Ageing Research Reviews 9S (2010) S36S46

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Ageing Research Reviews

journal homepage: www.elsevier.com/locate/arr

Review

Ageing and neurodegenerative diseases

Chia-Wei Hung a,c,1 , Yu-Chih Chen b,c,1 , Wan-Ling Hsieh d,e,1 , Shih-Hwa Chiou b,c,f , Chung-Lan Kao c,d,e,
a
Department of Neurology, Zhongxiao Branch, Taipei City Hospital/No.87, Tongde Rd., Nangang Dist., Taipei City 115, Taiwan
b
Department of Medical Research and Education, Taipei Veterans General Hospital/No.201, Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan
c
Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan/No.155, Sec. 2, Linong St., Taipei 112, Taiwan
d
Department of Physical Medicine & Rehabilitation, Taipei Veterans General Hospital/No.201, Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan
e
Center for Geriatrics & Gerontology, Taipei Veterans General Hospital/No.201, Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan
f
Department of Pharmacology, National Yang-Ming University; Taipei, Taiwan/No.155, Sec. 2, Linong St., Taipei 112, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Ageing, which all creatures must encounter, is a challenge to every living organism. In the human body,
Received 8 June 2010 it is estimated that cell division and metabolism occurs exuberantly until about 25 years of age. Beyond
Accepted 4 August 2010 this age, subsidiary products of metabolism and cell damage accumulate, and the phenotypes of age-
ing appear, causing disease formation. Among these age-related diseases, neurodegenerative diseases
have drawn a lot of attention due to their irreversibility, lack of effective treatment, and accompanied
Keywords:
social and economical burdens. In seeking to ameliorate ageing and age-related diseases, the search for
Stem cells
anti-ageing drugs has been of much interest. Numerous studies have shown that the plant polyphenol,
Neural stem cells
Neuroprotection
resveratrol (3,5,4 -trihydroxystilbene), extends the lifespan of several species, prevents age-related dis-
Neurodegenerative diseases eases, and possesses anti-inammatory, and anti-cancer properties. The benecial effects of resveratrol
Stem cell-based strategy are believed to be associated with the activation of a longevity gene, SirT1. In this review, we discuss
the pathogenesis of age-related neurodegenerative diseases including Alzheimers disease, Parkinsons
disease and cerebrovascular disease. The therapeutic potential of resveratrol, diet and the roles of stem
cell therapy are discussed to provide a better understanding of the ageing mystery.
Crown Copyright 2010 Published by Elsevier B.V. All rights reserved.

1. Introduction
In living organisms, ageing usually refers to a series of
time-dependent anatomical and physical changes that reduce
physiological reserve and functional capacity. The term may also
refer to the positive processes of maturation or acquisition of a
desirable quality (Ahmed and Tollefsbol, 2001). Biological ageing
is not necessarily conned to the later years of life; some decline
begins with conception. In general, ageing designates the phys-
ical changes that develop in adulthood, resulting in a decline in
efciency of function, reduced homeostasis, and ultimately, death.
The multiple processes of decline that are associated with grow-
ing old can be separated into primary and secondary ageing (Busse,
1987). Primary ageing is held to be intrinsic to the organism, and
the factors of decrement are determined by inherent or hereditary
inuences. The rate of ageing, which is presented by a functional
decline, varies widely among individuals. There are even extreme
Corresponding author at: Department of Physical Medicine and Rehabilitation,
Taipei Veterans General Hospital, No. 201, Sec 2, Shih-Pai Road, Taipei 112, Taiwan.
Tel.: +886 2 28757363; fax: +886 2 28757359.
E-mail address: clkao@vghtpe.gov.tw (C.-L. Kao).
1
Authors who contributed equally to this work.
ageing variations among different systems, organs, and cells in one
individual. Secondary ageing refers to defects and disabilities that
are caused by hostile factors in the environment, including trauma
and acquired diseases. This operational separation of primary and
secondary ageing processes has limitations, because both heredi-
tary and acquired decremental ageing changes are often resulted
from multiple etiologies. Inherent defects that make an organism
vulnerable may not appear unless and until the organism is exposed
to hostile precipitating events.
Denitions of ageing that have been offered are not consistently
accepted and applied. Ageing of living organisms is a universal phe-
nomenon, but the rate of ageing varies between individuals and
groups. In humans, ageing differences are, in part, genetically deter-
mined, but also are substantially inuenced by nutrition, lifestyle
and environment (Busse, 1987). Some scientists dene primary
ageing as rst-cause and secondary ageing as the pathological pro-
cesses that ensue from the rst-cause. Many ageing changes are
relatively benign. The ageing person still has adequate biological
and social function to satisfy his or her personal needs, and to main-
tain a place in society. Ageing changes are recognized as a decline
in efciency or performance, but in the extreme are often labeled as
diseases. Examples of ageing changes that are sufciently severe to
become a disease include a decline in renal function, reduced res-
piratory performance, an increase in systolic blood pressure, and

1568-1637/$ see front matter. Crown Copyright 2010 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.arr.2010.08.006
 C.-W. Hung et al. / Ageing Research Reviews 9S (2010) S36S46
an impaired response to oral glucose tolerance tests (Tobin and
Snyder, 1984).
An important change during ageing is the loss of irreplaceable
cells, most noticeably in the skeletal muscles, heart, and brain.
Striated musculature diminishes by about one-half by around 80
years of age. When the muscle cells disappear, they are replaced
by fat cells and brous connective tissue. Hence, the body achieves
increased storage capacities for certain drugs that are stored in fat
cells. The decrease in heart cells results in alterations in cardiac
functions, and changes of cells and supportive tissues cause declin-
ing pulmonary function. In the brain, neurons shrink and disappear,
and alterations occur in neuronal synapses and networks. The loss
of neurons, particularly those in the vulnerable areas of hypotha-
lamus, may contribute to certain physiological changes including
altered metabolism and circadian rhythm, and are associated with
mental and emotional aberrations in the elderly. Ageing results in a
decrease of dopamine, norepinephrine, serotonin, tyrosine hydrox-
ylase, and cholinesterase; however, the activity of monoamine
oxidase increases.
In the cellular level, ageing is associated with accumulat-
ing oxidative stress, declining mitochondrial function, telomere
erosion, impaired DNA repair and decreased tissue regeneration
(Sahin and Depinho, 2010). Oxidative stress-induced damage has
been proposed as a major risk for cardiovascular disease, and
increased oxidative stress of vessel wall is a pathogenic feature of
atherosclerosis and hypertension (Liao et al., 1994; Rajagopalan et
al., 1996). Increased oxidative stress is a major cause of endothe-
lial dysfunction. By attenuation of nitric oxide (NO) production,
inammation, and activation of intracellular signal transduction
pathways, increased oxidative stress can inuence ion channel
activation, intercellular communication, and gene expression to,
ultimately, elicit cessation of cell division and premature senes-
cence. Reactive oxygen species (ROS), such as hydrogen peroxide
(H2 O2 ), superoxide (O2 ), and hydroxyl radical (OH ), are gen-
erated by various different pathways. Data from several studies
indicate that ROS activate protein tyrosine kinases, followed by
the stimulation of downstream signaling events that regulate gene
expression, resulting in modication of cardiovascular cells (Rao et
al., 1993; Ushio-Fukai et al., 1996). Redox-sensitive proteins, such
as c-Src, PYK2, ERK1/2, and BMK1 (Abe et al., 1996; Baas and Berk,
1995; Tai et al., 2002), are likely critical mediators of these changes
in gene expression.
Pathological studies have demonstrated increased ROS indices
in affected brain tissues of patients with neurodegenerative dis-
eases, including Alzheimers diseases (AD), Parkinsons disease (PD)
and amyotrophic lateral sclerosis (ALS) (Andersen, 2004). These
changes can occur as early as in the preclinical stages. In one study,
increased iron and free radical generation were found in the cor-
tex and cerebellum from patients with preclinical AD and mild
cognitive impairment (Smith et al., 2010). However, the increase
of ROS in the brain is not caused by elevation of oxidative stress
(Andersen, 2004). Studies shown that the activities of superoxide
dismutase (SOD), catalase, glutathione peroxidase and glutathione
reductase were reduced in affected brain regions in AD (Zemlan et
al., 1989; Pappolla et al., 1992). The amount of glutathione (GSH)
also reduced in the substantia nigra in PD (Perry et al., 1982; Perry
and Yong, 1986; Pearce et al., 1997). It is the decline of antioxi-
dant defense and repair mechanisms which results in accumulating
oxidative damage and leads to neurodegenerative disorders. In
addition, there are interactions among oxidative stress and other
molecular mechanisms which cause neurodegeneration, such as
protein misfolding, proteasomal malfunction, glial cell activation,
mitochondrial dysfunction and programmed cell death (Andersen,
2004). For instance, oxidative stress may activate p38 mitogen-
activated protein kinase (MAPK), and persistent activation of MAPK
within affected motor neurons and reactive glia is correlated with
S37
disease progression in an ALS-SOD1 mouse model (Tortarolo et al.,
2003).
Recent studies have shown a signicant association between
longevity and epigenetics. The silent information regulator 2
(Sir2), a NAD+ -dependent protein deacetylase, is able to promote
longevity in yeast. Cells lacking Sir2 protein have a reduced replica-
tive lifespan (Kaeberlein et al., 1999), and cells with increased Sir2
activity display a much longer lifespan than wild-type cells. This
event may be regulated through hyper silencing of the forma-
tion of extra chromosomal ribosomal DNA circles in the nucleoli
(Kaeberlein et al., 1999), a known cause of senescence in yeast.
Caloric restriction (CR) has been reported as a contributor to
longevity in species from yeast to nematodes, rodents and mon-
keys. It is thought that CR slows the metabolic rate and generates
more free NAD co-factors, which results in greater Sir2 activity
(Imai et al., 2000) and extends lifespan (Lin et al., 2000). Sir2
and other related members of the sirtuin family are highly con-
served from yeast to mammals. The SIRT1 gene, the mammalian
homologue of SIR2, encodes a member of the sirtuin family of pro-
teins, and contains the catalytic core domain of SIR2 (Blander and
Guarente, 2004; Frye, 1999). SirT1, which resides in the nucleus,
binds and deacetylates p53, NF-B, and forehead transcription
factors, as well as histones (Haigis and Guarente, 2006). SirT1 is pos-
tulated to protect against neurodegeneration. Kim et al. found that
injection of SirT1 lentivirus into the hippocampus of p25 transgenic
mice, a model of AD and tauopathies, caused signicant protec-
tion against neurodegeneration (Kim et al., 2007). Injection of SIRT1
activators signicantly ameliorated retinal ganglion cell in experi-
mental autoimmune encephalomyelitis mice, while administration
of SIRT1 inhibitors suppressed this protective effect (Shindler et al.,
2007). Immunohistouorescence and in situ hybridization results
obtained from the retinal degeneration 10 (rd10) mouse model
of retinitis pigmentosa illustrated that SirT1 was localized mostly
to the nucleus in the retina of normal mice, whereas to the reti-
nal outer nuclear layer of rd10 mouse eyes (Jaliffa et al., 2009).
These results suggest that increased SirT1 activity abrogates neu-
rodegeneration and highlights its therapeutic potential for human
neurodegenerative disorders.
