antiageing supplements

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Review

Aging: An important factor for the pathogenesis of neurodegenerative diseases

Tahira Farooqui a,*, Akhlaq A. Farooqui b

a Department of Entomology, The Ohio State University, 318 West 12th Avenue, Columbus, OH 43210, USAb Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH 43210, USA

1. Introduction

Aging is a time-dependent progressive functional impairment

process thatleads to mortality. The most prominent characteristics

of aging are a progressive decrease in physiological capacity, a

reduced ability to respond adaptively to environmental stimuli, an

increased susceptibility to diseases, and increased mortality. Many

theories have been advanced to explain aging, but the biological

mechanism(s) that underlie aging are still unknown. Major

hypotheses of aging include altered proteins (Levine and Stadtman,

1996); DNA damage and less efficient DNA repair (Harley, 1991);

inappropriate cross-linking of proteins, DNA, and other structural

molecules (Bjorksten, 1974); a failure of neuroendocrine secretion

(Mobbs, 1996); cellular senescence in the cell culture system

(Hayflick, 1965); an increase in free radical-mediated oxidativestress(Harman, 1981); andchangesin the order of gene expression

(Helfand and Rogina, 2000).

A widely accepted concept is that the pattern of ontogenic

development within each species is genetically determined

(Robert and Labat-Robert, 2003). Therefore, a possible cause of

aging may be genetic: a gradual deterioration in molecular

components (e.g., loss of code, loss of gene expression devices,

loss of conditions for gene expression, improper gene regulation), a

concerted functioning of which is vital for cell viability and

proliferation (Robert and Labat-Robert, 2003). Several classes of

genes that differentially express during aging have been identified

in monkeys using high-density oligonucleotide microarrays in the

corpus callosum (Duce et al., 2008). These genes predominantly

modulate an increase in stress factors and a decrease in cell

function. The cell function changes include increased cell cycle

inhibition and proteolysis, as well as a decrease in mitochondrial

function, signal transduction, and protein translation. While most

of these categories have previously been reported in functional

brain aging(Guttmann et al., 1998), this was the first timethey had

been associated directly with white matter. Microarray analysis

has also enabled the identification of age-activated neuroprotec-

tive response pathways in white matter, as well as several genesimplicated in lifespan. Of particular interest was the identification

of Klotho, a multifunctional protein that regulates phosphate and

calcium metabolism, as well as insulin resistance, and is known to

defend against oxidative stress and apoptosis (Duce et al., 2008).

Other factors that control aging are a decrease in the efficacy of

DNA repair (Barnett and King, 1995), telomere-associated end-

replication problems (Allsopp et al., 1995), and mitochondrial DNA

mutations (Ozawa, 1995). A decline in these components may also

be related to cellular senescence, apoptosis, and aging-associated

pathologies. While no single theory accounts for all aspects of

aging, recent studies suggest that the primary aging process is

Mechanisms of Ageing and Development 130 (2009) 203215

A R T I C L E I N F O

Article history:

Received 1 May 2008

Received in revised form 1 October 2008

Accepted 12 November 2008Available online 21 November 2008

Keywords:

Aging

Alzheimer disease

Parkinson disease

ROS-mediated damage

Neurodegenerative diseases

Anti-aging remedies

A B S T R A C T

Aging is a natural process that is defined as a progressive deterioration of biological functions after the

organism has attained its maximal reproductive competence. Aging leads to the accumulation of

disabilities and diseases that limit normal body functions and is a major risk factor for

neurodegenerative diseases. Many neurodegenerative diseases share oxidative stress and nitrosative

stress as common terminal processes. According to free radical theory of aging, an elevation in reactive

oxygen species (ROS) and reactive nitrogen species (RNS) damages neural membranes and induces

oxidative and nitrosative stress. The increase in oxidative and nitrosative stress is accompanied by the

concomitant decline in cognitive and motor performance in the elderly population, even in the absence

of neurodegenerative diseases. Markedly increased rates of oxidative and nitrosative stress are themajor

factors associated with the pathogenesis of neurodegenerative diseases. Diet is a key environmental

factor that affects the incidence of chronic neurodegenerative diseases. Dietary supplementation with

polyphenols, resveratrol, ginkgo biloba, curcumin, ferulic acid, carotenoids, flavonoids, and n-3 fatty

acids exerts beneficial effects not only through the scavenging of free radicals, but also by modulating

signal transduction, gene expression, and restoring optimal neuronal communication.

2008 Elsevier Ireland Ltd. All rights reserved.

* Corresponding author. Tel.: +1 614 783 4369.

E-mail address: [email protected] (T. Farooqui).

Contents lists available at ScienceDirect

Mechanisms of Ageing and Development

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m e c h a g e d e v

0047-6374/$ see front matter 2008 Elsevier Ireland Ltd. All rights reserved.

doi:10.1016/j.mad.2008.11.006
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under genetic control with contributions from environmental

factors, supporting a link between oxidative stress and life span

(Martin and Grotewiel, 2006).

2. Aging, diseases, and learning

Aging produces several changes in human brain. The human

brain shrinks with aging. It is presumed that decrease in weight

and volume in the aging brain occur due to a loss of neurons and

myelinated axons (Peters, 2002). Changesin brain whitematter are

prominent features of the aging brain. These changes are

accompanied by the overexpression and calpain-mediated pro-

teolytic fragmentation of 20,30-cyclic nucleotide 30-phosphodies-

terase, resulting in myelin and axonal pathology in the aging brain

(Hinman et al., 2008). An increase in microglial activation also

occurs in several brain regions, including the hippocampus, during

aging (Finch and Cohen, 1997). Possible mechanisms may include

microglial reaction to advanced glycation end products (AGEPs)

(Morgan et al., 1999), which activate nuclear transcription factor-

kappaB (NFkB) and induce the transcription of pro-inflammatory

cytokines during aging (May and Ghosh, 1998). Thus, age-

dependent alterations in gene expression cause a disruption of

metabolic homeostasis (Mattson, 2002; Mocchegiani et al., 2006).

Learning is one of the memory processes through which thebrain adapts in response to environmental input. Memory is

defined as the persistence of learning over time through the

storage and retrieval of information and accounts for all knowledge

gained through experience. Memory includes: (1) learning or

encoding, (2) short-term or long-term storage and (3) recall or

retrieval. Therefore, if we test recall, it will tell us what we learned.

We cannot considerlearningwithout memory, or memory without

learning (Agranoff et al., 1999). There are several forms of memory.

