Modification of Brain Aging

Physiol Rev
82: 637 672, 2002; 10.1152/physrev.00004.2002.
Modification of Brain Aging and Neurodegenerative Disorders

by Genes, Diet, and Behavior
MARK P. MATTSON, SIC L. CHAN, AND WENZHEN DUAN
Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland
I. Introduction 637
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II. Adaptive Cellular and Molecular Responses in Brain Aging 641
A. Neuroprotective mechanisms 641
B. Neurorestorative mechanisms 642
III. Genetic Factors in Brain Aging and Neurodegenerative Disorders 644
A. Genes that influence life span and brain health span 644
B. Genes that cause or increase risk of neurodegenerative disorders 644
IV. Dietary Factors in Brain Aging and Neurodegenerative Disorders 651
A. Effects of dietary restriction on brain aging: neuroplasticity and neuroprotection 651
B. Cellular and molecular mechanisms underlying the neural effects of dietary restriction 652
C. Folic acid 655
D. Antioxidants 657
V. Behavioral Modification of Brain Aging 658
A. Intellectual activity 659
B. Exercise 659
VI. Synapses and Aging: Emerging Concepts 660
VII. Implications for Prevention and Treatment of Neurodegenerative Disorders 660
Mattson, Mark P., Sic L. Chan, and Wenzhen Duan. Modification of Brain Aging and Neurodegenerative Disorders by
Genes, Diet, and Behavior. Physiol Rev 82: 637 672, 2002; 10.1152/physrev.00004.2002.Multiple molecular, cellular,
structural, and functional changes occur in the brain during aging. Neural cells may respond to these changes adaptively,
or they may succumb to neurodegenerative cascades that result in disorders such as Alzheimers and Parkinsons
diseases. Multiple mechanisms are employed to maintain the integrity of nerve cell circuits and to facilitate responses to
environmental demands and promote recovery of function after injury. The mechanisms include production of neuro-
trophic factors and cytokines, expression of various cell survival-promoting proteins (e.g., protein chaperones, antioxi-
dant enzymes, Bcl-2 and inhibitor of apoptosis proteins), preservation of genomic integrity by telomerase and DNA repair
proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such
neuroprotective and neurorestorative mechanisms. Genetic and environmental factors superimposed upon the aging
process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms
of Alzheimers disease (amyloid precursor protein and presenilins), Parkinsons disease (!-synuclein and Parkin), and
trinucleotide repeat disorders (huntingtin, androgen receptor, ataxin, and others) overwhelm endogenous neuroprotec-
tive mechanisms; other genes, such as those encoding apolipoprotein E4, have more subtle effects on brain aging. On the
other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction and folate and antioxidant
supplementation) and behavioral (intellectual and physical activities) modifications. At the cellular and molecular levels,
successful brain aging can be facilitated by activating a hormesis response in which neurons increase production of
neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to
environmental demands and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the
aging brain. The recent application of modern methods of molecular and cellular biology to the problem of brain aging
is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease.
I. INTRODUCTION accordingly, a major goal of research in the area of the

neurobiology of aging is to identify ways to facilitate
Many persons live for nine or more decades and successful brain aging in everyone. Studies of brains of
enjoy a well-functioning brain until the very end of life. the oldest old have provided evidence for stability as well
We therefore know what the brain is capable of and, as plasticity in successful brain aging (Fig. 1). In many
www.prv.org 0031-9333/02 $15.00 Copyright 2002 the American Physiological Society 637
638 MATTSON, CHAN, AND DUAN
Studies of embryonic and early postnatal develop-

ment, and of synaptic plasticity in the young adult, have
made a major contribution to our current understanding
of the molecular and cellular mechanisms that determine
whether brain aging occurs successfully or manifests dys-
function or disease. This is because the same intercellular
signals and intracellular transduction pathways that reg-
ulate neurite outgrowth, synaptogenesis, and cell survival
during development are also operative throughout life
(213). Although new signaling systems continue to be
discovered, the major classes of signaling molecules im-
portant in brain aging include neurotrophic factors, neu-
rotransmitters, cytokines, and steroids. Neurotrophic fac-

tors such as neurotrophins [brain-derived neurotrophic
factor (BDNF), nerve growth factor (NGF), neurotensin
FIG. 1. During aging there is a progressive accumulation of damaged (NT)-3, and NT-4], fibroblast growth factors, glial-derived
molecules and impaired energy metabolism in brain cells. Neurons and neurotrophic factor (GDNF), and ciliary neurotrophic fac-
glial cells may adapt to the adversities of aging by increasing their ability
to cope with stress, compensating for lost or damaged cells by produc-
tor (CNTF) have been shown to promote the survival of
ing new neurons and glia, and remodeling neuronal circuits. If adapta- specific populations of brain neurons under experimental
tion is not successful, then molecular damage to neurons and inflam- conditions relevant to brain aging and neurodegenerative
matory processes result in synaptic dysfunction and neuronal
degeneration and death.
disorders (232). In addition to their roles as mediators of
synaptic transmission, neurotransmitters such as gluta-
mate, acetylcholine, and dopamine also play important
brain regions, there is very little or no decrease in num- roles in regulating the formation of neuronal circuits dur-
bers of neurons, while in some brain regions neuronal ing development and in influencing the neurodegenerative
loss may occur but may be compensated by expansion of process in brain disorders of aging (215). Sex steroids
dendritic arbors and increased synaptogenesis in the re- (estrogen and testosterone) and stress steroids (glucocor-
maining neurons (19). It is thought that many neurons ticoids) have been shown to have quite striking effects on
remain in the brain for a lifetime, although in some brain brain function and structure, and alterations in regulation
regions such as the olfactory bulb and dentate gyrus of of their production and signaling mechanisms have been
the hippocampus, there may be a continuous replacement reported to occur during aging (239). The status of such
of neurons from a pool of progenitor (stem) cells (91, neurotransmitter, trophic factor, cytokine, and steroid
291). This regenerative capacity of some brain regions hormone signaling systems is likely to have a major influ-
may persist throughout life. Changes in the cellular struc- ence on the outcome of brain aging.
ture of the brain and the functions of its neuronal circuits While the brain can age successfully, its cells may
are controlled by an intricate array of intercellular signal- face considerable adversity during the journey (Fig. 1).
ing molecules and intracellular signal transduction path- Increased oxidative stress (oxyradical production) and
ways. Several such cellular signal transduction systems accumulation of oxidatively damaged molecules (pro-
are altered during brain aging. Examples of widely used teins, nucleic acids, and lipids) promote dysfunction of
signaling mechanisms affected by aging include protein various metabolic and signaling pathways (178). Neurons
phosphorylation (alterations in kinases and phospha- may also face energy deficits as the result of alterations in
tases) (150), cellular calcium homeostasis (215), and gene the cerebral vasculature and in mitochondrial function
transcription (180). Among neurotransmitter systems, do- (131). As in other organ systems, cells in the brain en-
paminergic signaling appears to be consistently altered counter a cumulative burden of oxidative and metabolic
during aging with a progressive decrease in signaling via stress that may be a universal feature of the aging pro-
the D2 subtype of receptor (303). In addition to signaling cess. Each of the major classes of cellular molecules,
pathways, cellular systems that regulate protein folding including proteins, nucleic acids, and lipids, is oxidatively
(chaperone proteins) and degradation (proteasomal and modified during brain aging. Protein modifications in-
lysosomal systems) are altered in brain cells during aging clude carbonyl formation (34, 35, 74); covalent modifica-
(158) (Fig. 2). These kinds of alterations that occur during tion of cysteine, lysine, and histidine residues by the lipid
normal aging may set the stage for catastrophic neurode- peroxidation product 4-hydroxynonenal (261, 268, 266);
generative disorders that may be triggered by particular nitration on tyrosine residues (326); and glycation (249).
genetic predispositions or environmental factors, while DNA and RNA bases are subject to oxidative modifica-
other age-related changes may represent adaptive protection, with a prominent example being the formation of
tive responses to the aging process. 8-hydroxydeoxyguanosine (331). Double bonds in mem-
Physiol Rev VOL 82 JULY 2002 www.prv.org

MOLECULAR MECHANISMS OF BRAIN AGING 639

FIG. 2. Mechanisms involved in regulating protein turnover and their modification by cellular stress. Proteins
damaged by oxidative stress or other modifications can be degraded by the proteasomal or lysosomal systems. Protein
chaperones such as heat shock proteins (HSP40, HSP70, and HSP90), glucose-regulated proteins (GRP78 and GRP94),
and ubiquitin play important roles in controlling protein folding and targeting proteins for proteolytic degradation. ER,
endoplasmic reticulum.
brane lipids are oxidized resulting in the production of a the brain (216). As amyloid "-peptide aggregates, it gen-
variety of lipid peroxides and aldehydes (218). These erates reactive oxygen species that can induce membrane
modifications of proteins, nucleic acids, and lipids are lipid peroxidation in neurons resulting in the impairment
greatly exacerbated in neurodegenerative disorders such of the function of membrane ion-motive ATPases and
as Alzheimers disease (AD) and Parkinsons disease (PD) glucose transporter proteins, which, in turn, disrupts cel-
consistent with a major role for oxidative stress of aging lular ion homeostasis and energy metabolism (216). These
in the pathogenesis of those disorders (207). oxidative actions of amyloid "-peptide can cause dysfunc-
Analyses of experimental animal and cell culture tion of synapses and may render neurons vulnerable to
models of age-related neurodegenerative disorders have excitotoxicity and apoptosis (80, 219). In PD, degenera-
provided insight into the mechanisms that result in in- tion of dopaminergic neurons in the substantia nigra may
creased oxidative stress and damage to proteins, nucleic be triggered by mitochondrial impairment and increased
acids, and membrane lipids (Fig. 3). The pathogenesis of oxidative stress resulting from aging and exacerbated by
AD involves altered proteolytic processing of the "-amy- environmental factors (147). In the common late-onset
loid precursor protein (APP) resulting in increased pro- forms of AD and PD, the neurodegenerative cascade is
duction of a long (42 amino acid) form of amyloid "-pep- most likely promoted by environmental factors (see sects.
tide which self-aggregates and forms insoluble plaques in IV and V) that result in increased oxidative and metabolic


FIG. 3. Examples of sources of oxidative stress in neurons during aging and examples of molecules damaged by free
radical-mediated processes. A major source of oxyradicals is mitochondria, in which superoxide anion radical (O! 2 !) is
produced during oxidative phosphorylation. Superoxide is converted to hydrogen peroxide (H2O2) via the actions of
mitochondrial manganese superoxide dismutase (Mn-SOD) and cytosolic Cu/Zn-SOD. Hydrogen peroxide is eliminated
from cells by conversion to water in reactions catalyzed by catalase and glutathione peroxidases. However, hydrogen
peroxide is an important source of hydroxyl radical (OH!) which is generated in the Fenton reaction which involves Fe2"
or Cu2". Hydroxyl radical is a potent inducer of membrane lipid peroxidation. Oxyradicals can also be generated in
response to calcium influx via the activation of nitric oxide (NO) synthase, resulting in NO production; NO can interact
with superoxide to produce peroxynitrite. In addition, various oxygenases can be activated by calcium resulting in
superoxide production. Oxyradicals (particularly hydroxyl, superoxide, and peroxynitrite) can damage proteins, lipids,
and nucleic acids. Lipid peroxidation products such as 4-hydroxynonenal (HNE) can covalently modify proteins and
impair their function. Arach acid, arachidonic acid; CaM, calmodulin; depol, depolarization; ER, endoplasmic reticulum;
GSH, glutathione; GSHPx, glutathione peroxidase; GSHR, glutathione reductase; GSSG, reduced glutathione; LP, lipid
peroxidation; PLA2, phospholipase A2; NOS, NO synthase; PS1, presenilin-1; PT, permeability transition pore; SOD1,
Cu/Zn-superoxide dismutase; SOD2, manganese superoxide dismutase.
stress. On the other hand, more rare inherited forms of PD, dopaminergic neurons in the substantia nigra degen-
these disorders in which disease onset occurs at an early erate resulting in motor dysfunction (147). A stroke oc-
age (30 60 years of age) are caused by specific mutations; curs when a cerebral blood vessel becomes occluded or
for example, mutations in APP and presenilins that cause ruptures resulting in the degeneration of neurons in the
AD (122) and mutations in !-synuclein and parkin that brain tissue supplied by that vessel (65). Several genetic
cause PD (165, 281). Some neurodegenerative disorders and environmental factors that may initiate the neurode-
are purely genetic including Huntingtons disease (HD) generative process in AD, PD, and stroke have been iden-
and related trinucleotide repeat disorders (389); such dis- tified, and this information has led to the development of
orders may not, therefore, be considered as diseases of valuable animal models of these disorders. Animal models
aging, although aging processes may affect the age of of AD include transgenic mice overexpressing mutant
disease onset and clinical course. forms of human APP (93, 133), transgenic and knockin
In the United States and other industrialized coun- mice expressing mutant forms of human presenilin-1
tries, life expectancy continues to increase, and therefore, (PS1) (75, 108), and infusion of amyloid "-peptide and
more people will suffer from age-related neurodegenera- excitotoxins into the brains of rats and mice (31, 97).
tive conditions. The negative impact of age-related neu- Animal models of PD include administration of the toxin
rodegenerative disorders on our societies is emphasized 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to
by the fact that more dollars are required to care for monkeys and mice resulting in selective degeneration of
patients with AD, PD, and stroke than are spent on the substantia nigra dopamine-producing neurons and asso-
combined care for patients with cardiovascular disease or ciated motor dysfunction (71), and transgenic mice ex-
cancer. Each neurodegenerative disorder is characterized pressing mutant human !-synuclein which exhibit degen-
by dysfunction and degeneration of specific populations eration of dopaminergic neurons and a behavioral
of neurons in the brain (246). Neurons in brain regions phenotype with features similar to PD (210). Stroke mod-
involved in learning and memory processes, such as the els involve transient or permanent occlusion of the middle
hippocampus and cerebral cortex, are afflicted in AD. In cerebral artery in rats and mice (65, 378). The mecha-

