. However, these neurons become vulnerable to the stress of excessive metabolic loads associated with spells of ischemia, trauma progressing to neuronal degeneration. Age-related neuronal dysfunction probably involves a host of subtle changes involving the synapses, receptors, neurotransmitters, cytological alterations, electrical transmission, leading to cognitive dysfunction. An exaggeration of it could be the clinical manifestation of dementia, with intraneuronal accumulation of protein aggregates deranging the metabolic state. This review deals with some of the structural, functional and metabolic features of aging nervous system and discusses briefly the functional consequences. Keywords: Aging brain, calcium homeostasis, mitochondria, neurodegeneration, reactive oxygen species
How to cite this article:
Shankar S K. Biology of aging brain. Indian J Pathol Microbiol 2010;53:595-604 |
| Introduction | |  |
Aging is a universal and secular phenomenon with no regard to geography, ethnicity, gender or religion. With advances in health care facilities, even in the developing countries, the aging population is increasing in number. In the year 2005, the world population stood at 6514.7 million, with India accounting for 1134.4 million and it has reached to 1147 million in the year 2008. [1] Of this, nearly 90 million (7.9%) are aged above 60 years (43 million males and 47 million females) and 0.6% are above the age of 80 years. There is always a murmur of curiosity and expectation when the discussion leans toward centurions. The Old Testament of the Bible is full of supercenturians. Adam lived for 930 years and Methuselah lived for 969 years. After the biblical flood, Abraham lived only till the age of 275 years and Joseph died at the age of 110. Till date, Madame Jeanne Calment holds the Guinness World Book of Record for the oldest certified life span of the human being, having lived for 122 years and 164 days, and she died in August 1997. Similarly, Indian mythology also has records of "Puranapurushas" who have lived long beyond the expected life span of today. In Himalayan monasteries, many of the Buddhist monks are said to be supercenturians. In the pre-Roman Italy, the life span was recorded at between 28 and 42 years. [2]
From 1840 onward to the present day, a steady pace in increase of life expectancy has been recorded, standing currently at 85 years for women and lesser for men. [3] People speculate that Madame Jeanne Calment is either an exception or a pioneer along the road to an ever-expanding life expectancy. The future prospects of relative immortality or negligible senescence may be achieved in the light of various new strategies in engineering, [4] including nanotechnology, as recently suggested by Ray Kurzweil. This year Nobel Prize winners Blackburn, Greider and Szostan have brought to the forefront the phenomenon of repairing of DNA, the building block of the living system in aging and cancer biology, by telomerase enzyme induction and altering the process of senescence. [5]
In the process of understanding the mechanism that regulates aging in organs like brain, cardiac myocytes and retinal pigment epithelial cells, all being post-mitotic cells, it is essential to realize that these cells do not follow the "rules of replicative senescence" which occurs in constantly dividing cells having entered the terminal differentiation, which is the beginning of their decline. [6] Aging is a three stage process of evolution: the metabolism, damage and pathology in the cells. [4] Metabolism, the life sustaining process, generates toxins, more in long-living post-mitotic cells like neurons (necessary for long time memory) and cardiac myocytes (to facilitate compensatory hypertrophy) and these toxins accumulate in the cells as toxic biological products. [7] They are stored in various cellular storage organelles like lysosomes, phagosomes and proteosomes, with differing degradation mechanism and kinetics. The only form of cell damage that is not eliminated, but reproduced during cell division, is nonlethal nuclear and mitochondrial DNA changes. [8] Lipofuscin is a nondegradable intralysosomal polymeric substance produced during aging. An interaction between senescent lipofuscin loaded lysosomes and mitochondria appears to play a pivotal role in the evolution of cellular senescences. [9] The toxic and degradation products in the cells hamper mitochondrial turnover, leading to accumulation of "aged" mitochondria deficient in ATP, but releasing reactive oxygen species, manifesting as "pathology" related to aging. [10] These sequences of events appear to compromise cellular adaptability, trigger proapoptotic pathway, finally leading to cell death. The complex interaction of various phases in aging needs to be correlated with organ-specific events to understand the biology of brain senescence and neurodegeneration.
