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: Abstract

MM Esiri, Neuropathology
Department, West Wing, John
Radcliffe Hospital, Headington,
Oxford OX3 9DU, UK.
E-mail:
margaret.esiri@clneuro.ox.ac.uk
No conflicts of interest were
declared.
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 so-
called ‘secular’ change in brain weights over time is
taken into account, and then, as other work suggests,
progressively decrease.

Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
www.pathsoc.org.uk
182
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 macro-
scopic 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 cere-
bellar Purkinje cells [18]. More recent studies employ-
ing 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 num-
bers, 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 ‘nor-
mal’ category. Relatively few brains of normal elderly
subjects checked in this way have had stereologically-
based estimates of neuronal population numbers. In
non-human primates, significant loss of neurons in the
hippocampus and most of the neocortex is not a fea-
ture 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 contro-
versial findings, there has been more agreement about
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.
MM Esiri
neuron size. This has been found to decrease mod-
estly with age, particularly in cerebral cortex [31–34].
Neuron size is thought to reflect the extent of the den-
dritic and axonal arborizations of the cell, as a more
extensive cell requires more energy, more protein syn-
thesis 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 over-
all 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 cor-
tical mini-columns in association cortex with human
ageing [37]. Mini-columns are arrays of cortical neu-
rons arranged in columns perpendicular to the pial sur-
face. 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 con-
sists of material derived from lysosomal degrada-
tion. 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 neurotrans-
mitter, dopamine. There is barely any detectable
melanin pigment in these cells at birth but it is
Ageing and the brain
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 neu-
romelanin 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 com-
monest 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 dis-
eases. 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 understand-
ing of brain ageing.
Cellular and molecular changes
Cellular and molecular changes in brain ageing have
been well reviewed recently [44–46]. Here we con-
sider 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 exception-
ally 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 machin-
ery.
• The electrical activity involved in impulse transmis-
sion, which requires ion gradients to be maintained
over long stretches of axonal membrane, at great
energetic expense.
Mitochondrial activity needed for oxidative meta-
bolism involves inevitable generation of oxygen free
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
183
radicals, which have the capacity to damage proteins,
nucleic acids and lipids. Highly reactive superox-
ide 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 reac-
tion 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 oxida-
tive damage to DNA. Mitochondria themselves suffer
oxidative damage, which may render them less effi-
cient 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 synap-
tic function and plasticity, vesicular transport, mito-
chondrial function and calcium homeostasis. In con-
trast, some gene expression was increased, includ-
ing genes involved in protein folding and stress
responses, antioxidant defence, metal ion homeosta-
sis 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 pro-
oxidant 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
184
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 alter-
ation in the calcium gradient across mitochondrial
membranes. These membranes can normally take up
calcium from the cytosol when calcium ions accu-
mulate there, secondary to neuronal membrane ionic
fluxes involved in impulse transmission. Impaired abil-
ity of the mitochondria to store calcium exposes the
neuronal cytosol to higher calcium levels, particularly
after excitatory stimulation.
Excitation opens voltage-dependent calcium and N-
methyl-D-aspartate (NMDA) glutamate receptor chan-
nels and leads to a transient rise in intracellular cal-
cium levels, even in healthy young neurons. This is
increased in normal ageing [46]. Ca2+ imaging stud-
ies have shown that the resting Ca2+ concentration in
CA1 hippocampal neurons does not change with age-
ing, but that these cells show a greater rise in Ca2+ in
response to stimulation [56]. Elevated levels of intra-
cellular 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, dis-
rupted Ca2+ homeostasis remains compatible with nor-
mal 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 Age-
ing Study [25], and many elderly subjects also suffer
from heart disease, which is likely to give rise to tran-
sient episodes of hypoxia. One of the consequences of
hypoxia is excess glutamate release, which operates
on postsynaptic membranes to open NMDA recep-
tor 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 self-
degenerative programmes, which may be important
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.