nisms that result in neuronal dysfunction and/or death in norepinephrine, and serotonin (89, 214, 288). During brain
these models are beginning to be understood, with in- aging, these neurotransmitters may contribute to either
creased oxidative stress, perturbed energy metabolism, degeneration or adaptive responses of neurons.
altered calcium homeostasis, and activation of apoptotic Neurotrophic factors promote the survival, out-
cascades playing important roles in most cases (219). growth, and/or synaptogenesis of neurons. Examples of
Data obtained using these various models have provided neurotrophic factors that have been shown to counteract
valuable insight into the cellular molecular mechansims untoward aspects of aging (oxidative stress and disturbed
of neurodegenerative disorders and will therefore be ion homeostasis, for example) include basic fibroblast
cited throughout the remainder of this article. growth factor (bFGF), NGF, BDNF, NT-4, transforming
growth factor-" (TGF-"), tumor necrosis factor (TNF),
and GDNF. These neurotrophic factors can protect one or
II. ADAPTIVE CELLULAR AND MOLECULAR
more populations of brain neurons against excitotoxic,
RESPONSES IN BRAIN AGING
oxidative, and metabolic insults in models of stroke, AD,

PD, and HD (232, 233). Signaling by cell adhesion proteins
A goal of basic and clinical neuroscientists is to
such as integrins may also play important roles in modu-
identify approaches for promoting the maintenance of
lating neuronal survival (94). Growth factors, cytokines,
cognitive, emotional, motor, and sensory functions
and integrin ligands promote neuronal survival by induc-
throughout the life span.
ing the expression of genes that encode proteins that
This could be accomplished by avoiding genetic
suppress oxidative stress, stabilize cellular calcium ho-
(through genetic counseling or germline gene therapy, for
meostasis, and antagonize neurodegenerative biochemi-
example) and environmental (dietary and behavioral fac-
cal cascades. Examples of three neuroprotective signaling
tors, for example) factors that facilitate neuronal dysfunc-
cascades, activated by BDNF, bFGF, and the secreted
tion and death, or by enhancing the ability of neurons to
form of APP are shown in Figure 4. bFGF, BDNF, TNF,
adapt to the aging process. Basic research is identifying
and NGF can increase the production of one or more
cellular signaling mechanisms that promote cell survival,
antioxidant enzymes [Cu/Zn-superoxide dismutase (SOD),
neurite growth, and/or synapse formation/plasticity; un-
Mn-SOD, glutathione peroxidase, and catalase] in hip-
derstanding these signaling pathways may reveal ways of
pocampal neurons (233, 229). NGF, BDNF, and TNF can
promoting successful brain aging. Clinicians, geneticists,
induce expression of anti-apoptotic Bcl-2 family members
and epidemiologists should therefore work together to
(32) and inhibitor of apoptosis proteins (IAP) (364). Neu-
identify genetic and environmental factors that cause or
rotrophic factors can also modulate the expression and/or
affect risk of age-related neurological disorders.
activity of subunits of glutamate receptors and voltage-
dependent calcium channels in ways that promote neuro-
A. Neuroprotective Mechanisms nal survival and synaptic plasticity (217, 225, 360). Ki-
nases such as mitogen-activated protein (MAP) kinase
Intercellular signaling mechanisms mediate the sec- and protein kinase C, and transcription factors such as
ond-to-second functions of neuronal circuits as well as NF-#B and CREB, transduce the cell survival signals of
long-term changes in the biochemistry and structure of neurotrophic factors and cytokines.
those circuits. Three major classes of intercellular signal- Another type of adaptive response that may protect
ing proteins that regulate neuronal survival and synaptic neurons against the adversities of aging and disease is a
plasticity are neurotransmitters, neurotrophic factors, stress response that involves protein chaperones that ex-
and hormones. Glutamate and GABA, the major excita- hibit neuroprotective properties. Examples of such stress
tory and inhibitory neurotransmitters in the brain, play proteins include heat shock proteins (e.g., HSP-70, HSP-
pivotal roles in regulating neuronal survival (231) and 90, and HSP-60) and glucose-regulated proteins (e.g.,
synaptic plasticity (18). By inducing the expression of GRP-78 and GRP-94). These chaperone proteins interact
neurotrophic factors such as BDNF, glutamate can pro- with many different proteins in cells and function to
mote neuronal survival (203). On the other hand, overac- ensure their proper folding, on the one hand, and degra-
tivation of glutamate receptors can cause neuronal death, dation of damaged proteins, on the other hand (86, 96).
particularly under conditions of increased levels of oxi- They may also interact with, and modify the function of,
dative and metabolic stress, as occurs during aging and in apoptotic proteins including caspases (14, 293). Levels of
age-related neurodegenerative disorders (224). By reduc- some of these chaperone proteins may be increased dur-
ing neuronal excitability, GABA can protect neurons in ing aging as a protective response (180, 182). Cell culture
experimental models of neurodegenerative disorders and in vivo studies have shown that HSP-70 and GRP-78
(231). Other neurotransmitters that can modify neuronal can protect neurons against injury and death in experi-
vulnerability in cell culture and animal models of neuro- mental models of neurodegenerative disorders (197, 380).
degenerative disorders include acetylcholine, dopamine, Interestingly, caloric restriction, a dietary manipulation

FIG. 4. Examples of cellular signal-

ing pathways that modulate neuronal
plasticity and survival during aging. Neu-
rotrophic factors such as brain-derived
neurotrophic factor (BDNF) activate
membrane receptor tyrosine kinases that
initiate kinase signaling cascades that ul-
timately regulate the expression of genes
that encode proteins which enhance neu-
ronal survival and plasticity. Such gene
targets include those encoding proteins
that suppress apoptotic cascades, reduce
oxidative stress, and stabilize cellular
calcium homeostasis. AKT/PKB, Akt ki-
nase; CaMKIV, calcium/calmodulin-de-
pendent protein kinase IV; CREB, cAMP
response element binding protein; IRS1,

insulin receptor substrate-1; MAPK, mi-
togen-activated protein kinase; MEK,
MAP kinase kinase; PI3K, phosphatidyl-
inositol 3-kinase; PKG, protein kinase G;
R, receptor; sAPP, secreted form of amy-
loid precursor protein; SHC, src homol-
ogy domain-containing adaptor protein;
trkB, high-affinity BDNF receptor.
that increases life span and brain health span (the time on the degree of specificity of neuronal connections in the
window of life during which the brain maintains a level of circuits involved. For example, reorganization of the mor-
function that permits a productive life-style), can increase phology of hippocampal neurites and synapses after
the expression of chaperone proteins in the brains of rats stress-induced damage correlates with behavioral im-
and mice (see sect. IV). provement (333). On the other hand, many brain functions
Synapses are sites where the actions of neurotro- rely on memories based on the past history of synaptic
phic factors, stress proteins, and anti-apoptotic Bcl-2 activity, and such memories are unlikely to be restored by
and IAP family members may play particularly impor- new synapse formation.
tant roles in preserving the integrity and function of Stem cell biology is a rapidly growing area in the
neuronal circuits (115, 228). The impact of aging is fields of neuroscience research and aging. Embryonic
likely to be most severe in synapses, because these stem cells have received considerable attention because
compartments are sites of repetitive calcium influx and of their ability to form any type of cell in the body includ-
oxyradical production; it is therefore of great impor- ing neurons (99). They are therefore a potential cell
tance to understand how genes and environment affect source for replacement of neurons lost in neurodegenera-
synaptic homeostasis (see sect. VI). tive disorders. Two major populations of pluripotent NPC
are present in the adult brain, one in the subventricular
B. Neurorestorative Mechanisms zone and the other in the subgranular layer of the dentate
gyrus of the hippocampus (91). These NPC cells can give
Research performed in many different laboratories rise to either neurons or astrocytes, and there is increas-
during the past 10 years has revealed that regeneration/ ing evidence that some of the progeny of the NPC survive
compensation can occur in the adult brain and that pop- and become functional, although many may undergo pro-
ulations of stem cells or neural progenitor cells (NPC) grammed cell death (Fig. 5). Newly generated cells in the
may play a role in this process by dividing and then brain can be identified by giving animals the thymidine
differentiating into neurons or glia (91). Various neurotro- analog bromodeoxyuridine (BrdU); the phenotype of their
phic factors and cytokines may promote neurogenesis, differentiated progeny can then be determined by double-
neurite outgrowth, and synaptic recovery after brain in- labeling using antibodies against neuronal (e.g., neural
jury (146, 232). Damage to axons and dendrites can result cell adhesion molecule or "3-tubulin) or astrocyte [glial
in regrowth of those processes; however, in contrast to fibrillary acidic protein (GFAP)] markers. Several signals
the peripheral nervous system, the brain contains a num- that control the proliferation, differentiation, and survival
ber of inhibitory signals that may prevent successful re- of NPC have been identified (91, 291). bFGF and epider-
innervation of target cells (312). If synaptogenesis does mal growth factor (EGF) can maintain NPC in a prolifer-
occur, it may or may not replace lost function depending ative state, whereas BDNF and NT-3 can promote their

FIG. 5. Regulation of neurogenesis and gliogenesis. Neural stem cells capable of producing neurons and astrocytes

are maintained in a self-replicating state by cytokines and neurotrophic factors such as leukemia inhibitory factor (LIF)
and epidermal growth factor (EGF). Under the appropriate conditions, the stem cells can form neuron- or glia-restricted
progenitor cells which, in turn, can cease dividing and differentiate into neurons or glia. New neurons may integrate into
neuronal circuits or may die, and glia may also live or die. BDNF, brain-derived neurotrophic factor; bFGF, basic
fibroblast growth factor; BMP, bone morphogenic protein; CNTF, ciliary neurotrophic factor; HB-EGF, heparin-binding
epidermal growth factor; IL-6, interleukin-6; NGF, nerve growth factor; NT-3, neurotrophin-3; NT-4, neurotrophin-4;
TGF-!, transforming growth factor-!; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; sAPP,
secreted form of amyloid precursor protein.
differentiation and/or survival, and bone morphogenetic generative processes, and telomerase may suppress such
protein can induce NPC to become astrocytes (91, 241). DNA damage responses (198); nuclear localization and
Additional signals that control NPC cell fate include reverse transcriptase activity appear to be critical for the
Notch (344), Numb (40), neurogenin (339), and the se- antiapoptotic function of TERT (P. Zhang and M. P. Matt-
creted form of APP (255). Brain injury is a potent stimulus son, unpublished data).
for neurogenesis (194), and this effect is likely mediated The possibility that the aging process impairs neuro-
by the trophic factors and cytokines induced by cell in- genesis is suggested by studies in which BrdU-labeled
jury (232). cells were quantified in the brains of middle-aged and old
Considerable interest in fundamental mechanisms of rats (174). This adverse effect of aging on neurogenesis
cellular aging has arisen from studies of telomerase, a may be counteracted by many of the same environmental
reverse transcriptase that adds a six-base DNA repeat conditions that promote successful brain aging. Indeed,
onto the ends of chromosomes (telomeres) and thereby dietary restriction can increase neurogenesis (183). Inter-
maintains their integrity during successive rounds of cell estingly, neurogenesis can also be increased by environ-
division (221). Expression of the catalytic subunit of te- mental enrichment (164, 254) and physical exercise (351).
lomerase (TERT) and telomerase activity are associated Because no specific molecular markers of NPC have been
with cell immortalization and cancer and are absent from established, and because NPC cannot be labeled by the
most somatic cells in the adult, suggesting an important usual BrdU method in clinical studies of humans, it is not
role in the aging process. Indeed, expression of TERT in known whether abnormalities in neurogenesis contribute
normal fibroblasts makes them immortal (without trans- to the pathogenesis of age-related neurodegenerative dis-
forming them) (24). Telomerase is present in brain cells orders. However, recent studies of experimental models
during development, where it is thought to play a role in of AD have shown that amyloid "-peptide can impair
the maintenance of NPC in a proliferative state, and in neurogenesis (124). Both the proliferation and survival of
promoting survival of NPC and their neuronal and glial NPC in the dentate gyrus of the hippocampus are reduced
progeny (87, 166). Telomerase is also present in NPC in in APP mutant mice. Infusion of amyloid "-peptide into
the adult brain where its expression may be influenced by the lateral ventricle of adult mice impairs neurogenesis of
brain injury and other environmental factors. Recent stud- NPC in the subventricular region. Moreover, exposure of
ies suggest that TERT expression can be induced by cultured human NPC to amyloid "-peptide impairs their
BDNF and sAPP! (W. Fu and M. P. Mattson, unpublished proliferation and differentiation and can induce apoptosis
data). It has been reported that TERT can prevent apo- (124). These experimental findings suggest that adverse
ptosis of cultured neurons in experimental models rele- effects of amyloid "-peptide on NPC may contribute to
vant to AD and stroke (87, 387), suggesting that if TERT depletion of neurons and cognitive impairment in AD.
expression could be induced in neurons or NPC in the Although it is not known whether a failure of neurogen-
adult brain, it may increase the resistance of neurons to esis contributes to the pathogenesis of PD, several studies
age-related neurodegenerative disorders (221). DNA dam- in rodents, nonhuman primates, and humans suggest that
age may trigger neuronal death in age-related neurode- functional recovery can occur after transplantation of