One form of memoryis the ability to consciously and directly recall

or recognize recently processed information, where impairment of

this form of memory is a defining feature of global amnesia. It is

well known that, with increasing age, recall andrecognition of new

facts and events decline. The decline in memory performance is

closely related to age-mediated structural and functional changesin the hippocampus (Rosenzweig and Barnes, 2003). Memory is

also affected by age-related changes in the prefrontal cortex and

frontal white matter tracts, which may lead to impaired

interactions between the prefrontal cortex and hippocampal

structures. In the elderly, memory loss occurs as a natural result

of aging. A decline in brain performance, including learning and

memory, in the elderly is due to a deterioration of synaptic contact

and changes in the levels of neurotransmitters and neurohormones

(Nieto-Sampedro and Nieto-Diaz, 2005). Since the elderly popula-

tion is growing, there is a need to synthesize new drugs with

memory-enhancing properties. Neurodegenerative diseases can

affect some forms of memory while leaving others relatively intact

(Pennanen et al., 2006; Hudson, 2008; Ohsawa et al., 2008).

3. Oxidative stress, aging, and neurodegenerative diseases

Oxidative stress refers to cytotoxic consequences caused by

oxygen free radicals generated in a cell by processes that utilize

molecular oxygen. Oxidative damage is inflicted by ROS, impli-

cated in the cause of certain diseases, and has an impact on the

bodys aging process. ROS is a collective term that includes oxygen

radicals and non-radical oxidizing agents that can be converted

into radicals. At low levels, ROS function as signalingintermediates

for the modulation of fundamental cell activities such as growth

and adaptation responses, but at higher concentrations, ROScontribute to neuronal membrane damage. Almost every gene that

has been implicated in the response to stress has been shown to be

affected by altered ROS levels (Allen and Tresini, 2000). Mitochon-

dria are the major producer of ROS (Fig. 1). Another source of ROS

generation is polyunsaturated fatty acids, which are components

of neural membrane glycerophospholipids. These glyceropho-

spholipids are enriched in arachidonic acid (AA) (20:4 n-6) and

docosahexaenoic acid (DHA) (22:6 n-3). Enzymic and non-enzymic

oxidation of these fatty acids generates ROS. Interactions of these

fatty acids with the trace metal ion Fe3+ results in membrane lipid

peroxidation and an intensification of ROS formation. In addition,

ROS are produced by NADPH oxidase 4 (Nox 4). NADPH oxidase in

astrocytes and microglial cells is regarded as a major sourceof ROS

for mediating oxidative stress and neuroinflammation (Qin et al.,2002; Zekry et al., 2003).

Fig. 1. Generation of reactive oxygenspecies (ROS) innormal agingand neurodegenerative diseases.Generationof lowlevelsof ROSduring normalagingis counteredby anti-

oxidant enzymes. Generation of high levels of ROS and downregulation of anti-oxidant mechanisms results in neural cell death in neurodegenerative diseases.

T. Farooqui, A.A. Farooqui / Mechanisms of Ageing and Development 130 (2009) 203215204


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ROS formation causes oxidative damage to membranes,

proteins, lipids and genes, where this can be controlled by the

bodys defense mechanisms. ROS-mediated oxidative damage has

been implicated in normal aging and various neurodegenerative

diseases (Selley et al., 2002; Zarkovic, 2003; Kikuchi et al., 2002;

Giuliano et al., 2003; Hartzler et al., 2002). Thus, levels of lipidperoxides, such as 4-hydroxynonenal (4-HNE) and 8-hydroxy-20-

deoxyguanosine, are markedly increased in neurodegenerative

diseases. 4-HNE reacts with nucleophiles to form Michael adducts

and Schiff bases, resulting in the modification of many enzymes

and cytoskeletal proteins (Musiek et al., 2005; Farooqui and

Horrocks, 2006).

During aging, astrocytes generate a large amount of nitric oxide

(NO), which may be deleterious to the neighboring neurons and

oligodendrocytes. The exact molecular mechanisminvolved in NO-

mediated neuronal damage is not known. However, the reaction

between NO and superoxide generates peroxynitrite (ONOO)

(Fig. 2), which not only interacts with sulfhydryl groups, but can

hydroxylate the aromatic rings of amino acid residues (Beckman

et al., 1992). S-nitrosylation of cysteine thiols contributes to NO-mediated neurotoxicity by triggering the misfolding of proteins, a

process that may contribute to the pathogenesis of neurodegen-

erative diseases in old age (Nakamura and Lipton, 2008).

Furthermore, the generation of NO leads to S-nitrosylation of

wild-type parkin and initially to a marked increase, followed by a

decrease, in the activity of E3 ligase-ubiquitin-proteasome

degradative pathway (Yao et al., 2004). The inhibition of parkins

ubiquitin E3 ligase activity by S-nitrosylation could contribute to

the degenerative process in neurodegenerative disorders by

impairing the ubiquitination of parkin substrates. In addition,

ONOO reduces mitochondrial respiration, inhibits membrane

pumps, depletes cellular glutathione, and damages DNA, thus

activating poly-(ADP-ribose) synthase, an enzyme that leads to

cellular energy depletion(Pryor and Squadrito, 1995) (Fig.2). Thus,

ONOO reacts with lipid, proteins, and DNA (Radi et al., 1991). It is

also reported that ONOO interferes with key enzymes of the

tricarboxylic acid cycle, the mitochondrial respiratory chain, and

mitochondrial Ca2+ metabolism (Bolanos et al., 1997). All these

processes may contribute to a deficiency of neuronal energy and

the oxidation of protein sulfhydryls caused by aging-associatedchanges as well as neurotraumatic situations (Thomas and Mallis,

2001).

Brain tissue contains specific enzymes to deal with ROS in the

cytoplasm, as well as in neural membranes, where catalase,

superoxide dismutase and glutathione peroxidase detoxify ROS.

Superoxide dismutase converts the superoxide anion radical

into hydrogen peroxide, which can readily diffuse through

neural membranes (Calabrese et al., 2004). Hydrogen peroxide

itself is not a free radical, but a major source for the generation

of hydroxyl radical that is formed in the Fenton reaction

catalyzed by iron and copper. Hydrogen peroxide is removed by

glutathione peroxidase and catalase. Collectively, these studies

suggest that oxidation of glycerophospholipids, chemical cross-

linking of neural membrane proteins and oxidation of neuralcell DNA are significant chemical events that are associated

with oxidative stress and the disruption of ion homeostasis

during lipid peroxidation. All these processes are related to

oxidative stress-mediated neurodegeneration in neurodegen-

erative diseases.

Interaction with iron ions perturbs the structure of glyceropho-

spholipid bilayers, producing changes in membrane fluidity and

affecting function. Several biomarkers of oxidative stress in

Alzheimers disease (AD) and Parkinsons disease (PD) have been

identified (Farooqui and Horrocks, 2007; Beal, 2004). The

accumulation of iron in these disorders occurs not only at the

sites of specific neurodegeneration, but also in other brain regions,

indicating that the accumulation of iron may be a secondary

process associated with neurodegeneration.