MM Esiri
in synaptic plasticity as well as in ageing and neu-
rodegeneration [60]. Some of these do appear to be
related to apoptosis [57]. Whether altered Ca2+ home-
ostasis 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 degen-
eration [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 age-
related 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
Ageing and the brain
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 enhanc-
ing maintenance of the soma, which improves the
repair of cellular damage and reduces the produc-
tion 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 caus-
ing brain damage in normal brain ageing is not clear
but vigilance is called for, as some environmental tox-
ins 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 influ-
ences, 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 understand-
ing 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:
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
185
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].
References
1. Miller AK, Corsellis JA. Evidence for a secular increase in
human brain weight during the past century. Ann Hum Biol
1977;4:253–257.
2. Dekaban AS. Changes in brain weights during the span of human
life: relation of brain weights to body heights and body weights.
Ann Neurol 1978;4:345–356.
3. Ho KC, Roessmann U, Straumfjord JV, Monroe G. Analysis of
brain weight. I. Adult brain weight in relation to sex, race, and
age. Arch Pathol Lab Med 1980;104:635–639.
4. Skoog I, Nilsson L, Palmertz B, Andreasson LA, Svanborg A.
A population-based study of dementia in 85 year-olds. N Engl J
Med 1993;328:153–158.
5. Fox NC, Schott JM. Imaging cerebral atrophy: normal ageing to
Alzheimer’s disease. Lancet 2004;363:392–394.
6. Blinkov S, Glezer I. The Human Brain in Figures and Tables: A
Quantitative Handbook. Plenum: New York, 1968.
7. Coffey CE, Wilkinson WE, Parashos IA, Soady SA, Sullivan RJ,
Patterson LJ, et al. Quantitative cerebral anatomy of the aging
human brain: a cross-sectional study using magnetic resonance
imaging. Neurology 1992;42:527–536.
8. Jernigan TL, Press GA, Hesselink JR. Methods for measuring
brain morphologic features on magnetic resonance images.
Validation and normal aging. Arch Neurol 1990;47:27–32.
9. Pfefferbaum A, Mathalon DH, Sullivan EV, Rawles JM,
Zipursky RB, Lim KO. A quantitative magnetic resonance
imaging study of changes in brain morphology from infancy to
late adulthood. Arch Neurol 1994;51:874–887.
10. Raz N. The ageing brain: structural changes and their implications
for cognitive ageing. In New Frontiers in Cognitive Ageing,
Dixon R, Backman L, Nilsson L (eds). Oxford University Press:
Oxford, 2004; 115–134.
11. Resnick SM, Pham DL, Kraut MA, Zonderman AB, Davatzikos C.
Longitudinal magnetic resonance imaging studies of older adults:
a shrinking brain. J Neurosci 2003;23:3295–3301.
12. Scahill RI, Frost C, Jenkins R, Whitwell JL, Rossor MN, Fox NC.
A longitudinal study of brain volume changes in normal aging
using serial registered magnetic resonance imaging. Arch Neurol
2003;60:989–994.
13. Trollor JN, Valenzuela MJ. Brain ageing in the new millennium.
Aust NZ J Psychiatr 2001;35:788–805.
14. Esiri M. Dementia and normal aging: neuropathology. In Dementia
and Normal Aging, Huppert F, Brayne C, O’Connor D (eds).
Cambridge University Press: Cambridge, 1994; 385–436.
15. Brody H. Organization of the cerebral cortex. III. A study of aging
in the human cerebral cortex. J Comp Neurol 1955;102:511–516.
16. Henderson G, Tomlinson BE, Gibson PH. Cell counts in human
cerebral cortex in normal adults throughout life using an image
analysing computer. J Neurol Sci 1980;46:113–136.
17. Ball MJ. Neuronal loss, neurofibrillary tangles and granulovacuo-
lar degeneration in the hippocampus with ageing and dementia.
A quantitative study. Acta Neuropathol (Berl) 1977;37:111–118.
