REVIEW ARTICLE

A metabolic and functional overview of brain aging linkedto neurological disorders

Najma Z. Baquer Æ Asia Taha Æ Pardeep Kumar ÆP. McLean Æ S. M. Cowsik Æ R. K. Kale ÆR. Singh Æ Deepak Sharma

Received: 6 February 2009 / Accepted: 2 April 2009 / Published online: 21 April 2009

� Springer Science+Business Media B.V. 2009

Abstract Close correlations have recently been

shown among the late onset complications encoun-

tered in diabetes and aging linked to neurobiological

disorders. Aging in females and males is considered

as the end of natural protection against age related

diseases like osteoporosis, coronary heart disease,

diabetes, Alzheimer’s disease and Parkinson’s dis-

ease, dementia, cognitive dysfunction and hyperna-

tremia. Beside the sex hormones other hormonal

changes are also known to occur during aging and

many common problems encountered in the aging

process can be related to neuroendocrine phenomena.

Diabetes mellitus is associated with moderate cogni-

tive deficits and neurophysiologic and structural

changes in the brain, a condition that may be referred

to as diabetes encephalopathy; diabetes increases the

risk of dementia especially in the elderly. The current

view is that the diabetic brain features many symp-

toms that are best described as accelerated brain

aging. This review presents and compares biochem-

ical, physiological, electrophysiological, molecular,

and pathological data from neuronal tissue of aging

and hormone treated control and diabetic animals to

arrive at the similarities among the two naturally

occuring physiological conditions. Animal models

can make a substantial contribution to understanding

of the pathogenesis, which share many features with

mechanism underlying brain aging. By studying the

pathogenesis, targets for pharmacology can be iden-

tified, finally leading to delay or prevention of these

complications. Antiaging strategies using hormone

therapy, chemical and herbal compounds were car-

ried out for reversal of aging effects. Neuronal

markers have been presented in this review and

similarities in changes were seen among the aging,

diabetes and hormone treated (estrogen, DHEA and

insulin) brains from these animals. A close correla-

tion was observed in parameters like oxidative stress,

enzyme changes, and pathological changes like

lipofuscin accumulation in aging and diabetic brain.

Keywords Brain aging � Diabetes � Endocrine �Glucose homeostasis � Neuronal markers �Neurodegenerative diseases � Pentose phosphate

pathway

Introduction

Aging is the underlying cause of almost all major

human diseases, and the optimal treatment for each

N. Z. Baquer (&) � A. Taha � P. Kumar �S. M. Cowsik � R. K. Kale � R. Singh � D. Sharma

School of Life Sciences, Jawaharlal Nehru University,

New Delhi 110067, India

e-mail: nzbaquer@gmail.com

P. McLean

Division of Infection and Immunity, University College

London Medical School, London W1T 4JF, UK

123

Biogerontology (2009) 10:377–413

DOI 10.1007/s10522-009-9226-2

and every disease is to prevent or delay the onset of

these age related diseases by intervening in the basic

process of aging, may be the ideal solution for

monitoring/or improving the quality of life. Recently

Rattan and Singh (2009) have reviewed and evaluated

the scientific basis for developing potential therapies

and modes of intervention in the process of aging,

with special reference to involving gene therapy, the

authors have also discussed the biological under-

standing of aging, a well understood problem in

biology. Age related neurological disorders like

Alzheimer’s disease (AD) and Type 2 diabetes

mellitus (T2DM) are conditions that affect a large

number of people, both conditions are on the increase

and finding novel treatments to cure or prevent them

are a major aim in research. AD and T2DM share

several molecular processes that underline the respec-

tive degenerative development. Disturbance in insu-

lin signaling appears to be the main common

impairment. Insulin signaling affects blood glucose

levels and also acts as a growth factor for all cells

including neurons in the CNS. The common patho-

logical processes in AD and T2DM have recently

been reviewed by Li and Holscher (2007). Harman

(1956, 1981) was the first to propose free radicals

vital role in aging and reported an age dependent

decrease in antioxidant defense system. The brain is

especially vulnerable to oxidative damage as a result

of its high oxygen consumption rate, its abundant

lipid content, and relative paucity of antioxidant

enzymes as compared to other tissue. The biological

system possesses defense mechanism against the

removal of reactive oxygen specie (ROS). Endoge-

nous reactive oxygen species that are generated from

aerobic metabolism are probably the most important

causes of age related neuronal damage. Under normal

physiological conditions, a balance exists between

the production of ROS and the systems antioxidant

mechanism. The toxic O2- and OH- radicals have

been implicated in age related disorders, diabetes and

many other disease like cancer, atherosclerosis and

others by causing non specific glycation of protein,

peroxidation of membrane lipid and cross linking of

proteins, causing loss of organelle function and cell

death.

Aging of the normal brain is accompanied by

changes in its structure, function and metabolism.

There are significant gender differences in brain

aging e.g., brain atrophy starts earlier in men than

women (Kaye et al. 1992), however, once started it is

relatively more rapid in women, than the age matched

men (Takeda and Matsuzawa 1985). These gender

differences occur in regions essential to cognitive

function and are implicated in neurological disorders.

The consequences of aging of the neuroendocrine

system have been incriminated in the development of

various age dependent conditions such as insulin

resistance, osteoporosis, muscular atrophy and abnor-

malities of fat deposition. Aging effects the endocrine

system by altering endocrine cells, the hormones

produced by these cells and hormone receptors or

post receptor processes in the target cells (Veiga et al.

2004). The sex hormones androgens, estrogen and

progestins are among the peripheral signals that

modulate neuronal function and development; they

act on the neurons and glial cells regulating differ-

entiation, survival and neuronal connectivity both in

the brain and spinal cord. They act in the adulthood

modulating neurotransmitter synthesis, neurotrans-

mitter receptor expression and synaptic transmission

and remodeling.

The implication for brain function in aging and

diabetes has been reviewed by Biessels et al. (2002b).

Diabetes is associated with moderate cognitive def-

icits and neurophysiologic and structural changes in

the brain. Emerging view is that the diabetic brain

features many symptoms that can be described as

accelerated brain aging. Authors have explored and

discussed the neurological complications of diabetes

focusing on brain particularly the metabolic and

pathogenic mechanism, and the possible interactions

of diabetes and aging. Aging being the progressive

and gradual accumulation of detrimental changes in

structure and function over time would also be

evident in nervous electrical activity of the brain.

Electrical activity will not only be a reflection of the

aging of some baseline process of the nervous system

but its alteration may contribute to physiological and

behavioral changes associated with aging (Nygard

et al. 2005)leading to decrement in neurological

function (Singh and Sharma 2005).

In this review an attempt has been made to

evaluate and present data highlighting the similarities

among physiological, biochemical, electrophysiolog-

ical, and molecular changes associated with aging,

diabetes and steroid hormone therapies to aging

animal models, also discussing some potential anti

aging strategies used.