NPC or mobilization of endogenous NPC (21, 323). The and on risk of age-related neurodegenerative disorders, is
development of methods for identifying NPC and their apolipoprotein E (327). Three alleles of apolipoprotein E
recent progeny in post mortem brain tissue sections from encode proteins that differ in two amino acids; E2 con-
human patients would greatly facilitate our understanding tains a cysteine in each position, E3 contains a cysteine in
of the relative contributions of neuronal degeneration and one of the positions, and E4 does not contain a cysteine in
impaired neurogenesis to neurodegenerative disorders. either position. Individuals with an E4 allele have a re-
The implications of neurogenesis for facilitating suc- duced life span (126) and are at increased risk of AD
cessful brain aging and treating age-related neurodegen- (157). The mechanism whereby E4 may accelerate brain
erative disorders are quite profound. It may be possible to aging has been suggested to involve a decreased antioxi-
mobilize endogenous NPC in the brain or to introduce dant and neuroprotective properties of this isoform (Fig.
exogenous NPC to replace dysfunctional or dead neurons 6). The cysteine residues in E2 and E3 may bind to and
and glia. As described above, three different behavioral thereby detoxify 4-hydroxynonenal, a cytotoxic product
modifications have been shown to enhance neurogenesis of lipid peroxidation (266).

(dietary restriction and increased intellectual and physi- Other genes linked to life span that may influence
cal activities). In addition, pharmacological approaches brain aging are those encoding growth hormone (10) and
for mobilizing NPC are being developed. For example, it major histocompatability complex (MHC) proteins (36).
has been shown that antidepressant drugs such as sero- Growth hormone levels decrease with aging, and this
tonin transport inhibitors can increase production of change is ameliorated by caloric restriction. The density
BDNF and stimulate neurogenesis (5, 201). There have of microvessels in the brains of rodents decreases during
already been reports of improved functional outcome aging, and this can be reversed by treating the animals
following NPC transplantation in models of traumatic with growth hormone, which may increase production of
central nervous system injury (238), demyelinating disor- insulin-like growth factor I (IGF-I) in the brain (332). The
ders (372), and PD (21). Particularly intriguing are reports latter studies further showed that IGF-I can reverse age-
suggesting that stem cells in other organs of the body, related impairment in learning and memory. IGF-I can
including bone marrow, are capable of forming neurons also protect neurons against injury and death in experi-
and glial cells (242). A major clinical hurdle in interindi- mental models of AD and related neurodegenerative dis-
vidual transplantations is immune attack on the trans- orders (46, 386). MHC genes are expressed in neurons
planted cells; this could be avoided by using a persons (58). Mice that are genetically deficient for class I MHC
own stem cells for transplantation. Embyronic stem cells proteins exhibit incomplete synaptogenesis in the devel-
may also prove valuable in treating various neurodegen- oping visual system and enhanced long-term potentiation
erative disorders because of their multipotent properties of synaptic transmission in the hippocampus (135), sug-
and their reduced reactivity toward immune cells. gesting important roles for MHC proteins in learning and
memory.
Inherited variability of mitochondrial genes encoding
III. GENETIC FACTORS IN BRAIN AGING
proteins involved in oxidative phosphorylation and other
AND NEURODEGENERATIVE DISORDERS
aspects of mitochondrial function may also contribute to
aging (60) and the pathogenesis of neurodegenerative
The probability of living a long life with preservation
disorders (258). Mitochondrial DNA damage has been
of a high level of brain function is strongly influenced by
shown to increase in brain cells during aging (121), and it
the genes one inherits. Accordingly, genetic factors also
has been proposed that accumulation of mitochondrial
play important roles in determining ones risk of age-
DNA mutations is a major factor in the aging process it-
related neurodegenerative disorders. In this section we
self (260).
review the evidence for the involvement of specific genes
in the determination of life span and risk of neurological
disorders of aging. B. Genes That Cause or Increase Risk
of Neurodegenerative Disorders
A. Genes That Influence Life Span and Brain
Health Span The past decade has been filled with major advances
in our understanding of the pathogenesis of age-related
There is ample evidence that life span (52, 193, 274), neurodegenerative disorders, as the result of the com-
intelligence (57, 240), and risk of various neurological bined efforts of molecular geneticists and cell and molec-
disorders (51, 337, 355) are determined, in part, by heri- ular biologists. More that 20 different genes have been
table factors. However, the specific genes involved and identified in which mutations cause an inherited form of a
their mechanisms of action are largely unknown. One neurodegenerative disorder. Once such a gene is discov-
gene that appears to have an influence on aging in general, ered, the pathogenic mechanism of the mutated form of


FIG. 6. Possible mechanisms of action of different apolipoprotein E isoforms in promoting or preventing age-related
pathological changes in the brain and periphery. In the brain, apolipoprotein E is produced mainly by astrocytes.
Apolipoprotein E can promote neuronal survival and outgrowth and may play important roles in adaptive responses to
aging and brain injury. The beneficial effects of apolipoprotein E may involve an antioxidant function. The E2 and E3
isoforms are more effective than the E4 isoform in their antioxidant and biological activities. Mechanisms of apoli-
poprotein production and metabolism in the periphery are shown in the bottom panel. Individuals with the E4 isoform
are prone to atherosclerosis, which may be due to a diminished antioxidant activity of this isoform resulting in enhanced
damage to vascular endothelial cells.
the gene can be elucidated in studies of cultured cells and onset (70s and 80s), some cases are inherited in an auto-
transgenic mice expressing the mutant gene. In this sec- somal dominant manner with complete penetrance and
tion we describe how the discovery of such disease-caus- an early age of onset (40s and 50s). The first gene linked
ing genes has revealed why neurons become dysfunc- to familial AD is located on chromosome 21 and encodes
tional and die in several of the most prominent the APP, the source of the 40- to 42-amino acid amyloid
neurodegenerative disorders including AD, PD, HD, and "-peptide (A") that forms insoluble amyloid plaques in
amyotrophic lateral sclerosis (ALS). What emerges from the brains of all AD patients (122). Several different dis-
the studies described below is a view of neurodegenera- ease-causing mutations in APP have been reported, all of
tive disorders in which genetic compromise renders the which are located within or adjacent to the A" sequence,
brain vulnerable to the aging process, with specific pop- and all of which increase production of A"-(1O42). The
ulations of neurons being disproportionately affected. In most intensely studied APP mutations are the Swedish
general, disease-causing mutations appear to act mainly mutation (a 2-amino acid substitution adjacent to the NH2
by accelerating the same neurodegenerative cascade that terminus of A"; Ref. 177) and the London mutation (a
occurs in more common sporadic forms of the disease. missense mutation adjacent to the COOH terminus of A";
Although the vast majority of cases of AD are spo- Ref. 42). In addition, several AD kindreds have been iden-
radic with no clear pattern of inheritance and a late age of tified in which mutations within the A" sequence are

pathogenic (253). Two other genes linked to early-onset creased production of A" [particularly A"-(1O42)] and
familial AD are those encoding PS1 (chromosome 14) and decreased production of sAPP! (6, 122, 216). A" can
PS2 (chromosome 1); more than 70 different PS1 muta- impair synaptic function and can render neurons vulner-
tions (all except one are missense mutations), and 2 PS6 able to excitotoxicity and apoptosis by the following
mutations have been reported (122). PS1 and PS2 are mechanism. During the process of self-aggregation, A"
structurally similar integral membrane proteins with eight generates reactive oxygen species (hydrogen peroxide
transmembrane domains and are localized mainly in the and hydroxyl radical) by a mechanism that may involve
endoplasmic reticulum (ER). The presenilin-1 mutations metal-catalyzed oxidation of methionine (128, 134, 353).
tend to cluster in the cytoplasmic loop region and in or When this process occurs in the immediate vicinity of cell
near transmembrane domain 2. The identification of the membranes, lipid peroxidation is initiated (204, 205). In
mutations in the APP and presenilin genes has led directly neurons, A"-induced lipid peroxidation impairs the func-
to experiments that have revealed, at least in part, how tion of ion-motive ATPases (sodium and calcium pump
they cause AD (Fig. 7; Ref. 226). proteins), glucose transporter proteins (204 206), and

A well-documented abnormality that results from GTP-binding proteins (163). A" can also induce oxidative
APP mutations, as well as presenilin mutations, is in- stress in astrocytes resulting in impaired glutamate trans-
FIG. 7. Mechanisms underlying the pathogenic actions of mutations in amyloid precursor protein (APP) and
presenilins. Mutations in APP, as well as presenilin mutations, shift the proteolytic processing of APP such that more A"
is produced and less sAPP! is produced. Presenilins play an essential role in $-secretase cleavage of APP and may also
facilitate Notch cleavage and release of the transcription-regulating Notch COOH-terminal domain (NICD). Presenilin
mutations have a major impact on endoplasmic reticulum (ER) calcium signaling, effectively increasing the pools of
ryanodine- and inositol trisphosphate-sensitive stores. The normal functions of APP and presenilins, and the conse-
quences of Alzheimers disease-linked mutations in these proteins, may be particularly important in synapses.

port (23). By this mechanism, A" disrupts neurotransmit- MAP kinase (272). These findings suggest roles for CRH
ter signaling, destabilizes cellular calcium homeostasis, and urocortin in antagonizing the neurodegenerative pro-
and renders neurons vulnerable to excitotoxicity and ap- cess in AD. It remains to be determined whether pharma-
optosis (204, 227). Oxidative stress induced by A" may be cological manipulations of CRH/urocortin signaling will
particularly detrimental for neuronal function and sur- benefit AD patients.
vival when it occurs in synapses (162). Two major consequences of presenilin mutations are
Exposure of cultured neurons to A" can trigger pro- perturbed cellular calcium homeostasis (226) and altered
grammed cell death which manifests characteristic mito- APP processing (122) (Fig. 6). At this point in time, it
chondrial membrane alterations and release of cyto- remains unclear which defect is a primary consequence of
chrome c and caspase activation. A" stimulates the the mutations and which is secondary. PS1 and PS2 mu-
production of apoptotic proteins including Par-4, Bax, tations increase the vulnerability of cultured cells to ap-
and the tumor suppressor protein p53 (55, 80, 109, 111, optosis and excitotoxicity (108, 110, 112, 367). Hippocam-
262). Analyses of post mortem brain tissue from AD pa- pal neurons in PS1 mutant knockin mice are more

