Ageing And The Brain

Journal of Pathology J Pathol 2007; 211: 181–187 Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/path.2089

Review Article

Ageing and the brain MM Esiri* Department of Clinical Neurology, University of Oxford, and Department of Neuropathology, Oxford Radcliffe NHS Trust, Oxford, UK

*Correspondence to: MM Esiri, Neuropathology Department, West Wing, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. E-mail: [email protected] No conflicts of interest were declared.

Abstract In this review, the evidence for changes in the human brain with ageing at both the macroscopic and microscopic levels is summarized. Loss of neurons is now recognized to be more modest than initial studies suggested and only affects some neuron populations. Accompanying loss of neurons is some reduction in the size of remaining neurons. This reflects a reduced size of dendritic and axonal arborizations. Some of the likely causes of these changes, including free radical damage resulting from a high rate of oxidative metabolism in neurons, glycation and dysregulation of intracellular calcium homeostasis, are discussed. The roles of genes and environmental factors in causing and responding to ageing changes are explored. Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Keywords: human brain; ageing; oxidative damage; advanced glycation end products (AGEs); calcium homeostasis

Our brains are seventy-year clocks. The Angel of Life winds them up once for all, then closes the case, and gives the key into the hand of the Angel of Resurrection. [Oliver Wendell Homes (1809–1894), physician and poet]

Introduction For many people approaching old age, deteriorating brain function is the aspect of growing old that they most fear. The brain seems to contain one’s essence and the thought of losing that is hard to contemplate. But the changes that occur in the brain as it ages we now recognize to be much less tied to chronological time than Holmes suggested. Some peoples’ brains age much better than others. In this review I consider what is known about why this might be, and how more of us can improve the chances of preserving our brains as they age. I first consider the evidence about what changes occur in human brains with ageing and then consider additional evidence about the likely cellular and molecular underpinnings of these, much of it derived from animal studies.

the last 100 or so years as a result of improved nutrition during development. Thus, as the twentieth century progressed, young brains in the developed world, where most measurements have been made, became larger and heavier by about 1 g/year [1]. Second, although weights and volumes of thousands of brains have been recorded over the years, the number of very elderly brains examined has been relatively low until recently [2,3]. Third, it is known that diseases that cause a reduction in brain weight and volume, particularly Alzheimer’s disease (AD), increase in prevalence exponentially with age [4] and many studies of brain weight and volume in old age have not taken steps to exclude brains with the pathology of this disease from their studies. Fourth, it is only recently, with the advent of non-invasive brain imaging, that longitudinal measures on the same brains over time have been possible and studies of this type have followed changes over relatively short periods of time [5].

Macroscopic brain changes with age Ageing of the human brain Brain changes with ageing have been studied since the nineteenth century but there is still a surprising degree of uncertainty about what constitutes these changes. There are several reasons why this is so. First, measures of weight and volume of the brain as it ages need to take account of changes in these measures in young brains that have occurred over

Most studies of large numbers of post mortem human brains indicate that in adults between the ages of approximately 20 and 60 years there is a small loss of brain weight of about 0.1%/year, but more rapid loss thereafter [1–3,6] suggested that weights remain stable until about the age of 50 years if the socalled ‘secular’ change in brain weights over time is taken into account, and then, as other work suggests, progressively decrease.

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When non-invasive brain imaging was introduced in the 1970s, brain volume was similarly found to decrease with age [7–9]. This decrease is relatively diffuse and uniform in cerebral white matter but shows some regional differences in grey matter, with frontal and parietal cortex more affected than temporal and occipital cortex and with the striatum also affected [10–13]. Brain volume reductions increase from about 0.1–0.2%/year at age 30–50 years to 0.3–0.5%/year over the age of 70 years, in agreement with brain weight studies. The ventricular system expands to fill the space vacated by reduced brain volume. The leptomeninges tend to thicken slightly with age and the subarachnoid space enlarges.