Biological aging is not tied absolutely to chronological aging, as exemplified by dementing illnesses with cognitive deficits manifesting at a younger age. Based on cross-cultural epidemiological studies, dementia is reported to be somewhat lower in Asian countries compared to the West. [11],[12] To gain an insight into the evolution of dementia and cognitive failure, it is essential to have a phenomenological understanding of the biology of aging.
| Age-Related Changes in the Brain | | |
The volume and weight of the brain decline with age at a rate of about 5% per decade after the age of 40 years, the decline increasing with age over 70 years. The decrease in volume is relatively diffuse and uniform in cerebral white matter; the gray matter of frontal and parietal cortex, and striatum are more affected compared to temporal cortex, cerebellar vermis and hippocampus; and the occipital cortex is least affected. [13] The finding that prefrontal cortex is most affected and the occipital the least affected fits well with cognitive changes observed with aging. [14],[15] Frontal and temporal cortex is more affected in men in contrast to hippocampus and parietal cortex in women. [16]
The classical age-related features in the brain recognized by the pathologists are shown in [Figure 1]. | Figure 1 :Spectrum of pathological changes in aging human brain . (a) Brain with thickened leptomeninges in the left side. On the right, the arachnoid is stripped off to show sulcal widening and atrophy of frontal and parietal lobes (70-year-old male); (b) coronal slice of brain highlighting frontal and temporal atrophy, mild dilation of ventricle and atherosclerosis of the middle cerebral artery (70-year-old male); (c) Bielschowski's silver stain showing diffuse granular and mature SP with central core of amyloid in the frontal cortex (72-year-old male with early cognitive deficits, silver stain ×80); (d) flame shaped neurofibrillary tangle in a pyramidal neuron (note a large nucleus in the cell reflecting viability of the neuron yet; Bodian silver stain ×240); (e) pyramidal neurons, viewed under crossed polarized light following congo red staining, show greenish birefringence, indicating beta pleated fibrillar nature of cytoskeletal proteins in the neurofibrillary tangles (congo red ×200); (f) tau immunolabeling of the neurofibrillary tangles in the neurons (tau ×200); (g) Bodian silver staining of a mature SP; the central amyloid core (arrow) and bulbous threads of neurites are argentophilic; Bodian silver ×320; (h) the mature senile plaque with central core and the Carona around (arrow) and another small plaque immunolabeled by antibody to Aß (ß amyloid ×240); (i) tau antibody immunolabeling: the neuropil threads with bulbous ends in a senile plaque (tau ×300); (j) glial fibers and reactive astrocytes participating in the formation of SP encircling the central pale core of amyloid (arrow) (GFAP ×320); (k) glial fibers around a small, thickened and hyaline arteriole in the cerebral cortex containing amyloid deposit (arrow) (GFAP ×200); (l) congophilic amyloid angiopathy viewed under crossed polarized light showing the characteristic birefringence (congo red ×300); (m) subpial concentrically calcified corpora amylacea representing degenerated astrocytes (H and E ×240); (n) subpial corpora amylacea immunolabeled with ubiquitin antibody (ubiquitin ×120); (o) Lewy body in a melanized neuron in substantia nigra in a 68-year-old lady with Parkinson's disease (H and E ×320)
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- The leptomeninges, especially along the parasagittal zone, show thickening and sclerosis of the arachnoidal villi, partially obliterating the microchannels for cerebrospinal fluid (CSF) drainage into superior sagittal sinus. Focal ossification of dura and arachnoid is not unusual, as evident on imaging. The dura is adherent to the interior of the skull vault with fenestrations and collagen breakdown.
- The ventricular system and subarachnoid space expands to fill the space created by shrinkage of brain and volume loss. With aging, the CSF production falls while the outflow resistance increases due to sclerosed arachnoids villi. [17],[18],[19] The decline in CSF turnover and the age-associated arteriolosclerosis and capillary basement membrane thickening is believed to compromise periarteriolar interstitial fluid drainage pathway in the brain., leading to defective nutrient and oxygen exchange at the microvascular level. [20],[21],[22] This facilitates deposition of amyloid b (Ab) protein in the aged brain and much more in Alzheimer's disease. [23],[24],[25] Probably, a similar mechanism is operational in diabetics, in cases ofCcerebral Autosomal Dominat Aretriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) and those with metabolic and genetic risk factors for cerebral stroke.