tients reveals evidence for neuronal apoptosis including vulnerable to excitotoxicity and apoptosis (108). Per-
upregulation of Par-4 (109) and caspase activation (38). turbed calcium regulation in the ER is central to the cell
Agents that stabilize mitochondrial function and caspase death-promoting effects of PS1 mutations (Fig. 7). The
inhibitors protect neurons against A"-induced death (109, abnormality involves an increased pool of ER calcium
111, 234). resulting in increased calcium responses when cells are
In addition to increasing production of A", APP and challenged with glutamate or agonists that stimulate cal-
presenilin mutations decrease the production of sAPP! cium release from the ER (39). Abnormal ER calcium
(6). A decrease in sAPP! levels may contribute to the signaling caused by presenilin mutations may promote
pathogenesis of AD, because sAPP! normally functions in altered capacitative calcium influx through voltage-de-
modulating synaptic plasticity (learning and memory) and pendent channels in the plasma membrane (186, 375).
in promoting survival of neurons (90, 142, 230). The mech- Presenilin mutations result in altered APP processing, and
anism whereby sAPP! promotes neuronal survival and there is evidence that presenilins are critical for $-secre-
synaptic plasticity involves activation of potassium chan- tase activity (369) and Notch cleavage (63). Altered APP
nels and of the transcription factor NF-#B; these actions processing may not account for the spectrum of effects of
of sAPP! stabilize cellular Ca2" homeostasis and sup- PS mutations. Instead, altered APP and Notch processing
press oxyradical production (225). caused by PS mutations may result from altered calcium-
AD patients typically exhibit emotional disturbances mediated regulation of the enzyme activities that mediate
and abnormal stress responses involving increased glu- cleavage of the two proteins (191, 276, 284, 316, 361).
cocorticoid production that likely result from pathologi- Indeed, one or more secretase activities are sensitive to
cal changes in brain regions that control such behaviors calcium (44). Notch signaling may promote neuronal sur-
and stress responses including limbic structures such as vival by enhancing cellular calcium homeostasis, an ac-
the amygdala and hippocampus and the frontal cortex tion antagonized by a protein called Numb; alterations in
(300). Studies of APP mutant transgenic mice suggest that Notch and Numb functions may play roles in the patho-
such abnormal stress responses are the result of in- genesis of AD (40).
creased levels of A" in these brain regions. APP mutant Mutations in genes encoding the proteins !-synuclein
mice exhibit an age-dependent increase in sensitivity to and Parkin can cause early-onset familial PD; !-synuclein
physiological stressors, which is associated with abnor- mutations are inherited in an autosomal dominant man-
malities in hypothalamic-pituitary-adrenal function and ner, while mutations in parkin are inherited in an autoso-
dysregulation of blood glucose levels (267). Two related mal recessive manner (280). The !-synuclein gene is lo-
neuropeptides that may play a role in the alterations in cated on chromosome 4, and the Parkin gene is located on
affective behaviors in AD patients and APP mutant mice chromosome 6. !-Synuclein is a vesicle-associated pro-
are corticotropin-releasing hormone (CRH) and urocor- tein, and Parkin is a cytoplasmic protein. !-Synuclein is
tin. CRH is expressed in brain regions prone to degener- axonally transported and associates with vesicles in pre-
ation in AD, and CRH can protect cultured hippocampal synaptic terminals, suggesting a role in regulation of ves-
and cortical neurons against cell death caused by A" icle trafficking (148). Parkin is expressed primarily in
(271). Urocortin and urocortin II are CRH-related neu- neurons where it is localized at particularly high levels in
ropeptides that act on CRH receptors expressed by neu- neurites (137). Studies of the pathogenic actions of three
rons in the hippocampus and functionally related brain missense mutations in !-synuclein (A53T, A30P, and
regions. Urocortin can protect hippocampal neurons G209A) have provided new insight into the events that
against excitotoxic and oxidative injury by activating the lead to the dysfunction and degeneration of dopaminergic
type I CRH receptor and a signaling pathway involving neurons in PD (Fig. 8). Expression of !-synuclein muta-
cAMP-dependent protein kinase, protein kinase C, and tions in cultured cells increases their vulnerability to ox-


FIG. 8. Mechanisms of neuronal degeneration in familial Parkinsons disease (PD). In sporadic PD, alterations in
dopamine metabolism and/or exposure to environmental toxins such as MPTP and rotenone can induce oxidative stress
in dopaminergic neurons resulting in their dysfunction and death. Familial PD can be caused by mutations in !-synuclein
or Parkin. Mutations in !-synuclein may cause excessive protein aggregation that triggers apoptosis and/or impair
presynaptic function. Parkin mutations may interfere with protein degradation by the proteasome. In both sporadic and
familial PD, dopaminergic neurons are subjected to increased oxidative stress that may trigger apoptosis.
idative stress and apoptosis (342). Overexpression of stress. Some data point to a loss of function, as opposed
wild-type or mutant !-synuclein induces apoptosis in cul- to a gain of function in the pathogenic action of !-synclein
tured neurons (305); PC12 cells overexpressing mutant mutations. Thus !-synuclein knockout mice exhibit a de-
!-synuclein exhibit decreased proteasome activity and fect in dopamine release (1), and overexpression of wild-
increased vulnerability to mitochondrial dysfunction and type (but not mutant) !-synuclein protects cultured neu-
apoptosis (343). Masliah et al. (210) reported evidence for ral cells against apoptosis (56).
loss of dopaminergic neurons and Lewy body-like cyto- Parkin is a ubiquitin-protein ligase that presumably
plasmic inclusions in !-synuclein mutant mice. However, functions in protein degradation; Parkin mutations result
another line of mice expressing mutant !-synuclein in loss of the ubiquitin-protein ligase activity (320). It was
driven by a tyrosine hydroxylase promoter did not exhibit recently reported that parkin can ubiquitinate !-synuclein
pathology in the substantia nigra (211). !-Synuclein forms (321), suggesting a link between impaired proteasomal
aggregates that may exhibit toxic properties similar to degradation of !-synuclein and the neurodegenerative
those of A" including production of reactive oxygen spe- process. These observations strongly suggest that a defect
cies (347) and increased membrane ion permeability in protein degradation is central to the pathogenesis of PD
(357). Collectively, these findings suggest that !-synuclein and further suggest strong mechanistic interactions be-
mutations may promote neuronal degeneration by caus- tween oxidative stress and protein degradation in neuro-
ing abnormalities in protein degradation and oxidative degenerative disorders in general, since oxidative damage

to proteins often makes them targets for ubiquitination generative process may spread to regions of the cerebral
and proteasomal degradation. In addition to disease-caus- cortex, thalamus, and cerebellum resulting in cognitive
ing mutations, risk of PD may be influenced by genetic dysfunction and emotional disturbances. Recently, a
polymorphisms, a possibility that is currently being inves- closely related familial HD-like disorder was described
tigated by several laboratories (43, 356). that appears to result from a trinucleotide expansion in a
The genetics of HD are seemingly straightforward; all yet-to-be identified gene (202).
cases of this disease are believed to be caused by the The alterations caused by polyglutamine expansions
expansion of trinucleotide (CAG) repeats in the hunting- in huntingtin that result in neuronal death are beginning
tin gene (located on chromosome 4) resulting in long to be revealed (Fig. 9). Overexpression of mutant human
stretches of polyglutamine repeats in the huntingtin pro- huntingtin in cultured cells and transgenic mice can in-
tein (76, 199). However, the consquences of the huntingtin duce spontaneous cell death (apoptosis) and can increase
mutation may be subject to modification by aging, as the vulnerability of neurons to excitotoxicity (130, 192,
suggested by evidence for variability in age of disease 294, 346). Several different behavioral abnormalities have

onset and progression of the clinical phenotype. HD pa- been described in mice expressing mutant huntingtin in-
tients manifest progressive motor dysfunction character- cluding motor deficits and cognitive dysfunction (250,
ized by involuntary body movements due to degeneration 311). The reason that trinucleotide expansions in hunting-
of neurons in the basal ganglia, principally the caudate tin promote degeneration of striatal neurons in HD is
and putamen (3). As the disease progresses, the neurode- unclear. Mutant huntingtin self-aggregates resulting in the
FIG. 9. Pathogenic mechanisms of mutant huntingtin. Huntingtons disease is caused by polyglutamine expansions
in the huntingtin protein. Mutant huntingtin may self-aggregate and trigger activation of caspases. Data also suggest that
mutant huntingtin can cause a depletion of BDNF production by suppressing transcriptional activity.

formation of inclusions in the nucleus and cytoplasm (62, 302). Transgenic mice expressing mutant Cu/Zn-SOD
(120, 311). Neurons in mice expressing mutant huntingtin exhibit progressive motor neuron degeneration and a clin-
exhibit increased caspase activation, and administration ical phenotype remarkably similar to ALS patients (118,
of caspase inhibitors to the mice can suppress the neuro- 368). Lipid peroxidation is increased in spinal cord motor
degenerative process (257), suggesting that mutant hun- neurons of ALS patients and transgenic mice (268, 269),
tingtin triggers programmed cell death. Cells expressing and administration of vitamin E to Cu/Zn-SOD mutant
mutant huntingtin exhibit altered proteasomal function mice delays disease onset (117), suggesting an important
that may trigger apoptosis (145). Mutant huntingtin may role for lipid peroxidation in the neurodegenerative pro-
trigger apoptosis by weakening the interaction of hunting- cess. In addition, creatine delayed the neurodegenerative
tin with huntingtin interacting protein-1 (Hip-1), thereby process in a mouse model of ALS (168). ALS Cu/Zn-SOD
allowing Hip-1 to interact with a protein called Hippi that mutations cause impairments in synaptic glucose and
then recruits caspase-8 and thereby initiates the cell death glutamate transport (114) and increase the vulnerability
cascade (223). of motor neurons to excitotoxic injury by increasing ox-

Interestingly, adverse effects of mutant huntingtin on idative stress and perturbing cellular calcium homeosta-
cell function are not limited to the nervous system be- sis (172, 185).
cause abnormalities in adipocytes have been described The remarkably large size of axons of motorneurons
that may be related to the well-known alterations in en- and their correspondingly high density of neurofilaments
ergy metabolism in HD patients (82). The ability of dietary has led to the suggestion that impaired axonal transport
supplementation with creatine to delay motor symptoms plays a role in the pathogenesis of ALS. Studies of axonal
and increase survival in huntingtin mutant mice (7) is transport in Cu/Zn-SOD mutant mice and of mice lacking
consistent with impaired cellular energy metabolism in or overexpressing neurofilament proteins support a role
the neurodegenerative process. Finally, it was recently for impaired axonal transport in ALS (365, 383). Apoptosis
reported that levels of BDNF are decreased in HD (390), of motor neurons in ALS is suggested by studies showing
suggesting that decreased neurotrophic support may be a that levels of the proapoptotic protein Par-4 are increased
consequence of huntingtin mutations that promotes the in spinal cord motor neurons of ALS patients and Cu/Zn-
degeneration of striatal neurons. SOD mutant mice (269), and levels of caspase activation
In each of the three neurodegenerative disorders just are also increased in spinal cord tissue from Cu/Zn-SOD
described (AD, PD, and HD), there is considerable evi- mutant mice (264). In addition, caspase inhibitors (190)
dence suggesting that abnormalities in mitochondrial and the antiapoptotic protein Bcl-2 (358) can protect mo-
function contribute to the disease process. In each dis- tor neurons in Cu/Zn-SOD mutant mice. Moreover, neuro-
order, alterations in activities of enzymes involved in trophic factors that can prevent apoptosis of motor neu-
oxidative phosphorylation have been demonstrated in- rons in culture can also prevent motor neuron loss and
cluding a decrease in activity of the !-ketoglutarate de- disease progression in Cu/Zn-SOD mutant mice (243).
hydrogenase complex in AD (97a) and a defect in com- Genetic risk factors for stroke, an age-related neuro-
plex I in PD (306b). Such abnormalities in mitochondrial logical disorder, overlap with risk factors for coronary
energy metabolism may precede and contribute to the artery disease due to shared mechanisms of atheroscle-
increased oxidative stress and perturbations in neuronal rosis and blood clot formation in each disorder. Familial
calcium homeostasis that occurs in each disorder. Inter- hypercholesterolemia caused by mutations in the low-
estingly, the metabolic deficits, and oxidative stress and density lipoprotein receptor results in early-onset athero-
calcium dysregulation, may not be limited to the brain sclerotic vascular disease (334). Apolipoprotein E geno-
cells affected in the disorders, as they have been docu- type affects risk of atherosclerosis (286). Polymorphisms
mented in peripheral cells including fibroblasts and lym- in the apolipoprotein(s) gene and the gene for methylene
phocytes (95a, 306b). Based on these and additional data, tetrahydrofolate reductase have been shown to be prom-
Blass (23a) has introduced the concept of a mitochon- inent risk factors for atherosclerotic vascular disease
drial spiral, in which metabolic deficits result in oxyradi- (252). Polymorphisms in the fibrinogen and factor XIII
cal production and calcium dysregulation, to explain the genes have been linked to stroke (37), suggesting a con-
pivotal role of mitochondrial alterations in neurodegen- tribution of genetic differences in regulation of clot for-
erative disorders. Both genetic and environmental factors mation to disease risk. An inherited stroke syndrome
may promote such neurodegenerative mitochondrial spi- called CADASIL (cerebral autosomal dominant arteriopa-
rals (97a). thy with subcortical infarcts and leukoencephalopathy)
ALS involves degeneration of spinal cord motor neu- was recently linked to mutations in the Notch-3 gene on
rons resulting in progressive paralysis and death (196, chromosome 19 (59), and the cellular and molecular al-
301). Most cases of ALS are sporadic, but some result terations caused by these mutations are currently being
from mutations in the gene encoding the antioxidant en- investigated.
zyme Cu/Zn-SOD, which is located on chromosome 21 Collectively, the data that have accumulated in stud-

ies of the age-related neurodegenerative disorders de- Biochemical and molecular analyses of the brains of
scribed above suggest that each disorder shares abnor- old rats and mice that had been maintained on calorie-
malities that contribute to neuronal dysfunction and restricted diets reveal a retardation of changes that occur
death. The alterations include increased oxidative stress, during aging of animals fed ad libitum including increases
dysregulation of protein trafficking and processing, met- in levels of GFAP and oxidative damage to proteins and
abolic impairment, and disruption of cellular calcium ho- DNA (74, 245). Gene array analysis of the expression
meostasis. Genetic factors that cause, or increase risk of, levels of thousands of genes in the brains of young rats
a disorder do so by impacting directly or indirectly one or and old rats that had been maintained on control or
more of the cellular systems involved in oxyradical me- restricted diets revealed changes in gene expression in
tabolism, protein processing, energy metabolism, and cal- brain cells during aging and showed that DR can suppress
cium homeostasis. Section IV describes a rapidly growing many of those changes (180). Age-related changes in the
body of evidence demonstrating that age-related neuro- expression of genes that encode proteins involved in in-
degenerative cascades can be influenced by environmen- nate immune responses, oxidative stress, and energy me-