Microscopic brain changes with age Views about the microscopic basis for the macroscopic brain changes that are observed with ageing have changed over the years. The main controversy has been over the presence and extent of neuron loss. Initial studies, commenced in the 1950s, examined changes in neuron density in two-dimensional space. They concluded that substantial loss of neurons occurs with age, varying in the range 10–60%, depending on the study and on the neuronal population examined. However, some populations were recognized to show no loss of neurons with age, eg cranial nerve nuclei [14]. Cerebral cortex [15,16] and hippocampus [17] were thought to be particularly affected, but also cerebellar Purkinje cells [18]. More recent studies employing stereologically-based sampling [19–22] to derive estimates of neuronal numbers in three-dimensional space have arrived at more conservative conclusions, that neuron loss with ageing is either undetectable or relatively mild [23,24]. Estimating the magnitude of neuronal loss in humans is complicated by the fact that most elderly brains from subjects over the age of 80 years are affected by the pathological changes of amyloid plaque and neurofibrillary tangle formation, the two hallmarks, when present in substantial numbers, of AD. They are also affected by cerebrovascular disease [25]. There is, of course, a debate to be had over whether these features represent part of ‘normal ageing’ or ‘disease’, but for the purposes of this review I have considered that they represent ‘disease’. Taking this view, these features need to be checked for before allocating the brain of an elderly subject to the ‘normal’ category. Relatively few brains of normal elderly subjects checked in this way have had stereologicallybased estimates of neuronal population numbers. In non-human primates, significant loss of neurons in the hippocampus and most of the neocortex is not a feature of ageing. However, a 30% reduction in neurons in seen in dorsolateral prefrontal cortex, a change that correlates with impairment on a working memory task which is dependent on the function of this region of the brain [26–30]. If studies of neuron numbers have yielded controversial findings, there has been more agreement about

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neuron size. This has been found to decrease modestly with age, particularly in cerebral cortex [31–34]. Neuron size is thought to reflect the extent of the dendritic and axonal arborizations of the cell, as a more extensive cell requires more energy, more protein synthesis and so on, requiring a larger cell body to furnish these. It is therefore no surprise to find that studies of synapses, located mainly, although not exclusively, on dendritic spines in cerebral cortex, have shown overall decreases with age, although the branching patterns of dendrites suggests that there may be compensatory increases in some dendrites to make up for loss of others [35]. A 46% reduction in spine number and density has been reported in humans over 50 years of age [36]. Shrinkage of the dendritic trees probably accounts for subtle changes in the parameters of cortical mini-columns in association cortex with human ageing [37]. Mini-columns are arrays of cortical neurons arranged in columns perpendicular to the pial surface. Mini-columns in normal elderly subjects become narrower in auditory association cortex, a region that retains some plasticity in adult life. In contrast, the normally more narrowly spaced mini-columns of the less plastic primary auditory cortex show little change with age [37]. Some of the other microscopic alterations that occur in the brain with ageing are: • An increase in the number of corpora amylacea [38]; these are spherical laminated polyglycosan bodies, prominent in periodic acid–Schiff (PAS)stained sections. They have a preferential location around blood vessels or close to pial or ependymal surfaces. Some are localizable ultrastructurally to astrocyte processes. • Increase in the amount of detectable iron [39]; iron reaches the brain by a selective uptake mechanism operating across the blood–brain barrier but little is known of how it is released and why it accumulates with age. Iron is an essential component of many enzymes in the brain but high concentrations of reactive iron can facilitate oxidative stress. • Increase in the amount of advanced glycation end products [40]. • Increase in the number and size of astrocytes and microglia. Microglia are generally thought of as pathogenic when activated but they may also be neuroprotective under some circumstances [41]. • An increase in the lipofuscin content of neurons [42]. The amount of lipofuscin that accumulates varies considerably from one type of neuron to another, but it tends to accumulate more in large cortical and thalamic neurons, inferior olive neurons and motor neurons than in others. Lipofuscin consists of material derived from lysosomal degradation. In neurons of the substantia nigra, the melanin pigment that accumulates does so as a by-product of synthesis by the cells of their specific neurotransmitter, dopamine. There is barely any detectable melanin pigment in these cells at birth but it is