- An increase in the number of corpora amylacea, which are PAS positive, spherical, polyglucosan bodies, considered to be dystrophic and calcified glial elements. [13],[26] These are preferentially located around blood vessels in basal ganglia and thalamus, subependymal and subpial zones diffusely.
- Increase in the size of astrocytes and microglia. Both these cells, especially the microglia, are found in association with senile plaques (SP). Thorn shaped, tau positive astrocytes increase in frequency with aging, and are observed in nearly 50% of individuals by the eighth decade, in subpial and subependymal zones. [27] The microglia show signs of activation and expression of class II, MHC antigens. [28] Oligodendroglia do not reveal overt structural changes with aging.
- Increase in lipofuscin (insoluble, autofluorescent glycolipoprotein) content of neurons, especially in large cortical and thalamic neurons, inferior olivary nuclei and spinal motor neurons. [29],[30],[31] Neuromelanin in substantia nigra and locus coeruleus, barely visible at birth, but readily visible by 5-6 years of age, is a byproduct of dopamine synthesis and storage, and remains s table with age. Neuromelanin is rich in Fe ++ ion that participates in oxidative stress and can be visualized by magnetic resonance imaging (MRI).
- Increased amount of iron reaches the brain with aging and concentrates in the cortical ribbon and nuclear areas by selective uptake mechanism, traversing the blood brain barrier. It is not clear how the Fe ++ ion is released and accumulates in the brain with age. [32] Iron is an essential component of many enzymes in the nervous system.
- Neurofibillary tangles (NFT), (hyperphosphorylated neurifilaments forming compact skeins inside the cortical neurons, with preference to certain cortical areas) and senile plaques (SP) (extracellular round, plaque like structures formed by axonal terminals around a central granular or compact amyloid) the hallmarks of Alzheimer's disease, also occur as an almost invariant feature of aging. The NFT and SP occur within the same stereotyped anatomical regions, both in normal aging and Alzheimer's disease, the severity of the lesions increases with age and disease. [33],[34],[35] Similar to Western developing countries, the brains of aged people from India also reveal NFT and SP with a similar frequency and phosphorylated cytoskeletal protein profile. [36] These features are sparse in the frontal cortex of nondemented aged. The hippocampus and frontal cortex appear to be more vulnerable than the other regions for the formation of NFT/SP in cases of Alzheimer's disease (AD). They are also found in the temporal cortex, amygdala and basal nucleus of Meynert, but not in cerebellum, thalamus, striatum, motor cortex, midbrain and spinal cord. The lack of consistent correlation between the presence of SP and NFT to any specific topographic area in the aged brain suggests that NFT and SP formation are independent events, though structurally and antigenically related. Neuronal loss and synaptic dysfunction secondary to NFT and dystrophic neuritis (ubiquitinated neuropil threads) could be the cause for cognitive impairment than just accumulation of Ab and structural changes. [37]
- Increase in the amount of advanced glycation end products [38] promoting Ab protein deposition in aged brain contributes to the pathology. Other amyloidogenic proteins like a synuclein, apolipo protein-E, tau also participate in the process. Common and almost universal functional diseases in cognition and motor function in normal aging and neurodegenerative diseases like AD and Parkinson's disease (PD) suggest participation of altered protein sequences in the evolution. However, the factors responsible for the shift from normal aging to dementing illness are not clear. It appears that the shift from relative health to disease is related to neuronal network, synaptic reparative process and plasticity, than the classically described pathological hallmarks described from the time of Alzheimer.