In the following sections, we will introduce some anti-ageing
therapeutic strategies, which include antioxidants, diet and stem
cell-based treatment.
2. Ageing and neurologic or neurodegenerative diseases
Ageing is a major risk factor of neurodegenerative diseases.
Ageing not only makes patients more prone to neurodegenerative
diseases, but also impairs their abilities of self-repair. For exam-
ple, hippocampal neurogesis in response to partial hippocampal
deafferentation is lost in old rats (Shetty et al., in press). With
advances in molecular biology, our knowledge of ageing and cogni-
tive decline is accumulating. Many signaling pathways involved in
the regulation of ageing and lifespan have been identied, including
insulin/IGF-1 signaling, target of rapamycin (TOR) signaling, mito-
chondrial function, sirtuins, and caloric restriction (Bishop et al.,
2010). Recent studies have implicated the involvement of these
signaling pathways in age-related cognitive decline. Alteration of
the molecular mechanisms of ageing may contribute to the patho-
genesis of neurodegenerative diseases (Bishop et al., 2010).
Many age-related neurodegenerative diseases are character-
ized by accumulation of disease-specic misfolded proteins in
the central nervous system (van Ham et al., 2009). These include
-amyloid peptides and tau/phosphorylated tau proteins in AD,
-synuclein in PD, superoxide dismutase in amyotrophic lateral
sclerosis (Durham et al., 1997), and mutant huntingtin in Hunting-
tons diseases (Scherzinger et al., 1997). The association between
S38 C.-W. Hung et al. / Ageing Research Reviews 9S (2010) S36S46
age and protein misfolding is not been clear yet. It may be related to
cellular changes that occur during ageing. For example, cells shrink
and the quality control of protein synthesis declines with ageing
(Gaczynska et al., 2001; Reznick and Gershon, 1979). This may cause
or contribute to the formation of misfolded protein aggregates and
subsequently lead to disease (Gaczynska et al., 2001; Reznick and
Gershon, 1979).
2.1. Alzheimers disease
As life span increases, dementia becomes an emerging prob-
lem in developed countries. The most common type of dementia
is AD. It is characterized by progressive memory impairment and
other cognitive decits. Age is the greatest risk factor in AD. In a
prospective cohort study, AD rates rose from 2.8 per 1000 person-
years in the age group of 6569 years to 56.1 per 1000 person-years
in the older than 90 years age group (Kukull et al., 2002). The
main pathological ndings of AD are senile plaques and neurob-
rillary tangles in the cortex which contain -amyloid peptides
and tau/phosphorylated tau proteins, respectively. The accumula-
tion of these misfolded proteins causes neuronal loss and synaptic
damage, but the pathogenesis of protein misfolding is not clearly
understood. As the key risk factor for AD, the cellular changes in
the process of ageing may be associated with the mechanism of
protein misfolding and aggregation (van Ham et al., 2009). Age-
ing is also related to accumulating oxidative stress and dysfunction
of mitochondria. The brain is particularly susceptible to defective
mitochondrial function because of its great bioenergetic demands
(Bishop et al., 2010). In the human brain, neural populations with
larger energetic demands, such as the large pyramidal neurons that
degenerate in AD, may be affected selectively by declining mito-
chondrial function (Bishop et al., 2010). Declining mitochondrial
function may contribute to brain ageing and make neurons more
vulnerable to age-dependent pathological changes (Bishop et al.,
2010).
Although memory impairment is the hallmark of both AD and
normal brain ageing, the pathology and neurophysiology of the
two conditions are different. Functional magnetic resonance imag-
ing (fMRI) (Small et al., 2002) and histopathological studies in AD
showed that reduced metabolic activity and neuronal loss began
in the entorhinal cortex and the CA1 region of the hippocampus
(Gomez-Isla et al., 1996; Price et al., 2001; Rodrigue and Raz, 2004;
West et al., 1994). In the normal ageing brain, reduced activity
rst occurred in the subiculum and the dentate gyrus instead of
the hippocampus (Small et al., 2002). In normal ageing brains,
functional brain imaging studies have revealed that the separate
brain regions interacting to facilitate higher-order cognitive func-
tion became less-coordinated (Andrews-Hanna et al., 2007). This
was not due to the loss of cortical neurons, which is minimal in the
normal ageing brain but prominent in AD (Yankner et al., 2008). The
altered connectivity of higher-order brain systems may be related
to disruption of myelinated bers that connected neurons in dif-
ferent cortical regions (Andrews-Hanna et al., 2007) or changes
in the synaptic physiology of ageing neurons (Loerch et al., 2008;
Lu et al., 2004). In AD, stored memories are lost; in normal age-
ing brains, it is probable that loss of the ability to access stored
memories underlies age-dependent memory decits (Bishop et al.,
2010).
2.2. Parkinsons disease
PD is another prevalent age-related neurodegenerative disorder
involving misfolded proteins (van Ham et al., 2009). This misfolded
protein is -synuclein, which accumulates and forms Lewy bodies
(van Ham et al., 2009). The presence of Lewy bodies begins in the
olfactory regions and lower brain stem, gradually extending to the
midbrain and cortex (Braak et al., 2006, 2003). A staging scheme of
the extension of Lewy-body depositions has been proposed (Braak
et al., 2006, 2003), and it is correlated with the progression of clin-
ical symptoms and signs (Halliday and McCann, 2010). The main
pathology of PD is the cellular loss of the substantia nigra pars
compacta dopamine neurons that project to the striatum (Samii
et al., 2004). Clinical signs of PD, which include rest tremor, rigid-
ity, and bradykinesia become evident when about 80% of striatal
dopamine and 50% of nigral neurons are lost (Fearnley and Lees,
1991).
Age is the greatest risk factor for occurrence and progression
in PD (Hindle, 2010). Age-related factors can inuence its clini-
cal course and pathological progression. In a longitudinal cohort
study, dementia occurred earlier in older onset PD patients (>70
years old), and their disease courses were much shorter than
younger onset patients (Halliday and McCann, 2010). These older
onset patients had far more -synuclein-containing Lewy bodies
throughout the brain and additional age-related plaque pathol-
ogy (Halliday and McCann, 2010). In patients with dementia with
Lewy bodies, whose disease durations are shortest, brain autopsies
have revealed substantive amounts of Lewy bodies and Alzheimer-
type pathologies (Halliday and McCann, 2010). Age may also affect
responsiveness to medications. Older PD patients are more liable
to suffer adverse events of anti-cholinergic medications, but have
less levodopa-induced dyskinesia. A sham surgery-controlled study
demonstrated that fetal mesencephalic transplantation was bene-
cial for younger but not for older patients (Freed et al., 2001a). The
extra-pyramidal symptoms (EPS) in patients with PD can also occur
in the elderly (Louis and Bennett, 2007). Elderly people may have
rigidity, bradykinesia, impaired postural control, gait difculty, and
more falls. However, the clinical pictures are different between PD
patients and non-PD aged people with EPS. For example, rest tremor
is absent in non-PD aged people. In contrast to the characteristic
unilateral onset of PD, these age-related EPS are symmetric (Louis
and Bennett, 2007) and are nonresponsive to dopaminergic therapy
(Hindle, 2010).
2.3. Stroke
In addition to neurodegenerative diseases, age is also an impor-
tant risk factor of stroke and the strongest predictor of prognosis
after stroke (Macciocchi et al., 1998; Nakayama et al., 1994). The
characteristics of ageing compromise energy metabolism at cel-
lular levels; impaired energy metabolism, in turn, is the hallmark
of tissue susceptibility to ischemia (Ay et al., 2005). In a prospec-
tive study, age was related to an increase in conversion of ischemic
tissue into infarction (Ay et al., 2005). Age also diminishes the pro-
tective effects of energy restriction for cerebral infarction in mice
(Arumugam et al., 2010). Brain damage and functional impairment
after middle cerebral artery occlusion were reduced by intermit-
tent fasting in young and middle-aged mice, but not in old mice
(Arumugam et al., 2010). An increase of neurotrophic factors (brain-
derived neurotrophic factor (BDNF) and basic broblast growth
factor), protein chaperones (heat shock protein 70 and glucose reg-
ulated protein 78), and the antioxidant enzyme heme oxygenase-1,
and a decrease in inammatory cytokines in the cerebral cortex
and striatum is facilitated by intermittent fasting (Arumugam et al.,
2010). However, the phenomenon is absent in old mice (Arumugam
et al., 2010). The severity of brain edema after stroke is also affected
by age. In one study, edema formation was signicantly more
robust in young mice and was reduced by the Na-K-Cl cotransporter
(NKCC) inhibitor, bumetanide (Liu et al., 2010). NKCC expression
and edema formation are age dependent after ischemic stroke (Liu
et al., 2010).
 C.-W. Hung et al. / Ageing Research Reviews 9S (2010) S36S46
3. Resveratrol and other anti-ageing compounds
3.1. Molecular roles of resveratrol
There are a great amount of studies and discussions associ-
ated with anti-ageing drugs. Among them, the natural phenolic
compounds give promising evidence for treatment of car-
diovascular diseases, cancer, and neurodegenerative diseases.
These compounds possess anti-inammatory, anti-proliferation,
anti-oxidation and anti-senescence effects. Resveratrol (trans-
3,5,4 -trihydroxystilbene) is a compound found largely in the skins
of red grapes, nuts, pomegranates, and red wine (Chaudhary and
Puger, 2009; Penumathsa and Maulik, 2009). It is a scavenger of
ROS and has anti-inammatory properties (Chaudhary and Puger,
2009; Penumathsa and Maulik, 2009; Kao et al., 2009, 2010; Lin
et al., 2008; Sun et al., 2010; Whyte et al., 2007). Resveratrol can
prevent tumor progression by blocking NF-B expression and pro-
moting apoptosis of cancer cells (Chaudhary and Puger, 2009;
Penumathsa and Maulik, 2009; Kao et al., 2009, 2010; Lin et al.,
2008; Sun et al., 2010; Whyte et al., 2007). It also has neuroprotec-
tive and cardioprotective effects, can the slow ageing process and
can delay the onset of chronic diseases (Penumathsa and Maulik,
2009; Barger et al., 2003; Baur and Sinclair, 2006; Mancuso et al.,
2007). Wallerath et al. (2005) showed that resveratrol was able
to increase the expression level of endothelial nitric oxide syn-
thase (eNOS). Penumathsa et al. (2008) and Rush et al. (1981)
both demonstrated the cardioprotectives effect of resveratrol in
hypercholesterolemic rats and spontaneously hypertensive rats,
respectively. Resveratrol supplementation signicantly reduced
the presence of atherosclerotic lesions and lipid levels in the apo
E-decient mice (Do et al., 2008; Norata et al., 2007) and type 1
diabetic LDL receptor-decient mice (Zang et al., 2006).
3.2. Anti-ageing effects of resveratrol in metazoans
As rst tested in Saccharomyces cerevisiae, resveratrol was
shown to mimic caloric restriction, increase DNA stability, pro-
duce the highest level of activated Sir2, and extend lifespan by
70%; signicantly longer than other tested polyphenols (Howitz
et al., 2003). Since then, several studies have evaluated the age-
ing intervention capability of resveratrol in Caenorhabditis elegans
and Drosophila melanogaster (Wood et al., 2004). By taking advan-
tage of the short lifespan of these two model systems, Wood et
al. showed that resveratrol extended the lifespan of C. elegans and
D. melanogaster in a dose-dependent manner via Sir2 activation
(Wood et al., 2004). Resveratrol was further shown to increase the
mean and maximum life span by delaying the onset of the expo-
nential increase in mortality in C. elegans (Gruber et al., 2007).