J Pathol 2007; 211: 181–187 DOI: 10.1002/path Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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readily visible by the time children reach the age of 8 years. Neuromelanin and lipofuscin have some features in common and it is interesting that neuromelanin starts to accumulate long before old age is reached. Lipofuscin accumulation, as a product of lysosomal degradation, is related to autophagy. Recently it has been shown that mice engineered to lack genes enabling autophagy to occur develop neurodegeneration, illustrating the importance of autophagy in the housekeeping functions in neurons [43]. It is possibly no coincidence that the two commonest neurodegenerative diseases of ageing, AD and Parkinson’s disease (PD), particularly affect cells that are selectively vulnerable to ageing itself — cortical and hippocampal pyramidal cells in the case of AD and pigmented brain stem neurons in PD. Common, almost universal, functional changes occur in memory and motor performance with age. These are functions that depend on networks involving these neurons that are affected in AD and PD. We need to understand the brain changes that occur with ageing if we are to understand the common, sporadic, forms of these diseases. Although early-onset forms of both diseases are recognized that are caused by genetic mutations, most cases of these diseases (ca. 95%) occur in old age and the factors that cause late-onset disease are likely to be much more heterogeneous, involving both genetic and environmental risk factors. To understand the interplay between these factors, we have to improve understanding of brain ageing.

Cellular and molecular changes Cellular and molecular changes in brain ageing have been well reviewed recently [44–46]. Here we consider some of the more important factors. High energy demands of neurons render them vulnerable to ageing

A key factor that plays a role in brain ageing is the great demand that neurons have for oxidative metabolism in the generation of energy. The energy needs of neurons throughout a lifetime are exceptionally high, driven by: • The enormous size of some neurons, necessitating maintenance of a very large surface membrane and an energy-hungry system of transport of molecules and organelles to enable distant parts of the cell to be supplied with nutrients and subcellular machinery. • The electrical activity involved in impulse transmission, which requires ion gradients to be maintained over long stretches of axonal membrane, at great energetic expense. Mitochondrial activity needed for oxidative metabolism involves inevitable generation of oxygen free

radicals, which have the capacity to damage proteins, nucleic acids and lipids. Highly reactive superoxide ion radicals are produced that lead to generation of hydrogen peroxide, hydroxyl radicals, which are formed by the reaction of hydrogen peroxide with iron and copper ions, and peroxynitrite, formed by the reaction of superoxide with nitric acid. These molecules oxidize proteins, lipids and DNA, yielding a large number of compounds, which can be estimated to give a measure of how much oxidative damage a brain has been exposed to. These compounds include oxidized proteins [47] 4-hydroxynonenal, which results from peroxidation of ω-6-conjugated fatty acids [48], and 8-hydroxy-2
-deoxyguanosine, a measure of oxidative damage to DNA. Mitochondria themselves suffer oxidative damage, which may render them less efficient at energy generation and liable to generate more superoxide ions. These alterations interfere with many aspects of normal cell metabolism and function. DNA damage leads to reduced gene expression, or to the generation of abnormal proteins that have to be eliminated by processes such as proteosomal degradation. A recent study of RNA obtained from human frontal cortex of individuals in the age range 26–106 years found that many genes — about 4% of the 11 000 genes studied — showed reduced expression after the age of 40 years. These genes were involved in synaptic function and plasticity, vesicular transport, mitochondrial function and calcium homeostasis. In contrast, some gene expression was increased, including genes involved in protein folding and stress responses, antioxidant defence, metal ion homeostasis and the inflammatory response [49]. This increased gene expression is readily interpretable as a response to the oxidative and other stresses referred to above. Antioxidant enzymes and growth factors, which might be expected to combat the effects of oxidative damage, have altered effectiveness through alterations in their signalling pathways or lower production with ageing [45]. Antioxidant defences in the brain are, at best, relatively low. Conversely, the brain is rich in prooxidant iron and in unsaturated fatty acids that are particularly vulnerable to peroxidation [50]. Another change to which proteins, lipids and nucleic acids are vulnerable with ageing is the production of advanced glycation end-products (AGEs), which are adducts or cross-links that form non-enzymatically in a reaction between reducing sugars, including glucose, and the amino groups of proteins and other compounds through the Maillard reaction, a process that can occur extra- or intracellularly. The effects of AGEs are diverse; some are receptor-dependent and some are mediated via other endogenous binding sites, including lactoferrin and the macrophage scavenger receptors. Engagement of AGEs with the receptor (RAGE) can result in oxidant stress, and by directly affecting proteins AGEs can alter the shape and interfere with the function of proteins. AGEs have been reported to accumulate with age in many tissues, including the