- Aging is associated with widespread neuronal shrinkage and structural changes in the dendritic morphology, alterations in neurotransmitter receptors and electrophysiological properties. Buell and Coleman suggested that dendritic growth is still possible in old age, similar to reparative processes in synaptic structure. [39] Dendritic branching and length appeared to be greater in aged individuals than in younger adults and people with dementia. No regression in dendritic length with age is noted. With increasing age, swollen axonal spheroids are found in globus pallidum, pars reticulata of substantia nigra, caudal medulla and anterior horns of spinal cord. The age-related changes in the dendritic arbor and dendritic spines of pyramidal neurons in prefrontal, superior temporal and precentral cortices are noted in humans. This dendritic regression and spine loss may probably underlie the first signs of cognitive decline in learning and memory performance noted in normal aging. With advancing age, the number of neurons expressing ionotrophic neurotransmitter receptors and the frequency of spontaneous excitatory postsynaptic currents are reduced while the electrical firing pattern in the neurons involved in information processing is perturbed leading to disturbed cognitive performance. [40]
- White matter lesions like lenkoariosis increase with age, MRI studies have shown their prevalence in over 90% of individuals above the age of 65 years. The prevalence increases with age and associated diabetes and hypertension, correlating with impaired cognitive function. [40],[41],[42],[43],[44]
| Relook into Quantitative Studies | | |
Though a large body of literature describing age-related changes in the brain is available, surprisingly, for a long time, people have not verified the technological issues in the methodology employed. This has resulted in erroneous data gaining currency as facts. Many of the studies on aging have been carried out in developing countries and the observations have been considered secular to diverse geographic and ethnic populations. Even though the weights and volumes of thousands of brains have been recorded, the members of very elderly have been relatively low. [45],[46] Many of the studies recording the normal brain weight and volume in the old age have neglected to exclude the brains from individuals with Alzheimer's disease and multisystem atrophy, the incidence of which increases significantly with age and the brains are atrophic. With the advent of MRI, the brain volume was found to decrease with age. [47] Following the study by Brody in 1955 on a limited number of brains and in two-dimensional space, and further corroborated by subsequent workers following similar methodology, it is believed that 10-60% decline in cortical neuronal density occurs between late childhood and old age. [48] Introduction of stereological principles with optical dissector and precise mathematical rules has facilitated reliable, reproducible estimates of neuronal number in an unbiased way, in a three-dimensional plane. This has led to the conclusion that the cell loss described in certain anatomical areas does not reflect a feature in normal aging, but is indeed pathological. The overall data suggested a remarkable preservation of neurons across the age span in a vast majority of brain regions examined (contrary to the general impression perpetuated in general scientific literature) in humans, [49],[50] non-human primates [51] and rodents. [52] Similarly, contrary to earlier reports of significant depletion of neuronal dendritic branching in human hippocampus, the dendritic branching and length appeared to be greater in the aged people than in young adults and patients of senile dementia. [39] However, preferential reduction in dendritic branching in certain anatomical areas is confirmed. Similarly, the spine density changes are also region-specific, [53],[54] with advancing age, contrary to earlier belief.
| Age-Related Behavior Changes | | |
In aged non-human primates, there is a 30% reduction in neuronal number in area 8A of dorsolateral prefrontal cortex, which correlates with impaired performance on working memory task. [55] As hippocampus and prefrontal cortex are particularly vulnerable to the aging process, performance of tasks that require information processing in these regions declines with age. Compared with younger adults, the aged show a decline in spatial memory and episodic memory, and thus have deficits in retrieving the contextual details of these memories. [56],[57] An association has been found between the age, reduction in prefrontal cortex volume, increased subcortical white matter lesions (WML) and increase in preservative behavior of the aged (decreased executive function). [58] This is also the feature in Alzheimer's disease. Based on functional MRI and neurophysiological testing, the older brains show more symmetric activation, especially for episodic memory tests and visual perception. [59] The enhanced symmetric