Microarray analysis of resveratrol-treated C. elegans demonstrated
the elevation of a family of genes involved in endoplasmic reticu-
lum (ER) stress response to unfolded proteins. Results from RNA
interference and overexpression further conrmed that resver-
atrol prolonged C. elegans lifespan by inciting ER stress genes
(Viswanathan et al., 2005). Bauer et al. established an acceler-
ated assay to evaluate potential lifespan-altering interventions and
identied resveratrol as an ameliorator of lifespan in Drosophila
(Bauer et al., 2004). The spontaneous physical activity of Drosophila
on a high caloric diet was advanced, dependent on the presence
of Sir2, by feeding resveratrol (Parashar and Rogina, 2009). These
reports have provided strong evidence about the benecial effect
of resveratrol on lifespan in simple organisms.
3.3. Anti-ageing effects of resveratrol in vertebrates
To study the effects of resveratrol on vertebrate ageing, the
short-lived seasonal sh Nothobranchius furzeri has proven to be
S39
a good model. Resveratrol treatment caused a dose-dependent
increase of lifespan by up to 59% and delayed the onset of
age-related dysfunctions in this sh (Valenzano and Cellerino,
2006; Valenzano et al., 2006). The lifespan-extending effects of
resveratrol in mammals are still uncertain, while some studies
have reported that resveratrol improves general health in mouse
models. Daily supplementation of resveratrol shifted the physi-
ology of middle-aged mice on a high-calorie diet towards that
of mice on a standard diet. Parameters associated with longevity
were analyzed, including increased insulin sensitivity, increased
mitochondrial number, elevated peroxisome proliferator-activated
receptor- coactivator 1 (PGC-1) activity, improved motor func-
tion, and increased survival rate (Baur et al., 2006). Lagouge et
al. demonstrated that resveratrol protected mice against diet-
induced-obesity and insulin resistance, and signicantly increased
their aerobic capacity by inducing genes for oxidative phospho-
rylation and mitochondrial biogenesis (Lagouge et al., 2006). In
these studies, resveratrol displayed the potential for modulation
of insulin action and postponed the onset of type 2 diabetes, one
of the age-related diseases, in mammals (Frojdo et al., 2008). In
addition, circumstantial evidence indicated that resveratrol medi-
ated lifespan extension via inducing autophagy; a cellular process
involving the degradation of old, damaged or ectopic organelles, in
yeast and mammal cultured cells (Morselli et al., 2009).
3.4. Therapeutic potential of resveratrol in neurodegenerative
diseases
A large number of studies have established that resveratrol
possesses neuroprotective properties in various in vitro and in
vivo models of neurodegenerative disease. Resveratrol delivery,
either during or after common carotid artery occlusion, signi-
cantly ameliorated ischemia-induced neuron cell death in gerbils
(Wang et al., 2002). Administration of resveratrol for 21 days pre-
vented motor impairment, and decreased infarct volume after
middle cerebral artery occlusion in rats (Sinha et al., 2002). Resver-
atrol also exhibited anti-epilepsy properties which protect neurons
against kainate-induced temporal lobe epilepsy in rats (Wu et
al., 2009). The neuroprotective effects of resveratrol were evalu-
ated in a 6-OHDA-induced PD rat model. Oral administration of
resveratrol attenuated apomorphine-induced turns and alleviated
aberrant cellular morphology of dopaminergic neurons in rat sub-
stantia nigra (Jin et al., 2008). In Huntingtons disease, Parker et al.
(2005) reported that resveratrol rescued mutant polyglutamine-
induced cytotoxicity in transgenic C. elegans, and in neuronal cells
derived from the striatum of HdhQ111 knock-in mice. Although it
is believed that the benecial effects of resveratrol were adminis-
tered by activation of SirT1, Pacholec et al. employed biochemical
assays utilizing native substrates and concluded that resveratrol is
not a direct activator of SirT1 (Pacholec et al., 2010). Therefore, the
mechanism mediated by resveratrol still remains elusive.
3.5. Therapeutic role of resveratrol in cardiovascular diseases
Accumulating evidence has indicated that the benets of resver-
atrol are due to its ability to activate SirT1 (Sun et al., 2010; Albani et
al., 2009). A well-designed study by Orimo and colleagues showed
that overexpression of SirT1, either by virus or by resveratrol, inhib-
ited high glucose-induced senescence and dysfunction in human
umbilical vein endothelial cells (HUVECs) (Orimo et al., 2009). The
latter study further showed that resveratrol not only increased
expression of SirT1 in H2 O2 -treated HUVECs, but also aided in
recovery from the oxidative stress-induced senescence process.
ROS play a critical role in limiting the lifespan of organisms, as
well as initiating the process of cellular senescence (Yan and Sohal,
2002). Increasing levels of ROS have also been shown to restrict
S40 C.-W. Hung et al. / Ageing Research Reviews 9S (2010) S36S46
the lifespan of hematopoietic stem cells (Ito et al., 2006). Recently,
Robb et al. (2008) demonstrated that resveratrol can dramatically
increase mitochondrial MnSOD expression and activity in MRC-5
cells, as well as in mouse brain tissues. Moreover, resveratrol has
also been shown to protect against ROS-induced cell death by acti-
vating AMP-activated kinase in cardiac muscle cells (Hwang et al.,
2008). Kaos nding demonstrated that, even with resveratrol treat-
ment, knockdown of SirT1 in HUVECs increased ROS production
and further promoted the development of oxidative stress-induced
senescence in human endothelial cells (Kao et al., in press). Indeed,
the senescence of endothelial cells leads to endothelial dysfunc-
tion and may result in advanced atherosclerotic lesions in the
cardiovascular system. In conclusion, the results demonstrate that
SirT1, a landmark gene of extended lifespan, plays an important
role in the endothelial cells of vital organ vessels during oxidative
stress-induced atherosclerotic processes or ageing change. Fur-
thermore, our study also indicated that resveratrol is a potential
candidate for preventing and treating the oxidative stress-induced
damage of endothelial cells, and its potential utility in protection
against cardiovascular dysfunction should be further studied. These
data show that resveratrol may prevent ROS-induced ageing and
senescence via increased endothelial SirT1 expression. resveratrol
appears to be a potential anti-oxidant that may prevent or slow
down the process of atherosclerosis induced by ROS. The mecha-
nism of resveratrol-mediated SirT1 activation in the endothelium
of atherosclerotic vessels needs further study.
3.6. Nutritional supplementation, anti-ageing compounds, and
neuroprotection
Nutrition is an important issue in health maintenance, preser-
vation of physical function and life prolongation. As people age,
changes in body composition alter their nutritional needs. Progres-
sive loss of lean body mass from the third to the eighth decade of
life can be up to 45% (Frontera et al., 1991). The ratio change of fat to
lean mass will lead to decreases in basal metabolic rate, decreasing
energy expenditure in elderly. Relatively declining activity levels
accompanied by a decrease in nutrient consumption threaten the
health status with advancing age. Central nervous system degen-
erative diseases affecting the motor pathways can also accelerate
the process of muscle loss, spurring a vicious cycle. Age-related dis-
eases hamper longevity. Some drugs for the treatment of chronic
diseases have been found to extend lifespan. For instance, stud-
ies have proven that metformin decreases breast cancer incidence
(Evans et al., 2005a; Johnson et al., 2002). Controversies exist in
some other widely used nutrient supplements, for example Coen-
zyme Q10 (CoQ10), which is believed to reduce the adverse effects
of neurodegenerative diseases such as Parkinsons and Hunting-
tons diseases (Shults and Haas, 2005). Another study suggested
that CoQ10 at higher concentrations has a negative impact on
cognitive and sensory function in old mice (Sumien et al., 2009).
Vitamin deciency has been linked to cognitive decline in AD.
Intake of mixed forms of alpha and other tocopherols from foods
has been proven to slow the rate of cognitive decline due to age-
ing. Even though it has been well documented that deciencies
of vitamin B12 and folic acid are common in frail, older, cogni-
tively impaired adults, the effects of vitamin B12 and folic acid
supplementation in slowing the progress of cognitive decline is
still under debate (Sullivan and Johnson, 2009). Antioxidants have
been promoted as protective compounds for cardiovascular dis-
ease. Many studies have shown a lower rate of cardiac death in
people who consume a diet rich in the antioxidant vitamins E and
C, and carotenoids (Sullivan and Johnson, 2009). Homocysteine is
associated with thrombogenicity and vascular disease. Folic acid
(and, to a lesser extent, vitamin B-12, vitamin B-6, riboavin) can
lower homocysteine levels (Sullivan and Johnson, 2009; Willett and
Stampfer, 2001). The specic actions of nutrient supplements in
various diseases require further investigation.
Recent reports suggested that environmental factors, especially
the detrimental factors induced by neuronal injury, have a critical
impact on neuroprotection as well as adult neurogenesis. Several
environmental factors are also involved in adult neurogenesis, diet
being one of them. Interested readers can refer to a recent compre-
hensive review (Stangl and Thuret, 2009). The same authors wrote
that the inuence of diet on adult neurogenesis comes from four
domains: meal content, meal texture, meal frequency and calorie
intake. With regards to meal content, zinc, thiamine and vitamin
A deciencies decrease cell proliferation in the adult hippocam-
pus (Stangl and Thuret, 2009). Similarly, excess retinoic acid and
increased homocysteine levels also decrease or inhibit cell prolif-
eration in the adult hippocampus. In contrast, low-dose curcumin
and avonoids have benecial effects on adult hippocampal cell
proliferation and neuroprotection in rodents (Stangl and Thuret,
2009). Notably, most avonoids are extensively metabolized in
vivo and the bioavailability of avonoids after the consumption
of avonoid-rich food can only reach very low concentrations in
human plasma (Lotito and Frei, 2006). In addition, it is interest-
ing that calorie restriction and extending the time between meals
increases adult hippocampal neurogenesis, while diets with a high-
fat content are detrimental and weaken neurogenesis in male rats
(Stangl and Thuret, 2009).
3.7. Exercise in senior, frail adults
In humans, the level of physical activity is believed to be
inversely related to mortality. Decreases in physical activity have
been noted to be associated with cardiovascular disease, stroke,
hypertension, obesity, type II diabetes, osteoporosis and cancer.
It is evidenced in one previous animal study that ageing reduced
SirT1 activities in the hearts of aged rats, and exercise training
could counteract age-related symptoms by promoting SirT1 activ-
ities (Ferrara et al., 2008). Physical functioning of individuals can
be reduced after 30 years of age (Kottke and Lehmann, 1990),
and changes in physical tness include a decrease in maximal
heart rate (Max HR), maximal cardiac output, muscle strength and
exibility; and increases in blood pressure and body fat during
rest and exercise. Appropriate exercise can slow down the speed
of ageing, maintain physical function, and promote the quality
of life. According to individuals functional performance, elderly
people are grouped into well elderly, frail elderly and ill elderly
(Cohen, 1984). Intervention in these three elderly groups is dif-
ferent. For well elderly, maintaining health, physical tness and
preventing degeneration should be the priority issue. Exercise pro-
grams in the well elderly should include joint range of motion
(ROM) and muscle strengthening exercises. In frail elderly, inter-
vention should emphasize correcting and conditioning programs,
improving safety of living surroundings, and enhancing self-care
abilities (Yeh, 1991). Therefore, rehabilitation intervention for age-
ing populations in this review article will be focused on disease
treatment, complication prevention, and modication and adapta-
tion of lifestyle.