Fig. 2. Production of ROS and RNS and synthesis of peroxynitrite through interactions of nitric oxide and superoxide radical in neural and non-neural cells during aging.

T. Farooqui, A.A. Farooqui / Mechanisms of Ageing and Development 130 (2009) 203215 205


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To manage andsurvivethe effects of aging and differenttypes ofinjuries, brain cells have evolved integrated responses. These are

called longevity assurance processes. These processes involve

several genes (vitagenes) that include members of the HSP system,

such as HSP70 and HSP32, which detect and control diverse forms

of stress. In particular, HSP32, also known as heme oxygenase-1

(HO-1), has received considerable attention, as it has been recently

shown that HO-1 induction, by generating the vasoactive molecule

carbon monoxide and the potent anti-oxidant bilirubin, may

represent a protective system potentially active against oxidative

stress-mediated brain injury (Calabrese et al., 2004). It is proposed

that the maintenance of vitagene activity may possibly delay the

aging process and decrease the occurrence of age-related diseases,

resulting in the prolongation of a healthy life span (Calabrese et al.,

2004).

4. Glycerophospholipids, neurodegenerative diseases, and cell

death

Glycerophospholipids form the backbone of neural membranes.

Aging produces changes in glycerophospholipid-fatty acid com-

position. Arachidonic and docosahexaenoic acids are important

components of neural membranes. A decrease in arachidonic and

docosahexaenoic acids may be related to the activities of

phospholipases A2, C, and D, and enzymic and non-enzymic

oxidation of these fatty acids (Gaiti et al., 1986; Giusto et al., 2002;

Farooqui and Horrocks, 2007). The enzymic oxidation of arachi-

donic acid through cyclooxygenases and lipoxygenases results in

the generation of prostaglandins, leukotrienes, thromboxanes, and

lipoxins. Collectively, these metabolites are called as eicosanoids(Fig. 3). They act through EP1, EP2 and thromboxane receptors

(Phillis et al., 2006). Lipoxins (Fig. 4), generated through the

lipoxygenase pathway, are involved in the resolution of inflam-

mation (Farooqui and Horrocks, 2007). They act through a lipoxin

receptor (ALX), and are involved in the regulation of calcium

mobilization and leukocyte trafficking (Chiang et al., 2006).

The non-enzymic oxidation of arachidonic acid also results in

the generation of isoprostanes (IsoPs) and 4-HNE (Fig. 4) (Farooqui

and Horrocks, 2007). IsoPs are prostaglandin-like mediators

formed non-enzymically by free radical-catalyzed peroxidation

of esterified arachidonic acid in vivo (Greco and Minghetti, 2004).

Non-enzymic oxidation of arachidonic acid also produces isoketals

(Morrow, 2006). Collective evidence suggests that IsoPs and

isoketal are in vivo markers of oxidative stress. In plasma, free andtotal (free plus esterified) F2-isoPs increase with age. In addition,

levels of esterified F2-isoPs increase 68% with age in the liver, and

76% with age in the kidneys. These age-related increases in

esterified F2-isoPs levels correlate well with DNA oxidation, as

measured by 8-oxodeoxyguanosine production, demonstrating

that F2-isoPs are an excellent biomarker for age-related changes in

oxidative damage to membranes (Roberts and Reckelhoff, 2001;

Ward et al., 2005).

In contrast, docosahexaenoic acid is not a substrate for

cyclooxygenases. The action of a 15-lipoxygenase-like enzyme

on docosahexaenoic acid produces 17S-resolvins, 10-17S-docosa-

trienes, and protectins (Hong et al., 2003; Marcheselli et al., 2003;

Serhan and Savill, 2005) (Fig. 4). These second messengers are

collectively known as docosanoids, act through resolvin D

Fig. 3. Interactions between enzymic and non-enzymic lipid mediators of arachidonic acid and docosahexaenoic acid metabolism in the brain. Glutamate receptor, R1 is

coupled to phosphatidylcholine (PtdCho) catabolism, R2 is coupled to plasmalogen (PlsEtn) degradation, R3 is prostaglandin receptors (EP receptors), and R4 is resolvin D

receptors (resoDR1), resolvin E receptors (resoER1), neuroprotectin D receptors (NPDR). Docosanoids not only inhibit the generation of eicosanoids but also modulate signal

transduction through resoDR1, resoER1, and NPDR. Arachidonic acid (AA); docosahexaenoic acid (DHA); 4-hydroxynonenal (4-HNE); and 4-hydroxyhexenal (4-HHE).



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receptors (resoDR1), resolvin E receptors (resoER1), and neuro-

protectin D receptors (NPDR), and are potent endogenous anti-

inflammatory and pro-resolving chemical lipid mediators (Serhan

et al., 2006). They not only antagonize the effects of eicosanoids

and modulate leukocyte trafficking, but also downregulate the

expression of cytokines in glial cells (Hong et al., 2003; Marcheselli

et al., 2003). DHA also undergoes non-enzymic oxidation and

generates neuroprostanes (NP) (Roberts andFessel, 2004; Yinet al.,

2005; Greco and Minghetti, 2004) (Fig. 4). Levels of F4-neuro-

prostanes have been determined in 4-, 10-, 50-, and 100-week-old

male Fischer 344 rats. Levels of F4-neuroprostanes were approxi-

mately 20-fold higher than those of F2-isoprostanes in all age

groups, despite the fact that the brain levels of docosahexaenoic

acid are only twice as high as those of arachidonic acid (Youssefet al., 2003).

Non-enzymic oxidation of DHA also produces neuroketals

(NKs) (Fig. 5) (Bernoud-Hubac et al., 2001). Like IsoK, NKs are very

reactive. They not only form lactam and Schiff base adducts, but

also generate lysine adducts, suggesting that these metabolites

may be involved in proteinprotein cross-linking in brain tissue

under oxidative stress. These metabolites are in vivo markers and

may have neurochemical effects that intensify both neuroinflam-

mation and oxidative stress in acute neural trauma and

neurodegenerative diseases (Roberts and Fessel, 2004; Farooqui

and Horrocks, 2006, 2007).

Although each neurodegenerativedisease has a separate etiology

with distinct morphological and pathophysiological characteristics,

they share oxidative stress as a common mechanism (Farooqui and

Horrocks, 1994). It remainscontroversialwhether oxidative stress is

the cause or consequence of neurodegeneration (Andersen, 2004;

Juranek and Bezek, 2005). Very little information is available on the

rate of neurodegeneration and clinical expression of neurodegen-

erative diseases with age.