hemispherical activation referred to as HAROLD (hemispheric asymmetry reduction in old age) is probably an attempt to compensate and recruit additional neural networks, as some of the specific areas are not accessible. [60] In the hippocampus, following neuronal cell recordings, patterned neuronal activity is noted, reflecting the special position of the animal in an environment (the position in space-map like), with the neurons being labeled as "place cells". [61] This field expands asymmetrically during repeated trials. The magnitude of this field expansion decreases in aged rats. In the young rats, the "place map" for a given environment remains s table for months and rat can retrieve the map to find special orientation and the target learnt. The aged rats, removed from the environment and returned later, fail to retrieve the original map and an independent group of neurons is activated. [62] This feature is similar to spatial disorientation and difficulty in tracing the known path experienced in the aged and more so in Alzheimer's disease. This is partly mediated by NMDA (N-methyl-D-aspartic acid) receptors and protein synthesis, which is depleted with age. [63]
| Synapses and Aging | | |
The number and size of synapses change during aging and in response to environmental stimuli. During the normal aging, the number of synapses may alter depending on the anatomical area. [34],[64],[65] In areas with decreased number, the size of the synapses increases as a compensatory phenomenon. In contrast to normal aging, profound fall in synaptic number occurs in case of Alzheimer's disease in anatomical areas involved in memory and learning, [66] and lesser in cases of Parkinson's disease and Huntington's disease. The synaptic degeneration precedes the cell death in the disease process. Synaptic alterations, abnormalities in signal transduction pathways and associated functional deficits may be the pivotal events in neurodegenerative changes. Ab protein deposition in synaptic terminals leads to impairment of ATPases, glucose and glutamate transporters. [67],[68] Similarly, intracellular accumulation leads to mitochondrial dysfunction, oxidative stress and activation of caspase cascade and altered Ca ++ ion homeostasis. Neurotrophic factors and estrogen may protect against Alzheimer's disease, preserving the transporter function of synapse in the presence of Ab. A vast majority of signal transduction pathways regulating the structural and functional plasticity and survival of neurons are located in synapses and these are sensitive to age-related low energy states and oxidative stress. Cellular adaptation to aging, like enha nced neurotrophic factor signaling supports resistance to oxidative stress and metabolic insults and maintains mitochondrial function, mediated through heat shock proteins (HSPs). [15] Many of these adaptive pathways are positively influenced by intellectual and physical activity, coupled with caloric restriction and low cholesterol-low fat diet and less exposure to environment toxins. [69]
| Stress Proteins in Neurodegeneration | | |
Accumulation of abnormal protein aggregates by misfolding of constitutive intracellular proteins and failure to clear them has been considered the pathogenetic basis of various neurodegenerative diseases. Stress proteins or "Heat Shock Proteins" are ubiquitous cellular components functioning as molecular chaperons controlling molecular folding and transport of proteins, and they regulate apoptosis, control inflammatory pathway and secrete inflammatory mediators. Accumulation of the misfolded, easily non-degradable proteins in the cell, leading to formation of hyperphosphorylated insoluble inclusions is considered the "dysfunction or failure" of HSPs. [70] HSPs are also found to be relevant to more acute forms of brain trauma like spinal card injury, stroke, to limit the degree and extent of injury. HSP 70 and 73 are constitutive and HSP 72 is an inducible form, following any form of stressor to nervous system. [71] HSP 70 and 72 are induced in reactive astrocytes, oligodendroglia, microglia and neurons in various neurodegenerative diseases, in an attempt to prevent intracellular aggregation of amyloid peptides and phosphorylated tau in Alzheimer's disease, [72] block nuclear aggregation of "huntingtin" in Huntington's disease, etc. [73] Upregulation of gate keeper tumor suppressor gene, p53, diminishes the risk of developing cancer, but simultaneously accelerates aging phenomenon. [74]
| Calcium Homeostasis in Aging | | |