3.8. Principles of rehabilitation for neurodegenerative diseases
Rehabilitation is an important therapy for aged patients with
neurodegenerative diseases. Sedentary lifestyle, bedridden, or
muscular disuse due to neuromuscular disease may lead to many
physiological problems such as muscular atrophy, limited ROM,
decrease of endurance, and nally, to a deconditioned status. By the
age of 7080, 2040% of muscle strength will be lost, and this may
cause some disability (Boelen, 2007). Appropriate exercises can
play a crucial role in improvement and prevention of degenerative
 C.-W. Hung et al. / Ageing Research Reviews 9S (2010) S36S46
disease (Hillman et al., 2008; Kramer et al., 2005), maintenance of
cognitive function (Kramer and Erickson, 2007), decrease of depres-
sion, and improvement in quality of life. Some muscle strength can
be regained (540%) with training (Doherty, 2003). The advantages
of exercise also include neuroplasticity and the ability of self repair
of the brain (Smith and Zigmond, 2003).
4. Ageing, depression, neurodegenerative diseases, and
neurogenesis
4.1. Ageing, depression, and neurogenesis
Depression is one of the most common psychiatric disorders,
with a 1020% lifetime prevalence (Gurvits et al., 1996; Wong and
Licinio, 2001). Depression has been likened to a state of acceler-
ated ageing, affecting the hippocampus and the cardiovascular,
cerebrovascular, neuroendocrine, metabolic, and immune systems
(Bauer, 2008; Heuser, 2002; McIntyre et al., 2007). Depressed indi-
viduals have a higher incidence of various diseases associated
with ageing, such as type II diabetes mellitus, metabolic syn-
drome, osteoporosis, cardiovascular disease, stroke and dementia
(McIntyre et al., 2007; Brown et al., 2004; Evans et al., 2005b;
McIntyre et al., 2009; Speck et al., 1995; Vogelzangs et al., 2007).
Depression is also associated with signicantly worse outcomes in
a number of medical conditions, and is an independent risk factor
for early mortality, even after accounting for potential confound-
ing factors (Chodosh et al., 2007; Gump et al., 2005; McCusker
et al., 2007; Musselman et al., 1998; Schulz et al., 2000). Chronic
exposure to certain interlinked biochemical pathways that mediate
stress-related depression may contribute to accelerated ageing,
cell damage, and certain comorbid medical illnesses. Various expla-
nations for accelerated ageing in depression have been proposed,
including involvement of the hypothalamic-pituitary-adrenal axis
(Sapolsky, 1999; Sapolsky et al., 1996), neurosteroids (Grifn and
Mellon, 1999; Patchev et al., 1996; Uzunova et al., 1998; Wolkowitz
and Reus, 2003) such as dehydroepiandrosterone and allopreg-
nanolone, BDNF (Fu et al., 2002; Hashimoto et al., 2004; Kaufman
et al., 2006; Naert et al., 2007; Nitta et al., 1999; Sen et al., 2008;
Strohle et al., 2010), excitotoxicity, oxidative and inammatory
stress (Joseph et al., 2005; Khanzode et al., 2003; Ng et al., 2008),
and disturbances of the telomere/telomerase maintenance system
(Aviv, 2004; Epel et al., 2009). Current research suggests that mod-
els need to be rened to a re-conceptualization of depression as a
whole body disease rather than just a mental illness. Discovering
the pathological processes in depression at the cellular level could
help identify novel targets for treating depression and its comorbid
medical conditions (Wolkowitz et al., 2010).
Neurogenesis derived from adult neural stem cells (NSCs) plays
a critical role in a plethora of central nervous functions, such
as spatial learning and memory, mood regulation, and motor
control. In general, the quiescent or dormant NSCs are primar-
ily located in the subventricular zone of the lateral ventricle
and the subgranular zone of the hippocampal dentate gyrus of
the adult brain. The hippocampus plays an important role in
learning, memory, and emotion and is the key niche of NSCs
(Kempermann et al., 2008; Moser and Moser, 1998). Preclinical
and clinical studies suggest involvement of the hippocampus in
the pathogenesis of depression and other neurological diseases.
Recent clinical ndings and a MRI survey have provided evidence
that hippocampal volume in patients with depression and other
psychiatric diseases is reduced in comparison to the volume in
healthy people (Gurvits et al., 1996; Sapolsky, 1996). Increased
neurogenesis in the hippocampus by administration of antide-
pressant drugs can result in altered behavior in stress-induced
models and patients (Lee et al., 2001; Santarelli et al., 2001). Two
S41
meta-analyses have demonstrated a reduction in hippocampal vol-
ume in patients with recurrent depression in comparison to age-
and sex-matched controls (Campbell et al., 2004; Videbech and
Ravnkilde, 2004). Chen et al. showed evidence that desipramine
can promote neurogenesis in the hippocampus and reverse learned
behavior in learned helplessness rats (Chen et al., 2006). Moreover,
most antidepressants and environmental interventions that confer
antidepressant-like behavioral effects stimulate adult hippocam-
pal neurogenesis (Sahay and Hen, 2007). Indeed, these observations
imply that adult hippocampal neurogenesis is decreased by stress
and this process of neuron loss may be involved in both the patho-
genesis and treatment of mood disorders.
Neurostem cells can be isolated from the brains and are capa-
ble of self-renewal and multilineage differentiation (Gage, 2000).
They have the potential to develop transplantation therapies, and
can be used to screen candidate agents for neurogenesis in neu-
rodegenerative diseases (Goldman, 2005). By using cultures of
hippocampal-derived NSCs from adult rats, antidepressants of dif-
ferent classes were proven to have neuroprotective effects and to
assist neurogenesis (Chen et al., 2007; Chiou et al., 2006a,b; Huang
et al., 2007; Peng et al., 2008). Antidepressants could also increase
the viability and promote the differentiation of NSCs, and further
decrease levels of proinammatory cytokines (Chen et al., 2007;
Chiou et al., 2006a,b; Huang et al., 2007; Peng et al., 2008). These
aforementioned studies have also shown that antidepressants, such
as uoxentine, imipramine are able to prevent Fas ligand- and
lipopolysaccharide-induced apoptosis of NSCs through the upreg-
ulation of Bcl-2 and Bcl-XL expression (Peng et al., 2008). These
studies support the suggestion that hippocampal neurogenesis is
essential for antidepressant therapy in patients.
4.2. Neurodegenerative diseases, neurogenesis, and stem cell
therapy
Current therapeutic strategies for neurodegenerative diseases
are focused on neurotransmitters, such as acetylcholine for AD
and dopamine for PD. Although these treatments can bring tran-
sient relief of symptoms, they cannot affect the diseases courses.
When more neurons are lost during disease progression, the medi-
cations become less effective. Thus new therapeutic strategies such
as neuroprotection or neurorestoration are needed to improve the
prognosis of neurodegenerative diseases.
Cell transplantation has been used in PD patients since more
than 10 years ago. The rst attempt was to use fetal mesencephalic
tissue for transplantation, and the results were successful in the
earliest reports (Kordower et al., 1995; Lindvall and Hagell, 2000;
Lindvall et al., 2004). However, not all trials showed benecial out-
comes (Freed et al., 2001b; Olanow et al., 2003). Moreover, fetal
mesencephalic transplantation was associated with adverse events
including off-medication dyskinesia (Freed et al., 2001b; Olanow
et al., 2003) and graft-induced inammatory responses (Hedlund
and Perlmann, 2009). Tissue availability also limits the clinical use
of fetal mesencephalic transplantation (Lindvall et al., 2004). The
development in stem cells provides an alternative cell source for
replacement therapy. The main pathology of PD is single-type neu-
ron cell loss, the dopaminergic neurons located in the substantia
nigra pars compacta, making PD a good target for stem cell replace-
ment therapy. Recent evidence has shown that dopamine neurons
derived from embryonic stem (ES) cells and bone marrow-derived
neural progenitors are functional when grafted into parkinsonian
rats (Lindvall et al., 2004; Yang et al., 2008; Glavaski-Joksimovic
et al., 2009). Several methods are able to improve the effective-
ness of midbrain dopamine neuron generation and/or retrieval
from stem cells. These include manipulating transcription factor
like Nurr1, Pitx3 or Lmx1a, co-culture with astrocytes and using
uorescence-activated cell sorting (Hedlund and Perlmann, 2009).
S42 C.-W. Hung et al. / Ageing Research Reviews 9S (2010) S36S46

Fig. 1. The ageing process, together with genetic and environmental factors, causes various physiological responses including oxidative stress, mitochondrial dysfunction,
telomere erosion, impaired DNA repair and decreased tissue regeneration. These processes may contribute to the formation of neurodegenerative diseases. Neurotransmitter-
based therapy and rehabilitation provide treatment for neurodegenerative diseases. Neuroprotective drugs and food supplements, and stem cell therapy may reverse the
progression of neurodegenerative disease.
The pathogenesis and therapeutic strategies of ageing-related neurodegenerative diseases.
We used the word exercise instead of rehabilitation. Maybe we should cross out the brackets?

The replacement of fetal tissue by stem cells also solves the prob-
lem of availability and ethical issue (Hedlund and Perlmann, 2009).
The ability of deriving large quantities of correctly differentiated
dopamine neurons makes stem cells promising cell sources for
transplantation in PD.
Ischemic strokes affect the behavior and proliferation status of
NSCs. Focal ischemia of the brain enhances endogenous neurogen-
esis, angiogenesis, axonal sprouting and synaptogenesis (Arvidsson
et al., 2002; Zhang and Chopp, 2009). However, the proportion of
damaged or dead neurons replaced by the new neurons is small
(Arvidsson et al., 2002). Cell transplantation therapy is more dif-
cult in patients with ischemic stroke, because more than one type
of cells are damaged, which include neurons, astrocytes, oligoden-
drocytes and endothelial cells of blood vessels (Zhang and Chopp,
2009). One study proved that transplantation of embryonic stem
cells recovered behavioral dysfunction induced by middle cerebral
arterial occlusion in an animal model (Yanagisawa et al., 2006).
However, the ethical considerations, limited availability, and the
possibility of immune rejection after transplantation restrict the
accessibility of ES cells.