ROS also attack proteins and nucleic acids. ROS cross-link

intracellularproteinsandgenerate ceroidpigment,age pigment, and

lipofuscin that accumulates in postmitotic tissues. There is a good

correlation between the accumulation of oxidized/cross-linked

proteins and the decline in proteasome activity and overall cellular

protein turnover during in vitro senescence. These events may

predict a causal relationship during actual cellular aging (Sitte et al.,

2000). Age-mediated ROS generation involves an increase in the

oxidationofDNAandRNAinthecerebellumofmalerats( Cuietal.,inpress). The oxidation of DNA results not only in the generationof 8-

hydroxy deoxy guanosine, but also in DNA protein cross-links in

discrete brain regions of young and aged rats. This age-related

damagein thecortex,striatum, andhippocampuscan be reversed by

glutathione monoester (Murali and Panneerselvam, 2007).

The onset and progression of neurodegenerative diseases may

not only depend upon genetic factors and oxidative stress, but also

on complex interactions between individual genetic background

and environmental factors. The exact role of the risk factors

involved,and theirinfluence on the onset and pacingof thedisease,

is not yet fully understood. Similarly, the relationship between the

rate of neuronal death and the clinical expression of a disease is a

matter for discussion, and more studies of these important topics

are required.

Fig. 4. Chemical structures of enzymic and non-enzymic oxidation products of arachidonicand docosahexaenoic acids. 12-F2t-isoprostane (a); isofuran (b); lipoxin A4 (c); 4-

HNE (d); 16,17-docosatriene (e); 4S5,17S-resolvin (f); 7,16,17S-resolvin (g); and neuroprostane (h).



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Neurodegenerative diseases are marked by site-specific pre-

mature and slow death of certain neuronal populations (Wijsman

et al., 2005; Mizuta et al., 2006; Seonget al., 2005; Pickering-Brown

et al., 2004; Alexander et al., 2002) (Table 1). For example, in AD,

neuronal degeneration occurs in the nucleus basalis, whereas, in

PD, neurons die in the substantia nigra. The most severely affectedneurons in Huntington disease (HD) are striatal medium spiny

neurons. The affected populations of neurons are often, but not

always, synaptically interconnected. The mechanisms associated

with the specificity of neuronal cell death in the nucleus basalis in

AD, the substantia nigra in PD, and the striatum in HD are not

known. However, it is becoming increasingly evident that many

factors including alterations in the energy status of degenerating

neurons, defects in the ubiquitin-proteasome system, the presence

of abnormal aggregated proteins (b-amyloid and tau proteins inAD, a-synuclein and parkin in PD, prion protein in Creutzfeldt-

Jakobs disease (CJD), and huntingtin in HD), a lack of trophic

factors, alterations in the levels of cytokines, along with the

disruption of the ionic gradient and the signal transduction

processes, may contribute to the specificity of neurodegenerative

processes (Farooqui and Horrocks, 2007; Farooqui et al., 2008a).

The most important risk factors for neurodegenerative diseases

are old age and a positive family history. The onset of

neurodegenerative diseases is often subtle, usually occurs in

mid to late life, and their progression depends not only on geneticbut also on environmental factors. Mitochondrial dysfunction and

oxidative stress in neurodegenerative diseases lead to progressive

cognitive and motor disabilities with devastating consequences to

the patients (Farooqui and Horrocks, 2007; Farooqui et al., 2008a).

5. Diagnosis of neurodegenerative diseases

Lipidomics and proteomics have emerged as important

technologies (German et al., 2007; Watson, 2006; Bowers-Gentry

et al., 2006) for the identificationand full characterization ofin vivo

markers for oxidative stress (F2-isoprostane, prostaglandins,

leukotrienes, lipoxins, hydroxyeicosatetraenoic acids, nitrotyro-

sine, carbonyls in proteins, oxidized DNA bases and 4-HNE in the

Fig. 5. Effects of caloric restriction on the brain during aging.

Table 1

Onset, genes, and sites of neuronal loss in familial neurodegenerative diseases.

Neurodegenerative diseases Onset (age) Mutation in genes Site of neuronal loss Reference

AD 3065 PS1, PS2 Nucleus basalis Wijsman et al. (2005)

PD 4060 a-Synuclein,

ubiquitin-protein

ligase (parkin)

Substantia nigra and striatum Mizuta et al. (2006)

HD 2050 Huntingtin Striatum Seong et al. (2005)

P Dis 4060 Tau Frontal and temporal lobes Pickering-Brown et al. (2004)

MSA 52.555 a-Synu clein Sub st an tia nigr a and st riatu m Mizuta et al. (2006)

ALS 4060 SOD1 Upper (brain) and lower (spinal cord) muscles Alexander et al. (2002)

Presenilin1 (PS1), presenilin2 (PS2), amyloid precursor protein (APP), apolipoprotein E (APOE), Huntington gene (HD), superoxide dismutase mutation (SOD1), Picks Disease

(P Dis), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), reactive oxygen species (ROS), multiple system atrophy (MSA), amyotrophic lateral sclerosis

(ALS).



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cerebrospinal fluid (CSF)) (Serhan, 2005; Serhan et al., 2006;

Adibhatla et al., 2006; Milne et al., 2006; Hunt and Postle, 2006;

Morrow, 2006; Lu et al., 2006; Perluigi et al., 2005). The

establishment of automatic systems, including databases, and

accurate analysis of various lipid mediators derived from enzymic

and non-enzymic metabolism of neuronal membrane polyunsa-

turated fatty acids and their metabolites (eicosanoids, resolvins,

neuroprotectins, isoprostanes, neuroprostanes, and isofurans), has

facilitated the identification of key biomarkers associated with

neurodegenerative diseases (Lu et al., 2006).

New mass spectrometry technologies have recently emerged as

important procedures for performing direct tissue analysis using

matrix-assisted laser desorption/ionization (MALDI) sources. This

technique takes mass spectral snapshots of intact tissue slices and

reveals how proteins and peptides are spatially distributed within

a given sample. A major advantage of direct MALDI analysis is the

ability to avoid time-consuming extraction, purification or

separation steps, which may have potential for errors and the

introduction of artifacts (Wisztorski et al., 2007). Direct MALDI

analysis is performed on tissue sections. It allows for the

acquisition of cellular expression profiles while maintaining the

cellular and molecular integrity. With automation and the ability

to reconstruct complex spectral data using imaging software, it is

now possible to produce multiplex imaging maps of selected bio-molecules within tissue sections (Wisztorski et al., 2007). Thus,

direct MALDI spectral data obtained from tissue sections can be

converted into imaging maps, a method now known as MALDI-

imaging. MALDI-imaging combines the power of mass spectro-

metry, namely exquisite sensitivity and unequivocal structural

information, within an intact and unaltered morphological

context. One of the most important developments in recent years

has been the ability to carry out either direct MALDI analysis or

MALDI-imaging on paraffin tissue sections. This capability

provides new avenues for biomarker hunting and diagnostic

follow-up in the clinical setting (Wisztorski et al., 2007).