18. Hall T, Miller K, Corsellis JA. Variations in the human Purkinje
cell population according to age and sex. Neuropathol Appl
Neurobiol 1975;1:267–292.
19. Benes FM, Lange N. Two-dimensional versus three-dimensional
cell counting: a practical perspective. Trends Neurosci
2001;24:11–17.
20. Howard C, Reed M. Unbiased Stereology: Three-dimensional
Measurement in Microscopy. Bios Scientific: London, 1998.
21. West MJ. New stereological methods for counting neurons.
Neurobiol Aging 1993;14:275–285.
J Pathol 2007; 211: 181–187 DOI: 10.1002/path
186
22. West MJ. Stereological methods for estimating the total number of
neurons and synapses: issues of precision and bias. Trends Neurosci
1999;22:51–61.
23. Hof PR, Morrison JH. The aging brain: morphomolecular
senescence of cortical circuits. Trends Neurosci 2004;27:607–613.
24. West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in
the pattern of hippocampal neuronal loss in normal ageing and
Alzheimer’s disease. Lancet 1994;344:769–772.
25. Neuropathology Group of the Medical Research Council Cognitive
Function and Ageing Study (MRC CFAS). Pathological correlates
of late-onset dementia in a multicentre, community-based
population in England and Wales. Lancet 2001;357:169–175.
26. Gazzaley AH, Thakker MM, Hof PR, Morrison JH. Preserved
number of entorhinal cortex layer II neurons in aged macaque
monkeys. Neurobiol Aging 1997;18:549–553.
27. Keuker JI, Luiten PG, Fuchs E. Preservation of hippocampal
neuron numbers in aged rhesus monkeys. Neurobiol Aging
2003;24:157–165.
28. Merrill DA, Roberts JA, Tuszynski MH. Conservation of neuron
number and size in entorhinal cortex layers II, III, and V/VI of
aged primates. J Comp Neurol 2000;422:396–401.
29. Peters A, Leahu D, Moss MB, McNally KJ. The effects of aging
on area 46 of the frontal cortex of the rhesus monkey. Cereb Cortex
1994;4:621–635.
30. Smith DE, Rapp PR, McKay HM, Roberts JA, Tuszynski MH.
Memory impairment in aged primates is associated with focal
death of cortical neurons and atrophy of subcortical neurons.
J Neurosci 2004;24:4373–4381.
31. Anderson JM, Hubbard BM, Coghill GR, Slidders W. The effect
of advanced old age on the neurone content of the cerebral cortex.
Observations with an automatic image analyser point counting
method. J Neurol Sci 1983;58:235–246.
32. Haug H. Are neurons of the human cerebral cortex really lost
during ageing? A morphometric examination. In Senile Dementia
of the Alzheimer Type, Traber J, Gispen W (eds). Springer: Berlin,
1985; 150–163.
33. Meier-Ruge W, Iwangoff P, Reichlmeier K, Sandoz P. Neuro-
chemical findings in the aging brain. Adv Biochem Psychophar-
macol 1980;23:323–338.
34. Terry RD, DeTeresa R, Hansen LA. Neocortical cell counts in
normal human adult aging. Ann Neurol 1987;21:530–539.
35. Buell SJ, Coleman PD. Quantitative evidence for selective
dendritic growth in normal human aging but not in senile dementia.
Brain Res 1981;214:23–41.
36. Jacobs B, Driscoll L, Schall M. Life-span dendritic and spine
changes in areas 10 and 18 of human cortex: a quantitative Golgi
study. J Comp Neurol 1997;386:661–680.
37. Chance SA, Casanova MF, Switala AE, Crow TJ, Esiri MM.
Minicolumn thinning in temporal lobe association cortex but not
primary auditory cortex in normal human ageing. Acta Neuropathol
(Berl) 2006;111:459–464.
38. Mrak RE, Griffin ST, Graham DI. Aging-associated changes in
human brain. J Neuropathol Exp Neurol 1997;56:1269–1275.
39. Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR. Iron,
brain ageing and neurodegenerative disorders. Nat Rev Neurosci
2004;5:863–873.
40. Schmitt HP. ε-Glycation, APP and Aβ in ageing and Alzheimer
disease: a hypothesis. Med Hypotheses 2006;66:898–906.
41. Esiri MM. The interplay between inflammation and neurodegen-
eration in CNS disease. J Neuroimmunol 2006;(in press).
42. Mann DM, Yates PO, Stamp JE. The relationship between
lipofuscin pigment and ageing in the human nervous system.
J Neurol Sci 1978;37:83–93.
43. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y,
Suzuki-Migishima R, et al. Suppression of basal autophagy in
neural cells causes neurodegenerative disease in mice. Nature
2006;441:885–889.
44. Burke SN, Barnes CA. Neural plasticity in the ageing brain. Nat
Rev Neurosci 2006;7:30–40.
45. Mattson MP, Maudsley S, Martin B. BDNF and 5-HT. a dynamic
duo in age-related neuronal plasticity and neurodegenerative
disorders. Trends Neurosci 2004;27:589–594.
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.
MM Esiri
46. Toescu EC. Normal brain ageing: models and mechanisms. Phil
Trans R Soc Lond B Biol Sci 2005;360:2347–2354.
47. Stadtman ER. Protein oxidation and aging. Science
1992;257:1220–1224.
48. Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry
of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free
Radic Biol Med 1991;11:81–128.
49. Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, et al. Gene
regulation and DNA damage in the ageing human brain. Nature
2004;429:883–891.
50. Floyd RA, Hensley K. Oxidative stress in brain aging. Implica-
tions for therapeutics of neurodegenerative diseases. Neurobiol
Aging 2002;23:795–807.
51. Kimura T, Takamatsu J, Ikeda K, Kondo A, Miyakawa T, Hori-
uchi S. Accumulation of advanced glycation end products of the
Maillard reaction with age in human hippocampal neurons. Neu-
rosci Lett 1996;208:53–56.
52. Kimura T, Takamatsu J, Miyata T, Miyakawa T, Horiuchi S.
Localization of identified advanced glycation end-product
structures, N-ε (carboxymethyl)lysine and pentosidine, in age-
related inclusions in human brains. Pathol Int 1998;48:575–579.
53. Chen F, Wollmer MA, Hoerndli F, Munch G, Kuhla B, Rogaev EI,
et al. Role for glyoxalase I in Alzheimer’s disease. Proc Natl Acad
Sci USA 2004;101:7687–7692.
54. Thornalley PJ. Glyoxalase I — structure, function and a critical
role in the enzymatic defence against glycation. Biochem Soc Trans
2003;31:1343–1348.
55. Xiong J, Verkhratsky A, Toescu EC. Changes in mitochondrial
status associated with altered Ca2+ homeostasis in aged cerebellar
granule neurons in brain slices. J Neurosci 2002;22:10761–10771.
56. Thibault O, Hadley R, Landfield PW. Elevated postsynaptic
[Ca2+ ]i and L-type calcium channel activity in aged hippocampal
neurons: relationship to impaired synaptic plasticity. J Neurosci
2001;21:9744–9756.
57. Cowan CM, Thai J, Krajewski S, Reed JC, Nicholson DW,
Kaufmann SH, et al. Caspases 3 and 9 send a pro-apoptotic signal
from synapse to cell body in olfactory receptor neurons. J Neurosci
2001;21:7099–7109.
58. Gilman CP, Mattson MP. Do apoptotic mechanisms regulate
synaptic plasticity and growth-cone motility? Neuromol Med
2002;2:197–214.
59. Sagot Y, Dubois-Dauphin M, Tan SA, de Bilbao F, Aebischer P,
Martinou JC, et al. Bcl-2 overexpression prevents motoneuron cell
body loss but not axonal degeneration in a mouse model of a
neurodegenerative disease. J Neurosci 1995;15:7727–7733.