Recent progress in stem cell research has demonstrated that
induced pluripotent stem (iPS) cells could be generated from mouse
embryonic broblasts as well as from adult human broblasts via
the retrovirus-mediated transfection of four transcription factors;
Oct3/4, Sox2, c-Myc, and Klf-4 (Okita et al., 2007; Park et al., 2008;
Takahashi et al., 2007; Yu et al., 2007). Recent data has shown
that iPS cells are indistinguishable from ES cells in morphology,
proliferative ability, surface antigens, gene expression, epigenetic
status of pluripotent cell-specic genes, telomerase activity, and
differentiation into three germ layers, offering potential for clin-
ical cell therapies (Kao et al., in press; Takahashi and Yamanaka,
2006). Notably, it has been demonstrated that neuronal and glial
cell types could be derived from iPS cells in vitro and that trans-
plantation of iPS cell-derived neuronal cells into the brain was able
to improve behavior in a rat model of PD (Wernig et al., 2008). Fur-
thermore, our in vivo study showed that direct injection of iPS cells
into damaged areas of the rat cortex signicantly decreased infarct
size, improved motor function, attenuated inammatory cytokines,
and mediated neuroprotection after middle cerebral artery occlu-
sion (Kao et al., in press). The pluripotent characteristic of iPS cells
is the ability to form the teratoma in vivo, which would be an
unacceptable adverse effect for cell transplantation therapy. To pre-
vent teratoma formation in pluripotent stem cells or iPS cells, a
recent report showed that the elimination of nonneural progeni-
tors can be achieved by the elaboration of differentiation protocols
to allow maximal homogeneity of the transplant (Brederlau et al.,
2006) or by cell sorting before transplantation (Chung et al., 2006;
Guillaume et al., 2006; Hedlund et al., 2008; Tabar et al., 2005). In
addition, because iPS cells can be derived from somatic cells, poten-
tial immune rejection and ethical considerations can be avoided
by autologous transplantation. Therefore, the development of by-
products from iPS cells could provide an additional option for
replacement therapy.
5. Conclusion
Compelling evidence s revealed the molecular mechanisms
associated with ageing, including accumulated oxidative stress,
mitochondrial dysfunction, progressive telomere erosion, impaired
DNA repair and decreased tissue regeneration. The variation speed
of ageing process among individuals and the development of
neurodegenerative diseases may be due to different genetic and
environmental factors. Understanding the pathophysiology of age-
ing and neurodegenerative diseases provides insightful knowledge
for future treatment. In addition to neurotransmitter-based thera-
pies and rehabilitation, treatments focus on neuroprotection and
neurorestoration have shed new light on reversing the adverse
progression in neurodegenerative diseases. These include antioxi-
dants, diet and stem cell-based replacement therapies. A summary
 C.-W. Hung et al. / Ageing Research Reviews 9S (2010) S36S46
scheme is shown in the Fig. 1. Investigations on novel therapeutic
strategies can lead to innovations in disease prevention, health pro-
motion and life expectancy prolongation. More attention needs to
be paid to research into anti-ageing interventions to enable a more
healthy, dignied, and sophisticated late-life of humans.
Conict of interest
The authors declare that there is no conict of interests in the
study.
Acknowledgments
We thank Dr. Chia-Fen Tsai and Dr. Ying-Jay Liou for correction
and organization of this manuscript.
Role of the funding source: This work was supported by the
National Science Council (NSC-97-3111-B-075-001-MY3; (NSC 96-
2314-B-075-056-MY3), the Veterans Affairs Commission (98-X2-2,
99-X2-8), Yen-Tjing-Ling Medical Foundation, and National Yang-
Ming University, Ministry of Education, Aim for the Top University
Plan.
References
Abe, J., Kusuhara, M., Ulevitch, R.J., Berk, B.C., Lee, J.D., 1996. Big mitogen-activated
protein kinase 1 (BMK1) is a redox-sensitive kinase. J. Biol. Chem. 271,
1658616590.
Ahmed, A., Tollefsbol, T., 2001. Telomeres and telomerase: basic science implications
for aging. J. Am. Geriatr. Soc. 49, 11051109.
Albani, D., Polito, L., Batelli, S., De Mauro, S., Fracasso, C., et al., 2009. The SIRT1 activa-
tor resveratrol protects SK-N-BE cells from oxidative stress and against toxicity
caused by alpha-synuclein or amyloid-beta (1-42) peptide. J. Neurochem. 110,
14451456.
Andersen, J.K., 2004. Oxidative stress in neurodegeneration: cause or consequence?
Nat. Med. 10 (Suppl.), S18S25.
Andrews-Hanna, J.R., Snyder, A.Z., Vincent, J.L., Lustig, C., Head, D., et al., 2007. Dis-
ruption of large-scale brain systems in advanced aging. Neuron 56, 924935.
Arumugam, T.V., Phillips, T.M., Cheng, A., Morrell, C.H., Mattson, M.P., et al., 2010. Age
and energy intake interact to modify cell stress pathways and stroke outcome.
Ann. Neurol. 67, 4152.
Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z., Lindvall, O., 2002. Neuronal replace-
ment from endogenous precursors in the adult brain after stroke. Nat. Med. 8,
963970.
Aviv, A., 2004. Telomeres and human aging: facts and bs. Sci. Aging Knowledge
Environ., pe43.
Ay, H., Koroshetz, W.J., Vangel, M., Benner, T., Melinosky, C., et al., 2005. Conversion
of ischemic brain tissue into infarction increases with age. Stroke 36, 26322636.
Baas, A.S., Berk, B.C., 1995. Differential activation of mitogen-activated protein
kinases by H2 O2 and O2 - in vascular smooth muscle cells. Circ. Res. 77, 2936.
Barger, J.L., Walford, R.L., Weindruch, R., 2003. The retardation of aging by caloric
restriction: its signicance in the transgenic era. Exp. Gerontol. 38, 13431351.
Bauer, M.E., 2008. Chronic stress and immunosenescence: a review. Neuroim-
munomodulation 15, 241250.
Bauer, J.H., Goupil, S., Garber, G.B., Helfand, S.L., 2004. An accelerated assay for the
identication of lifespan-extending interventions in Drosophila melanogaster.
Proc. Natl. Acad. Sci. U.S.A. 101, 1298012985.
Baur, J.A., Sinclair, D.A., 2006. Therapeutic potential of resveratrol: the in vivo evi-
dence. Nat. Rev. Drug Discov. 5, 493506.
Baur, J.A., Pearson, K.J., Price, N.L., Jamieson, H.A., Lerin, C., et al., 2006. Resvera-
trol improves health and survival of mice on a high-calorie diet. Nature 444,
337342.
Bishop, N.A., Lu, T., Yankner, B.A., 2010. Neural mechanisms of ageing and cognitive
decline. Nature 464, 529535.
Blander, G., Guarente, L., 2004. The Sir2 family of protein deacetylases. Annu. Rev.
Biochem. 73 (2994) 417435.
Boelen, M., 2007. The role of rehabilitative modalities and exercise in Parkinsons
disease. Dis. Mon. 53, 259264.
Braak, H., Del Tredici, K., Rub, U., de Vos, R.A., Jansen Steur, E.N., et al., 2003. Staging
of brain pathology related to sporadic Parkinsons disease. Neurobiol. Aging 24,
197211.
Braak, H., Bohl, J.R., Muller, C.M., Rub, U., de Vos, R.A., et al., 2006. Stanley Fahn Lecture
2005: the staging procedure for the inclusion body pathology associated with
sporadic Parkinsons disease reconsidered. Mov. Disord. 21, 20422051.
Brederlau, A., Correia, A.S., Anisimov, S.V., Elmi, M., Paul, G., et al., 2006. Transplan-
tation of human embryonic stem cell-derived cells to a rat model of Parkinsons
disease: effect of in vitro differentiation on graft survival and teratoma forma-
tion. Stem Cells 24, 14331440.
Brown, E.S., Varghese, F.P., McEwen, B.S., 2004. Association of depression with med-
ical illness: does cortisol play a role? Biol. Psychiatry 55, 19.
S43
Busse, E.W., 1987. Hypochondriasis in the elderly. Compr. Ther. 13, 3742.
Campbell, S., Marriott, M., Nahmias, C., MacQueen, G.M., 2004. Lower hippocampal
volume in patients suffering from depression: a meta-analysis. Am. J. Psychiatry
161, 598607.
Chaudhary, N., Puger, P.T., 2009. Metabolic benets from Sirt1 and Sirt1 activators.
Curr. Opin. Clin. Nutr. Metab. Care 12, 431437.
Chen, H., Pandey, G.N., Dwivedi, Y., 2006. Hippocampal cell proliferation regulation
by repeated stress and antidepressants. Neuroreport 17, 863867.
Chen, S.J., Kao, C.L., Chang, C.L., Yen, C.J., Shui, J.W., et al., 2007. Antidepressant admin-
istration modulates neural stem cell survival and serotoninergic differentiation
through bcl-2. Curr. Neurovasc. Res. 4, 1929.
Chiou, S.H., Chen, S.J., Peng, C.H., Chang, Y.L., Ku, H.H., et al., 2006a. Fluoxetine
up-regulates expression of cellular FLICE-inhibitory protein and inhibits LPS-
induced apoptosis in hippocampus-derived neural stem cell. Biochem. Biophys.
Res. Commun. 343, 391400.
Chiou, S.H., Ku, H.H., Tsai, T.N., Lin, H.L., Chen, L.H., et al., 2006b. Moclobemide
upregulated Bcl-2 expression and induced neural stem cell differentiation into
serotoninergic neuron via extracellular-regulated kinase pathway. Br. J. Phar-
macol. 148, 587598.
Chodosh, J., Kado, D.M., Seeman, T.E., Karlamangla, A.S., 2007. Depressive symptoms
as a predictor of cognitive decline: MacArthur Studies of Successful Aging. Am.
J. Geriatr. Psychiatry 15, 406415.
Chung, S., Shin, B.S., Hedlund, E., Pruszak, J., Ferree, A., et al., 2006. Genetic selec-
tion of sox1GFP-expressing neural precursors removes residual tumorigenic
pluripotent stem cells and attenuates tumor formation after transplantation.
J. Neurochem. 97, 14671480.
Cohen, B.S., 1984. Geriatric rehabilitation. Am. Family Physician 30, 133137.
Do, G.M., Kwon, E.Y., Kim, H.J., Jeon, S.M., Ha, T.Y., et al., 2008. Long-term effects
of resveratrol supplementation on suppression of atherogenic lesion forma-
tion and cholesterol synthesis in apo E-decient mice. Biochem. Biophys. Res.
Commun. 374, 5559.
Doherty, T.M., 2003. Physiology of aging invited review: aging and sarcopenia. J.
Appl. Physiol. 95, 17171727.
Durham, H.D., Roy, J., Dong, L., Figlewicz, D.A., 1997. Aggregation of mutant Cu/Zn
superoxide dismutase proteins in a culture model of ALS. J. Neuropathol. Exp.
Neurol. 56, 523530.
Epel, E., Daubenmier, J., Moskowitz, J.T., Folkman, S., Blackburn, E., 2009. Can medi-
tation slow rate of cellular aging? Cognitive stress, mindfulness, and telomeres.
Ann. NY Acad. Sci. 1172, 3453.
Evans, J.M., Donnelly, L.A., Emslie-Smith, A.M., Alessi, D.R., Morris, A.D., 2005a.
Metformin and reduced risk of cancer in diabetic patients. BMJ 330,
13041305.
Evans, D.L., Charney, D.S., Lewis, L., Golden, R.N., Gorman, J.M., et al., 2005b. Mood
disorders in the medically ill: scientic review and recommendations. Biol. Psy-
chiatry 58, 175189.
Fearnley, J.M., Lees, A.J., 1991. Ageing and Parkinsons disease: substantia nigra
regional selectivity. Brain 114 (Pt 5), 22832301.