Furthermore, MALDI-imaging may provide information on the

validation of disease-marker-gene RNA transcripts, which can be

analyzed along with their translational products by targeting theirspecific protein or metabolites. Neurodegenerative diseases, as

well as normal health states, can thus be closely monitored, with a

single technique, at the level of proteins and nucleic acids.

Similarly, single photon emission computed tomography (SPECT),

positron emission tomography (PET), and magnetic resonance

imaging (MRI) are highly sensitive techniques for the early

diagnosis of neuronal cell death in neurodegenerative diseases

and functional changes in the basal ganglia (Gratz et al., 2008).

These have all recently begun to be applied to the diagnosis of

neurodegenerative diseases (Hahn et al., 2008). It may be possible

to use these techniques for the early and reliable diagnosis of

neurodegenerative diseases. SPECT, PET, and MRI scans have

demonstrated diagnostic and prognostic utility for clinicians

evaluating patients with cognitive impairment, and in distinguish-ing among primary neurodegenerative disorders and other

etiologies that contribute to cognitive decline. In addition to

focusing on the cerebral metabolism effects examined with (18)F-

fluorodeoxyglucose, SPECT, PET, and MRI scans can provide

information about other changes that occur in the brains of

patients with neurodegenerative diseases, and cognitively

impaired patients assessable with other radiotracers (Sixverman

et al., 2008). These techniques can also be used to monitor

therapeutic responses in patients with neurodegenerative dis-

eases.

Despite the recent advances in the imaging techniques, the

diagnosis of neurodegenerative diseases is still made by accurate

history and examination (Farooqui and Horrocks, 2007; Farooqui

et al., 2008a,b). Diagnostic accuracy in epidemiological studies

depends on the careful and correct use of clinical diagnostic

criteria. Identificationof molecular biomarkers associated with the

progression of neurodegenerative diseases is necessary for their

detection. Cerebrospinal fluid is important for the detection of

neurodegenerative diseases. Especially early in the course of the

disease, when a correct diagnosis is most difficult, biomarkers like

4-HNE, isoprostanes, isoketal, 8-hydroxy guanosine, b-amyloid,tau protein, and a-synuclein may be quite valuable.

In AD, reduced CSF levels of the Ab42, and increased levels oftotal tau (T-tau) have been detected in numerous studies with a

high degree of sensitivity. However, the specificity of this test in

the diagnosis of other dementiasis lower.The addition of phospho-

tau(P-tau)seems to increase the specificity, since normal levels are

found in other dementias and in cerebrovascular disease

(Andreasen et al., 2003). Increased levels of a-synuclein havebeen found in the CSF of PD patients (El-Agnaf et al., 2006). Levels

of transaminase acting on huntingtin are markedly increasedin the

CSF of HD patients (Jeitner et al., 2001). The CSF levels of these

markers reflect changes in the metabolism of these proteins in the

central nervous system. Other biomarkers, such as increased levels

of 4-HNE,are an indication of oxidative stress. These biomarkers in

the CSF can be used not only to diagnose neurodegenerative

conditions, but also to monitor the patients response to the

therapeutic drugs. This may simplify and shorten early clinicaltrials that examine the efficacy of various drugs. The diagnosis of

neurodegenerative diseases by CSF markers can be combined with

the clinical information and brain-imagingtechniques (SPECT, PET,

and MRI) for improved detection of neurodegenerative diseases.

Accurate early diagnosis is the key for effective long-term

treatment and management of neurodegenerative diseases. Early

referral of all cases suspected of having neurodegenerative

diseases for specialist assessment and advice is strongly recom-

mended.

6. Can aging be delayed?

Aging is a complex, progressive and universal process,

originating endogenously, that manifests during postmaturationallife. It is controlled not only by genes, but also by common factors

such as nutrition, exercise, attitude, mental relaxation, and

socialization (Karting, 2001). In addition, environmental factors

influence the human lifespan. Two basic molecular traits are

associated with the rate of aging and thus with the maximum life

span: the presence of low rates of mitochondrial oxygen radical

production, and low levels of fatty acid unsaturation in the cellular

membranes in postmitotic tissues of long-lived homeothermic

vertebrates compared with those of short-lived ones (Pamplona

et al., 2002). The mortalityrates of lifestyle-related diseases suchas

heart disease, stroke, neurodegenerative diseases, and cancer are

increasing in United States, where much of the baby boomer

population is becoming old (Shimizu and Shirasawa, 2008). The

preventive measures for lifestyle-related diseases, such as nutri-tional intervention or regular physical exercise, may extend the

healthy lifespan. Caloric restriction (CR) in experimental animals

has been shown to extend the lifespan of animals with a decrease

in the frequency of age-related neurodegenerative diseases.

Although aging can not be controlled, it is certainly possible to

stay healthy and to delay aging by monitoring factors such as the

selection of diet, caloric restriction, physical activity, and regular

consumption of anti-aging remedies (Shimizu and Shirasawa,

2008).

6.1. Selection of diet

In order to increase the quality of life in the aging population, it

is crucial to explore methods that may retard or reverse the



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deleterious effects of aging. Diets enriched with anti-oxidant and

anti-inflammatory agents (curcumin, green tea, and ferulic acid)

may lower the risk of developing age-related neurodegenerative

diseases such as AD and PD (Table 2). Many studies indicate that

dietary supplementation with fruit or colored vegetable extracts

can decrease the age-enhanced vulnerability to oxidative stress

and inflammation. Additional studies indicate that polyphenolic

compounds found in red wine and fruits such as blueberries mayexert their beneficial effects through signal transduction and

neuronal communication, delaying dementia (Ruitenberg et al.,

2002; Lau et al., 2007; Joseph et al., 2007). Other food-based anti-

oxidants (such as vitamins C and E, b carotene, curcumin, andgreen tea) may modulate primary as well as secondary processes

of aging by neutralizing free radicals. An imbalance between free

radical production and anti-oxidant defense leads to an oxidative

stress state, which may be involved in aging processes and even

in some pathologies. Therefore, diet enrichment with anti-

oxidants may protect brain tissue and result in successful aging

(Suter and Vetter, 1994; Cabrera et al., 2006). Another important

dietary factor is the ratio between arachidonic acid and

docosahexaenoic acid. Both these fatty acids are essential for

human health. AA and DHA cannot be synthesized de novo bymammals; they, or their precursors, must be ingested from

dietary sources and transported to the brain (Horrocks and

Farooqui, 2004; Marszalek and Lodish, 2005; Farooqui, 2009). AA

is found in vegetable oil, whereas DHA in enriched in fatty fish

and fish oil. In the present day Western diet, the ratio of AA to

DHA is about 18:1. The Paleolithic diet, on which human beings

evolved and lived for most of the species existence, has a ratio of

1:1 (Simopoulos, 2006; Cordain et al., 2005; Farooqui, 2009).