378 Biogerontology (2009) 10:377–413

123

Glucose utilization by the brain

The brain utilizes approximately 20% of all the glucose

metabolized by the entire body at rest (Sacks 1965)

mainly via the two major alternative pathways of

carbohydrate metabolism that is glycolysis coupled to

the tricarboxylic acid cycle and pentose phosphate

pathway. The largest proportion of glucose consumed

is via the energy producing glycolytic and tricarboxylic

acid pathway (Fig. 1). The pentose phosphate path-

way, although quantitatively a minor route of glucose

metabolism, appears to provide essential function in

cerebral tissue depending on the stage of development

(Baquer et al. 1977) or the region of the brain (Lowry

1964). The role in the brain of the glycolytic pathway

and the tricarboxylic acid cycle and the route by which

glucose carbons are incorporated into glutamate and

GABA (c-amino butyric acid) through the action of

these pathways have been amply reviewed (Baquer

et al. 1977; Balazs 1971; McIlwain and Bachelard

1985; Himwich 1974; Zubairu et al. 1983).

Pathways of glucose metabolism

The pattern of glucose metabolism in brain during

development and aging changes both in enzyme

profile (Wilson 1973; Mac Donnell and Greengard

1974; Leong et al. 1981; El-Hassan et al. 1981) and

the proportioning of glucose among different path-

ways (Baquer et al. 1973, 1975; Zubairu et al. 1983)

of its metabolism. Age related changes have been

reported to occur in the rate of glucose utilization

(Smith and Thompson 1987), oxygen uptake (Peng

et al. 1977), lipid synthesis (Mcilwain and Bachelard

1985), and monoamine metabolism (Carlsson et al.

1980; Leong et al. 1981). Hence corresponding

changes in the pathways of glucose metabolism will

occur to meet the shifting requirements of aging

Fig. 1 Interrelationships of

pathways of glucose

metabolism. The glucose

carbon from which the CO2

of each pathway originates

is shown in brackets.

Calculation for each

pathway contribution is

shown in Table 1. Adapted

from Baquer et al. (1975)

Biogerontology (2009) 10:377–413 379

123

brain. The pattern of glucose metabolism in the brain

of rats has been elucidated in ages ranging from

20 days to adult (Hothersall et al. 1979; Zubairu et al.

1983). The glucose flux through glycolysis, the

tricarboxylic acid cycles, pentose phosphate pathway

and glutamate-c-amino butyrate pathway had been

carried out by earlier described procedures (Table 1).

Experimental approaches to study of metabolic

pathways

The nature and metabolic function of the component

pathways can be achieved and arrived at by using

three different types of experimental approaches each

of which contribute a different type of information.

These may be summarized.

a. Enzyme studies which yield information on the

presence or absence of enzymes, the maximal

potential activity of the enzymes present and the

existence or appearance of enzymes of special

significance to the tissue, from an analysis of the

occurrence of constant and specific proportion

enzymes (Pette 1966; Baquer et al. 1973). Such

studies can be extended by histochemical inves-

tigation of the regional and subcellular location

of important enzymes.

b. The measurement of the actual flow of substrates

through pathways or segments of pathways

(utilizing labeled 14C-substrates) which in com-

bination with (a) yield information on the

existence of control mechanisms either regulat-

ing the flow of such substrates through a pathway

Table 1 Alternative pathways of glucose utilization in aging rat brain using differentially labelled 14C substrate

Labeled substrate 20 days 4 months 12 months 26 months % Decrease 26/

4 months 9 100

CO2 yields

[1-14C]glucose 4.41 ± 0.20 4.0 ± 0.22 3.41 ± 0.15 2.17 ± 0.05 54

[1-14C]glucose ? PMS 31.0 ± 1.8 26.2 ± 0.9 23.0 ± 0.9 13.4 ± 1.1 51

[2-14C]glucose 8.65 ± 0.48 9.07 ± 0.48 6.95 ± 0.43 5.76 ± 0.22 64

[3,4-14C]glucose 15.4 ± 0.70 15.6 ± 0.9 15.8 ± 0.5 11.8 ± 1.1 76

[6-14C]glucose 3.69 ± 0.14 3.26 ± 0.21 3.12 ± 0.08 2.53 ± 0.19 78

[6-14C]glucose ? PMS 3.8 ± 0.37 3.5 ± 0.3 2.94 ± 0.17 2.76 ± 0.29 79

[1-14C]pyruvate 33.2 ± 0.24 27.3 ± 1.5 28.1 ± 2.1 30.9 ± 2.2 113

Pathway estimates

Glycolysis ? TCA14CO2 ? C3,4/C6

4.17 ± 0.50 4.78 ± 0.35 5.06 ± 0.44 4.66 ± 0.6 97

Pyruvate dehydrogenase14CO2 ? Py-1

33.2 ± 0.24 27.3 ± 1.5 28.1 ± 2.1 30.9 ± 2.1 113

Pentose phosphate pathway (PPP)14CO2 ? C1–C6

0.71 ± 0.13 0.74 ± 0.17 0.30 ± 0.09 0.36 ± 0.10 Not detected

Activated ? PPP14CO2 ? C1–C6

26.9 ± 2.1 22.3 ± 0.9 20.4 ± 1.1 10.6 ± 0.9 48

Glutamate: GABA pathway14CO2 ? C2–C6

5.17 ± 0.45 6.12 ± 0.37 3.88 ± 0.32 3.23 ± 0.22 53

Biodata

Body weight (gm) 40.8 ± 1.4 396 ± 18 687 ± 13 630 ± 19

Brain weight (gm) 1.23 ± 0.06 2.15 ± 0.14 2.27 ± 0.07 1.92 ± 0.04

Protein mg/g WH 108 ± 8.0 224 ± 19.0 240 ± 26 188 ± 18.0

The values are given in lmoles/g/h and are mean ± SEM of 4–6 values. Table derived from Zubairu et al. (1983) and all procedures

and calculation of pathways are as described there. The PMS concentration was 0.1 mM. Subscripts designate the position of the 14C

label in glucose and pyruvate

380 Biogerontology (2009) 10:377–413

123

or apportioning substrates between pathways

(Zubairu et al. 1983).

c. Measurements of the standing concentration of

the metabolic intermediates of pathways usually

before and after a particular treatment which

pinpoint the location of the control points

indicated in (b) and help define the factors which

regulate such control points (Exton 1975). Such

measurements have been done under ischemia,

anaesthesia and hypo and hyperthermia and

during intoxication such as fluoroacetate or

indoacetate poisoning (Kauffman et al. 1969),

ammonia intoxication and 6-aminonicotinamide

poisoning (Kauffman 1972; Hothersall et al.