Ferrara, N., Rinaldi, B., Corbi, G., Conti, V., Stiuso, P., Boccuti, S., Rengo, G., Rossi,
F., Filippelli, A., 2008. Exercise training promotes SIRT1 activity in aged rats.
Rejuvenation Res. 11, 139150.
Freed, C.R., Greene, P.E., Breeze, R.E., Tsai, W.Y., DuMouchel, W., et al., 2001a. Trans-
plantation of embryonic dopamine neurons for severe Parkinsons disease. N.
Engl. J. Med. 344, 710719.
Freed, C.R., Greene, P.E., Breeze, R.E., Tsai, W.Y., DuMouchel, W., Kao, R., Dillon, S.,
Wineld, H., Culver, S., Trojanowski, J.Q., Eidelberg, D., Fahn, S., 2001b. Trans-
plantation of embryonic dopamine neurons for severe Parkinsons disease. N.
Engl. J. Med. 344, 710719.
Frojdo, S., Durand, C., Pirola, L., 2008. Metabolic effects of resveratrol in mammalsa
link between improved insulin action and aging. Curr. Aging Sci. 1, 145151.
Frontera, W.R., Hughes, V.A., Lutz, K.J., Evans, W.J., 1991. A cross-sectional study of
muscle strength and mass in 45- to 78-yr-old men and women. J. Appl. Physiol.
71, 644650.
Frye, R.A., 1999. Characterization of ve human cDNAs with homology to the yeast
SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein
ADP-ribosyltransferase activity. Biochem. Biophys. Res. Commun. 260, 273279.
Fu, W., Lu, C., Mattson, M.P., 2002. Telomerase mediates the cell survival-promoting
actions of brain-derived neurotrophic factor and secreted amyloid precursor
protein in developing hippocampal neurons. J. Neurosci. 22, 1071010719.
Gaczynska, M., Osmulski, P.A., Ward, W.F., 2001. Caretaker or undertaker? The role
of the proteasome in aging. Mech. Ageing Dev. 122, 235254.
Gage, F.H., 2000. Mammalian neural stem cells. Science 287, 14331438.
Glavaski-Joksimovic, A., Virag, T., Chang, Q.A., West, N.C., Mangatu, T.A., McGro-
gan, M.P., Dugich-Djordjevic, M., Bohn, M.C., 2009. Reversal of dopaminergic
degeneration in a parkinsonian rat following micrografting of human bone
marrow-derived neural progenitors. Cell Transplant 18, 801814.
Goldman, S., 2005. Stem and progenitor cell-based therapy of the human central
nervous system. Nat. Biotechnol. 23, 862871.
Gomez-Isla, T., Price, J.L., McKeel Jr., D.W., Morris, J.C., Growdon, J.H., et al., 1996. Pro-
found loss of layer II entorhinal cortex neurons occurs in very mild Alzheimers
disease. J. Neurosci. 16, 44914500.
Grifn, L.D., Mellon, S.H., 1999. Selective serotonin reuptake inhibitors directly
alter activity of neurosteroidogenic enzymes. Proc. Natl. Acad. Sci. U.S.A. 96,
1351213517.
Gruber, J., Tang, S.Y., Halliwell, B., 2007. Evidence for a trade-off between survival
and tness caused by resveratrol treatment of Caenorhabditis elegans. Ann. NY
Acad. Sci. 1100, 530542.
S44 C.-W. Hung et al. / Ageing Research Reviews 9S (2010) S36S46
Guillaume, D.J., Johnson, M.A., Li, X.J., Zhang, S.C., 2006. Human embryonic stem
cell-derived neural precursors develop into neurons and integrate into the host
brain. J. Neurosci. Res. 84, 11651176.
Gump, B.B., Matthews, K.A., Eberly, L.E., Chang, Y.F., 2005. Depressive symptoms and
mortality in men: results from the Multiple Risk Factor Intervention Trial. Stroke
36, 98102.
Gurvits, T.V., Shenton, M.E., Hokama, H., Ohta, H., Lasko, N.B., et al., 1996. Magnetic
resonance imaging study of hippocampal volume in chronic, combat-related
posttraumatic stress disorder. Biol. Psychiatry 40, 10911099.
Haigis, M.C., Guarente, L.P., 2006. Mammalian sirtuinsemerging roles in physiol-
ogy, aging, and calorie restriction. Genes Dev. 20, 29132921.
Halliday, G.M., McCann, H., 2010. The progression of pathology in Parkinsons dis-
ease. Ann. NY Acad. Sci. 1184, 188195.
Hashimoto, K., Shimizu, E., Iyo, M., 2004. Critical role of brain-derived neurotrophic
factor in mood disorders. Brain Res. Brain Res. Rev. 45, 104114.
Hedlund, E., Perlmann, T., 2009. Neuronal cell replacement in Parkinsons disease. J.
Intern. Med. 266, 358371.
Hedlund, E., Pruszak, J., Lardaro, T., Ludwig, W., Vinuela, A., et al., 2008. Embry-
onic stem cell-derived Pitx3-enhanced green uorescent protein midbrain
dopamine neurons survive enrichment by uorescence-activated cell sort-
ing and function in an animal model of Parkinsons disease. Stem Cells 26,
15261536.
Heuser, I., 2002. Depression, endocrinologically a syndrome of premature aging?
Maturitas 41 (Suppl. 1), S19S23.
Hillman, C.H., Erickson, K.I., Kramer, A.F., 2008. Be smart, exercise your heart: exer-
cise effects on brain and cognition. Nature 9, 5865.
Hindle, J.V., 2010. Ageing, neurodegeneration and Parkinsons disease. Age Ageing
39, 156161.
Howitz, K.T., Bitterman, K.J., Cohen, H.Y., Lamming, D.W., Lavu, S., et al., 2003. Small
molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature
425, 191196.
Huang, C.J., Cheng, H.H., Chou, C.T., Kuo, C.C., Lu, Y.C., et al., 2007. Desipramine-
induced Ca2+ movement and cytotoxicity in PC3 human prostate cancer cells.
Toxicol. In Vitro 21, 449456.
Hwang, J.T., Kwon, D.Y., Park, O.J., Kim, M.S., 2008. Resveratrol protects ROS-induced
cell death by activating AMPK in H9c2 cardiac muscle cells. Genes Nutr. 2,
323326.
Imai, S., Armstrong, C.M., Kaeberlein, M., Guarente, L., 2000. Transcriptional silencing
and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature
403, 795800.
Ito, K., Hirao, A., Arai, F., Takubo, K., Matsuoka, S., et al., 2006. Reactive oxygen species
act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat. Med.
12, 446451.
Jaliffa, C., Ameqrane, I., Dansault, A., Leemput, J., Vieira, V., et al., 2009. Sirt1 involve-
ment in rd10 mouse retinal degeneration. Invest. Ophthalmol. Vis. Sci. 50,
35623572.
Jin, F., Wu, Q., Lu, Y.F., Gong, Q.H., Shi, J.S., 2008. Neuroprotective effect of resveratrol
on 6-OHDA-induced Parkinsons disease in rats. Eur. J. Pharmacol. 600, 7882.
Johnson, J.A., Majumdar, S.R., Simpson, S.H., Toth, E.L., 2002. Decreased mortality
associated with the use of metformin compared with sulfonylurea monotherapy
in type 2 diabetes. Diabetes Care 25, 22442248.
Joseph, J.A., Shukitt-Hale, B., Casadesus, G., Fisher, D., 2005. Oxidative stress and
inammation in brain aging: nutritional considerations. Neurochem. Res. 30,
927935.
Kaeberlein, M., McVey, M., Guarente, L., 1999. The SIR2/3/4 complex and SIR2 alone
promote longevity in Saccharomyces cerevisiae by two different mechanisms.
Genes Dev. 13, 25702580.
Kao, C.L., Huang, P.I., Tsai, P.H., Tsai, M.L., Lo, J.F., et al., 2009. Resveratrol-induced
apoptosis and increased radiosensitivity in CD133-positive cells derived from
atypical teratoid/rhabdoid tumor. Int. J. Radiat. Oncol. Biol. Phys. 74, 219228.
Kao, C.L., Tai, L.K., Chiou, S.H., Chen, Y.J., Lee, K.H., et al., 2010. Resveratrol pro-
motes osteogenic differentiation and protects against dexamethasone damage
in murine induced pluripotent stem cells. Stem Cells Dev. 19, 247258.
Kao, C.L., Chen, L.K., Chang, Y.L., Yua, M.C., Hsu, C.C., et al. Reseveratrol protects
human endothelium from H2 O2 induced oxidative stress and senescence via
SirT1 activation, J. Atheroscler. Thromb., in press.
Kaufman, J., Yang, B.Z., Douglas-Palumberi, H., Grasso, D., Lipschitz, D., et al., 2006.
Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environ-
mental modiers of depression in children. Biol. Psychiatry 59, 673680.
Kempermann, G., Krebs, J., Fabel, K., 2008. The contribution of failing adult hip-
pocampal neurogenesis to psychiatric disorders. Curr. Opin. Psychiatry 21,
290295.
Khanzode, S.D., Dakhale, G.N., Khanzode, S.S., Saoji, A., Palasodkar, R., 2003. Oxida-
tive damage and major depression: the potential antioxidant action of selective
serotonin re-uptake inhibitors. Redox Rep. 8, 365370.
Kim, D., Nguyen, M.D., Dobbin, M.M., Fischer, A., Sananbenesi, F., et al., 2007. SIRT1
deacetylase protects against neurodegeneration in models for Alzheimers dis-
ease and amyotrophic lateral sclerosis. EMBO J. 26, 31693179.
Kordower, J.H., Freeman, T.B., Snow, B.J., Vingerhoets, F.J., Mufson, E.J., et al., 1995.
Neuropathological evidence of graft survival and striatal reinnervation after
the transplantation of fetal mesencephalic tissue in a patient with Parkinsons
disease. N. Engl. J. Med. 332, 11181124.
Kottke, F.J., Lehmann, J.F., 1990. Krusens Handbook of Physical Medicine and Reha-
bilitation, 4th ed. W. B. Saunders Co., Philadelphia.
Kramer, A.F., Erickson, S.I., 2007. Effects of physical activity on cognition, well-being,
and brain: humans interventions. Alzheimers Dement 3, S45S51.
Kramer, A.F., Colcombe, S.J., McAuley, E., Scalf, P.E., Erickson, K.I., et al., 2005. Fitness,
aging and neurocognitive function. Neurobiol. Aging 26 (Suppl.), S124S127.
Kukull, W.A., Higdon, R., Bowen, J.D., McCormick, W.C., Teri, L., et al., 2002. Dementia
and Alzheimer disease incidence: a prospective cohort study. Arch. Neurol. 59,
17371746.
Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., et al., 2006.
Resveratrol improves mitochondrial function and protects against metabolic
disease by activating SIRT1 and PGC-1alpha. Cell 127, 11091122.
Lee, H.J., Kim, J.W., Yim, S.V., Kim, M.J., Kim, S.A., et al., 2001. Fluoxetine enhances cell
proliferation and prevents apoptosis in dentate gyrus of maternally separated
rats. Mol. Psychiatry 6, 618725.
Liao, F., Andalibi, A., Qiao, J.H., Allayee, H., Fogelman, A.M., et al., 1994. Genetic evi-
dence for a common pathway mediating oxidative stress, inammatory gene
induction, and aortic fatty streak formation in mice. J. Clin. Invest. 94, 877884.