The Ca ++ ion is a central signaling molecule in various vital cellular functions like energy production, cell proliferation, gene regulation, membrane excitability, synaptic transmission and apoptosis. Because of its ubiquitous nature, vital role in cell signaling and detrimental effect at high levels, it is maintained in the cell at a level 10,000 times lower than the concentration in extracellular space. [75] Ca ++ signaling depends essentially on a rapid and transient increase in intracellular level by influx through ligand gated glutamate receptors (NMDA-receptor), and voltage dependent Ca ++ channels and release from intracellular stores like mitochondria and endoplasmic reticulum. [76],[77],[78],[79] In the case of neurons, Ca ++ sources vary depending on their size, transmitter system and location in neural circuits, whether excitatory or inhibitory. Usually, a modest rise in intracellular calcium levels is countered by rapid calcium buffering, involving calcium binding proteins in the cytosol like parvalbumin, calbindin, calretinin, calmodulin, hippocalcin, etc., and extrusion to extracellular space or to endoplastic reticulum and mitochondria for sequestration. [80],[81] A decrease in Ca ++ buffering or delayed removal results in larger or prolonged calcium responses, characteristic of aged neurons. [82] Na + and Ca ++ exchangers and plasma membrane Ca ++ ATPases are the major transport systems capable of rapidly extruding large amount of Ca ++ from the cell cytoplasm to extracellular space. An age-related decline in the function of these transport systems disturbing calcium homeostasis has been suggested to contribute to age-related neurodegenerative diseases. [83] During aging, endoplasmic reticulum related buffering system is deranged in peripheral nervous system, [84] while mitochondrial buffering system is altered at the synapses in CNS, [85] thus revealing regional variation. Mitochondria from aged animals show structural alterations in mitochondrial DNA and mitochondrial membrane, reduced mitochondrial buffering capacity, chronically depolarized state of the membrane and reduced ATP synthesis. [86] Age also induces a decrease in the number of mitochondria, large bioenergetically inefficient ones replacing the functionally efficient, small-sized forms. [87] Following neuronal activity, the ATP content falls significantly in aged neurons in contrast to young ones, though the resting levels are comparable. New evidence suggests that the mechanisms of calcium dysregulation are restricted to certain neuroanatomical sites and specific cell populations. For example, an age-related increase in L-type calcium channels is relatively specific for hippocampus pyramidal cells and decrease in N. Methyl D. Aspartate (NMDA) receptor function in hippocampus and frontal cortex. Though the fall in NMDA r eceptor function with age may protect against rise in intracellular calcium facilitating cell survival, the same decline of NMDA receptor leads to memory decline as an important epiphenomenon. The genetic factors controlling cell-specific susceptibility to calcium dysregulation and oxidative stress can produce patterns of neuronal death, which characterize neurodegenerative disease. [88]
| Neuroendocrine Changes and Aging | | |
Age results in a decline in neuroendocrine functions and constitutes a potential factor in the development of several neurodegenerative diseases. Interest in preventive and therapeutic potential of hormonal substitution therapy for the age-related disorders has increased. Many of the common ailments encountered in the aging individual can be related to neuroendocrine dysfunction. The examples include (a) Parkinson's disease: reduced dopaminergic function, (b) Alzheimer's disease: reduced hypothalamic/cholinergic/noradrenergic function, (c) depression: loss of serotoninergic neurons, (d) insomnia: depletion of functional GABA activity, (e) weakness and asthenia: deficiency of growth hormone, (f) osteoporosis: growth hormone and sex steroid deficiency. The list grows with muscular atrophy, abnormalities of fat deposition, etc., manifesting due to endocrine abnormalities in aging. [89]
| Aging and Blood Vessels | | |
The conducting arteries become stiffer with age, altering the hemodynamics. With aging, the elastic fibers and collagen undergo fragmentation and thinning due to mechanical factors, further accelerated by hypertension, diabetes, uremia and atherosclerosis. [90] The possible causes for the age-related fragmentation of elastic and collagen fibers are mechanical features, the matrix matelloproteases and formation of protein crosslinks due to advanced glycation end products (AGES) and calcification by enhanced expression of bone morphogenetic proteins 2 and 4 (BMP 2,4), inability of smooth muscle cells to prevent calcification and expression of endothilin by vascular endothelial cells. AGES in the arteries, especially in diabetics, by cross linking of collagen fibers, cause stiffening of arteries. [91],[92],[93] Soluble AGES activate monocytes and suppress macrophage migration and enhance endothelial permeability. [94] At morphological level, the cerebral vessels, including the ones at arteriolar and capillary level, show essentially similar features as noted in peripheral parenchymal organs, even with hypertension and diabetes. With cerebral atrophy following aging, the vessels in the cortical ribbon become tortuous and thickened, resulting in reduced perfusion pressure and nutrient supply.