Changes in eating habits, natural versus processed food, and

agriculture development within the past 100150 years have

caused these changes in the n-6 to n-3 ratio, which has affected

human health remarkably.

The consumption of fish and fish oil has numerous beneficial

effects on the health of the human brain (Horrocks and Farooqui,2004; Farooqui, 2009). The beneficial effects of docosahexaenoic

acid on the human brain are not only due to its effect on the

physicochemical properties of neural membranes, but also to the

modulation of neurotransmission (Chalon et al., 1998; Hogyes

et al., 2003; Chalon, 2006; Joardar et al., 2006), gene expression

(Farkas et al., 2000; Barcelo-Coblijn et al., 2003; De Caterina and

Massaro, 2005; Deckelbaum et al., 2006), enzyme activities, ion

channels, receptors, and immunity (Yehuda et al., 2005; Isbilen

et al., 2006). Extra-virgin olive oil (unprocessed olive oil) contains

micronutrients and polyphenolic anti-oxidants including tyrosol

[2-(4-hydroxyphenyl)ethanol], hydroxytyrosol, oleuropein, and

oleocanthal. These compounds may not only increase longevity,

but also retard neurodegenerative diseases (Lopez-Miranda et al.,

2007).

6.2. Caloric restriction

Caloric restriction is considered to be a non-genetic interven-

tion that has consistently been shown to slow the intrinsic rate of

aging in mammals. Caloric restriction refers to the reduction in

calorie intake by maintaining essential nutrient requirements.

According to Dr. Mark Mattson, CR is the most prominent dietary

factor that affects aging and susceptibility to chronic diseases,including neurodegenerative diseases, heart disease and cancer

(Mattson, 2008). Excessive calorie intake increases the risk of age-

related chronic diseases such as AD, PD, and HD. Reducing energy

intake by controlled CR or intermittent fasting increases lifespan

and protects brain against neurodegenerative diseases in part, due

to hormesis mechanisms that increase cellular stress resistance

(Mattson, 2008).

Several interrelated cellular signaling molecules are associated

with hormesis. These include gases (like oxygen, carbon monoxide

and nitric oxide), a neurotransmitter (glutamate), the calcium ion,

and tumor necrosis factor. In each case, low levels of these

signaling molecules are beneficial and protect against neurode-

generative disease, whereas high levels can cause neurodegenera-

tion (Mattson, 2008). Cellular signaling pathways and molecularmechanisms that mediate hormetic responses involve genes and

enzymes such as kinases and deacetylases, the sirtuin-FOXO

pathway, and transcription factors such as Nrf-2 and NF-kB. As a

result, cells increase the expression of cytoprotective and

restorative proteins including growth factors, anti-oxidant

enzymes, and protein chaperones (Mattson, 2008; Son et al.,

2008). Phytochemicals that protect neural cells (Liu et al., 2008)

exhibit biphasic dose responses on cells, with low doses activating

signaling pathways that result in increased expression of genes

encoding cytoprotective proteins including anti-oxidant enzymes,

protein chaperones, growth factors and mitochondrial proteins

(Mattson, 2008; Son et al., 2008) (Fig. 5). Examples include the

activation of the nuclear factor-E2-related factor-2-Nrf2-anti-

oxidant response element (Nrf-2-ARE) pathway by sulforaphane(an anticancer and antimicrobial compound) and curcumin

(principal component of turmeric), the activation of transient

receptor potential (TRP) ion channels by allicin (major component

of garlic) and capsaicin (the active component of chili peppers),

and the activation of sirtuin-1 by resveratrol. A better under-

standing of hormesis mechanisms at the cellular and molecular

levels may lead to prevention and treatment of many chronic

neurodegenerative diseases. Thus, studies on dose response and

kinetic characteristics of the effects of dietary factors on human

brain tissue are urgently needed (Mattson, 2008; Son et al., 2008).

Studies of CR in animals indicate that it not only enhances

immune responses and stimulates DNA repair systems, but also

handles outside threats, suchas infectious agents, toxins, radiation,

extreme temperatures, and may delay the onset of chronic visceral

Table 2

Currently available anti-aging remedies for elderly population.

Anti-aging remedies Beneficial activity Reference

Curcumin Anti-oxidant and anti-inflammatory Aggarwal et al. (2007)

Blueberry (anthocyanins) Anti-oxidant, anti-angiogenic and anti-atherosclerotic Zafra-Stone et al. (2007)

Polyphenolic compounds and resveratrol Anti-oxidant, anti-athero-genic and anti-inflammatory Liu et al. (2008)

Sulfur compounds (allicin, alliin and agoene) Anti-platelet aggregatory, Anti-atherosclerotic, anti-oxidative,

anti-tumor, anti-thrombotic, anti-bacterial, anti-fungal

and anti-hypertensive

Amagase (2006)

n-3 fatty acids (DHA and EPA) Anti-oxidant and anti-inflammatory Horrocks and Farooqui (2004); Farooqui (2009);Antypa et al. (in press)

Extr a-virgin olive oil Ant i-p latelet aggregatory , anti-t um or and anti-oxidative Lopez-Miranda et al. (2007)

Ginkg o bilo ba Anti-platel et agg regatory, anti-oxidative and memo ry enhancer Bastianetto and Quirion (2002)

Ferulic acid Anti-oxidant Calabrese et al. (2004); Mamiya et al. (2008)

Dark choco late Improve s coronary va scul ar func ti on a nd dec reases platelet adhesio n Flammer et al. (2007)



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and brain diseases (Masoro, 2000; Longo and Finch, 2003).

Alterations in the characteristics of carbohydrate and oxidative

metabolism in response to CR have been observed (Masoro, 2000).

These alterations may, at least in part, underlie the anti-aging

action of CR. Several theories have recently been proposed to

explain molecular mechanisms responsible for the anti-aging

action of CR, but none has been tested by rigorously designed

studies (Hart et al., 1999).

One theory involves the altered metabolic characteristics of

glucose fuel use and of oxidative metabolism. The other relates to

the enhanced ability of food intake-restricted rodents to cope with

challenges, a process linked in turn to the glucocorticoid system

and to the heat-shock protein system (Calabrese et al., 2004).

