Ageing and the BrainNaftali Raz, Wayne State University, Detroit, USA

Anatomical, neurochemical and functional characteristics of themammalian brain change

with age. Although some of these changes are generalized, many aspects of the brain are

affected differentially.

Introduction

Mammalian ageing is accompanied by significant struc-tural and functional transformations of virtually all organsand systems. The central nervous system (CNS) is no ex-ception. Age-related alterations are observed at every levelof the CNS, from neuronal organelles to the cerebrum as awhole, and are diverse in their appearance, timing andaetiology. Some of the changes are global, universal andinevitable, others are regional, species-specific and pre-ventable; some seem to emerge as a matter of mere passageof time, whereas others stem from age-related diseaseprocesses and cumulative exposure to toxins and patho-gens. In spite of significant advancement in understandingof cellular mechanisms of senescence, the complex patternof brain ageing is still largely unexplained. Some modestprogress has beenmade in identifying negative andpositivemodifiers of ageing. See also: Ageing; Ageing as a globalchallenge in the new millennium; Vertebrate centralnervous system

Generalized Brain Ageing

Ageing of brain microstructure

Structural and neurochemical properties of neuronschange with age. Age-related differences are apparent onthemost fundamental cellular level and include cumulativemitochondrial damage, reduction in deoxyribonucleic acid(DNA) repair ability and failure to remove neurons withdamaged nuclear DNA (Brunk and Terman, 2002). As theorganism progresses into senium, lipofuscin, a yellowish-brown lipid, accumulates throughout the cerebral cortexand the cerebellum, affecting mainly pyramidal cells. Neu-ritic plaques, neuropathological formations of amyloidorigin that are associated with Alzheimer disease, are rel-atively uncommon in the brains of older individuals, whodied without signs of dementia. Neurofibrillary tangles,which constitute the key neuropathological feature ofAlzheimer disease and are sometimes dubbed neuronal‘tombstones’ (Kemper, 1994), are rarely seen in the brainsof nondemented elderly people. Further neurodegenera-tive changes, such as granulovacuolar inclusions that dis-tort the inner structure of the cell and the formation of

Hirano bodies that result from distortion of the microfil-aments, are observed in the brains of cognitively intactelderly individuals on postmortem examination. Age-related changes occur in the vascular system that suppliesbrain with oxygen, glucose and other vital substances.These changes include rarefication of cerebral vasculatureand reduction in elasticity of cerebral vessels (Riddle et al.,2003). See also: Alzheimer disease; Macular degeneration,age related; NeuronsAlthough, in the past, many studies reported extensive

age-related attrition of neurons in the hippocampus andthe neocortex of mammals, from mice to humans, thenotion of inevitable and widespread neuronal loss in lateadulthood is no longer a commonly accepted dictum. Re-cent stereological studies based on improved methods ofneuron counting suggest that the magnitude of age-relatedneuronal loss might have been exaggerated by brain-processing artefacts and by inadequacies of measurementtechniques. It has been proposed that shrinkage of neuronsrather than their total demise may be a more decisive age-related change. Because neuronal connectivity is one of themost plastic aspects of the adult brain, age-related changesin the structural substrates of interneuronal communica-tionmay play an important role in brain ageing. Indeed, inthe ageing brain, themeans bywhich the neurons exchangeinformation undergo systematic changes. These changesinclude debranching of the dendritic arborization and de-clines in synaptogenesis (Kemper, 1994; Morrison andHof, 1997). See also: Cortical plasticity: use-dependentremodeling; Dendrites; Neural information processing;Synapse formation

Gross neuroanatomy of the ageing brain

Noninvasive neuroimaging techniques (magnetic reso-nance imaging (MRI)) and computed tomography havegreatly advanced the inquiry into age-related changes inhuman brain structure. Two decades of in vivo studies ofhuman brain ageing have yielded several well-replicatedfindings, although the degree of their agreement with theresults of postmortem studies varies.