Changes in cerebral microcirculation have been found to be associated with WML observed with aging. [95] The microvascular ability to respond to metabolic demands falls with aging. This could be responsible for significant overlaps between Alzheimer's disease and multi-infarct dementia. A postmortem study reported 77% of patients with vascular dementia having AD pathology, [96] and high blood pressure has been found to be associated with increased formation of neurofibrillary tangles characteristic of AD. [97] This suggests that vascular factors may unmask or enhance the underlying AD pathology. [98]
| Gene Expression in Aging | | |
It is known that to maintain the neural network and appropriate electrical potentials for acquiring and storing memory, gene expression and consequent protein synthesis are essential. Immediate early genes (IEG) are expressed for neural plasticity. They are regulated by specific patterns of synaptic activity underlying information storage. [99] The inducible forms of IEG as transcriptional factors include CJun, Cfos and Zif268. The effector proteins of IEG are neuronal activity regulated pentraxin (NARP) and activity-regulated cytoskeletal gene (Arc). NARP localizes to synapses, [100],[101] while Arc selectively localizes to dendrites that receive synaptic input from axons. [102] Arc expression is necessary for maintenance of long-term memory. Using gene microarray technology and proteomics, it is found that behaviorally relevant upregulated genes include those associated with intracellular Ca ++ releasing pathway and inflammation and the downregulated ones are those modulating energy metabolism and biosynthesis of activity regulated synaptogenesis. [103] This upregulated Ca ++ releasing pathway and inflammation related genes reflect the participation of microglia and astroglia in the formation of SP and activation of amyloid precursor protein to form fibrillar Ab protein in neurodegenerative diseases like AD. Downregulated gene for energy metabolism and synaptogenesis accounts for cognitive deficiency and memory failure.
It is essential to realize that microarray analysis of genes and proteins is a single point study, probably at a resting stage. This may not truly reflect the dynamic changes that take place during learning and memory and synaptic modulations. Two more often talked about genes influencing brain aging are apolipo protein E (ApoE) and prion protein (PRNP). ApoE has four alleles. The isoform ApoE-Ξ4 is associated with lower cognitive performance, thus forming a risk factor for AD, and defective repair processes following neurotrauma and stroke. [104] ApoE-Ξ2 isoform is overexpressed in centurions, [105] reflecting its role in normal aging. Prion protein, on the other hand, plays a protective role against oxidative and other cellular stresses. [106] Individuals homozygous for methionine at codon 129 of prion protein are found to be cognitively better at the age of 79 in contrast to heterozygotes in a Scottish Cohort. [107] The other genes influencing the aging and related repair mechanism are those associated with insulin signaling, [108] DNA methylation, [109] DNA repair and lipid metabolism. [110] Alzheimer's disease is considered to be related to cholesterol metabolism. The other genetic pathways found to have a role in evolution of aging are p53 (controlling cell cycle arrest, neoplastic transformation, apoptosis) and genetically controlled proteolytic pathways in amyloidogenesis in aging and Alzheimer's disease.
| Probable Mechanisms of Aging | | |
As the often repeated concept of fall in neuronal number with aging is not completely true (except for anatomical region specific neuronal depletion like in prefrontal cortex), the reason for system failure and cognitive decline needs a more dynamic and functional model. [4] The perturbation in the interaction between mitochondrial function, reactive oxygen species toxicity and deranged cellular calcium homeostasis renders neurons vulnerable to the effect of excessive metabolic stress associated with ischemia, trauma, environmental toxins and neurodegeneration. Chronically depolarized state of the mitochondrial membrane, enhanced threshold required for Ca ++ uptake, fall in their number and accumulation of bioenergetically inefficient mitochondria thus reduce the availability of ATP [111] for neuronal activity and significantly contribute to neuronal senescence. [86],[87],[112] The high levels of unsaturated fatty acids liable to peroxidation and low reserve of free radial neutralization mechanisms render the nervous system vulnerable. [113] The lipid peroxidation affects the synaptic function mediating excitotoxicity and neuronal death. [114] The interaction between senescent lipofuscin loaded lysosomes and mitochondria seems to play a pivotal role in the progression of cellular senescence. [6]
DNA repetitive sequences (TTAGGG), telomeres, which are found at the end of linear chromosome, are lost during repetitive cell division, rendering chromosomes vulnerable to damage. With shortening of telomere and thus the chromosomal length, the cell enters an irreversible growth arrest, replicative senescence. [115] Cellular senescence acts as a "cancer break" reducing the number of cell divisions and accumulation of oncogene mutations, and thus suppresses oncogenesis. Telomerase, a cellular reverse transcriptase, helps to maintain the telomere length by adding the repetitive sequences. Introduction of telomerase catalytic protein component (h TERT) can restore telomerase activity in telomerase silent cells, extending the life span. [116],[117] Oxidative intermediates can travel along DNA, preferentially producing damage at triples, GGG, and the damage repair process is inefficient in cells due to fundamental biochemical nature of telomere protein. [118] This promotes cellular senescence. These multifactorial events in the cells' life span dictate the aging process in the whole organisms.