60. Gillingwater TH, Thomson D, Mack TG, Soffin EM, Mattison RJ,
Coleman MP, et al. Age-dependent synapse withdrawal at
axotomized neuromuscular junctions in Wld(s) mutant and
Ube4b/Nmnat transgenic mice. J Physiol 2002;543:739–755.
61. Guo ZH, Mattson MP. Neurotrophic factors protect cortical
synaptic terminals against amyloid and oxidative stress-induced
impairment of glucose transport, glutamate transport and
mitochondrial function. Cereb Cortex 2000;10:50–57.
62. Mattson MP, Guo ZH, Geiger JD. Secreted form of amyloid
precursor protein enhances basal glucose and glutamate transport
and protects against oxidative impairment of glucose and glutamate
transport in synaptosomes by a cyclic GMP-mediated mechanism.
J Neurochem 1999;73:532–537.
63. Coleman MP, Perry VH. Axon pathology in neurological disease:
a neglected therapeutic target. Trends Neurosci 2002;25:532–537.
64. Gillingwater TH, Ribchester RR. The relationship of neuromus-
cular synapse elimination to synaptic degeneration and pathol-
ogy: insights from WldS and other mutant mice. J Neurocytol
2003;32:863–881.
65. Peters R. Ageing and the brain. Postgrad Med J 2006;82:84–88.
66. Goyns MH. Genes, telomeres and mammalian ageing. Mech
Ageing Dev 2002;123:791–799.
67. Kirkwood TB. Time of our lives. What controls the length of life?
EMBO Rep 2005;6:S4–8.
68. Kirkwood TB. Understanding the odd science of aging. Cell
2005;120:437–447.
Ageing and the brain
69. Deary IJ, Wright AF, Harris SE, Whalley LJ, Starr JM. Searching
for genetic influences on normal cognitive ageing. Trends Cogn
Sci 2004;8:178–184.
70. Kachiwala SJ, Harris SE, Wright AF, Hayward C, Starr JM,
Whalley LJ, et al. Genetic influences on oxidative stress and
their association with normal cognitive ageing. Neurosci Lett
2005;386:116–120.
71. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE,
Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type
4 allele and the risk of Alzheimer’s disease in late-onset families.
Science 1993;261:921–923.
72. Deary IJ, Whiteman MC, Pattie A, Starr JM, Hayward C,
Wright AF, et al. Apolipoprotein e gene variability and cognitive
functions at age 79: a follow-up of the Scottish mental survey of
1932. Psychol Aging 2004;19:367–371.
73. Brown DR. Prion protein expression aids cellular uptake
and veratridine-induced release of copper. J Neurosci Res
1999;58:717–725.
74. Dermaut B, Croes EA, Rademakers R, Van den Broeck M,
Cruts M, Hofman A, et al. PRNP Val129 homozygosity increases
risk for early-onset Alzheimer’s disease. Ann Neurol
2003;53:409–412.
75. Golanska E, Hulas-Bigoszewska K, Rutkiewicz E, Styczynska M,
Peplonska B, Barcikowska M, et al. Polymorphisms within the
prion (PrP ) and prion-like protein (Doppel ) genes in AD.
Neurology 2004;62:313–315.
76. Knight RS, Will RG. Prion diseases. J Neurol Neurosurg Psychiat
2004;75(Suppl 1):i36–42.
77. Riemenschneider M, Klopp N, Xiang W, Wagenpfeil S,
Vollmert C, Muller U, et al. Prion protein codon 129 polymor-
phism and risk of Alzheimer disease. Neurology 2004;63:364–366.
78. Deary IJ, Hamilton G, Hayward C, Whalley LJ, Powell J, Starr JM,
et al. Nicastrin gene polymorphisms, cognitive ability level and
cognitive ageing. Neurosci Lett 2005;373:110–114.