Article Contents

Keynote article

. Introduction

. Generalized Brain Ageing

. Differential Vulnerability of Brain Regions and

Components to Ageing

. Mechanisms and Modifiers of Brain Ageing

. Summary

doi: 10.1038/npg.els.0004063

1ENCYCLOPEDIA OF LIFE SCIENCES & 2005, John Wiley & Sons, Ltd. www.els.net

Multiple structural alterations of the ageing cerebralwhite matter have been reported. In asymptomatic elderlypeople, age-related changes in the white matter are ex-pressed as circumscribed areas of hyperintensity observedonMRI. A typical pattern of age-related differences in theappearance of deep white matter and periventricular areasis displayed in Figure 1. In addition, age-related differencesin the microstructural integrity of myelinated fibres havebeen observed, with greater effects evidenced by the ante-rior white matter and the genu of the corpus callosum(Sullivan and Pfefferbaum, 2003). See also: Computedtomography; Imaging: an overview; Magnetic resonanceimaging

The origins of age-related white matter abnormalitiesare manifold. Pathological changes observed in vivo reflectvascular and neuropathological phenomena such as re-duction in cerebral perfusion, especially in the borderzones, subclinical ischaemia, expansion of perivascularspaces stemming from axonal degeneration, gliosis, myelinpallor and breakdown of the ependymal ventricular lining.Age-related loss of myelin is especially pronounced in thefibres projecting to and from the association and limbiccortices, with some evidence supporting the view that thebulk of age-related loss of white matter is borne by smallmyelinated axons. Besides age per se, transient cerebralischaemia and hypertension are associated with increasedburden of age-related white matter abnormalities. The lat-ter are also linked to cognitive slowing, and to deficits inmemory and executive functions in normal elderly people.See also: Axons;Hypertension; Limbic system;Myelin andaction potential propagation; Stroke

In accord with postmortem neuroanatomical studies, invivo neuroimaging reveals age-related expansion of thecerebral ventricles (ventriculomegaly), generalized en-largement of cerebral sulci and reduction in gross cerebral

volume (Figure 1). Ventriculomegaly, the most global indexof brain integrity, is especially clear in the ageing brain.Ventricular enlargement (at almost 3% per annum) seemsto start in relatively young adulthood and accelerates withadvancing age. By comparison, shrinkage of the ‘totalbrainparenchyma’ observed inhealthy adults is small, witha median value of only 0.18% per annum (Raz, 2004),which is comparable to the rate of neuronal loss in neo-cortex observed postmortem (Pakkenberg andGundersen,1997).Age-related deterioration of brain structure is accom-

panied by decline in the physiological indices of brainworkand in global physiological indices of brain function. Nor-mal ageing is associated with a moderate reduction in re-gional cerebral bloodflow, regional cerebralmetabolic rateof oxygen utilization and grey matter blood volume. Incontrast, the evidence concerning age effects on the totalbrain metabolism of glucose is equivocal.

Differential Vulnerability of BrainRegions and Components to Ageing

Against the backdrop of generalized age-related changes, apattern of differential vulnerability emerges. Several linesof evidence converge on to the notion of selective sensitiv-ity of specific brain regions to ageing. When synaptic den-sity and dendritic arborization of the cortical neurons arereducedwith age, the reduction is particularly significant inthe prefrontal cortex.Moreover, in normal ageing (but notin those with Alzheimer disease), this effect may be espe-cially pronounced in the large pyramidal cells and inter-neurons of lamina V and less severe (although stillsignificant) in lamina III of the middle frontal gyrus pop-ulated by small- and medium-sized pyramidal neurons.Unlike neuritic plaques, neurofibrillary tangles show apropensity to accumulate in the frontal and temporal cor-tices, especially in lamina V in which corticocortical andcorticosubcortical (corticostriatal and corticothalamic)fibres originate. Granulovacuolar degeneration and emer-gence of Hirano bodies show predilection of the hippo-campus. b-amyloid deposits that augur neuronal demiseare very sparse in the primary motor and sensory cortices,moderately dense in visual and auditory cortices, and sub-stantial (up to 25% of the total neuron area) in the asso-ciation cortices. Although some shrinkage of Betz cells inthe primary motor cortex of primates has been noted, nodecline in the total neuronal population of this region hasbeen observed.Because of their involvement in the early stages of

Alzheimer disease (Braak and Braak, 1991), longitudinalstudy of the medial temporal structures (the hippocampusand the entorhinal cortex) has attracted special attentionfrom researchers. The results suggest somewhat steeperdecline in hippocampal volume (Figure 2a) than estimated

Figure 1 Ventriculomegaly, sulcal expansion and white matter

hyperintensities are typical in the brains of asymptomatic elderly. The brainimages of two women aged (a) 25 years and (b) 82 years are compared.