tal factors. tabolism are counteracted by DR. This retardation of
brain aging at the molecular level may underlie the pres-
ervation of brain function during aging in animals main-
IV. DIETARY FACTORS IN BRAIN AGING
tained on DR. For example, DR attenuates age-related
AND NEURODEGENERATIVE DISORDERS
deficits in learning and memory ability and motor function
in rodents (140, 336). Studies of human populations sug-
There are numerous dietary factors that have been
gest that DR can promote successful brain aging in hu-
reported to affect brain physiology in ways that could, in
mans. For example, epidemiological data suggest that the
theory, modify brain aging and the pathogenesis of neu-
risk of developing AD, PD, and stroke is lower in individ-
rodegenerative disorders (221a). These range from amino
uals with a low calorie intake (30, 195, 235).
acids such as tryptophan (16) to caffeine and related
Beneficial effects of DR have been demonstrated in
stimulants (85) to omega-3 fatty acids (348). Many such
several of the animal models just described. The two DR
dietary factors have been shown to affect mood or cog-
protocols most commonly used in such studies are every-
nition. However, this review focuses on a more limited
other-day feeding (the animals must go a whole day with-
number of dietary factors for which considerable support-
out food and then eat ad libitum on the next day) and
ive experimental, clinical, and epidemiological data have
paired feeding (the restricted animals are given food pel-
accrued to justify the development of recommendations
lets that contain 30 40% fewer calories than the pellets
to the general public vis-a-vis risk reduction for neurode-
given to the control animals). Both of these feeding regi-
generative disorders. These factors include caloric intake,
mens increase the life spans of rats and mice by 30 40%
folic acid, and antioxidants.
(103, 362). Rats maintained on DR for 2 4 mo exhibit
increased resistance of hippocampal neurons to kainate-
A. Effects of Dietary Restriction on Brain Aging: induced degeneration in a model relevant to the patho-
Neuroplasticity and Neuroprotection genesis of AD and epilepsy; kainate selectively damages
hippocampal pyramidal neurons and there is a profound
The mean and maximum life spans of many different deficit in learning and memory (31). When rats were
organisms including yeast, roundworms, rodents, and maintained for several months on DR, damage to hip-
monkeys can be increased by up to 50% simply by reduc- pocampal neurons was decreased, and learning and mem-
ing their food intake (9, 176, 362). The incidence of age- ory were preserved compared with rats fed ad libitum
related cancers, cardiovascular disease, and deficits in (31). Studies of PS1 mutant knockin mice showed that the
immune function is decreased in rodents maintained on PS1 mutations increase the vulnerability of hippocampal
such dietary restriction (DR) feeding regimens (362). Data and cortical neurons to excitotoxicity and apoptosis by a
from clinical and epidemiological studies in humans sup- mechanism involving enhanced calcium release from the
port the antiaging and disease prevention effects of DR. ER (108, 111). When PS1 mutant knockin mice were
Thus a low-calorie diet decreases the risk of the most maintained on DR, they exhibited increased resistance of
prominent age-related diseases in humans including car- hippocampal CA1 and CA3 neurons to excitotoxic injury
diovascular disease, diabetes, and cancers (29, 179, 187). compared with mice fed ad libitum (388). Lipid peroxida-
Recent findings reviewed in this section strongly suggest tion in the hippocampus after kainate administration was
that DR can delay age-related functional deficits in the decreased in DR PS1 mutant mice, suggesting that sup-
brain and may reduce the risk of major neurodegenerative pression of oxidative stress is one mechanism whereby
disorders including AD, PD, and HD. DR may also in- DR protects neurons (388).
crease resistance of neurons to acute insults such as DR has beneficial effects in animal models of PD and
stroke and severe epileptic seizures. HD. The vulnerability of midbrain dopaminergic neurons

to MPTP toxicity was decreased in mice maintained on populations that is consistent with the possibility that DR
dietary restriction with more dopaminergic neurons sur- can reduce the risk of human neurodegenerative disor-
viving exposure to MPTP; the motor function of the mice ders. The following epidemiological data suggest that in-
was also improved in the restricted mice (69). Adminis- dividuals with a low calorie intake may have reduced risk
tration of the succinate dehydrogenase inhibitor (mito- for AD and PD. There is a strong correlation between per
chondrial toxin) 3-nitropropionic acid (3-NP) to rats and capita food consumption and risk for AD (105). For ex-
mice results in selective degeneration of striatal neurons ample, the reported incidence of AD in China and Japan is
and motor impairment, a model of HD. When rats were approximately one-half that in the United States and
maintained on DR for several months before administra- Western Europe, and this is correlated with a lower cal-
tion of 3-NP, more striatal neurons survived exposure to orie intake in China and Japan (1,600 2,000 calories/day)
3-NP, and their motor function was improved (31). The compared with the United States and Western Europe
ability of DR to improve outcome after a stroke was (2,500 3,000 calories/day). Overeating is also a major risk
demonstrated in a rat model in which the middle cerebral factor for stroke (30). Although there are caveats with the

artery was transiently occluded resulting in damage to the latter observations (for example, per capita food con-
cerebral cortex and striatum supplied by that artery and sumption is a very poor measure of energy intake, and
unilateral motor dysfunction. When rats were maintained disease diagnosis may differ among the countries), they
on DR for several months and then subjected to a stroke, are consistent with a protective effect of low-calorie diets
they exhibited reduced brain damage and improved be- against age-related neurodegenerative disorders. More
havioral outcome (380). The neuroprotective effects of convincing evidence that DR can protect against neuro-
DR in animal models of several different neurodegenera- degenerative disorders comes from population-based
tive disorders suggest that low-calorie diets may prove case-control studies by Mayeux and colleagues who
beneficial in reducing the incidence and/or severity of the found that individuals with the lowest daily calorie in-
corresponding human neurodegenerative disorders. takes had the lowest risk of AD (235) and PD (195).
Although the findings described in the preceding Interestingly, the risk of PD and AD was more strongly
paragraphs document quite striking neuroprotective ef- correlated with calorie intake than with weight or body
fects of DR, this dietary manipulation has not proven mass index. More recently, Hendrie et al. (127) reported
beneficial in all animal models of neurodegenerative dis- findings from a population-based longitudinal prospective
orders. For example, when one line of APP mutant trans- study which indicate that the incidence of AD increases
genic mice was maintained on an every-other-day feeding among individuals living in industrialized countries com-
regimen or was fed ad libitum, they died within 23 wk pared with genetically similar individuals that live in non-
(267). Additional analyses in the latter study showed that industrialized countries. Although the environmental fac-
the APP mutant mice were hypersensitive to the stress tors that increase risk of AD in industrialized countries
associated with fasting for an entire day and became are not known, one clear difference between the two
severely hypoglycemic during the days they were without environments is calorie intake, which is much higher in
food. The APP mutant mice exhibited abnormalities in the industrialized countries. Together, the epidemiological
regulation of the stress-responsive hypothalamic-pitu- and experimental data provide strong evidence that DR
itary-adrenal axis including altered glucocorticoid and can reduce risk of AD, PD, and stroke, three of the most
blood glucose regulation in response to restraint stress. devastating neurodegenerative conditions in the elderly.
However, when every-other-day feeding was begun in
APP mutant mice that were less than 3 mo of age, they
survived, suggesting a role for age-dependent amyloid B. Cellular and Molecular Mechanisms Underlying
deposition in the aberrant stress response. Transgenic the Neural Effects of Dietary Restriction
ALS mice expressing the G93A Cu/Zn-SOD mutation did
not benefit from DR. When they were maintained on an Because dietary restriction increases life span and
every-other-day feeding regimen, the age of disease onset reduces risk of many different age-related diseases in-
was unchanged (270). Moreover, once the ALS mice on cluding cardiovascular disease, diabetes, and cancers, it
DR became symptomatic, the disease progressed more might be expected that it modifies shared biochemical
rapidly and they died sooner than did ALS mice that were cascades that lead to cell dysfunction and disease. In the
fed ad libitum. These findings are interesting in that they case of neurodegenerative disorders, it is clear that while
suggest that the pathogenic mechanism of action of the different genetic and environmental factors may initiate
Cu/Zn-SOD mutation is not subject to modification by DR the neurodegenerative process in different disorders, a
and/or that DR does not exert the same kind of neuropro- shared biochemical cascade ensues. Increased oxidative
tective action on spinal cord motor neurons that it exerts stress, perturbed cellular calcium homeostasis, and im-
on neurons in the brain. paired energy metabolism occur in every neurodegenera-
There is emerging evidence from studies of human tive disorder studied to date (216, 219). These alterations

render neurons vulnerable to apoptosis, a biochemical bolic, and apoptotic insults (217). Levels of NGF (67) and
cascade of molecular interactions involving proteins such CNTF (W. Duan and M. P. Mattson, unpublished data) are
as Par-4, Bcl-2 family members, and caspases (219). also increased by DR in one or more brain regions. Neu-
It has been shown that DR can stabilize mitochon- rotrophic factors may protect neurons by stimulating the
drial function and reduce oxidative stress in brain cells of production of proteins that suppress oxidative stress (an-
rodents (113), and this may increase the resistance of tioxidant enzymes and Bcl-2) and stabilize cellular cal-
neurons to many different types of genetic and environ- cium homeostasis (calcium-binding proteins and gluta-
mental factors. DR can induce the expression of genes mate receptor subunits) (4, 98, 141, 233). BDNF and other
that encode proteins that promote neuronal survival and neurotrophic factors might also counteract the adverse
plasticity (Fig. 10). For example, levels of heat shock effects of aging on synaptic function because they can
protein-70 (HSP-70) and glucose-regulated protein-78 modify synaptic plasticity in ways that facilitate learning
(GRP-78) are increased in cortical, striatal, and hippocam- and memory (115, 146). Evidence for an important role for
pal neurons of rats and mice maintained for several neurotrophic factors in the beneficial effects of DR in the

months on a dietary restriction feeding regimen (69, 380). brain is suggested by studies showing that infusion of a
HSP-70 and GRP-78 can protect neurons against excito- BDNF blocking antibody into the lateral ventricles of
toxic and oxidative injury (197, 379), suggesting that their DR mice significantly attenuates the protective effect of
increased levels contribute to the neuroprotective effect DR (67).
of dietary restriction. Protein chaperones and neurotrophic factors are
DR can induce the expression of several different known to be induced by cellular stress, and it is therefore
neurotrophic factors in brain cells. Levels of BDNF are very likely that DR elicits a cellular stress response; this
increased in neurons in the cerebral cortex, hippocam- might result from decreased energy (glucose) availability
pus, and striatum of rats and mice maintained on dietary to the cells, or from increased activity in neuronal circuits
restriction (67, 183). It is known that BDNF can protect as the result of increased arousal due to hunger. Evidence
neurons in culture and in vivo against excitotoxic, meta- supporting a role for a cellular stress response in the
neuroprotective effects of DR was obtained in studies
showing that the neuroprotective effects of DR can be
mimicked by giving 2-deoxy-D-glucose (a nonmetaboliz-
able analog of glucose) to rats and mice fed ad libitum.
Animals given 2-deoxy-D-glucose exhibit increased levels
of protein chaperones in their brain cells and increased
resistance of neurons to excitotoxic, oxidative, and isch-
emic injury. Seizure-induced damage to hippocampal neu-
rons is decreased, and learning and memory are pre-
served in rats given 2-deoxy-D-glucose (182). In the MPTP
model of PD, mice given 2-deoxy-D-glucose exhibit de-
creased damage to dopaminergic neurons in the substan-
tia nigra and a marked reduction in motor deficits (69).
Rats admistered 2-deoxy-D-glucose also exhibit reduced
damage to cortical and striatal neurons and improved
behavioral outcome after transient occlusion of the mid-
dle cerebral artery (380).
The adult brain contains populations of cells that are
capable of dividing and then differentiating into neurons
(neurogenesis) or glial cells (gliogenesis). In rodents and
humans, neural stem cells are most abundant in the sub-
ventricular zone and in the subgranular layer of the den-
tate gyrus of the hippocampus (91). It is thought that
FIG. 10. Model of the mechanisms whereby dietary restriction, in-
neural stem cells in the adult brain may provide a cellular
tellectual activity, and exercise promote neuronal survival and plasticity. reserve to replace neurons and glia that die as the result
Dietary restriction, activity in neuronal circuits, and physical exercise of various injuries and diseases. In support of the latter
each induces a mild cellular stress response, as a result of energetic
factors (reduced glucose availability in dietary restriction and increased function of neural stem cells, it has been shown that
energy demand during intellectual and physical activity, for example). neurogenesis can be stimulated by ischemic and excito-
Neurons respond to these stresses by activating signaling pathways that toxic brain injuries (194, 263). We discovered that caloric
induce the expression of genes encoding proteins, such as growth
factors and protein chaperones, that promote neuronal survival and restriction can increase neurogenesis in the brains of rats
plasticity (neurogenesis, neurite outgrowth, and synaptic plasticity). and mice (183, 184). Animals that had been maintained on

a restricted diet or a control ad libitum diet for 3 mo were like growth factors, and neuropeptides that control feed-
given five daily injections of the DNA precursor BrdU and ing behavior in the brain, and insulin in peripheral tissues
were killed either 1 day or 3 4 wk after the last BrdU (Fig. 11).
injection. Numbers of BrdU-positve (newly generated) Although DR clearly has beneficial effects in the
cells in the dentate gyrus were quantified by unbiased nervous system, there are several aspects of its mech-
stereological methods. At the 1-day time point there was anism of action that remain to be explained. For exam-
no difference in BrdU-labeled cells between calorie-re- ple, animals maintained on DR exhibit increased levels
stricted and control animals, indicating that calorie re- of glucocorticoids consistent with an increased level of
striction does not affect the proliferation rate of the neu- stress (250a). In animals fed ad libitum, increased glu-
ral stem cells. Instead, DR resulted in a significant cocorticoids associated with chronic stress have been
increase in the number of BrdU-positive cells remaining at shown to promote neuronal degeneration (306a) and
the 3- or 4-wk time points, suggesting that DR promotes impair neurogenesis (35a). Why then does DR prevent
the survival of newly generated neural cells (183, 184). neuronal degeneration and enhance neurogenesis? One