The aging process progresses insidiously from the middle age similar to neurodegenerative diseases, thus leading to the concept that neurodegenerative processes are accelerated aging. This is further reinforced by the incidental observation of cytoskeletal pathology with associated post translational hyperphosphorylation and formation of insoluble protein aggregates in normal aged brain similar to that found in neurodegenerative diseases. Whatever is the initial trigger for the initiation, the consequent events progress insidiously and inexorably to evolve from subtle subclinical stage to overt disease. At the cellular level, the deranged milieu and energy depletion, and failure of antioxidant system result in excessive neuronal excitation, exhaustion, still not exceeding the life-threatening limit for the neuron and manifesting as a "sick neuron", finally culminating in death. [119] These events occur during natural aging as well, but the protective factors step in to salvage the neuron from becoming "too sick" and degenerate and die. Various cellular hallmarks of neurodegenerative diseases like NFT and SP in Alzheimer's disease, Lewy bodies in Parkinson's disease, ubiquitinated intraneuronal inclusions in Huntington's disease, motor neuron disease caused by protein misfolding and precipitation, used by pathologists as gold standard to diagnosis, in reality, are epiphenomenon affecting the cytoskeletal framework. It is not unusual to find an intact nucleus and nucleolus (indicative of metabolically viable and active cell) in a cell with Lewy body or neurofibrillary skeins, suggesting that these cells are still viable and metabolically active. At best, they may represent "early sickness" of the neuron. The real "sickness" of neuron is culmination of failure of energy system in mitochondria, failure of protective antioxidant system, deranged calcium homeostasis leading to exhaustion and death. With advances in biotechnology, facility for single neuron laser dissection, systematic proteomic analysis of young and sick neuron will offer some answers to yet eluding questions in aging biology. In a mouse model of Huntington's disease, using DNA microarray analysis, the brain is found to express reduced levels of mRNA of certain receptors and second messengers, but sparing the mitochondrial or apoptosis related proteins. [120] In case of Parkinson's disease, the remaining neurons of substantia nigra are seen to express normal levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA, but reduced levels of tyrosine hydroxylase, dopamine decarboxylase and a-synuclein mRNA. [121] Vaccination with Ab peptide was reported to reduce amyloid load in a transgenic animal model of Alzheimer's disease [122] and enhance the learning ability, [123] in contrast to the unvaccinated model. These observations suggest the possibility of reversing the degenerating "sick" neurons to relative normalcy, though one may need to face secondary immune injuries. [124]
Human brain is slow to reveal its secrets. The challenge of mapping this convoluted organ to locate its precise activity that offers specific experiences and behavioral responses is the driving passion of the present day neurobiologist. This probing is providing greater understanding about one of the oldest and profound metaphysical mysteries - the relationship between the mind and brain - an insight into "ourselves". Brain mapping is providing a navigational tool to record brain activity in a precise and radical way. To gain an insight into the evolution of mental illness and degeneration of the mind, it is essential to have a phenomenological understanding of biology of aging of the whole organism to the subcellular organelle. This forms the bed rock to understand system biology and neural network evolving from birth to old age.
"Aging reflects how close the living is to the dead. The hovering spirit comes to life as it enters the new" - African proverb
| Acknowledgments | | |
We would like to thank Mrs. Kanakalakshmi AV and Mrs. Manjula of Human Brain Tissue Repository (Human Brain Bank), Department of Neuropathology, NIMHANS, Bangalore, for their secretarial assistance. Mr. K. Manjunath, for his photographic work, and the editorial inputs of Dr. Anita Mahadevan, Department of Neuropathology, are gratefully acknowledged.
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|
Correspondence Address:
S K Shankar
Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore - 560 029, Karnataka
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0377-4929.71995
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