1981). This approach has also been used in the

study of changes in the brain in experimental

diabetes and following insulin treatment (Thur-

ston et al. 1975). The time sequence according to

which the brain taps the reserve supply of energy

has been revealed in this way (Lowry 1964).

The extension of these approaches to human

studies present considerable ethical and technical

problems. Isotope studies have been carried out using

arterio-venous difference (Sacks 1965). Specialized

micro techniques for enzyme determination on

microgram quantities of tissue developed by Lowry

and his collaborators (Kauffman 1972; Kato and

Lowry 1973) may possibly be applied to biopsy

samples or the possibility of parallel changes which

mirror brain enzyme lesions occurring in other, more

readily available cells-such as leucocytes, may pro-

vide a useful probe for the study of brain disorders of

genetic origin. It is important to note that metabolic

derangements can arise not only from enzyme

deletions but also from a modification of the control

elements regulating enzymes and their pathways.

Elucidation of pathways of carbohydrate

metabolism using 14C labeled substrates

The oxidation of differentially labeled glucose pyru-

vate, and glutamate measured in brain slices from

cerebral hemispheres of aging rat has been studied by

Zubairu et al. (1983). Pathways calculated using this

study over aging from 20 days to adult brain were

measured and their contribution calculated.

The glycolytic and tricarboxylic acid pathway, the

pentose phosphate pathways and the Glutamate

GABA shunt (latter very specific to the brain) have

been calculated and the percentage changes over the

age span have been shown in Table 1. Results

showed that over 4–26 months there was an approx-

imately 20% decrease in the production of 14CO2 via

the glycolytic tricarboxlic acid cycle route, the

Glutamate GABA pathway falls by about 50% over

this same life span. The broad activity of the pentose

phosphate pathways falls rapidly and cannot be

detected in the brain of rats aged 18 months or more,

whereas the fully stimulated pathway, i.e., in the

presence of artificial electron acceptors, phenazine

methosulphate decline only marginally over this

period. The pentose phosphate pathway is stimulated

by the presence of 5-hydroxytyptamine and this

stimulation appears to increase with age, the latter

effect on the pentose phosphate pathway has been

described in detail elsewhere (Hothersall et al. 1982;

Table 1).

Pentose phosphate pathway

Baquer et al. (1977) discussed the connection

between pentose phosphate pathway activity and the

presence of the neurotransmitters, that it could be

related either to the process of transmission itself or

to the metabolism of the neurotransmitters. It was

proposed that the aldehydes produced by the action of

MAO on the catecholamine were reduced to the

corresponding alcohols by NADPH-linked aldehyde

reductase. Baquer et al. (1975) also suggested that

NADPH produced by the pentose phosphate pathway

also served an additional function, i.e., the protection

of membrane lipids, from peroxidative damage

resulting from the appearance of the monoamine

degradation product hydrogen peroxide. The pentose

phosphate pathway does protect the brain from

peroxidative damage via the glutamate peroxides

and glutathione reductase The significance of the role

of pentose phosphate pathway in brain during aging

has been reviewed by Baquer et al. (1975, 1988;

Fig. 2) the presence of these enzymes in synapto-

somes and their linkage with peroxidative mecha-

nisms, monoamine oxidase and glutathione pathway

suggested that they may be serving an important role

in the brain in vivo (Hothersall et al. 1982).

Saggerson (2009) in a classic paper series has

recently shown that research into the pentose phos-

phate pathway has arisen from the realization that

Biogerontology (2009) 10:377–413 381

123

NADPH is essential for the protection of cells against

reactive oxygen species through coupled actions of

glutathione peroxidase and reductase and that glucose

6 phosphate dehydrogenase gene, through this adap-

tivity to oxidants appears to act as a sentinel against

potential damage by these agents (Fig. 2).

Glutamate: GABA pathway

The activity of the glutamate: GABA pathway falls

sharply between 4 and 8 months and very slowly

thereafter (Zubairu et al. 1983), in 26 months the

pathway exhibits only about 50% of the activity of

the young adult. Calculation of the partition of the

oxidation of glutamate through either the TCA or

through glutamate decarboxylation (Hothersall et al.

1979; Zubairu et al. 1983), shows that neither of these

pathways change appreciably over the time range of

20 days to 26 months, indicating that the inhibitors of

the glutamate: GABA route arise earlier in the

metabolic sequences, agreeing with the earlier obser-

vation (Epstein and Barrows 1969) that glutamate

decraboxylase, the rate limiting enzyme of the

glutamate GABA pathway, does not change with

age (Table 1).

Ketone body metabolism

Though we are talking about and discussing the

significance of carbohydrate metabolism (mainly

glucose), it must, however, be emphasized that the

ketone bodies also constitute a major source of

energy and substrate for the brain, particularly in

periods of high fat utilization, e.g., during suckling of

the young, or in the starving or diabetic adult. During

such periods changes in the enzymes profile reflect

the adaptation to high ketone body utilization (Klee

and Sokoloff 1967). Interactions between ketone

body and glucose metabolism have also been

reviewed (Buckley and Williamson 1973).

By the time adult stage is reached the normal brain

uses carbohydrate almost exclusively. This almost

total dependence of the brain on the utilization of

glucose carries a significant corollary for clinicians

Fig. 2 Role of glutathione cycle and the pentose phosphate

pathway in the detoxification of hydrogen peroxide and

biogenic amines in rat brain. Activation of the pentose

phosphate pathways linked to the degradation of biogenic

amines by monoamine oxidase (MAO) through the formation

of H2O2. Adapted from Baquer et al. (1977)

382 Biogerontology (2009) 10:377–413

123

investigating nervous disorders, that any major

defects in the pathways of glucose degradation are

likely to be lethal. It is only in the subsidiary

pathways of glucose utilization, or in pathways which

partially depend on an aberration could produce a

nonfatal condition.

It is clear that a tissue which has so many

specialized functions must also have a variety of

metabolic pathways which are either unique to the

tissue, or of special significance in it, nevertheless it

is true that the major pathways of glucose metabolism

are the same in brain as they are in other tissues. The

importance of these main pathways of glucose

utilization and the specialized role they play, how

they are controlled and integrated and how these

change with development, through the stages of

growth and aging myelination and the onset of

neurotransmission in the brain have been amply

reviewed (Baquer et al. 1975, 1990; Hothersall et al.

1979; McIlwain and Bachelard 1985). A knowledge

of these basic processes is essential to the study of

brain disorder and brain aging in which aberrations of

certain routes of glucose metabolism may occur.

Developmental changes in carbohydrates metabo-

lism and the regulatory features of key control

reactions have of necessity been investigated mostly

in experimental animals and it is from these sources

that our main evidence on the detailed biochemical

knowledge of the regulation of glucose metabolism in

the brain has come.