Many of the newly generated cells become dentate gran- possibility is that the specific responses of neural cells
ule neurons. Although not yet established, it is conceiv- to DR stress are different from responses to the kinds
able that BDNF plays a role in the enhanced survival of of chronic psychosocial stress that have been shown to
newly generated neural stem cells in the dentate gyrus of be deleterious to the brain. Indeed, we have docu-
rats maintained on DR because BDNF is known to have a mented a different profile of changes in the expression
similar effect on neural stem cells. When taken together of glucocorticoid and mineralocorticoid receptors in
with the fact that learning and memory is preserved in the hippocampus in response to DR than are seen in
aging rodents maintained on dietary restriction (140), and animals subjected to psychosocial stress (183a). The
that suppression of NPC proliferation can impair learning ability of DR to increase neurotrophic factor produc-
and memory (322), it is possible that DR promotes main- tion and the expression of cytoprotective stress pro-
tenance of cognitive function during aging by enhancing teins may override any potentially deleterious effects of
neurogenesis. elevated glucocorticoids. Indeed, stress and glucocor-
Interestingly, increasing data suggest that the brain ticoids decrease the expression of BDNF in the hip-
may control life span by regulating energy metabolism of pocampus (327a), and BDNF can protect neurons
the entire organism (222). Because systems that regulate against the adverse effects of glucocorticoids (254a).
energy metabolism, such as the insulin signaling pathway, Therefore, DR elicits cellular and molecular responses
are believed to play major roles in the aging process (366), that allow enhanced activation of the hypothalamic-
they are likely to have an important influence on brain pituitary-adrenal axis to occur, but without the delete-
aging. Key signaling pathways involved in the regulation rious effects that might otherwise result from this
of energy metabolism by the brain include BDNF, insulin- heightened state of neuroendocrine function.
FIG. 11. Regulation of energy metabo-

lism by interactions between the brain and
peripheral tissues. The brain controls feed-
ing behaviors through complex neural cir-
cuits involving sensory inputs, cortical and
hippocampal connections, and hypotha-
lamic interactions with higher brain re-
gions via neurotransmitters and modula-
tors such as serotonin and neuropeptide Y
as well as circulating hormones such as
leptins. See text for further information.
AgRP, agouti-related protein; BBB, blood-
brain barrier; BDNF, brain-derived neuro-
trophic factor; CNS, central nervous sys-
tem; MAPK, mitogen-activated protein
kinase; MC4R, receptor for MSH; MCH,
melanocyte concentrating hormone; MSH,
melanocyte stimulating hormone; NPY,
neuropeptide Y; Ob-R, leptin receptor;
PI3K, phosphatidylinositol 3-kinase.

C. Folic Acid enzyme, plays an important role in facilitating the conver-

sion of extracellular 5-methyltetrahydrofolate to mono-
Humans cannot synthesize folic acid and therefore glutamyl tetrahydrofolate, a form of folic acid that can be
must obtain it in the diet; major sources of folate are readily used in nucleotide biosynthesis. Membrane trans-
green vegetables, citrus fruits, liver, and whole grains. The porters for folic acid are expressed in cells throughout the
predominant dietary folates are 5-methyltetrahydrofolate body including brain cells, and it is therefore likely that
and formyltetrahydrofolate, which are readily transported folic acid plays a critical role in one-carbon metabolism in
across the intestinal epithelium. The reason that many neural cells (325). An array of biochemical reactions re-
processed foods contain folic acid is that it was recog- quire methyl groups, and the normal dietary supply of
nized decades ago that babies born to women that have a methyl groups is insufficient to meet these demands and
diet deficient in folic acid are at increased risk of birth must be synthesized from the one-carbon folic acid pool.
defects. The fact that such birth defects most commonly Folic acid (5#-methyltetrahydrofolate) is required for con-
involve the nervous system (spina bifida, meningocoele, version of methionine to S-adenosylmethionine (SAM),

encephalocoele, and anencephaly) indicates that neural the latter being the major methyl donor in most biochem-
cells may be particularly sensitive to folic acid. Folic acid ical reactions (Fig. 12). Folic acid deficiency results in
deficiency causes abnormalities in cell proliferation, dif- depletion of SAM and a reduction in the methylation of
ferentiation, and survival. The important role for folic acid cytosine in DNA. The decreased DNA methylation that
in development of the nervous system is further demon- can result from folic acid deficiency may enhance gene
strated by genetic alterations in methyltetrahydrofolate transcription and DNA strand breakage which can trigger
reductase (MTHFR), which decreases enzyme activity, malignant transformation (279, 359).
resulting in decreased folic acid levels and increased risk During the past decade it has become clear that folic
of neural tube defects (319, 328). In addition, targeted acid deficiency can increase risk for coronary artery dis-
gene deletion of the folic acid transporter results in em- ease and stroke (28, 77) and that this adverse effect of
bryonic lethality in mice (277). Recent studies have dem- folic acid deficiency is associated with an elevation in
onstrated direct consequences of folic acid deficiency on plasma homocysteine levels (104). Homocysteine is pro-
neurons by showing that simply depriving cultured em- duced from methionine by demethylation (Fig. 12), and
bryonic brain cells of folate can induce apoptosis (pro- homocysteine levels are kept low by its remethylation to
grammed cell death) in developing neurons (171). methionine by a reaction requiring folic acid and vitamin
Folic acid acts as a cofactor in many different bio- B12, or by conversion of homocysteine to cystathionine by
chemical reactions by donating and accepting one-carbon the activity of the enzyme cystathionine-"-synthase
units (314). Methionine synthase, a vitamin B12-dependent (CBS). Alterations in the expression or enzyme activities
FIG. 12. The involvement of folic acid

and homocysteine in one-carbon metabo-
lism. Homocysteine is a metabolite of me-
thionine, an amino acid that plays a key role
in the generation of methyl groups required
for numerous biochemical reactions; homo-
cysteine can either be remethylated to me-
thionine by enzymes that require folic acid
or catabolized by cystathionine-"-synthase
(CBS), a vitamin B6-dependent enzyme, to
form cysteine. SAH, S-adenosyl-L-homocys-
teine; SAM, S-adenosyl-L-methionine; MTase,
methyltransferase.

of methionine synthase and CBS can affect levels of ho- tion in their brains, were maintained on a low-folate/high-
mocysteine. Indeed, levels of homocysteine are increased homocysteine diet, neurons in the hippocampus degener-
in the cerebrospinal fluid of children with mutations in ated (171). This contrasted with nontransgenic mice in
CBS (340) and may contribute to the abnormalities in which the experimental diet did not cause degeneration
brain function documented in such patients. Homocys- of neurons. Folic acid deficiency may render neurons
teine can damage cells by inducing oxidative stress and vulnerable to being damaged and killed by amyloid be-
DNA damage and impairing DNA repair (170, 171). cause exposure of cultured rat hippocampal neurons to
The importance of folic acid in the developing ner- folic acid-deficient medium or to homocysteine increases
vous system suggests the possibility that folic acid defi- the vulnerability of the neurons to being killed by A" (170,
ciency and elevated homocysteine levels might also have 171). It has also been reported that dietary folic acid
adverse effects in the adult nervous system. Possible links deficiency sensitizes mice to MPTP-induced PD-like pa-
between folic acid, homocysteine, and neurological disor- thology and motor dysfunction (68). Direct application of
ders have therefore been looked for and found. Data have homocysteine into either the substantia nigra or striatum

accumulated that suggest links between dietary folic acid, exacerbated dopamine depletion, neuronal degeneration,
homocysteine levels, and the pathogenesis of AD and PD. and motor dysfunction. Moreover, homocysteine in-
AD patients have significantly lower levels of folic acid creased the vulnerability of cultured human dopamine-
and higher levels of homocysteine in their blood com- producing cells to rotenone and iron. The ability of folic
pared with neurologically normal age-matched control acid deficiency and elevated homocysteine levels to sen-
patients (49, 188). Elevated levels of homocysteine have sitize neurons to amyloid and MPTP toxicities suggests a
also been reported in PD patients (175). A caveat with the mechanism whereby dietary folic acid may modify risk of
studies just described is that all analyses were performed AD and PD.
on blood samples from symptomatic patients, and it is The mechanism whereby homocysteine damages and
therefore unclear whether decreased folic acid levels and kills neurons has been elucidated in recent studies. Ho-
elevated homocysteine levels precede and contribute to
mocysteine induced DNA damage in cultured hippocam-
the neurodegenerative process. Thus the nutritional ab-
pal neurons, which resulted from a combination of im-
normalities might result from altered diet in these sick
paired DNA repair and increased oxidative stress, as
patients. Additional evidence from studies of patients and
indicated by increased uracil misincorporation and in-
animal models described below do, however, support
creased oxidative modification of DNA bases (171). Ho-
roles for homocysteine in the early pathogenesis of neu-
mocysteine-induced DNA damage can trigger a pro-
rodegenerative disorders.
grammed cell death pathway involving poly(ADP-ribose)
The major risk factor for AD, PD, and stroke is age,
polymerase and the tumor suppressor protein p53, lead-
and studies have shown that homocysteine levels progres-
sively increase with age (27). Deficiencies in folic acid and ing to mitochondrial dysfunction and activation of death
vitamin B12 may also contribute to the declines in cogni- proteases (170). Impaired DNA repair may play a role in
tive and other neurological functions that occur during the pathogenesis of AD because fibroblasts from AD pa-
normal aging (315) including psychiatric disorders (25). A tients exhibit a defect in repair of DNA lesions (189, 297).
study of geriatric patients admitted to a psychiatric hos- In cultured dopaminergic cells, homocysteine can exac-
pital revealed that individuals with below median values erbate oxidative stress, mitochondrial dysfunction, and
of folic acid and vitamin B12 performed worse on tests of apoptosis in cells exposed to the pesticide rotenone or the
cognitive function than did individuals with above-median pro-oxidant Fe2". The dopaminergic cells can be pro-
levels of folic acid and vitamin B12 (17). On the other tected against the adverse effects of homocysteine by
hand, elevated plasma homocysteine levels were not as- administration of the antioxidant uric acid and by an
sociated with cognitive impairment in centenarians (292). inhibitor of poly(ADP-ribose) polymerase (68).
Genetic variations in the MTHFR gene may be associated Alterations in folate and one-carbon metabolism may
with risk of PD with individuals with the C677T genotype also contribute to several other neurodegenerative condi-
(which increases homocysteine levels) being at increased tions. For example, the huntingtin protein interacts with
risk (374). Mice deficient in MTHFR exhibit hyperhomo- CBS (26), and alterations in folate metabolism have been
cysteinemia and neuropathological alterations (45), con- documented in patients with ALS (376). ALS is a disorder
sistent with a loss of function of the enzyme in humans in which spinal cord motor neurons degenerate resulting
with disease-promoting forms of the enzyme. in progressive paralysis and death. It has been proposed
Animal and cell culture models of neurodegenerative that an abnormality in folate metabolism accounts for the
disorders have provided evidence that folic acid defi- reported reduction of RNA and the elevation of taurine
ciency and elevated homocysteine levels can render neu- in the nervous system of ALS patients (376). Homocys-
rons vulnerable to dysfunction and death. When APP teine can also induce seizures in rodents (173), and
mutant mice, which develop progressive amyloid deposi- alterations in homocysteine levels may occur in human

epilepsy patients (313), suggesting a possible contribu- and cancers (129), although it is not established that
tion to epilepsy. ubiquinone supplementation can reduce risk of these dis-
orders. The potential of dietary supplementation with
ubiquinone to prevent or treat age-related neurodegenera-
D. Antioxidants tive disorders remains to be determined.
!-Lipoic acid is an endogenous disulfide compound
There are tens of thousands of natural and synthetic that is present in small amounts in most animal cells
compounds that possess antioxidant activity, and a rap- where it functions as a coenzyme in the !-ketoglutarate
idly growing number of these agents have been reported dehydrogenase and pyruvate dehydrogenase enzyme
to have beneficial effects in one or more experimental complexes (208). The antioxidant and cytoprotective ac-
models of age-related disorders. It is beyond the scope of tions of lipoic acid have been documented in a variety of
this article to review the field of antioxidants and brain cell culture and animal models of age-related disease
aging; instead, examples of results obtained with several (237). A number of clinical trials of lipoic acid have been