Lin, S.J., Defossez, P.A., Guarente, L., 2000. Requirement of NAD and SIR2 for life-
span extension by calorie restriction in Saccharomyces cerevisiae. Science 289,
21262128.
Lin, H.Y., Sun, M., Tang, H.Y., Simone, T.M., Wu, Y.H., et al., 2008. Resveratrol causes
COX-2- and p53-dependent apoptosis in head and neck squamous cell cancer
cells. J. Cell. Biochem. 104, 21312142.
Lindvall, O., Hagell, P., 2000. Clinical observations after neural transplantation in
Parkinsons disease. Prog. Brain Res. 127, 299320.
Lindvall, O., Kokaia, Z., Martinez-Serrano, A., 2004. Stem cell therapy for human neu-
rodegenerative disorders-how to make it work. Nat. Med. 10 Suppl., S42S50.
Liu, F., Akella, P., Benashski, S.E., Xu, Y., McCullough, L.D., 2010. Expression of Na-K-
Cl cotransporter and edema formation are age dependent after ischemic stroke.
Exp. Neurol. 224, 356361.
Loerch, P.M., Lu, T., Dakin, K.A., Vann, J.M., Isaacs, A., et al., 2008. Evolution of the
aging brain transcriptome and synaptic regulation. PLoS One 3, e3329.
Lotito, S.B., Frei, B., 2006. Consumption of avonoid-rich foods and increased plasma
antioxidant capacity in humans: cause, consequence, or epiphenomenon? Free
Radic. Biol. Med. 41, 17271746.
Louis, E.D., Bennett, D.A., 2007. Mild Parkinsonian signs: an overview of an emerging
concept. Mov. Disord. 22, 16811688.
Lu, T., Pan, Y., Kao, S.Y., Li, C., Kohane, I., et al., 2004. Gene regulation and DNA damage
in the ageing human brain. Nature 429, 883891.
Macciocchi, S.N., Diamond, P.T., Alves, W.M., Mertz, T., 1998. Ischemic stroke: rela-
tion of age, lesion location, and initial neurologic decit to functional outcome.
Arch. Phys. Med. Rehabil. 79, 12551257.
Mancuso, C., Bates, T.E., Buttereld, D.A., Calafato, S., Cornelius, C., et al., 2007. Natural
antioxidants in Alzheimers disease. Expert Opin. Investig. Drugs 16, 19211931.
McCusker, J., Cole, M., Ciampi, A., Latimer, E., Windholz, S., et al., 2007. Major depres-
sion in older medical inpatients predicts poor physical and mental health status
over 12 months. Gen. Hosp. Psychiatry 29, 340348.
McIntyre, R.S., Soczynska, J.K., Konarski, J.Z., Woldeyohannes, H.O., Law, C.W., et
al., 2007. Should depressive syndromes be reclassied as Metabolic Syndrome
Type II? Ann. Clin. Psychiatry 19, 257264.
McIntyre, R.S., Rasgon, N.L., Kemp, D.E., Nguyen, H.T., Law, C.W., et al., 2009.
Metabolic syndrome and major depressive disorder: co-occurrence and patho-
physiologic overlap. Curr. Diab. Rep. 9, 5159.
Morselli, E., Galluzzi, L., Kepp, O., Criollo, A., Maiuri, M.C., et al., 2009. Autophagy
mediates pharmacological lifespan extension by spermidine and resveratrol.
Aging (Albany NY) 1, 961970.
Moser, M.B., Moser, E.I., 1998. Functional differentiation in the hippocampus. Hip-
pocampus 8, 608619.
Musselman, D.L., Evans, D.L., Nemeroff, C.B., 1998. The relationship of depression to
cardiovascular disease: epidemiology, biology, and treatment. Arch. Gen. Psy-
chiatry 55, 580592.
Naert, G., Maurice, T., Tapia-Arancibia, L., Givalois, L., 2007. Neuroactive steroids
modulate HPA axis activity and cerebral brain-derived neurotrophic fac-
tor (BDNF) protein levels in adult male rats. Psychoneuroendocrinology 32,
10621078.
Nakayama, H., Jorgensen, H.S., Raaschou, H.O., Olsen, T.S., 1994. The inuence of age
on stroke outcome. The Copenhagen Stroke Study. Stroke 25, 808813.
Ng, F., Berk, M., Dean, O., Bush, A.I., 2008. Oxidative stress in psychiatric disorders:
evidence base and therapeutic implications. Int. J. Neuropsychopharmacol. 11,
851876.
Nitta, A., Ohmiya, M., Sometani, A., Itoh, M., Nomoto, H., et al., 1999. Brain-derived
neurotrophic factor prevents neuronal cell death induced by corticosterone. J.
Neurosci. Res. 57, 227235.
Norata, G.D., Marchesi, P., Passamonti, S., Pirillo, A., Violi, F., et al., 2007. Anti-
inammatory and anti-atherogenic effects of cathechin, caffeic acid and
trans-resveratrol in apolipoprotein E decient mice. Atherosclerosis 191,
265271.
Okita, K., Ichisaka, T., Yamanaka, S., 2007. Generation of germline-competent
induced pluripotent stem cells. Nature 448, 313317.
Olanow, C.W., Goetz, C.G., Kordower, J.H., Stoessl, A.J., Sossi, V., Brin, M.F., Shannon,
K.M., Nauert, G.M., Perl, D.P., Godbold, J., Freeman, T.B., 2003. A double-blind
controlled trial of bilateral fetal nigral transplantation in Parkinsons disease.
Ann. Neurol. 54, 403414.
Orimo, M., Minamino, T., Miyauchi, H., Tateno, K., Okada, S., et al., 2009. Protective
role of SIRT1 in diabetic vascular dysfunction. Arterioscler. Thromb. Vasc. Biol.
29, 889894.
Pacholec, M., Bleasdale, J.E., Chrunyk, B., Cunningham, D., Flynn, D., et al., 2010.
SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.
J. Biol. Chem. 285, 83408351.
 C.-W. Hung et al. / Ageing Research Reviews 9S (2010) S36S46
Pappolla, M.A., Omar, R.A., Kim, K.S., Robakis, N.K., 1992. Immunohistochemical evi-
dence of oxidative [corrected] stress in Alzheimers disease. Am. J. Pathol. 140,
621628.
Parashar, V., Rogina, B., 2009. dSir2 mediates the increased spontaneous physical
activity in ies on calorie restriction. Aging (Albany NY) 1, 529541.
Park, I.H., Zhao, R., West, J.A., Yabuuchi, A., Huo, H., et al., 2008. Reprogram-
ming of human somatic cells to pluripotency with dened factors. Nature 451,
141146.
Parker, J.A., Arango, M., Abderrahmane, S., Lambert, E., Tourette, C., et al., 2005.
Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mam-
malian neurons. Nat. Genet. 37, 349350.
Patchev, V.K., Hassan, A.H., Holsboer, D.F., Almeida, O.F., 1996. The neurosteroid
tetrahydroprogesterone attenuates the endocrine response to stress and exerts
glucocorticoid-like effects on vasopressin gene transcription in the rat hypotha-
lamus. Neuropsychopharmacology 15, 533540.
Pearce, R.K., Owen, A., Daniel, S., Jenner, P., Marsden, C.D., 1997. Alterations in the dis-
tribution of glutathione in the substantia nigra in Parkinsons disease. J. Neural.
Transm. 104, 661677.
Peng, C.H., Chiou, S.H., Chen, S.J., Chou, Y.C., Ku, H.H., et al., 2008. Neuroprotection
by Imipramine against lipopolysaccharide-induced apoptosis in hippocampus-
derived neural stem cells mediated by activation of BDNF and the MAPK
pathway. Eur. Neuropsychopharmacol. 18, 128140.
Penumathsa, S.V., Maulik, N., 2009. Resveratrol: a promising agent in promoting
cardioprotection against coronary heart disease. Can. J. Physiol. Pharmacol. 87,
275286.
Penumathsa, S.V., Koneru, S., Samuel, S.M., Maulik, G., Bagchi, D., et al., 2008.
Strategic targets to induce neovascularization by resveratrol in hypercholes-
terolemic rat myocardium: role of caveolin-1, endothelial nitric oxide synthase,
hemeoxygenase-1, and vascular endothelial growth factor. Free Radic. Biol. Med.
45, 10271034.
Perry, T.L., Yong, V.W., 1986. Idiopathic Parkinsons disease, progressive supranu-
clear palsy and glutathione metabolism in the substantia nigra of patients.
Neurosci. Lett. 67, 269274.
Perry, T.L., Godin, D.V., Hansen, S., 1982. Parkinsons disease: a disorder due to nigral
glutathione deciency? Neurosci. Lett. 33, 305310.
Price, J.L., Ko, A.I., Wade, M.J., Tsou, S.K., McKeel, D.W., et al., 2001. Neuron number
in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch. Neurol.
58, 13951402.
Rajagopalan, S., Kurz, S., Munzel, T., Tarpey, M., Freeman, B.A., et al.,
1996. Angiotensin II-mediated hypertension in the rat increases vascu-
lar superoxide production via membrane NADH/NADPH oxidase activation.
Contribution to alterations of vasomotor tone. J. Clin. Invest. 97, 1916
1923.
Rao, G.N., Lassegue, B., Griendling, K.K., Alexander, R.W., Berk, B.C., 1993. Hydrogen
peroxide-induced c-fos expression is mediated by arachidonic acid release: role
of protein kinase C. Nucleic Acids Res. 21, 12591263.
Reznick, A.Z., Gershon, D., 1979. The effect of age on the protein degradation system
in the nematode Turbatrix aceti. Mech. Ageing Dev. 11, 403415.
Robb, E.L., Winkelmolen, L., Visanji, N., Brotchie, J., Stuart, J.A., 2008. Dietary resver-
atrol administration increases MnSOD expression and activity in mouse brain.
Biochem. Biophys. Res. Commun. 372, 254259.
Rodrigue, K.M., Raz, N., 2004. Shrinkage of the entorhinal cortex over ve years
predicts memory performance in healthy adults. J. Neurosci. 24, 956963.
Rush, B.D., Ruwart, M.J., Day, C.E., 1981. The mechanism of action of the
hypocholesterolemic drug p-(1-adamantyloxy)-aniline. Atherosclerosis 39,
345351.
Sahay, A., Hen, R., 2007. Adult hippocampal neurogenesis in depression. Nat. Neu-
rosci. 10, 11101115.
Sahin, E., Depinho, R.A., 2010. Linking functional decline of telomeres, mitochondria
and stem cells during ageing. Nature 464, 520528.
Samii, A., Nutt, J.G., Ransom, B.R., 2004. Parkinsons disease. Lancet 363, 17831793.
Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., et al., 2001. Requirement of
hippocampal neurogenesis for the behavioral effects of antidepressants. Science
301, 805809.
Sapolsky, R.M., 1996. Why stress is bad for your brain. Science 273, 749750.
Sapolsky, R.M., 1999. Glucocorticoids, stress, and their adverse neurological effects:
relevance to aging. Exp. Gerontol. 34, 721732.
Sapolsky, R.M., Krey, L.C., McEwen, B.S., 1996. The neuroendocrinology of stress and
aging: the glucocorticoid cascade hypothesis. Endocr. Rev. 7, 284301.