Note numerous punctate lesions of the white matter, periventricular capsand relatively large areas of white matter hyperintensity in the brain of the

older person. Themagnetic resonance (MR) images were acquired using aT2-weighted fast-spin echo sequence (repetition time/echo time53300/

90ms) in a 1.5 T magnet. In this mode of MR image acquisition, the whitematter appears dark and the fluid-filled spaces white. Axial images through

the basal ganglia are presented.

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from cross-sectional investigations (more than 1.2% perannum). Moreover, shrinkage of the hippocampus accel-erates with age, although in healthy adults it does not reachthe annual rates of 3–4% observed in Alzheimer dementia(AD) (Jack et al., 2000). While significant declines in theentorhinal volume were documented in older adults, insamples with broader age range, much slower or negligibledeclines are observed.A studyof haemodynamic propertiesof the medial temporal regions in healthy adults revealed asimilar pattern of significant age-related decline in the hip-pocampus but not in the entorhinal cortex, with the excep-tion of the oldest participants (Small et al., 2000). Notably,healthy older adults who show entorhinal volume loss per-form worse on the memory tests than those whose ent-orhinal cortices remain stable (Rodrigue and Raz, 2004).

Various degrees of age-related shrinkage of grossly de-fined brain regions have been revealed in several in vivo

studies. The strongest negative association between ageand regional volume has been observed in the prefrontalcortex (Figure 2b), in cross-sectional and longitudinal stud-ies. The temporal and parietal regions appear more stable(at least in the cross-sectional studies), and occipital lobesshow the weakest effect of age. However, in contrast tocross-sectional studies that are subjected to confoundingeffects of individual variability and secular trends, longi-tudinal investigations of the posterior association cortices(e.g. inferior parietal) reveal shrinkage at a rate compara-ble to that of the prefrontal cortex. Primary visual cortexshows the weakest, if any, age-related changes in volume(Raz, 2004). The age-related shrinkage of the hemisphericwhite matter seems to be limited to the oldest adults, assuggested by the curvilinear age trajectories derivedfrom cross-sectional studies (Bartzokis, 2004; Raz, 2004).See also: HippocampusThe ‘striatum’ (Figure 2c), for which cross-sectional find-

ings estimate only mild decline, shows significant age-re-lated shrinkage in all of its components. The rate of striatalshrinkage, however, varies across its nuclei, with the cau-date showing the pace of volume reduction comparable tothat of the association cortices and the globus pallidus be-ing only modestly affected. Longitudinal studies of chang-es in the ‘metencephalic volumes’ revealed significantannual shrinkage of the cerebellar hemispheres that wassomewhat greater than that of the vermis. The ventral ponsexhibits virtually no cross-sectional age-related differencesand only a slight, although significant, longitudinal vol-ume change (Raz, 2004).Although the neurochemistry of the ageing cerebral

cortex is still insufficiently understood, some regional dis-tribution trends can be discerned. Ageing is accompaniedby significant declines in all major monoaminergic sys-tems. For example, the density of noradrenergic a2 recep-tors declines with age in the frontal and temporal cortex,and to a lesser extent in the hippocampus; the changes areeven less severe in the visual cortex. The synthesis andconcentration of dopamine and density of dopaminergicD1 receptors are reduced in the prefrontal cortex, whereasparietal association areas evidence smaller deficits, andsensory cortices exhibit no age-related effects at all. Whileserotonergic receptor availability decreases significantlywith age across the brain, the trend is substantially strongerin the prefrontal than in the occipital cortex. The relativedensity of cholinergic (muscarinic) receptors is moderatelyreduced in the frontal but not in the cerebellar cortex of theageing brain. Nicotinic cholinergic receptors evidencereduced reactivity in the hippocampus, parietal lobe andneostriatumof normal elderly people. See also: Adrenergicreceptors; Amine neurotransmitters; Dopamine receptors:molecular pharmacology; Muscarinic acetylcholine recep-tors; Serotonin receptorsAgeing is accompanied by alterations in the distribution

of iron in the brain. The striatum (especially the putamen)tends to accumulate iron, and ageing is accompanied by