of the most widely studied antioxidants are presented. completed or are in progress in patients with cardiovas-
These include vitamin E, coenzyme Q10, lipoic acid, cre- cular disease, cancer, and diabetes. Dietary supplementa-
atine, and Ginko biloba extract. tion with lipoic acid has proven beneficial in normalizing
Vitamin E (!/$-tocopherol) is a lipid-soluble antioxi- glucose metabolism in patients with type II diabetes
dant that is very effective in suppressing membrane lipid (143). Lipoic acid and the related compound dihydroli-
peroxidation. Data have accumulated that suggest that poate were effective in protecting cultured neurons
dietary supplementation with vitamin E can reduce risk of against death induced by hypoxia, glutamate, and iron
cardiovascular disease and many cancers (64). Chronic and were effective in reducing focal ischemic brain injury
treatment of rodents with vitamin E can preserve learning in vivo (248, 283). Lipoic acid was also effective in pro-
and memory function, which otherwise declines during tecting cultured rat cortical neurons against death in-
aging (330). Treatment of rat hippocampal slices with duced by A" (384). Dietary supplementation with lipoic
!-tocopherol enhanced long-term potentiation of synaptic acid increased the survival of Cu/Zn-SOD mutant trans-
transmission, a cellular correlate of learning and memory genic mice (8), suggesting that this antioxidant may prove
(370). Clinical trials of vitamin E in AD patients have beneficial in ALS patients.
yielded positive results with patients receiving this anti- Creatine increases phosphocreatine levels in muscle
oxidant exhibiting a slowing of disease progression com- and brain cells and may thereby improve cellular energet-
pared with those receiving placebo (106). Vitamin E may ics and reduce oxyradical production (220). Creatine is
counteract the effects of aging and neurodegenerative now widely employed as a dietary supplement by athletes
disorders by suppressing membrane lipid peroxidation to improve their performance (79). Creatine significantly
and thereby preserving membrane transporter function reduced brain damage in a rat model of traumatic brain
and stabilizing cellular ion homeostasis. As evidence, vi- injury, suggesting that it may not only enhance the per-
tamin E can protect cultured neurons and synaptosomes formance of athletes, but may also improve the outcome
against dysfunction and death induced by A" (102, 204) of head injuries (338). Head injury is an important cause
and can protect against amyloid-induced learning and of morbidity and mortality in the elderly (296). The pos-
memory deficits in adult rats (371). Vitamin E has also sibility that creatine may protect against neurodegenera-
been reported to be effective in animal and cell culture tive conditions has been tested in several animal models.
models of ALS (117, 172, 265) and PD (299), although Dietary supplementation with creatine delayed motor
clinical benefit in human patients has not yet been estab- dysfunction and increased survival in a transgenic mouse
lished. model of HD (7), protected dopaminergic neurons against
Coenzyme Q10 (ubiquinone) is associated with the MPTP toxicity in mice (212), and increased the survival of
mitochondrial oxidative phosphorylation enzyme com- Purkinje cells in a transgenic mouse model of spinocere-
plexes where it serves an antioxidant function. Adminis- bellar ataxia type 1 (155). Preliminary results of a recent
tration of ubiquinone to rodents can enhance learning and clinical trial of creatine supplementation in ALS patients
memory (156). Ubiquinone protected cultured neural cells suggest that it can increase muscle strength (236).
against insults relevant to the pathogenesis of AD (273). The public has recently been barraged with adver-
Dietary supplementation with ubiquinone resulted in in- tisements touting the health benefits of Gingko biloba
creased resistance of midbrain dopaminergic neurons to with a particular emphasis on its benefits for the brain
MPTP-induced damage in a mouse model of PD (13) and (251). Ginkgo biloba extract enhanced performance of
increased resistance of striatal neurons to the succinate aged mice in a learning and memory task (50). In a rat
dehydrogenase inhibitor malonate in a rodent model of model of severe diabetes, Gingko biloba was effective in
HD (12). Clinical trials of ubiquinone have proven effec- improving learning and memory performance (132).
tive in treating patients with myocardial infarction (324) Ginkgo biloba supplementation in a double-blind, place-

bo-controlled, 14-wk, parallel group, repeated assess-

ment, multi-center trial proved effective in improving cog-
nitive function in healthy middle-aged subjects (363).
However, other trials of Ginkgo extracts on memory per-
formance in normal adults (247) and elderly patients with
mild cognitive impairment (350) have not revealed a sig-
nificant effect of this dietary supplement (247). Ginkgo
extracts can protect cultured cortical neurons against
damage induced by iron (107) and protect cultured PC12
cells against A" toxicity (11, 373). Ginkgo extract reduced
damage to dopaminergic neurons caused by MPTP in a
mouse model of PD (287). Blindness due to degeneration
of photoreceptors occurs in many aged individuals, and it

was shown that Ginkgo biloba extract can protect photo-
receptors against light-induced damage (289). Overall, the
available data suggest that Ginkgo biloba has beneficial
effects in the nervous system, although further studies
will be required before this dietary supplement can be
recommended for primary prevention of neurodegenera-
FIG. 13. The antioxidant lycopene protects hippocampal neurons
tive disorders.
against excitotoxicity and against apoptosis induced by amyloid "-pep-
Other antioxidants that have been associated with tide. Primary rat hippocampal cell cultures were pretreated for 16 h with
reduced risk or disease and/or have exhibited neuropro- 1 %M lycopene and were then exposed to saline (control), 10 %M
tective effects in cell culture and animal models relevant glutamate, or 1 %M A"-(1O42) for 24 h. Neuron survival was quantified,
and values are means $ SD of determinations made in 4 cultures per
to age-related neurodegenerative disorders include estro- condition. **P % 0.01 compared with corresponding value for vehicle-
gen, carotenoids, uric acid, glutathione, and N-acetylcys- treated cultures (ANOVA with Scheffe post hoc tests).
teine. Epidemiological data and clinical studies suggest
that estrogens can improve memory and reduce risk of
dementia during aging (318). Estrogen can protect cul- trial in patients with probable AD (2), suggesting that this
tured neurons against death induced by A" (101, 278) and antioxidant may soon be used as a dietary supplement
can protect cortical neurons against ischemic injury in for patients in the early stages of neurodegenerative
vivo (73). However, clinical trials of estrogen in AD pa- disorders.
tients have not resulted in clear beneficial effects and
epidemiological studies aimed at determining whether
estrogens can prevent AD have generated mixed results. V. BEHAVIORAL MODIFICATION
Individuals over the age of 65 that have higher levels of OF BRAIN AGING
"-carotene perform better in learning and memory tests
compared with individuals with low "-carotene levels Studies performed during the past decade strongly
(275). Lycopene is a carotenoid that has been suggested suggest that our daily behaviors can affect the molecular
to protect against heart disease, stroke, and certain can- composition and cellular structure of our brain. When
cers (290, 295). Lycopene can protect cultured hippocam- adult rodents are housed in complex environments or
pal neurons against A" and glutamate toxicity (Fig. 13). exercised on a regular basis, there are increases in the
Levels of uric acid have been reported to be decreased in complexity of dendrites in cortical neurons and increased
patients with AD (200, 345). Uric acid administration to numbers of synapses (153). These structural changes are
adult rats reduced focal ischemic brain injury and im- associated with increased production of certain neurotro-
proved functional outcome in a stroke model (378). Uric phic factors and with enhanced performance on learning
acid is remarkably effective in protecting cultured neu- and memory and motor function tasks. Other behavioral
rons against insults relevant to AD and PD, including factors may have a negative impact on the brain, with the
exposure to A" and iron (111, 160, 161, 378). Glutathione best-documented example being psychosocial stress
is a major antioxidant in the brain and can protect neu- (239). The molecular and cellular mechanisms responsi-
rons against a variety of oxidative insults in experimental ble for beneficial or detrimental effects of different be-
models relevant to the pathogenesis of AD, PD, ALS, and haviors on the brain are beginning to be understood and
stroke (161, 205, 265). N-acetylcysteine has proven effec- may involve changes in neurotrophic factor, neurotrans-
tive in reducing age-related deficits in learning and mem- mitter, and hormonal signaling pathways. With respect to
ory (209). Encouraging beneficial effects of N-acetylcys- aging and age-related neurodegenerative disorders, the
teine supplementation were recently reported in a clinical available data suggest that those behaviors that enhance

dendritic complexity and synaptic plasticity also promote ceptor agonist) binding in response to calcium in hip-
successful aging and decrease risk of neurodegenerative pocampal neurons, without a change in levels of AMPA
disorders. Collectively, the emerging data suggest that receptor subunit mRNA or protein levels (92). Levels of
behavioral factors can have a major impact on the out- several different neurotrophic factors are increased in the
come of brain aging. brains of animals maintained in complex environments
compared with control animals maintained in simple en-
vironments. Levels of BDNF and NGF are increased in
A. Intellectual Activity cerebral cortex, hippocampus, basal forebrain, and hind-
brain, and levels of both the high- and low-affinity NGF
Epidemiological studies have documented an inverse receptors are increased in the basal forebrain of rats
relationship between educational attainment and risk for maintained in a complex environment (138). There are
AD such that more educated persons are at reduced risk striking similarities in the effects of DR and intellectual
(81). Particularly interesting are data suggesting that in- activity on neurotrophic factor expression and neuronal

tellectual function in early life can affect risk of AD. Thus, plasticity, suggesting a shared mechanism underlying
in a study of a population of nuns in Minnesota, Snowdon their beneficial effects in the brain (Fig. 10).
et al. (329) showed that nuns with the best linguistic
abilities as young adults were at reduced risk for AD. One B. Exercise
interpretation of these data is that intellectual activity is
neuroprotective. Animal studies are consistent with this Exercise benefits not only the musculoskeletal and
interpretation. Greenough and co-workers (22, 167) cardiovascular systems, but it also benefits the brain.
showed that rats raised in complex environments exhibit Regular vigorous exercise improves mood and cognition;
increased complexity of dendritic arbors and synapses in these effects of exercise have been clearly established in
the hippocampus and cerebellum, suggesting an in- controlled studies (84). Studies of elderly populations
creased functional reserve. During aging, synaptic density suggest that regular exercise can also promote mainte-
decreases in the hippocampus in rats, and maintenance of nance of cognitive function during aging (78, 349). Other
the rats in a complex environment can prevent such age- studies have shown that regular exercise in elderly men is
related synaptic loss (306). In addition, when rodents are particularly effective in improving cognitive performance
raised in complex environments in which they have many on tasks that require visuospatial processing (317). Four-
objects to play with, neurogenesis is enhanced and learn- teen-month-old rats that exercised regularly (swimming 1
ing and memory ability is improved (164, 254, 377). Com- h/day, 5 days/wk for 9 wk) exhibited improved perfor-
plex environments, which can be equated with intellec- mance in a learning and memory task and reduced levels
tual activity in humans, may also increase resistance of of membrane lipid peroxidation and oxidative damage to
neurons to injury and promote recovery after injury. As DNA (285). For example, mice allowed access to a run-
evidence, functional deficits caused by bilateral lesions of ning wheel exhibit increased neurogenesis and improved
the frontal cortex are ameliorated when rats are main- learning and memory compared with couch potato mice
tained in complex environments, and this was correlated (351). Exercise results in an increase in the level of BDNF
with reduced damage to cortical neurons (169). Further in the hippocampus in rats (304), suggesting a role for
studies have shown that, in addition to enhancing synap- BDNF in the beneficial effects of exercise on brain func-
tic connectivity and increasing resistance of neurons to tion and plasticity. Another neurotrophic factor upregu-
injury, complex environments can improve outcome after lated in the brain in response to learning and exercise is
ischemic stroke in rats (151). Similarly, maintenance of bFGF (100). The latter study showed that the increase in
rats in complex environments improves learning and bFGF levels was associated with an increase in astrocyte
memory performance in a water maze test after lesion of density, suggesting a potential role for astrocytes in the
cholinergic basal forebrain neurons (352). The latter find- beneficial effects of exercise in the brain. Further data
ings suggest that intellectual activity can enhance recov- supporting a beneficial effect of exercise on the brain
ery of function after brain injury. come from epidemiological studies in humans which
The cellular and molecular mechanisms whereby show that regular vigorous physical activity can reduce
complex environments enhance neuronal plasticity and risk for ischemic stroke (181); although it has not been
resistance to injury are beginning to be revealed. Presum- established that prior physical activity can improve out-
ably, the increased activity in neural circuits that results come after a stroke, this would seem plausible. Physi-
from intellectual activity leads to long-term changes in cal activity can also benefit the brain after injury. For
gene expression that play a role in its beneficial effects. example, exercise after brain injury improved func-
Indeed, rats raised in a complex environment exhibit tional outcome in rats, and the improved outcome was
changes in the upregulation of DL-!-amino-3-hydroxy-5- associated with enhanced structural plasticity in the
methylisoxazole-propionic acid (AMPA; a glutamate re- motor cortex (152).