Age related changes in brain parameters

Enzyme changes in whole brain

The effect of aging on brain enzymes has been

studied by many investigators (El-Hassan et al. 1981;

Hothersall et al. 1981; Zubairu et al. 1982; Baquer

et al. 1990; Kaur et al. 1998, 2001, 2003; Kaur and

Lakhman 1994). Measurements had been made of the

enzymes of the glycolytic, pentose phosphate and

lipogenic pathways and some marker enzyme of TCA

cycle in brains of rats between 20 days and

24 months. In general, the activity of most enzymes

remained unchanged; except that there was an

increase of hexokinase, glucose-6-phospahate dehy-

drogenase and malic enzyme and decrease of ATP

citrate-lyase, acetyl Co-A carboxylase and fatty acid

synthetase (El-Hassan et al. 1981). The enzymes of

glutathione metabolism and NADPH generation

showed a differential pattern, controlling the redox

state of the brain, the role of glutathione related

enzymes in controlling the hydrogen peroxide metab-

olism and suppressing peroxidative damage to the

brain was discussed (Hothersall et al. 1981). The flux

of glucose in the pathways of acetyl group formation

and disposal and the activities of a range of enzymes

related to these were measured in aging rats up to

24 months. The pattern of enzyme changes in system

involving hydrogen transfer system appears to

increase disproportionately relative to the glycolytic

flux in the brain. Results suggested that these

increases are an essential corollary to the need for a

maintained glycolytic flux in a tissue dependent upon

glucose as a fuel and one in which alternative routs of

NADPH oxidation diminish with age (Zubairu et al.

1982; Baquer et al. 1988).

Synaptosomal and membrane linked enzymes

Baquer et al. (1988, 1990) had studied a number of

soluble and membrane associated enzymes of gly-

colysis, pentose phosphate pathways, and other

related enzymes from three different brain regions

of aging animals and enzymes utilizing and synthe-

sizing peroxides. Increasing levels of peroxidative

products are known to accumulate in the brain with

age. The membrane associated enzymes were found

to be the primary focus of damage. Phosphofructo-

kinase and glucose 6 phosphate dehydrogenase

exhibited an unusual pattern when measured in whole

homogenates. A progressive decrease in the synap-

tosomal bound hexokinase was found with increasing

age. The synaptosomal phosphofrucktokinase also

showed a significant decrease with aging. Significant

decrease in the incorporation of myoinositol into

phospholipids and a loss of activity of membrane

bound adenylate cyclase must be occurring in the

structure of the brain and the loss of cerebral

competence in the senescent brain may arise from

peroxidative damage to membranes (Table 2; Fig. 3).

Baquer et al. (1990) had shown a clear decrease in

myoinositol incorporation into phospholipids with

aging. The result was important since it is known

that phospholipids are the most rapidly renewed

components of the nerve sheath, that they bind Ca2?,

one of the source of fatty acid precursors of the

Biogerontology (2009) 10:377–413 383

123

prostaglandin and are associated with transport

phenomenon. This fall in the myoinositol incorpora-

tion would be reflected in changes in the structure and

fluidity of the membranes (Mantha et al. 2006) and

hence would produce wide spread changes in aspects

of nerve behaviour.

The formation of C’AMP by adenylate cyclase is

one of the key steps in neurotransmission and has been

implicated as an essential step in the mechanism of

action of noradrenalin and dopamine and to a lesser,

but still important extent of serotonin. The decrease in

the activity of adenylate cyclase with age is notable in

the cerebral hemispheres, but is very large in the

cerebellum and the brain stem, latter not shown in

Table 2 (Greengard and Kebabian 1974; Baquer et al.

1983, 1990; Hothersall et al. 1983; Table 2).

Table 2 Effect of aging on

glycolytic NADP linked

and other membrane linked

enzymes in rat brain

cerebral hemispheres

Myoinositol incorporation

is given as pmoles/g/h at

37�C. Values are given as

mean SEM each group not

less than six. Detail

described in Baquer et al.

(1990). Units are l moles

substrate converted per

minutes at 25�C, with the

exception of adenylate

cyclase which is in nmoles/

g/min/g/min

WH whole homogenate

Enzymes Age (months) (l moles/g/min)

Glycolytic 0.7 6 12 30

HK 11.5 ± 0.3 18.6 ± 3.1 18.5 ± 1.9 16.8 ± 1.5

PFK 17.54 ± 1.55 18.75 ± 1.4 21.03 ± 1.4 18.8 ± 2.8

Gly-3-P-D 0.93 ± 0.15 1.42 ± 0.3 1.78 ± 0.21 2.03 ± 0.09

Membrane linked

Na?K? ATPase 15.3 ± 0.15 10.3 ± 2.3 11.3 ± 4.5 11.5 ± 1.6

Adenylate cyclase 68.9 ± 7.5 87.7 ± 13.2 84.0 ± 16.0 75.4 ± 1.0

Myoinositol incorporation 4.34 ± 0.64 2.71 ± 0.3 1.75 ± 0.14 1.06 ± 0.11

Glutamate dehydrogenase (NAD) 28.5 ± 8.0 36.3 ± 7.0 62.3 ± 9.0 32.0 ± 2.8

NAPD-linked

G 6 P dehydrogenase 1.11 ± 0.1 1.3 ± 0.07 1.21 ± 0.05 1.2 ± 0.08

6 P G dehydrogenase 0.75 ± 0.06 0.55 ± 0.07 0.75 ± 0.09 0.60 ± 0.07

Malic enzyme 0.97 ± 0.08 1.51 ± 0.12 1.55 ± 0.09 1.78 ± 0.03

Glutamate dehydrogenase 22.3 ± 2.6 25.6 ± 2.5 23.3 ± 6.8 15.0 ± 1.4

Antioxidant

Glutathione peroxidase 1.4 ± 0.14 1.93 ± 0.13 2.22 ± 0.19 4.23 ± 1.39

Glutathione reductase 0.98 ± 0.07 1.06 ± 0.13 1.18 ± 0.15 1.63 ± 0.21

Biodata

Brain weight (CH) 0.99 ± 0.02 1.28 ± 0.12 1.25 ± 0.04 1.38 ± 0.1

Protein (mg/g)

Whole homogenate 76.3 ± 3.3 82.3 ± 4.1 78.5 ± 3.2 61.0 ± 5.0

Synaptosomes 16.3 ± 4.9 19.4 ± 2.8 24.5 ± 3.6 17.0 ± 2.0

Fig. 3 Synaptosomal

enzymes in Aging rat brain

cerebral hemispheres.

Percentage changes in the

activities of NADP linked,

glycolytic and membrane

associated enzymes from

synaptosomes prepared

from cerebral hemispheres

of aging rat brain taking

20 days old as 100%.