J Pathol 2007; 211: 181–187 DOI: 10.1002/path Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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brain [51,52]. There are enzymes (glyoxalases) that provide protection against glycation. These have been found to be up-regulated in the brain in a transgenic model of AD [53,54]. Calcium dysregulation

Decreasing mitochondrial efficiency with ageing, and its knock-on effects in increasing oxidative stress in neurons, is intimately coupled to changes in calcium homeostasis. Aged brain mitochondria are persistently depolarized [55], which is likely to result in an alteration in the calcium gradient across mitochondrial membranes. These membranes can normally take up calcium from the cytosol when calcium ions accumulate there, secondary to neuronal membrane ionic fluxes involved in impulse transmission. Impaired ability of the mitochondria to store calcium exposes the neuronal cytosol to higher calcium levels, particularly after excitatory stimulation. Excitation opens voltage-dependent calcium and Nmethyl-D-aspartate (NMDA) glutamate receptor channels and leads to a transient rise in intracellular calcium levels, even in healthy young neurons. This is increased in normal ageing [46]. Ca2+ imaging studies have shown that the resting Ca2+ concentration in CA1 hippocampal neurons does not change with ageing, but that these cells show a greater rise in Ca2+ in response to stimulation [56]. Elevated levels of intracellular Ca2+ are liable to activate calcium-activated proteases (caspases), with potentially damaging effects on cells. At their worst, these effects can include cell death by apoptosis, but it is possible that they can have more localized effects in brain ageing, for example, causing apoptosis limited to dendrites [57,58]. A likely scenario is that, in the ageing brain, disrupted Ca2+ homeostasis remains compatible with normal impulse transmission and neurotransmitter release, but that it renders the brain very liable to damage if there is an imposed stress, such as mild hypoxia. Mild degrees of cerebrovascular disease were found to be present in over 75% of elderly unselected UK subjects in the MRC Cognitive Function and Ageing Study [25], and many elderly subjects also suffer from heart disease, which is likely to give rise to transient episodes of hypoxia. One of the consequences of hypoxia is excess glutamate release, which operates on postsynaptic membranes to open NMDA receptor channels, leading to calcium entry and the risk of calcium overload, with the consequences this may have for the cell. Whether apoptosis is the mode of death of neurons that are lost with ageing remains uncertain. Non-apoptotic modes of death of neurons or sub-regions of neurons are also recognized, and may be important in dendritic spine loss and dying back of axons, for example. Anti-apoptotic interventions do not prevent axonal degeneration [59]. Dendrites and synapses also seem to contain compartmentalized selfdegenerative programmes, which may be important

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in synaptic plasticity as well as in ageing and neurodegeneration [60]. Some of these do appear to be related to apoptosis [57]. Whether altered Ca2+ homeostasis plays a role in these forms of degeneration is not clear, but neurotrophic factors such as bFGF can exert a direct protective effect on synapses [61,62]. The ubiquitin–proteosome system appears to play an important role in dendritic, synaptic and axonal degeneration [63,64]. Genes that influence brain ageing

