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Ageing Research Reviews 9S (2010) S36–S46

Ageing Research Reviews 9S (2010) S36–S46 Contents lists available at ScienceDirect Ageing Research Reviews

Contents lists available at ScienceDirect

Ageing Research Reviews

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

Reviews journal homepage: www.elsevier.com/locate/arr Review Ageing and neurodegenerative diseases Chia-Wei Hung

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

article

info

Article history:

Received 8 June 2010 Accepted 4 August 2010

Keywords:

Stem cells Neural stem cells Neuroprotection Neurodegenerative diseases Stem cell-based strategy

abstract

Ageing, which all creatures must encounter, is a challenge to every living organism. In the human body, it is estimated that cell division and metabolism occurs exuberantly until about 25 years of age. Beyond 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 social and economical burdens. In seeking to ameliorate ageing and age-related diseases, the search for anti-ageing drugs has been of much interest. Numerous studies have shown that the plant polyphenol, resveratrol (3,5,4 -trihydroxystilbene), extends the lifespan of several species, prevents age-related dis- eases, and possesses anti-inflammatory, and anti-cancer properties. The beneficial effects of resveratrol 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 Alzheimer’s disease, Parkinson’s 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 confined 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 efficiency 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 influences. 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 vulnerablemay not appear unless and until the organism is exposed to hostile precipitating events. Definitions 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 influenced by nutrition, lifestyle and environment (Busse, 1987). Some scientists define primary ageing as first-cause and secondary ageing as the pathological pro- cesses that ensue from the first-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 efficiency or performance, but in the extreme are often labeled as diseases. Examples of ageing changes that are sufficiently 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

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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 fibrous 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, inflammation, and activation of intracellular signal transduction pathways, increased oxidative stress can influence 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 (H 2 O 2 ), superoxide (O 2 ), 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 modification 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 Alzheimer’s diseases (AD), Parkinson’s 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

disease progression in an ALS-SOD1 mouse model (Tortarolo et al.,

2003).

Recent studies have shown a significant 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 significant protec- tion against neurodegeneration (Kim et al., 2007). Injection of SIRT1 activators significantly ameliorated retinal ganglion cell in experi- mental autoimmune encephalomyelitis mice, while administration of SIRT1 inhibitors suppressed this protective effect (Shindler et al., 2007). Immunohistofluorescence 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 identified, 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-specific 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- ton’s diseases (Scherzinger et al., 1997). The association between

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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). Thismay 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. Alzheimer’s 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 deficits. 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 65–69 years to 56.1 per 1000 person-years in the older than 90 years age group (Kukull et al., 2002). The main pathological findings of AD are senile plaques and neurofib- 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 first 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 fibers 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 deficits (Bishop et al.,

2010).

2.2. Parkinson’s 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 influence 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- ficial 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 difficulty, 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 fibroblast 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 inflammatory 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 significantly 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).

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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-inflammatory, 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 Pfluger, 2009; Penumathsa and Maulik, 2009). It is a scavenger of ROS and has anti-inflammatory properties (Chaudhary and Pfluger, 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 Pfluger, 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 significantly reduced the presence of atherosclerotic lesions and lipid levels in the apo E-deficient mice (Do et al., 2008; Norata et al., 2007) and type 1 diabetic LDL receptor-deficient mice (Zang et al., 2006).

3.2. Anti-ageing effects of resveratrol in metazoans

As first 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%; significantly 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 confirmed 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 identified 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 beneficial 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 fish Nothobranchius furzeri has proven to be

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 fish (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 significantly 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, signifi- 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 Huntington’s 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 beneficial 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 benefits 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 H 2 O 2 -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

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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). Kao’s finding 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 Parkinson’s and Hunting- ton’s 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 deficiency 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 deficiencies 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, riboflavin) can lower homocysteine levels (Sullivan and Johnson, 2009;Willett and

Stampfer, 2001). The specific 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 influence 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 deficiencies 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 flavonoids have beneficial effects on adult hippocampal cell

proliferation and neuroprotection in rodents (Stangl and Thuret, 2009). Notably, most flavonoids are extensively metabolized in vivo and the bioavailability of flavonoids after the consumption

of flavonoid-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 fitness include a decrease in maximal heart rate (Max HR), maximal cardiac output, muscle strength and flexibility; 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 fitness 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 modification 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 finally, to a deconditioned status. By the age of 70–80, 20–40% 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

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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 (5–40%) 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 10–20% 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 significantly 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 (Griffin 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 inflammatory 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 refined 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 findings 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

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 proinflammatory 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 fluoxentine, 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 first 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 beneficial 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 inflammatory 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 fluorescence-activated cell sorting (Hedlund and Perlmann, 2009).

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Hung et al. / Ageing Research Reviews 9S (2010) S36–S46 Fig. 1. The ageing process, together

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 diffi- 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 frommouse embryonic fibroblasts as well as from adult human fibroblasts 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-specific 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 significantly decreased infarct size, improved motor function, attenuated inflammatory 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

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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, dignified, and sophisticated late-life of humans.

Conflict of interest

The authors declare that there is no conflict 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.

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