Figure derived from Baquer

et al. (1990)

384 Biogerontology (2009) 10:377–413

123

Earlier work and ample evidence has shown that

peroxidative damage to lipid and protein occurs with

the aging process and the products of these reactions

accumulate in the brain with age (Bondereff 1964;

Mann and Yates 1974; Davison and Wright 1980;

Baquer et al. 1990; Moorthy et al. 2004a, 2005a, b;

Bala et al. 2006; Sinha et al. 2005, 2008).

The changes observed in the activity of enzymes in

isolated synaptosomes seemed to be more severely

affected with aging in brain region. These changes

(decrease) could be due to the extreme complexity of

brain structure and the compartmentalization of vari-

ous modulators for enzyme activities. For example the

concentration of the allosteric activator of phospho-

fructokinase, namely fructose 2, 6, bisphosphate may

decrease with age, or it may be in some other cellular

compartment, unavailable to the enzyme. The concen-

tration of glucose-6-phosphate or NADPH may also

modulate hexokinase and glucose-6-phosphate dehy-

drogenase activities, respectively (Fig. 3).

The significance of the pentose phosphate dehy-

drogenases in brain fractions has been discussed in

detail in earlier section of the review (Baquer et al.

1975, 1977, 1988). Among the factors that could be

important in relation to the apparent age-related

decrease in the activity of the pentose phosphate

pathway are two prominent ones (1) possible

decrease in the activity of hexokinase and the two

oxidative enzymes of the pathway glucose-6-phos-

phate dehydrogenase and 6 phosphogluconate dehy-

drogenase (2) a decrease in the availability of NADP.

The synaptosomal hexokinase also decreased with

aging (Fig. 3). The flux through the pathway may

also be decreased or shut off by increase in the

concentration of NADPH, a very strong inhibitor of

the two pentose phosphate pathway dehydrogenases

since three systems utilizing NADPH, i.e., the

lipogenic route: glutamate, GABA synthesis and

antioxidant system (glutathione) are depressed with

aging, leading to a concomitant fall in the expressed

activity of the pentose phosphate pathway (Hothersall

et al. 1981; Zubairu et al. 1983; Table 1).

Changes in membrane linked enzymes with age

As lipid and protein are essential components of

membranes, a change in the enzymes linked to

membrane may occur during the aging process.

Baquer et al. (1990) measured membrane linked

enzymes, namely adenylate cyclase, synthesizing

C’AMP, involved in neurotransmission in the brain

(Greengard and Kebabian 1974) and Na?K? ATPase

(Baquer et al. 1990; Moorthy et al. 2004a, 2005a, b;

Siddiqui et al. 2005) both enzymes controlling the

polarization of neurons.

A number of glycolytic and other soluble enzymes

were found to be bound to the membrane (Baquer

et al. 1975, 1990). It has been reported (Svoboda and

Mosinger 1981) that the microsomal brain Na?K?

ATPase can be selectively inactivated by an endog-

enous system (Ascorbic acid and Fe2?) which

appears to act via a mechanism identical with the

free radical induced phospholipid peroxidation. Sim-

ilar results had been reported by Sun and Samorajiski

(1975). This conclusion together with the results of

Logan and George 1982, Logan and Newland 1982

and Logan et al. (1982) on the catecholamine

inhibition of Na?K? ATPase elucidates and shows

changed neurotransmitter sensitivity with age.

Moorthy et al. (2005a, b) and Mantha et al. (2006)

had also shown that the activity of AChE decreased

with increasing age in different regions of the brain

and also in peripheral nerve. The decline in the

activity of the enzyme in old age may be due to loss of

neuron/or a decrease in protein synthesis and a

decrease in the number of synapse with aging, making

synaptic transmission less effective (Table 3).

The role of the enzyme acetyl choline esterase

(AChE) has been recently reviewed in the nervous

system and other tissues. AChE inhibitors have been

clinically used in neurodegenerative disease (Tripa-

thy and Srivastava 2008). These disorders are neu-

romuscular disorders like Myasthenia Gravis and

glaucoma, and the cholinergic deficient glaucoma

associated with AD. Clinically, moderate inhibitors

of AChE are given in the treatment of these diseases

to prolong the effect of acetylcholine (ACh) on the

receptor, such treatments are desirable either if there

is reduced concentration of ACh, as shown in AD, or

if there are fewer receptors for acetylcholine as in the

case of Myasthenia Gravis.

Mantha et al. (2006) also showed changed neuronal

markers with aging in female rat brain synaptosomes.

AChE and Na?K? ATPase activity in synaptosomes

decreased with age as compared to young rats. A

decreased activity of Na?K? ATPase with aging

has been reported in female rat brain synaptosomes

and its significance discussed (Fraser and Arieff

Biogerontology (2009) 10:377–413 385

123

2001). A decreased Na?K? ATPase activity with age

could result in neurotoxicity resulting in neuronal

vulnerability to excitotoxic insults to the neuronal

cells. The authors also showed changes in the fluidity

of membrane lipids during aging and lipid peroxida-

tion. Vitorica and Satrustegui (1986) had earlier

evaluated the influence of an altered lipid phase in

rat brain mitochondria with aging. Changes in neuro-

nal markers with aging have been presented in

Table 3.

Changes in membrane structure with aging

The changes in myoinositol incorporation, showing a

clear decrease in the myoinositol incorporation into

phospholipids with aging and the loss of activity of

adenylate cyclase with aging indicate that changes

must be occurring in the structure of the brain

membrane, particularly the integrity of the membrane

associated hormone binding site and the linking of

these sites to their effectors system in the membrane

in aged rats, can these deleterious effects be pre-

vented? For example, by dietary regime or hormonal

administration to aging animals to suppress formation

of free radicals. Moorthy et al. (2005a) have shown

that administration of estradiol and progesterone

reverse some of the aging effects in older animals.

Mantha et al. (2006) had shown the changes in

membrane fluidity in synaptosomes with age. Effects

of estrogen and DHEA administration have recently

been shown on aging brain in female and male aging

animals (Moorthy et al. 2004b; Kumar et al. 2008;

Sinha et al. 2008; Tables 3, 6).