Scherzinger, E., Lurz, R., Turmaine, M., Mangiarini, L., Hollenbach, B., et al.,
1997. Huntingtin-encoded polyglutamine expansions form amyloid-like protein
aggregates in vitro and in vivo. Cell 90, 549558.
Schulz, R., Beach, S.R., Ives, D.G., Martire, L.M., Ariyo, A.A., et al., 2000. Association
between depression and mortality in older adults: the Cardiovascular Health
Study. Arch. Intern. Med. 160, 17611768.
Sen, S., Duman, R., Sanacora, G., 2008. Serum brain-derived neurotrophic factor,
depression, and antidepressant medications: meta-analyses and implications.
Biol. Psychiatry 64, 527532.
Shetty, A.K., Hattiangady, B., Rao, M.S., Shuai, B. Deafferentation enhances neu-
rogenesis in the young and middle aged hippocampus but not in the aged
hippocampus. Hippocampus, in press.
Shindler, K.S., Ventura, E., Rex, T.S., Elliott, P., Rostami, A., 2007. SIRT1 activation
confers neuroprotection in experimental optic neuritis. Invest. Ophthalmol. Vis.
Sci. 48, 36023609.
Shults, C.W., Haas, R., 2005. Clinical trials of coenzyme Q10 in neurological disorders.
Biofactors 25, 117126.
S45
Sinha, K., Chaudhary, G., Gupta, Y.K., 2002. Protective effect of resveratrol against
oxidative stress in middle cerebral artery occlusion model of stroke in rats. Life
Sci. 71, 655665.
Small, S.A., Tsai, W.Y., DeLaPaz, R., Mayeux, R., Stern, Y., 2002. Imaging hippocampal
function across the human life span: is memory decline normal or not? Ann.
Neurol. 51, 290295.
Smith, A.D., Zigmond, M.J., 2003. Can the brain be protected through exercise?
Lessons from an animal model of parkinsonism. Exp. Neurol. 184, 3139.
Smith, M.A., Zhu, X., Tabaton, M., Liu, G., McKeel, D.W., et al., 2010. Increased iron
and free radical generation in preclinical Alzheimer disease and mild cognitive
impairment. J. Alzheimers Dis. 19, 363372.
Speck, C.E., Kukull, W.A., Brenner, D.E., Bowen, J.D., McCormick, W.C., et al., 1995.
History of depression as a risk factor for Alzheimers disease. Epidemiology 6,
366369.
Stangl, D., Thuret, S., 2009. Impact of diet on adult hippocampal neurogenesis. Genes
Nutr. 4, 271282.
Strohle, A., Stoy, M., Graetz, B., Scheel, M., Wittmann, A., et al., 2010. Acute exercise
ameliorates reduced brain-derived neurotrophic factor in patients with panic
disorder. Psychoneuroendocrinology 35, 364368.
Sullivan, D.H., Johnson, L.E., 2009. Nutrition and aging. In: halter, J.B., et al. (Eds.),
Hazzards Geriatric Medicine and Gerontology, Sixth Edition. McGraw Hill, New
York, pp. 452453.
Sumien, N., Heinrich, K.R., Shetty, R.A., Sohal, R.S., Forster, M.J., 2009. Prolonged
intake of coenzyme Q10 impairs cognitive functions in mice. J. Nutr. 139,
19261932.
Sun, A.Y., Wang, Q., Simonyi, A., Sun, G.Y., 2010. Resveratrol as a therapeutic agent
for neurodegenerative diseases. Mol. Neurobiol. 41, 375383.
Tabar, V., Panagiotakos, G., Greenberg, E.D., Chan, B.K., Sadelain, M., et al., 2005.
Migration and differentiation of neural precursors derived from human embry-
onic stem cells in the rat brain. Nat. Biotechnol. 23, 601606.
Tai, L.K., Okuda, M., Abe, J., Yan, C., Berk, B.C., 2002. Fluid shear stress activates
proline-rich tyrosine kinase via reactive oxygen species-dependent pathway.
Arterioscler. Thromb. Vasc. Biol. 22, 17901796.
Takahashi, K., Yamanaka, S., 2006. Induction of pluripotent stem cells from mouse
embryonic and adult broblast cultures by dened factors. Cell 126, 663676.
Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., et al., 2007. Induction
of pluripotent stem cells from adult human broblasts by dened factors. Cell
131, 861872.
Tobin, M.J., Snyder, J.V., 1984. Cheyne-Stokes respiration revisited: controversies
and implications. Crit. Care Med. 12, 882887.
Tortarolo, M., Veglianese, P., Calvaresi, N., Botturi, A., Rossi, C., Giorgini, A., Migheli,
A., Bendotti, C., 2003. Persistent activation of p38 mitogen-activated protein
kinase in a mouse model of familial amyotrophic lateral sclerosis correlates with
disease progression. Mol. Cell. Neurosci. 23, 180192.
Ushio-Fukai, M., Zafari, A.M., Fukui, T., Ishizaka, N., Griendling, K.K., 1996. p22phox
is a critical component of the superoxide-generating NADH/NADPH oxidase
system and regulates angiotensin II-induced hypertrophy in vascular smooth
muscle cells. J. Biol. Chem. 271, 2331723321.
Uzunova, V., Sheline, Y., Davis, J.M., Rasmusson, A., Uzunov, D.P., et al., 1998. Increase
in the cerebrospinal uid content of neurosteroids in patients with unipolar
major depression who are receiving uoxetine or uvoxamine. Proc. Natl. Acad.
Sci. U.S.A. 95, 32393244.
Valenzano, D.R., Cellerino, A., 2006. Resveratrol and the pharmacology of aging: a
new vertebrate model to validate an old molecule. Cell Cycle 5, 10271032.
Valenzano, D.R., Terzibasi, E., Genade, T., Cattaneo, A., Domenici, L., et al., 2006.
Resveratrol prolongs lifespan and retards the onset of age-related markers in
a short-lived vertebrate. Curr. Biol. 16, 296300.
van Ham, T.J., Breitling, R., Swertz, M.A., Nollen, E.A., 2009. Neurodegenerative dis-
eases: Lessons from genome-wide screens in small model organisms. EMBO Mol.
Med. 1, 360370.
Videbech, P., Ravnkilde, B., 2004. Hippocampal volume and depression: a meta-
analysis of MRI studies. Am. J. Psychiatry 161, 19571966.
Viswanathan, M., Kim, S.K., Berdichevsky, A., Guarente, L., 2005. A role for SIR-2.1
regulation of ER stress response genes in determining C. elegans life span. Dev.
Cell 9, 605615.
Vogelzangs, N., Suthers, K., Ferrucci, L., Simonsick, E.M., Ble, A., et al., 2007. Hyper-
cortisolemic depression is associated with the metabolic syndrome in late-life.
Psychoneuroendocrinology 32, 151159.
Wallerath, T., Li, H., Godtel-Ambrust, U., Schwarz, P.M., Forstermann, U., 2005. A
blend of polyphenolic compounds explains the stimulatory effect of red wine
on human endothelial NO synthase. Nitric Oxide 12, 97104.
Wang, Q., Xu, J., Rottinghaus, G.E., Simonyi, A., Lubahn, D., et al., 2002. Resvera-
trol protects against global cerebral ischemic injury in gerbils. Brain Res. 958,
439447.
Wernig, M., Zhao, J.P., Pruszak, J., Hedlund, E., Fu, D., et al., 2008. Neurons derived
from reprogrammed broblasts functionally integrate into the fetal brain and
improve symptoms of rats with Parkinsons disease. Proc. Natl. Acad. Sci. U.S.A.
105, 58565861.
West, M.J., Coleman, P.D., Flood, D.G., Troncoso, J.C., 1994. Differences in the pattern
of hippocampal neuronal loss in normal ageing and Alzheimers disease. Lancet
344, 769772.
Whyte, L., Huang, Y.Y., Torres, K., Mehta, R.G., 2007. Molecular mechanisms of resver-
atrol action in lung cancer cells using dual protein and microarray analyses.
Cancer Res. 67, 1200712017.
Willett, W.C., Stampfer, M.J., 2001. Clinical practice. What vitamins should I be tak-
ing, doctor? N. Engl. J. Med. 345, 18191824.
S46 C.-W. Hung et al. / Ageing Research Reviews 9S (2010) S36S46
Wolkowitz, O.M., Reus, V.I., 2003. Neurotransmitters, neurosteroids and neu-
rotrophins: new models of the pathophysiology and treatment of depression.
World J. Biol. Psychiatry 4, 98102.
Wolkowitz, O.M., Epel, E.S., Reus, V.I., Mellon, S.H., 2010. Depression gets old fast:
do stress and depression accelerate cell aging? Depress. Anxiety 27, 327338.
Wong, M.L., Licinio, J., 2001. Research and treatment approaches to depression. Nat.
Rev. Neurosci. 2, 343351.
Wood, J.G., Rogina, B., Lavu, S., Howitz, K., Helfand, S.L., et al., 2004. Sirtuin activators
mimic caloric restriction and delay ageing in metazoans. Nature 430, 686689.
Wu, Z., Xu, Q., Zhang, L., Kong, D., Ma, R., et al., 2009. Protective effect of resveratrol
against kainate-induced temporal lobe epilepsy in rats. Neurochem. Res. 34,
13931400.
Yan, L.J., Sohal, R.S., 2002. Analysis of oxidative modication of proteins. Curr. Protoc.
Cell. Biol., Chapter 7, Unit 7.9.
Yanagisawa, D., Qi, M., Kim, D.H., Kitamura, Y., Inden, M., Tsuchiya, D., Takata,
K., Taniguchi, T., Yoshimoto, K., Shimohama, S., Akaike, A., Sumi, S., Inoue, K.,
2006. Improvement of focal ischemia-induced rat dopaminergic dysfunction
by striatal transplantation of mouse embryonic stem cells. Neurosci. Lett. 407,
7479.
Yang, D., Zhang, Z.J., Oldenburg, M., Ayala, M., Zhang, S.C., 2008. Human embryonic
stem cell-derived dopaminergic neurons reverse functional decit in parkinso-
nian rats. Stem Cells 26, 5563.
Yankner, B.A., Lu, T., Loerch, P., 2008. The aging brain. Annu. Rev. Pathol. 3, 4166.
Yeh, L.J., 1991. Physical therapy for common diseases in the elderly. JPTA ROC 16,
125132.
Yu, J., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J.L., et al., 2007.
Induced pluripotent stem cell lines derived from human somatic cells. Science
318, 19171920.
Zang, M., Xu, S., Maitland-Toolan, K.A., Zuccollo, A., Hou, X., et al., 2006. Polyphenols
stimulate AMP-activated protein kinase, lower lipids, and inhibit acceler-
ated atherosclerosis in diabetic LDL receptor-decient mice. Diabetes 55,
21802191.
Zemlan, F.P., Thienhaus, O.J., Bosmann, H.B., 1989. Superoxide dismutase activity in
Alzheimers disease: possible mechanism for paired helical lament formation.
Brain. Res. 476, 160162.
Zhang, Z.G., Chopp, M., 2009. Neurorestorative therapies for stroke: underlying
mechanisms and translation to the clinic. Lancet Neurol. 8, 491500.