VI. SYNAPSES AND AGING: vival of neurons are localized in synapses. Some of these
EMERGING CONCEPTS synaptic signaling systems may be particularly sensitive
to age-related increases in levels of oxidative stress and
The numbers and size of synapses change during decreases in energy availability (Fig. 14). For example,
aging and response to environmental stimuli. During suc- oxidative stress leading to membrane lipid peroxidation
cessful brain aging, numbers of synapses may or may not can impair the coupling of muscarinic cholinergic recep-
decrease depending on the brain region; in brain regions tors to the GTP-binding protein Gq11, apparently as the
in which synapse numbers do decrease, the size of the result of covalent modification of Gq11 by the lipid peroxi-
remaining synapses may increase, perhaps as a compen- dation product 4-hydroxynonenal (23, 163). Age-related
satory mechanism. For example, in a study of superior- decreases in levels of neurotrophic factors and/or their
middle frontal cortex (area 9) in cognitively normal indi- receptors have been reported (125, 381), and on the basis
viduals ranging in age from 20 to 89 yr, there was no of the localization of neurotrophic factor receptors in
change in synapse density in lamina III and V (308). On synapses, compromised neurotrophic signaling would be

the other hand, a decrease in synaptic density occurs in expected to promote synapse degeneration and cell
the lateral septal nucleus in a subset of aged rats (309). In death. On the other hand, cellular adaptations to aging
striking contrast to normal aging, clear and profound may include an enhancement of neurotrophic signaling
decreases in synapse numbers occur in brain regions that supports synaptic plasticity (Figs. 1 and 14).
involved in learning and memory in AD (307). Interest- Age- and disease-related synaptic dysfunction and
ingly, synapse loss also occurs in the cerebral cortex of degeneration may be subject to modification by dietary
many patients with HD and PD (382). Studies of animal and behavioral factors. Studies of cortical synaptosomes
models of age-related neurodegenerative disorders (AD, prepared from rats maintained on calorie-restricted or
HD, and PD) have documented synapse loss and have control diets have shown that caloric restriction can in-
provided evidence that the synapse degeneration occurs crease the resistance of synapses to oxidative and meta-
early in the disease process, well before cell death (256, bolic insults, as indicated by relative preservation of glu-
259, 298). cose and glutamate transport and mitochondrial function
Abnormalities in synaptic signal transduction path- (113). 2-Deoxy-D-glucose administration exerted similar
ways and associated functional deficits may occur during beneficial effects on synapses (116). The amounts of
aging and may be early and pivotal events in the patho- HSP-70 and GRP-78 were increased in synaptosomes from
genesis of neurodegenerative disorders. Several findings calorie-restricted rats and rats given 2-deoxy-D-glucose,
point to synaptic alterations occurring very early in AD demonstrating that energy restriction bolsters the ability
and being central to the cognitive deficits and neuronal of synapses to cope with the oxidative and metabolic
death. Studies of APP (41) and PS1 (263) mutant trans- stress associated with aging. As described in section V,
genic mice have documented alterations in synaptic plas- increased activity in neuronal circuits due to intellectual
ticity that occur without evidence of synapse loss or cell or physical activities may prevent age-related dysfunction
death. A" is deposited at high levels in synaptic regions, and loss of synapses. Presumably, many of the same
presumably because its protein precursor (APP) is ax- adaptive changes that occur in neurons subjected to di-
onally transported. Exposure of isolated synaptic termi- etary restriction, including increased neurotrophic factor
nals to A" results in impairment of ion-motive ATPases signaling and protein chaperone production, also occur in
and glucose and glutamate transporters (162). A" and response to intellectual and physical activity. These
oxidative stress can also induce apoptotic biochemical changes benefit synapses directly by enhancing their abil-
cascades in synapses and dendrites, including increased ity to tolerate oxidative and metabolic stress.
production of Par-4, mitochondrial alterations, and
caspase activation (70, 234). Neurotrophic factors (115)
and estrogen (159) that may protect against AD can pre- VII. IMPLICATIONS FOR PREVENTION AND
serve synaptic transporter functions during exposure to TREATMENT OF NEURODEGENERATIVE
A". PS1 mutations result in perturbed synaptic calcium DISORDERS
homeostasis and thereby promote synapse dysfunction
and degeneration (15). Although fewer studies have ad- Because of advances in the prevention and treatment
dressed the issue of synaptic dysfunction in PD and HD, of cardiovascular disease and cancers, many more people
studies of animal models are consistent with perturba- are living beyond the age of 70, and neurological disorders
tions in synaptic function and initiation of apoptotic bio- of aging have therefore become more common causes of
chemical cascades occurring early in the disease process disability and death. As described above, research efforts
(66, 71). on neurodegenerative disorders have rapidly expanded in
The vast majority of signal transduction pathways the past decade and have greatly advanced our under-
that regulate structural and functional plasticity, and sur- standing of the molecular and cellular mechanisms that


FIG. 14. Synaptic signaling systems that are subject to modification by aging, genes, and diet. Glutamate, the major
excitatory neurotransmitter in the brain, activates several different types of ionotropic rectors (including AMPA and
NMDA receptors) resulting in membrane depolarization and calcium influx. Glutamate can also activate metabotropic
receptors coupled to inositol phospholipid hydrolysis and the production of inositol 1,4,5-trisphosphate (IP3), which
triggers calcium release from endoplasmic reticulum stores, and diacylglycerol which activates protein kinase C. GABA
is the major inhibitory neurotransmitter in the brain and, by hyperpolarizing the membrane, can counteract the
excitatory effects of glutamate. Calcium influx induced by glutamate can activate transcription factors resulting in
changes in gene expression that mediate effects of glutamate on synaptic plasticity and cell survival. AMPA, L-!-amino-
3-hydroxy-5-methylisoxazole-4-propionate; CAMK, calcium/calmodulin-dependent protein kinase; CREB, cAMP response
element binding protein; DAG, diacylglycerol; NMDA, N-methy-D-aspartate; PKA, cAMP-dependent protein kinase; PKC,
protein kinase C; VDCC, voltage-dependent calcium channel.
result in neuronal dysfunction and death, and the genetic during adult life may be particularly effective in reducing
and environmental risk factors for the disorders. Basic risk of age-related neurodegenerative disorders. A link
and clinical research in this field have reached a point between high cholesterol levels and risk of stroke has
where recommendations can be made to the general pop- been established, and recent findings suggest that high
ulation concerning how they can reduce their risk of cholesterol levels may also increase risk of AD (54), sug-
age-related neurodegenerative disorders. Moreover, effec- gesting that a reduced fat diet may help ensure a healthy
tive treatments for symptomatic patients are beginning to brain as one ages. Links between pesticides and PD (20)
emerge. and dietary toxins and ALS (335) have been reported. The
As with other major age-related diseases, including latter findings suggest that reducing exposure to such
cardiovascular disease, type 2 diabetes, and some can- environmental toxins may reduce the incidence of these
cers, the most effective means of reducing risk for neu- disorders. New dietary and behavioral approaches for
rodegenerative disorder may be to modify ones diet and promoting healthy brain aging will undoubtedly emerge
behaviors. As described in section IVA, caloric restriction from ongoing research. By analogy with physical exercise

benefiting the musculoskeletal and cardiovascular sys- ing effective in counteracting age-related brain dysfunc-
tems, mental exercise may improve the ability of brain tion in studies in rodents (154).
cells to cope with the aging process. Preclinical studies in animal models of neurodegen-
Can pharmacological interventions retard brain ag- erative disorders have identified several approaches that
ing? Antioxidants such as vitamin E, coenzyme Q10, lipoic are efficacious in preventing neuronal degeneration
acid, and ginko extract, and supplements such as creatine and/or restoring lost function. Administration of A" to
that enhance cellular energy maintenance, may provide APP mutant transgenic mice results in reduced amyloid
some degree of protection (7, 1113, 50, 107, 119, 155, 168, deposition and increased clearance of amyloid deposits in
212, 354, 384). Recent studies have evaluated dietary sup- the brain and improved learning and memory perfor-
plements that mimic the physiological effects of caloric mance (244, 310). The latter studies have led to a clinical
restriction for their ability to enhance resistance of neu- trial of an amyloid vaccine in AD patients. Unfortu-
rons to age-related disease (69, 116, 380). Suppressing nately, the clinical trial was recently halted because sev-
apoptosis using agents that target key proteins in the cell eral patients developed encephalitis. Another promising

death process, such as p53 and caspases, is another po- approach for removing amyloid deposits from the brains
tentially effective strategy (55, 72). It has also been sug- of AD patients is based on a role for metals, copper, iron,
gested that cholesterol-lowering statins may protect the and zinc in particular, to promote aggregation of A". An
brain against age-related neurodegenerative disease via older study suggested a benefit of the iron chelator des-
actions on the vasculature or directly on neurons (83, ferroxamine in AD patients (53), and recent preclinical
149). In addition to preventative strategies that affect studies in APP mutant mice (47) have led to a clinical trial
pathways of neuronal degeneration or neuroprotection of a copper chelator in AD patients. Epidemiological and
that are shared among age-related neurodegenerative dis- animal studies suggest that antioxidants (282), estrogenic
orders, novel disease-specific approaches are also being steroids (239), and anti-inflammatory drugs (136) can re-
developed. In the case of AD, for example, drugs that duce risk of AD, presumably by reducing damage to neu-
inhibit "- and $-secretases and thereby reduce A" produc- rons and microglial activation. Amyloid deposition and
tion are being developed (48), as are amyloid vaccine- oxidative stress in AD may facilitate excitotoxic neuronal
based approaches (139). death (224). Glutamate receptor antagonists are therefore
Finding cures for age-related brain dysfunction and being evaluated for the treatment of AD patients (144).
disease is a worthy, but elusive and often frustrating, goal. Several types of drugs are in development for the treat-
By the time that patients with AD, PD, HD, and stroke ment of PD patients. Because excitotoxicity is thought to be
become symptomatic, extensive damage to neuronal cir- involved in the degeneration of dopaminergic neurons, N-
cuits has already occurred. Treatment strategies must methyl-D-aspartate receptor antagonists are being tested in
therefore focus on halting further neuronal degeneration animal models of, and patients with, PD and related move-
and promoting reestablishment of neuronal circuits. Re- ment disorders (61). Similar antiexcitotoxic approaches are
cent advances, many of which are described in this re- being applied to HD and stroke (33). Synthetic inhibitors of
view, suggest that the goal of curing patients with age- the proapoptotic protein p53 protected dopaminergic neu-
related neurodegenerative disorders is worth pursuing. rons against death and improved motor function, in a mouse
One reason for optimism is that the extent of neuronal model of PD (Duan). As described above, dietary supple-
death in PD and AD patients during the early period of the mentation with creatine has proven beneficial in mouse
diseases may not be as great as initially thought, because models of ALS and PD (168, 212).
many dysfunctional neurons may be able to recover (95). The kinds of data obtained in the studies of rodent
In addition, neural stem cells may be capable of replacing models of brain aging and neurodegenerative disorders de-
lost neurons (91). Moreover, it may be possible to manip- scribed above suggest that DR can increase health span of
ulate cell adhesion and signaling pathways in ways that the brain and effectively protect neurons against the dys-
enhance neurite outgrowth and synaptogenesis (312). function and death that occurs in neurodegenerative disor-
Neurotrophic factors and agents that stimulate their pro- ders. However, it remains to be conclusively demonstrated
duction as well as drugs that enhance synaptic transmis- that the results of the animal studies are directly applicable
sion are currently in clinical trials, as are several antioxi- to humans. Clinical trials of DR in humans will be difficult to
dants. In addition, trials are in progress to determine the perform because they will require long time periods (many
safety and efficacy of transplantation of neural stem cells years to decades) of compliance and extensive resources.
in PD patients. Cocktail treatments (e.g., multiple anti- Nevertheless, data emerging from a study of life-long DR in
oxidants) have proven most efficacious in preclinical rhesus monkeys begun here at the National Institute on
studies and are therefore likely to also achieve the great- Aging 14 years ago strongly suggest that DR increases life
est effects in human patients. In this regard, it is of span in primates (176a). In our view, there is no doubt that
considerable interest that dietary supplementation with DR is beneficial for the nervous system of humans, just as it
fruits and vegetables rich in multiple antioxidants is prov- benefits every other organ system studied. The major hurdle

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Modification of Brain Aging

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Physiol Rev

82: 637 672, 2002; 10.1152/physrev.00004.2002.

Modification of Brain Aging and Neurodegenerative Disorders

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I. INTRODUCTION accordingly, a major goal of research in the area of the

Studies of embryonic and early postnatal develop-

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FIG. 4. Examples of cellular signal-

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FIG. 11. Regulation of energy metabo-

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C. Folic Acid enzyme, plays an important role in facilitating the conver-

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FIG. 12. The involvement of folic acid

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bo-controlled, 14-wk, parallel group, repeated assess-

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