Aging and effect of hormone interactions,

peptide and steroid

Aging is an important event in the life of mammals,

including human beings, during which a number of

metabolic and hormonal changes take place. In the

female rat the concentration of circulating hormones,

estrogen (E2) and progesterone (P) decrease with age

(Lapolt et al. 1988; Moorthy et al. 2005a; Fig. 4)

leading to various health problem such as diabetes,

cardiovascular complications, osteoporosis and oth-

ers. Veiga et al. (2004) have reviewed the changes in

the sex hormones and brain aging, and the authors

have discussed the role of these hormones in

modulating neurotransmitter synthesis, neurotrans-

mitter receptor expression and synaptic transmission

and remodeling, emphasizing that the nervous system

Table 3 Changes in neuronal markers in aging brain cerebral hemispheres

Age/treatment AChE SOD GOT GPT MDA Na?K? ATPase

3 months

Control 75.1 ± 2.2 8.64 ± 0.64 38.66 ± 2.79 68.73 ± 4.05 0.23 ± 0.03 9.03 ± 0.12

12 months

Control 43.1 ± 2.6 5.12 ± 0.04 32.91 ± 1.56 48.67 ± 3.21 0.30 ± 0.015 3.59 ± 0.22

C ? E 52.6 ± 2.1 7.69 ± 0.09 27.9 ± 3.9 27.01 ± 3.9 0.22 ± 0.25

C ? E ? P 55.5 ± 1.9 8.82 ± 0.8 23.05 ± 1.3 25.21 ± 3.5 0.20 ± 0.30

18 months

Control 30.0 ± 1.1 3.03 ± 0.55 24.37 ± 1.06 30.95 ± 2.6 0.40 ± 0.035 0.97 ± 0.18

C ? E 36.9±1.8 6.94 ± 0.4 21.56 ± 1.43 22.15 ± 3.2 0.29 ± 0.025

C ? E ? P 40.1 ± 1.9 7.15 ± 0.6 17.56 ± 1.6 17.83 ± 2.7 0.25 ± 0.02

24 months

Control 24.0 ± 1.1 1.86 ± 0.2 20.98 ± 1.25 23.93 ± 2.11 0.45 ± 0.028 0.61 ± 0.03

C ? E 29.9 ± 1.3 3.56 ± 0.36 16.59 ± 1.41 18.12 ± 2.7 0.37 ± 0.02

C ? E ? P 33.1 ± 2.2 4.28 ± 0.41 14.75 ± 1.07 16.93±3.05 0.34 ± 0.31

Effect of estradiol and progesterone. Each value is a mean SEM of six or more values. The concentrations of MDA are given as

nmoles/mg protein. Units are defined as AChE is micro-units/mg protein and SOD as mu/mg protein. GOT and GPT are defined as

described in Moorthy et al. (2005a, b)

E estrogen, P progesterone

386 Biogerontology (2009) 10:377–413

123

is a target for sex hormones and a source of sex

steroids (Koricanac et al. 2004; Table 5).

The physiological variations in the concentration

of sex hormones could affect the insulin receptor

action and their interaction with glucose, thereby

altering the carbohydrate metabolism (Valdes et al.

1991). Various clinical and experimental data suggest

that insulin and sex hormones interact and affect the

carbohydrate metabolism. The rate of glucose trans-

port into the cells is regulated by both peptide and

steroid hormones, IRS-1, insulin receptor substrate is

down regulated with a high concentration of 17bestradiol in menopausal women which could be

responsible for the upregulation of IRS-1, increasing

insulin sensitivity in muscle and adipose tissue, Glut

1 is the glucose transporter expressed in most of the

tissues including uterus, the largest being in brain

cells (Roy and Jack 1999). Earlier report on the effect

of age and insulin showed that pancreatic insulin

secretion at the plasma membrane level is impaired in

older animals probably regulating the flux of glucose

into the brain, thus affecting glucose metabolism

(Draznin et al. 1985).

Variations in the physiological concentration of E2

also control and regulate the glycolytic pathway

required for the additional energy and/or metabolites

for the neurotransmitters (Fig. 4). Thomas et al.

(1986) had previously reported that the serum insulin

and glucose levels were increased by E2 administra-

tion and combined treatment of estrogen and proges-

terone, when compared with the ovariectomy and

intact groups. Reduced glucose uptake has been shown

to occur early in AD prior to neuronal degeneration

(Jay et al. 1994). The decreased rate of both glucose

Estradiol

0

10

20

30

40

50

60

70

80

Co

nce

ntr

aio

n i

n p

g/m

l

Proestrous

Estrous

Metaestrous

Diestrous

12 months

18 Months

24 Months

Proestrous

Estrous

Metaestrous

Diestrous

12 months

18 Months

24 Months

Progesterone

0

2

4

6

8

10

12

14

16

18

20

Co

nce

ntr

atio

n in

ng

/ml

Fig. 4 Estradiol and

progesterone levels in aging

female rats. Levels of

Estradiol and progesterone

in different stages of 3, 12,

18 and 24 months old rats.

Each value is a

mean ± SEM of six

separate values. Table

adapted from Moorthy et al.

(2005b)

Biogerontology (2009) 10:377–413 387

123

and ketone body utilization have been observed in

aged brain, but energy requirement remains the same

when compared with young animals (Smith et al.

1987; McIlwain and Bachelard 1985). The decreased

utilization of glucose in the brains of AD patients may

be related in part with reduction in the activity of

enzymes related to acetylcholine synthesis, the sensi-

tivity of this transmitter to dysfunction of glucose

metabolism has been reported (Dash et al. 1991; Gupta

et al. 1992a). Changes in acetylcholine esterase

activity have been shown to occur in brain of diabetic

and aging animals (Khandkar et al. 1995; Moorthy

et al. 2005a, b; Mantha et al. 2006; Table 4).

Meier-Ruge et al. (1984) have reported signifi-

cantly lower levels of activity of glycolytic enzymes

HK and PFK in sample taken from patients with

confirmed Alzheimer’s disease compared with age

matched control subjects. Dena and Phyllis (2001)

have reported that estradiol plays a neuroprotective

role in the injured brain of both young and middle

aged rats and data suggest, as reported by Moorthy

et al. (2004b) also, that older women might also

benefit from the protective effects of HRT(hormone

replacement therapy) that uses a relatively lower

concentration of hormones. Keller et al. (1997) have

demonstrated that estradiol can directly act on the

synapse and protect critical membrane transport

systems from oxidative impairment particularly

Na?K? ATPase. Steroid hormones are also known

to affect the sensitivity of cells to insulin.

Estrogen has been shown to rapidly activate

several components of signal transduction pathway

including those associated with glucose transport

translocation, such as MAP Kinase (Morley et al.

1992; Aronica et al. 1994; Migliaccio et al. 1996).

Results of Moorthy et al. (2004b), showed that

treatment of older rats with estrogen/progesterone

alleviate the glucose transport in the tissues of older

rats treated with the hormone. Results showed

(Moorthy et al. 2005a) that the hormone levels used

are at lower doses, than that given for HRT

treatments. The amount of estrogen levels taken were

equivalent to those found in 3 months old, adult rat

(Fig. 4). Estrogen and combined, estrogen and pro-

gesterone given to aging rats caused a series of

growth related responses, such as increase uptake of

glucose, increased protein levels, increased glucose

oxidation and decreased gluconeogenesis (Birge

2003; Veiga et al. 2004).