79. Deary IJ, Harris SE, Fox HC, Hayward C, Wright AF, Starr JM,
et al. KLOTHO genotype and cognitive ability in childhood and
old age in the same individuals. Neurosci Lett 2005;378:22–27.
80. Harris SE, Wright AF, Hayward C, Starr JM, Whalley LJ,
Deary IJ. The functional COMT polymorphism, Val 158 Met,
is associated with logical memory and the personality trait
intellect/imagination in a cohort of healthy 79 year olds. Neurosci
Lett 2005;385:1–6.
81. Wolkow CA. Life span: getting the signal from the nervous system.
Trends Neurosci 2002;25:212–216.
82. Mattson MP. Methylation and acetylation in nervous system
development and neurodegenerative disorders. Ageing Res Rev
2003;2:329–342.
83. Kyng KJ, Bohr VA. Gene expression and DNA repair in progeroid
syndromes and human aging. Ageing Res Rev 2005;4:579–602.
Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
187
84. Yehuda S, Rabinovitz S, Carasso RL, Mostofsky DI. The role
of polyunsaturated fatty acids in restoring the aging neuronal
membrane. Neurobiol Aging 2002;23:843–853.
85. Merry BJ. Molecular mechanisms linking calorie restriction and
longevity. Int J Biochem Cell Biol 2002;34:1340–1354.
86. Martin B, Mattson MP, Maudsley S. Caloric restriction and
intermittent tasting; two potential diets for successful brain aging.
Ageing Research Reviews 2006;5:332–353.
87. Budge M, Johnston C, Hogervorst E, de Jager C, Milwain E,
Iversen SD, et al. Plasma total homocysteine and cognitive
performance in a volunteer elderly population. Ann NY Acad Sci
2000;903:407–410.
88. Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatan-
paa K, et al. Involvement of oxidative stress-induced abnor-
malities in ceramide and cholesterol metabolism in brain
aging and Alzheimer’s disease. Proc Natl Acad Sci USA
2004;101:2070–2075.
89. Mayeux R. Epidemiology of neurodegeneration. Annu Rev
Neurosci 2003;26:81–104.
90. Cotman CW, Berchtold NC. Exercise: a behavioral intervention
to enhance brain health and plasticity. Trends Neurosci
2002;25:295–301.
91. Shenkin SD, Bastin ME, MacGillivray TJ, Deary IJ, Starr JM,
Wardlaw JM. Childhood and current cognitive function in healthy
80 year-olds: a DT-MRI study. NeuroReport 2003;14:345–349.
92. Staff RT, Murray AD, Deary IJ, Whalley LJ. What provides
cerebral reserve? Brain 2004;127:1191–1199.
93. Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics Z,
Lee VM, et al. Environmental enrichment reduces Aβ levels and
amyloid deposition in transgenic mice. Cell 2005;120:701–713.
94. Kyle D. The role of docosahexaenoic acid in the evolution and
function of the human brain. In Brain Lipids and Disorders
in Biological Psychiatry, Skinner E (ed.). Elsevier Science:
Amsterdam, 2002; 1–22.
95. Elias MF, Robbins MA, Budge MM, Elias PK, Brennan SL,
Johnston C, et al. Homocysteine, folate, and vitamins B6 and
B12 blood levels in relation to cognitive performance: the Maine-
Syracuse study. Psychosom Med 2006;68:547–554.
96. DeKosky ST. Statin therapy in the treatment of Alzheimer disease:
what is the rationale? Am J Med 2005;118(Suppl 12A):48–53.
97. Di Monte DA. The environment and Parkinson’s disease: is the
nigrostriatal system preferentially targeted by neurotoxins? Lancet
Neurol 2003;2:531–538.
98. Kisby GE, Ellison M, Spencer PS. Content of the neurotoxins
cycasin (methylazoxymethanol β-D-glucoside) and BMAA (β-
N-methylamino-L-alanine) in cycad flour prepared by Guam
Chamorros. Neurology 1992;42:1336–1340.
J Pathol 2007; 211: 181–187 DOI: 10.1002/path