Figure 2 Comparison of three cerebral structures in a young (24 years old)

and an older (81 years old) person. (a) Parasagittal slice containing thehippocampus. (b)Coronal slice through theprefrontal cortex andprefrontal

white matter. (c) Axial slice through the basal ganglia and ventricularsystem. The images were acquired in an axial plane on a 1.5 T magnetic

resonance imaging scanner using SPGR sequencewith echo timeTE55ms,repetition time TR524ms, flip angle5308, matrix5256�192. Coronal

and sagittal images were reconstructed from the original axial set.

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augmentation of iron deposits. Images of the ageing brainobtained in vivo show that the effects of iron accumulationare especially prominent in the neostriatum, the deep cer-ebellar nuclei and the motor cortex, whereas they are lesspronounced in the visual cortex. Age-related aggregationof iron abets the ongoing cellular ageing by providing cat-alyst for cytotoxic-free radicals. See also: Free radicals andother reactive species in disease; Oxidative stress-inducedcellular senescence

Mechanisms and Modifiers of BrainAgeing

Gerontological knowledge undergoes an epistemic equiv-alent of urban sprawl. Interpreting rapidly accumulatingdata, and divining general principles behind the observedpatterns of neural ageing, is a challenging task indeed. Al-though a comprehensive theory of brain ageing is not yet athand, signs and clues of its explanatory outline emerge.

Changes in calcium homeostasis have been proposed asthe core mechanism of physiological and pathologicalageing (Khachaturian, 1984; Mattson, 1992). A variety ofmechanisms based on [Ca2+] homeostasis are responsiblefor neuronal death and dendritic branching, as well aslong-term changes in electrophysiological properties of theneurons. In other words, modifiability of the neurons andtheir very existence depend on the same ion. Such is thedark side of plasticity. See also: Calcium signalling andregulation of cell function

Notably, the regions that exhibit the greatest vulnera-bility to ageing are also the most plastic structures of theadultmammalian brain. Primate adult neurogenesis, if andwhen it occurs, is limited to association (prefrontal, infe-rior temporal and posterior parietal) cortices and the hip-pocampus while excluding the primary sensory areas.Plasticity-promoting factors such as growth-associatedprotein (GAP-43) are rare in the brainstem, tectum andtegmentum but frequent in the associative areas of theneocortex, in the dentate gyrus (molecular layer), theneostriatum and the amygdala.

Multiple external pathological modifiers can shape theappearance of the ageing brain, in addition to or in inter-actionwith the basic cellularmechanisms. Brain tissuemaybe altered by inflammation, chronic or acute. Indeed,5-lipooxygenase, the key enzyme in the synthesis of in-flammatory eicosanoids that are capable of promoting ne-urodegeneration, is overabundant in the associationcortices and limbic structures of rodents. Thus, cumula-tive effects of subclinical inflammation in those regionsmay be more pronounced than in the primary cortices,creating the observed pattern of differential vulnerability.See also: Eicosanoid biosynthesis; Neuroimmunology

Vascular factors may contribute to shaping the obser-ved pattern of differential ageing. Brain regions located

upstream of the major cerebral arteries, especially at thewatershed areas, are more vulnerable to subclinicalischaemia and reperfusion; age-related rarefication ofmicrovasculature may contribute to impaired cerebralblood flow and increase the risk of such injury (Riddleet al., 2003). Such a mechanism can be offered to explainthe vulnerability of dorsolateral prefrontal and superiorparietal areas and the hippocampus (Raz et al., 2005). Hy-pertension, even at its mild forms,may preferentially affectthe prefrontal regions, which are vulnerable to ageing (Razet al., 2003) and accelerate shrinkage of the hippocampus(Raz et al., 2005). Notably, some antihypertensive agents(e.g. [Ca2+]-channel blockers) may act as neuroprotectorsby stimulating an increase in capillary density and creatingmore favourable conditions for recovery of neural activity.Age-related declines in specific brain neurotransmitter