Another promising hypothesis is based on the fact that CR protects

rats and mice of all ages against the damaging actions of acute

stressors (Orrell and ODwyer, 1995). This protective action against

stressors may play a major role in the anti-aging action of CR

(Masoro, 1996). Finally, another theory that may explain beneficial

effects of CR is regulation of cellular Ca2+-regulating system in

neural cells (Mattson, 2007).

Calcium is a universal second messenger within neural cells. It

is associated with multiplecellularfunctions,such as the release of

neurotransmitters, gene expression, proliferation, excitability, and

regulation of apoptosis. The magnitude, duration, and shape ofstimulation-evoked intracellular calcium are modulated not only

by the permeability of Ca2+ channels but also by the neuronal

calcium-buffering systems. Alterations in Ca2+-regulating system-

mediated signal transduction processes cause synaptic dysfunc-

tion, impaired plasticity and neuronal degeneration. It is becoming

increasingly evident that changes in Ca2+-regulating system-

mediated signal transduction processes at the cellular and

subcellular levels play an important role in normal aging and

age-related neuronal dysfunction in neurodegenerative diseases

(Mattson, 2007; Toescu and Verkhratsky, 2007; Thibault et al.,

2007). Thus, at the plasma membrane level, Ca2+-regulating

systems modulate the permeability of voltage-gated Ca2+ channels,

the activities of Ca2+-ATPases, and glucose and glutamate

transporters. At the endoplasmic reticulum level, changes inCa2+-regulating systems influence presenilin1 metabolism, and the

permeability of inositol trisphosphate receptors. At the mitochon-

drial level, Ca2+-regulating systems modulate electron transport

chain proteins, Bcl-2 family members, and proteins associated

with mitochondrial uncoupling (Mattson, 2007). Increased mito-

chondrial calcium uptake may represent a weak point in cellular

compensation, as this process overtime may contribute to cell

death. Adverse effects of aging on neural cell Ca2+-regulating

system-mediated signal transduction processes also include

perturbed energy metabolism, and mutations in the aggregation

of neurodegenerative disease-related proteins (amyloidb-peptide,a-synuclein, huntingtin, presenilins, Cu/Zn-superoxide dismutase,and apolipoprotein E). All these factors have been implicated in

normal aging and in the pathogenesis of neurodegenerativediseases (Mattson, 2007). Aging also disturbs the cellular redox

balance, producing higher levels of ROS and reactive nitrogen

species (RNS) that either directly damage cellular constituents or

indirectly alter cellular function through the activation of redox-

sensitive transcription factors, thus altering gene expression (Kim

et al., 2002). It has been reported that CR reduces the generation of

ROS and RNS, which suppress the activation of redox-sensitive

transcription factors, and minimizes the increase in expression of

inflammatory and oxidative stress gene clusters (Cao et al., 2001).

Furthermore, CR decreases the levels of F2-isoPs in plasma, liver,

and kidney (Ward et al., 2005).

Collectively, these studies suggest that caloric restriction not

only modulates Ca2+-dependent processes, but also reduces the

production of ROS and RNS (Barja, 2002). As stated above, CR

increases the expression of cytoprotective and restorative proteins,

including growth factors, anti-oxidant enzymes, and protein

chaperones such as heat-shock proteins. CR also reduces inflam-

matory risk factors by turning off activated transcription factors,

and thereby induces resistance to age-related chronic diseases. CR

modifies acyl composition of neural membrane bilayers, and is

associated with decreased membrane lipid peroxidation and

lifespan extension. These observations haveyielded the membrane

pacemaker hypothesis of aging (Hulbert, 2007). Collectively, these

studies suggest that CR and nutritional intervention may exert

therapeutic protection against age-related deficits and neurode-

generative diseases.

6.3. Planned exercise program

It is well known that mitochondrial dysfunction and oxidant

production, in association with an accumulation of oxidative

damage, contribute to the aging process. Regular physical exercise

can delay the onset of morbidity, increase mean lifespan, and

reduce the risk of developing neurological disorders. Exercise helps

to control weight, glucose levels, and blood pressure. It also

elevates high-density lipoprotein (HDL, good cholesterol) levels.

However, physical exercise also increases oxidative stress and

causes disruptions of the homeostasis. Planned training can havepositive or negative effects on oxidative stress depending on its

load, specificity and the basal level of training (Finaud et al., 2006).

Regular exercise helps in delaying aging and the onset of

neurodegenerative diseases (Larson et al., 2006). Collective

evidence suggests that lifelong exercise attenuates multiple

molecular markers of age-related oxidative damage in the

cerebellum. In addition, modest exercise initiated late in life can

have a beneficial effect on lipid oxidation and motor function ( Cui

et al., in press). In addition, exercise training also reduces oxidative

stress and glucocorticoid-mediated effects during aging and

neurodegenerative diseases (Kiraly and Kiraly, 2005).

7. Anti-aging medicine

Brains of neurodegenerative patients (such as in AD) undergo

many changes, such as the degradation of neural membrane

glycerophospholipids, the disruption of protein synthesis and

degradation, and the generation of ROS and RNS. Among these,

oxidative stress and nitrosative stress are major factors that affect

the aging process. In vertebrate models, maximum lifespan has

been shown to be inversely proportional to the rate of endogenous

free radical generation and the degree of unsaturation of tissue

fatty acids. Thus, by increasing the dietary intake of anti-oxidants

and DHA-enriched food, one can help the body to defend itself.

These factors can be modified through lifestyle changes, by using

pharmacological agents (such as statins, anti-hypertensive agents)

and age-related drugs (such as anti-oxidants and estrogen

replacement therapy). The expression and progression of theneurodegenerative processes of brain aging, AD, and other relative

neurodegenerative diseases can be delayed by altering the balance

between neuronal damage and repair (Ball and Birge, 2002;

Farooqui, 2009).