There is a vast array of genes that may potentially influence brain ageing. In principle, any of the genes involved in the control of all the factors discussed above could be involved. In addition, hormonal factors may be important [65]. Much more attention has been given to discovering genes that are important in agerelated neurodegenerative diseases, such as AD and PD, but some consideration has also been given to genes that are important in brain ageing [66]. We have already seen that many genes influencing the processes described above are either up- or down-regulated in human frontal cortex after the age of 40 years [49]. The ability to up-regulate genes that repair damage due to oxidation, glycosylation and so on probably has a major influence. This would be predicted by the attractive ‘disposable soma’ view of ageing as the result of a trade-off between somatic maintenance and repair and other functions, particularly reproduction, in the allocation of an animal’s metabolic resources [67,68]. Two genes with variants that influence successful brain ageing are the apolipoprotein E (ApoE ) gene and the prion protein gene, PRNP [69,70]. The ApoE gene has three isoforms, ε2 , ε3 and ε4 . ε3 is the commonest allele, ε4 the next most common and ε2 is uncommon. ApoE ε2 is protective against AD and ε4 is a risk factor for late-onset AD [71]. ApoE ε2 is over-represented in centenarians, suggesting that it influences successful brain ageing. It is uncertain exactly how ApoE exerts this influence. In normal individuals ApoE ε4 is associated with lower cognitive performance at 11 years and even more at 80 years of age [72]. Prion protein is the protein whose tertiary structure is altered in Creutzfeldt–Jakob disease (CJD). The normal function of the protein is not entirely clear but it is thought that it may play a role in protecting neurons from the effects of cellular stress. It may play an antioxidant role by influencing uptake of copper [73]. The PRNP codon 129 influences susceptibility to CJD and also to AD [74–77]. Individuals who were homozygous for the methionine allele at codon 129 were found to perform cognitively better at age 79 years than those who were heterozygous, in a study that measured cognitive ability at age 11 years and again at 79 years in a Scottish cohort [70]. Other genes that were found to exert a mild effect on cognitive ability at 79 years in this cohort were the genes for

J Pathol 2007; 211: 181–187 DOI: 10.1002/path Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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nicastrin, Klotho and catechol-O-methyl transferase [78–80]. Other genes thought to play a role in brain ageing are those involved in insulin signalling [81], DNA and protein methylation and acetylation [82], DNA repair [83] and lipid metabolism [84].

Environmental factors and brain ageing A major environmental factor in ageing generally and brain ageing in particular is diet. It has been known for many decades that restricting daily calorie intake in rodents and some other animals increases longevity substantially [85,86]. It is speculated that this may be because in times of famine reproductive activity is reduced, since any offspring would be unlikely to survive. Accordingly, energy is switched to enhancing maintenance of the soma, which improves the repair of cellular damage and reduces the production of reactive oxygen species. Calorie restriction also enhances brain-derived neurotrophic factor production and neurogenesis [45]. Conversely, it is likely that excess calorie intake has a deleterious effect on brain metabolism. Elevated cholesterol and blood pressure, both linked to obesity and excess calorie intake, and elevated blood homocysteine are risk factors for the development both of AD and cerebrovascular disease [87–89]. Other beneficial influences on brain function in old age are physical exercise [90], extended years of education [91,92], cognitive stimulation [93] and a high intake of polyunsaturated fatty acids [94] and B vitamins, particularly vitamins B6, B12 and folate [95] and statins [96]. The influence of toxins in causing brain damage in normal brain ageing is not clear but vigilance is called for, as some environmental toxins have been implicated as risk factors in age-related disease, for example, the pesticide rotenone and the herbicide paraquat in PD [97] and a product of cycad seeds, β-methylamino-L-alanine (BMAA), in Guam disease [98].

Conclusions The brain undergoes subtle but definite decline in structure and function with age. The extent of these changes is variable and subject to numerous influences, both genetic and environmental. Progressive, clinically significant, decline over a lifetime may not be inevitable and may even, in future, prove to be reversible, given relatively recent understanding that: (a) neurogenesis can persist into adulthood; (b) protective neurotrophic factor production can be enhanced under certain conditions (exercise, diet); and (c) oxidative damage to the brain can be influenced by diet and other lifestyle factors. To return to the quotation at the start of this review, I conclude with another quotation, admittedly about ageing in general, but equally pertinent to brain ageing:

The key questions with regard to ageing are whether the ageing process is in fact clock-driven and what evolutionary factors might have shaped the design of the clock . . .. Our answer to the question ‘Is it a clock?’ is a definite ‘No’ [67].

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J Pathol 2007; 211: 181–187 DOI: 10.1002/path Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.