systems (cholinergic and monoaminergic, especially dop-aminergic) may account for some features of the regionaldistribution of age-sensitive and -invariant areas. Indeed,age-related shrinkage of the nuclei in which the bulk of thecortical afferents of these systems originate is substantial.The effects of age on the substantia nigra, locus coeruleus,nucleus raphe dorsalis and nucleus basalis are on par withdeclines of the prefrontal cortex and neostriatum. Howev-er, such proposals fall short of explaining the pattern ofdifferential brain ageing that emerges from postmortemand in vivo studies. Moreover, while the evidence of theadverse effect of age on dopaminergic systems is compel-ling, it is unclear whether the cholinergic system is signif-icantly impaired in healthy elderly individuals who showno clinical signs of dementia. When deterioration of thecholinergic system is observed, it shows predilection forthe regions that exhibit only mild age-related shrinkage.See also: Acetylcholine; NeurotransmittersLifetime cumulative stress may contribute to brain age-

ing as well. In rodent hippocampus, glucocorticoids re-leased by prolonged stress produce demonstrable damage,primarily in the CA1 sector. Longitudinal studies ofhealthy adults show that high basal cortisol levels andsteep increase in cortisol concentration over time result inshrinkage of the hippocampus, but not of the temporaland fusiform cortices, whereas a progressive increase incortisol excretion is associated with age-related declines inmemory. However, the fact that the reported effects aremost palpable in the regions that show only moderate age-related shrinkage in humans and rodents suggests thatstress-related damage mediated by glucocorticoid releasemay be linked to age-related pathology rather than toageing per se.A look at the pattern of differential brain ageing suggests

that phylogenetically newer and ontogenetically less pre-cocious brain structures such as association cortices andthe neostriatum show increased vulnerability to the effectsof ageing. The gradient of differential vulnerability sug-gested by the reviewed studies seems to follow the rule of(phylogenetically andontogenetically) last in, first out. The

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correspondence between ontogenetic chronology and age-related vulnerability may be illustrated by the followingobservation. As illustrated in Figure 3, the magnitude ofage-related differences in regional cortical volumes corre-lates positively with the precedence rank in the order ofmyelination of intracortical fibres according to Flechsig(1901). The later the myelination of the region is complet-ed, the stronger the association between age and volumeobserved in vivo.

Is there anything that can change the path of age-relateddecline? Animal studies show a consistent life-extensioneffect of caloric restriction, but human data in general, andparticularly in the ageing brain context, are missing. Somepreliminary evidence suggests that aerobic exercisemay actas a neuroprotective intervention (Kramer et al., 2003),and the benefits of staving age-related depletion of sexsteroids and other hormones are being investigated withmixed results so far.

Summary

The ageing brain displays a complex pattern of multipledifferential changes. The most age-sensitive brain regionsare the association cortex and the neostriatum. The areasthat exhibit extended plasticity are located in the areas ofsparse vascularization and those that send and receivemonoaminergic projections show increased vulnerabilityto ageing. However, age-related changes in the brain ex-

hibit a high degree of interspecies and individual variabil-ity. Some of the factors that induce individual variabilityaffect various age-sensitive functions in a differential, evencontradictory, manner. Several major modifying factors –neurochemical, vascular and endocrine – may play a sig-nificant role in shaping the ageing brain for better and forworse.Connections between specific regional changes in brain

structure and function and specific alterations of cognitivefunction have not been clearly established. Individual var-iability, which can be treated statistically in the sizeablesamples customary in behavioural research, cannot be ad-dressed in the small-sample studies that are prevalent inhuman neuroscience. Thus, in elucidating the impact ofneurobiological changesonageing cognition, a study ratherthan a subject becomes a suitable unit of analysis. Thecreation of a cumulative record from multiple studiesspanning a wide range ofmethods and subjects is a priorityfor cognitive neuroscience of ageing in the near future.Illuminating the connections between brain and behav-iour, rather than cataloguing age-related differences in thebrain, is a prerequisite for future progress in understandingageing and developing beneficial interventions aimed atalleviating its negative effects.

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