It is well known that a neurons life span is modulated by its

energy status (Farooqui and Horrocks, 2007). Sirtuins are a family

of NAD+-dependent enzymes that deacetylate substrates ranging

from histones to transcriptional regulators, with the subsequent

formation of nicotinamide and O-acetyl-ADP ribose. The depen-

dence of sirtuins on NADlinks sirtuin activity directly to the energy

status of the cell via the cellular NAD:NADH ratio and the absolute

levels of NAD, NADH or nicotinamide. Sirtuins have been

implicated in the regulation of the molecular mechanisms of

aging. The overexpression of sirtuin leads to lifespan prolongation



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in Saccharomyces cerevisiae and Caenorhabditis elegans that canalso

be reached with CR. Increase in SIRT1 activity (a human NAD+-

dependent protein deacetylase) decreases glucose levels, improves

insulin sensitivity, increases mitochondrial number and function,

decreases production of ROS, improves exercise tolerance, and

potentially lowers body weight (Guarente, 2007). Activation of

SIRT1 mediates the enhancement in activity of multiple proteins,

including peroxisome proliferator-activated receptor coactivator-

1a (PGC-1a) and FOXO, which help in mediating some of the invitro and in vivo effects of sirtuins. SIRT1 not only modulates gene

silencing, DNA repair, rDNA recombination, and aging, but also

regulates apoptosis (Pallas et al., 2008). Thus, an increase in SIRT1

activity protects neural cells against b-amyloid-mediated ROSproduction and DNA damage, and protects against apoptotic death

in vitro. It is also reported that neurons in AD and HD can be

rescued by the over-expression of SIRT1, induced by either CR or

administration of resveratrol, a potential activator of this enzyme.

Pretreatment with resveratrol protects neural cells against

cerebral ischemia (Ravel et al., 2008). The resveratrol-mediated

neuroprotective effect is similar to ischemic preconditioning-

induced neuroprotection against lethal ischemic insult to the

brain. The inhibition of SIRT1 blocks ischemic preconditioning-

induced neuroprotection in the CA1 region of the hippocampus

(Ravel et al., 2008).In mammalian systems, sirtuin activators are known to protect

against axonal degeneration and poly-glutamine toxicity, suggest-

ing the potential therapeutic value of sirtuins in patients with

neurodegenerative diseases, such as AD, PD, and HD. Microarray

analysis of resveratrol-treated human dermal fibroblasts indicates

that genes involved in the Ras and ubiquitin pathways, Ras

protein-specific guanine nucleotide-releasing factor 1 (Ras-GRF1),

receptor-associated coactivator 3 (RAC3), and ubiquitin-conjugat-

ing enzyme E2D 3 (UBE2D3), are downregulated. Based on a

detailed investigation of theeffect of resveratrol, it is proposedthat

resveratrol-induced changes may alter sirtuin-regulated down-

stream pathways rather than sirtuin activity (Stefani et al., 2007).

Collective evidence suggests that the activation of sirtuin extends

lifespan and promotes longevity and healthy aging in a variety ofspecies, potentially delaying the onset of age-related neurode-

generative disorders (Pallas et al., 2008; Rossi et al., 2008; Gan,

2007; Alvira et al., 2007).

Anti-aging medicine is a field of clinical endeavors aimed at

preventing and curing age-related diseases. Anti-aging compounds

stimulate and add natural human elements to help ensure that

the body is able to repair, regenerate, and protect itself (Arking

et al., 2003). The development of specific anti-aging treatments

and the emergence of the practice of anti-aging medicine have

attracted considerable attention in recent years. The most common

anti-aging medicines include nootropic piracetam, ginkgo biloba,

resveratrol, quercetin, catechin, curcumin, ferulic acid, carote-

noids, flavonoids, and estrogens (Table 2). Molecular mechanisms

associated with the neuroprotective actions of these anti-agingmedicines are not fully understood. However, these medicines not

only block oxidative and nitrosylative stress but also exert health

benefits by inducing adaptive cellular stress responses. Available

datafrom limited human clinical practice and experimental animal

studies indicate that treatments with ginkgo biloba, resveratrol,

quercetin, catechin, curcumin, ferulic acid, and flavonoids not only

improve memory and brain metabolism, but also enhance

tolerance to oxidative and nitrosative stress. Collective evidence

from studies suggests that these compounds have great potential

to combat against normal human brain aging and age-related

neurodegenerative diseases.

Dietary supplementation with fruit or vegetable extracts

decreases the age-enhanced vulnerability to oxidative stress and

inflammation. Several studies have indicated that polyphenolic

compounds found in fruits such as blueberries may exert their

beneficial effects through signal transduction and neuronal

communication. Collective evidence suggests that nutritional

supplementation with polyphenolic compounds may exert ther-

apeutic protection against age-related deficits and neurodegen-

erative diseases (Lau et al., 2007). The use of anti-aging remedies

along with physical activity stimulate the regeneration of neurons

in the old brain, and boost the performance of mental and physical

tasks. Collective evidence suggests that physicians already have

anti-aging treatments at their disposal. However, the influence

of such treatments on life span of humans has not been studied.

The increase in humanlife expectancy at birth in the second half of

the last century is mostly caused by enhanced survival at old age.

The use of neuroprotective and regenerative drugs is increasing in

the elderly population of the Western world, and it is suggested

that the use of medicines exerting anti-aging properties may

contribute to an increase in human longevity.

Anti-aging remedies (active prevention) dose not stop or

reverse the aging process. By recognizing and decreasing the risks

of developing chronic diseases provoked by genetic disposition,

lifestyle, and biochemical changes, one can elaborate preventive

strategies. Several factors may account for the slow progress of

anti-aging research. Foremost is a practical problem: the

exceptionally slow biological process of human aging. Anotherproblem is that some of these anti-aging treatments and products

are actually ineffective, and can seriously harm the consumers

(Mehlman et al., 2004). Thus, current anti-aging therapies are

associated with a number of concerns regarding their safety and

efficacy, and the prescription of these therapies is becoming a

challenge from both a legal and ethical perspective (de Grey, 2003;

Grossman, 2005).

8. Conclusion

Aging is an important factor for the pathogenesis of neurode-

generative diseases. Many theories of aging have been proposed

over the years, and no single theory accounts for all the changesthat occur in aging. Aging is a multi-factorial, complex and

inexorable process. An increasedsusceptibility and vulnerability to

diseases at old age in humans may be due to a decline in

physiological functions and a decrease in the ability to cope with

oxidative stress. The field of aging research has exploded with new

information. Researchers have demonstrated the role of several

genes, including vitagenes and sirtuin genes that may modulate

aging and influence longevity. The goal of researchers should be to

not only evaluate how to enhance human longevity, but also to

determine how to remain active and disease-free during aging

(healthy longevity).

Neurodegenerative diseases are multi-factorial diseases that

have complex mechanisms due to multiple pathogenic events. An

unbalanced overproduction of ROS and RNS may give rise to

oxidative and nitrosylative stresses, which can induce neuronal

damage resultingin neuronal death by apoptosis or necrosis. These

diseases are a result multiple genetic defects, and they depend on

the mutations as well as susceptibility to epigenetic or environ-

mental factors. Understanding the pharmacogenomics of neuro-

degenerative diseases may prove beneficial, as it will accelerate the

development of new anti-aging drugs with higher efficacy and

fewer side effects.

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