Effect of aging and estrogen on neuronal enzymes

Oxidative stress and neuronal damage in aging

Brain is susceptible to oxidative stress which is

associated with age related brain dysfunction, due to

its high content of key compounds for oxidative

damage and the relevant scarcity of antioxidant

defense systems (Poon et al. 2006). Protein oxidation,

which results in functional disruption, appears to be

associated with increased oxidation in specific pro-

teins and has been implicated in the progression of

aging and age related neurodegenerative disorders

such as AD. Protein carbonyls, a marker of protein

oxidation are increased in Alzheimer’s brain (Caste-

gna et al. 2002; Poon et al. 2006). Oxidative damage

can lead to several events such as loss in specific

protein function, abnormal protein clearance, deple-

tion of cellular redox—balance and interference with

the cell cycle and ultimately to neuronal death.

Further it has been reported that creatine kinase BB

and b-actin are specifically oxidized in Alzheimer’s

brain. However, recently the powerful technique,

emerging from application of proteomics to neuro-

degenerative disease, revealed the presence of spe-

cific targets of protein oxidation in Alzheimer’s

brain: creatine kinase BB, glutamate synthase and

ubiquitin carboxy terminal hydrolase L-1 (Castegna

et al. 2002; Sultana et al. 2006; Butterfield and

Castegna 2003; Butterfield et al. 2006).

Recently it was shown that in aging tissues from

female and male animals the oxidative stress

increases due to decreased activity of antioxidant

enzymes and proteolysis increases due to decreased

activity of aminotransferase (Moorthy et al. 2005a, b;

Sinha et al. 2005; Bala et al. 2006). Oxidative stress

as well as gene expression profile has been identified

as causal factors in the aging process (Harman 1981;

Ames et al. 1993; Sohal et al. 2000).The brain is

especially vulnerable to the oxidative damage as a

result of its high oxygen consumption rate, its

abundant lipid content and the relative paucity of

anti-oxidant enzymes compared to other tissues. The

effect of estrogen and DHEA on aging brain enzymes

are presented in (Tables 3, 6).

Endogenous reactive oxygen species (ROS) that

are generated from aerobic metabolism are probably

the most important cause of age related neuronal

damage. ROS are continually produced within the

388 Biogerontology (2009) 10:377–413

123

Table 4 Changes in cerebral enzymes in experimental diabetes: effect of insulin

Enzyme/pathway Control Diabetic Diabetic ? Insulin Reference

Carbohydrate metabolism

Hexokinase (T)

(a) Brain 5.8 4.59 8.59 Ali et al. (1980a) and

Sochor et al. (1990)

(b) Sciatic nerve 0.87 0.60 0.76 Preet et al. (2005)

Phosphofructokinase 11.6 10.4 11.5 Srivastava and Baquer (1984)

Pyruvate kinase 67 75.2 66.5 Srivastava and Baquer (1984)

Lactate dehydrogenase 39.5 42.1 40.1 Ali et al. (1980a),

Mohamad et al. (2004)

Pyruvate dehydrogenase (T) 1.26 1.04 1.08 Murthy and Baquer (1980)

Glucose-6-phosphatasea 0.4 0.45 0.46 Kaur (unpublished, 1983)

Fructose 1,6 diphosphatasea 0.27 0.38 0.36 Kaur (unpublished, 1983)

Amino acid metabolism

Ornithine decarboxylase 0.183 0.086 – Sochor et al. (1977)

Arginase 54 83 42.2 Murthy et al. (1980)

Creatine kinase 2.98 1.82 2.89 Genet et al. (2000)

Glutamate dehydrogenase (NADP) 100 50 160 Ali et al. (1980b)

Neurotransmitter/membrane associated

Monoamine oxidasea 41.6 48 40.5 Mayanil et al. (1982a)

Na?K?ATPasea (lmol/mg protein) 2.05 1.46 2.01 Siddiqui et al. 2005

Acetylcholine esterase 2.6 1.7 2.0 Dash et al. (1991)

NADH oxidase 45 62 63 Askar and Baquer (1994)

Insulin receptor

Insulin receptor kinaseb 2.50 4.21 3.80 Gupta et al. (1992b)

Insulin degrading enzymee 0.41 0.43 0.44 Azam et al. (1990a)

Insulin receptorsd

(a) Brain 0.54 0.45 0.64 Azam et al. (1990b)

(b) Choroid plexus 0.53 0.051 0.140 Ansari et al. (1993)

Malate aspartate shuttle

(a) Alanine aminotransferase

Soluble 1.01 1.18 0.98 Kazmi and Baquer (1985)

Particulate 1.03 1.21 1.10 Kazmi and Baquer (1985)

(b) Aspartate aminotransferase

Soluble 32 28.5 27.6 Kazmi and Baquer (1985)

Particulate 50 51 43 Kazmi and Baquer (1985)

(c) Malate dehydrogenase

Soluble 230 238 219 Kazmi and Baquer (1985)

Particulate 206 173 159 Kazmi and Baquer (1985)

Catecholamine levels (ng/g tissue)

(a) Epinephrine 17.3 23.0 19.0 Gupta et al. (1992a)

(b) Norepinephrine 190 290 210 Gupta et al. (1992a)

(c) Dopamine 206 390 323 Gupta et al. (1992a)

Hexose monophosphate pathway14CO2 ? C-1–C-6c 0.95 0.80 0.85 Sumathy (unpublished 1988)

Biogerontology (2009) 10:377–413 389

123

body from normal oxidative metabolism. Sources of

ROS are mainly the mitochondrial electron transport

chain, and also the arachidomic acid cascade or nitric

oxide (Miquel 1992). During evolution living organ-

isms have been found with the compulsion to

inactivate these free radicals, and they have devel-

oped several ways to protect themselves from oxida-

tive attacks. These defense mechanism include a

variety of anti-oxidant enzymes like superoxide

dismuatase (SOD) or glutathione reductase, which

catalyze the NADPH-dependent reduction of gluta-

thione disulfide (GSSG) oxidised form, to glutathione

(GSH) reduced form. This reaction is essential for the

maintenance of glutathione levels.

Glutathione itself plays a major role as a reductant

in detoxification (Carlberg and Mannerik 1985).

Leutner et al. (2001) have studied in detail the

formation of ROS, lipid peroxidation and anti-

oxidant enzymes Cu-Zn-superoxidase dismutase and

glutathione reductase activities and found that the

two enzymes increased in brain with age, whereas

glutathione peroxidase remained unchanged. The

group also showed that the basal levels of LPO (lipid

peroxides) measured as malondialdehyde increased

gradually with a significant delay in mouse brain

homogenate. There was a significant delay in the time

course of ROS generation in brain cells from old

mice. Similar results have also been reported in brain

aging in female and male rats (Moorthy et al. 2005a,

b; Bala et al. 2006; Sinha et al. 2008).

A clear pattern emerges when analyzing the

relationship between the aging process and the gen-

eration and detoxification of oxygen free radicals.

Oxidative stress develops when the well regulated

balance between pro-oxidant and protective antioxi-

dant gets out of control, this seems to happen in the

brain of aged mice even if the activities of anti-oxidant

enzymes SOD and GR are considerably increased.

Any imbalance between pro-oxidant and antioxidant

factors can lead to a chronic accumulation of damag-

ing effects like lipid peroxidation (Leutner et al. 2001).

Antioxidant status in aging: effect of hormones

It can be reiterated that oxidative stress is one of the

most important mechanisms behind age related

changes in anti-oxidative enzymes and increased

apoptosis in aged rats (Kokoszka et al. 2001). Most of

the evidences indicate that SOD contributes in the

protection of cells from oxygen toxicity by catalyzing

the dismution of oxygen and it can be modified by

sex hormones in various tissues. Results of Pajovic

et al. (1993); Laloraya et al. 1989; D’Almeida et al.

(1995) showed that the activity of SOD (Mn) is

increased in the brains of proestrous rats, indicating

that estradiol and progesterone can modulates the

activity of SOD in tissues through its receptors. In

aging the levels of estradiol and progesterone were

reduced as compared to the normal cyclic rats,

therefore, aging rats treated with estradiol and

progesterone can reduce or delay the burden of free

radical induced aging disease as shown by Moorthy

et al. (2005a, b; Table 3). Beside the sex hormones

other hormonal changes are also known to occur

during aging. As reported by Rehman and Masson

(2001) many common problems encountered in the

Table 4 continued

Enzyme/pathway Control Diabetic Diabetic ? Insulin Reference

Glutamate—GABA pathway14CO2 ? C-2–C-6c 0.21 0.13 0.15 Sumathy (unpublished 1988)

Antioxidant enzymes/metabolites

Glutathione peroxidase 1.16 2.52 1.21 Siddiqui et al. (2005)

Glutathione reductase 0.96 1.30 1.03 Taha (unpublished 2006)

Catalasea 4.99 3.0 4.29 Siddiqui et al. (2005)

Superoxide dismutasea 8.63 6.5 8.26 Siddiqui et al. (2005)

Malondialdehydec (lipid peroxidation) 0.228 0.350 0.280 Genet et al. (2002)

Units: lmoles/gm tissue, a lmol/mg protein, b cpm/lg protein, c nmoles/mg protein, d ng/mg protein, e fmol/mg. The

hexosemonophosphate shunt and Glutamate GABA pathway are estimated using 14C-labelled substrates and 14CO2 measurements

as described in Table 1. The table is derived from values in the respective reference as given

T total

390 Biogerontology (2009) 10:377–413

123

aging patients can be related to neuroendocrine

phenomena (Table 5). These include AD, dementia

and cognitive dysfunction, depression, Parkinson’s

disease, hyponatraemia and the post menopausal

increase in both vascular risk and osteoporosis.

Effect of aging on the neuroendocrine system

The consequences of aging of the neuroendocrine

system have been incriminated in the development of

various age dependent conditions such as insulin

resistance, osteoporosis, muscular atrophy and abnor-

malities of fat deposition. Aging affects the endocrine

system by altering endocrine cells, the hormones

produced by these cells and hormone receptors or post

receptors processes in the target cells. Rehman and

Masson (2001) have reported some of the changes in

the hormones and their receptors and elaborated the

effects of aging on the hypothalamic neuroendocrine

system in detail. Age related deficits in neurotransmit-

ters may be functionally important in relation to

compensatory capability in response to pharmacolog-

ical challenges. Authors concluded that aging results in

a decline in neuroendocrine function, strength and

quality of life. Changes in hormone levels and

receptors are summarized in Table 5 and Fig. 4.

Alterations in electrophysiological parameters

with aging

Electrical signals and action potential

The processing of information in the brain (such as

sensory detection, higher mental functions, and

consciousness) has its basis in electrical signals

produced by changes in voltage across the plasma

membrane of particular collections of neurons (Fain

1999). Even during neural development, electrical

activity occurring in the developing brain guides the

formation of neural connections (Aamodt and Con-

stantine-Paton 1999). Electrical activity of the ner-

vous tissue (synaptic potentials, action potentials,

membrane potentials, single channel current, poten-

tiation and depression, electroencephalogram etc.)

thus may reflect intricacies of a variety of physio-

logical, biochemical and behavioral phenomena.

Thus relationship between neural function including

cognitive function and brain electrical activity are of

considerable importance in the objective assessment

of normality or impairment of neural function

including intellectual function (Pelosi et al. 1992).

Aging being the progressive and gradual accumu-

lation of detrimental changes in structure and functions

over time would thus also be evident in nervous

electrical activity. Electrical activity will not only be a

reflection of the aging of some baseline processes of the

nervous tissue but its marked alteration may contribute

to physiological and behavioral changes associated

with aging. For example, alteration in the pattern of

Table 5 Changes in the levels of hormones/receptors with

aging

Hormone/receptor Change

Increase Decrease None

Dopamine - ? -

Dopamine receptor 1 ? - ?

Dopamine receptor 2 - ? -

Monoamine oxidase A - ? ?

Monoamine oxidase B ? - -

Noradrenaline - ? -

Serotonin - ? ?

c-Aminobutyric acid - ? -

Muscarinic receptor - ? -

Nicotinic receptor - ? -

Choline acyltransferase - ? -

b-Endorphin - ? -

a-Melanocyte-stimulating hormone - ? -

Adrenocorticotrophic hormone - ? -

b-Lipotropin - ? -

Follicle stimulating hormone ? - -

Luteinising hormone ? - -

Inhibin - ? -

Testosterone - ? ?

Luteinizing hormone-releasing

hormone

- ? -

Aldosterone - ? -

Growth hormone - ? -

Insulin - ? -

Thyroid stimulating hormone - ? ?

Thyroxin - - ?

Tri-iodothyronine - - ?

Antidiuretic hormone ? - ?

Oxytocin - ? -

Prolactin ? ? ?

Melatonin - ? -

Biogerontology (2009) 10:377–413 391

123

firing spontaneous action potentials in the suprachias-

matic nucleus neurons in old age may disturb endog-

enous biological rhythm (Nygard et al. 2005), and

increased action potential firing rate in prefrontal

cortex of aged subjects appeared to be associated with

age-related prefrontal cognitive dysfunction (Chang

et al. 2005). Changes occurring with aging in neuronal

electrophysiologcal parameters such as action poten-

tials, synaptic potentials, spontaneous field potentials

(EEG), multiple unit and unit activities constitutive

electrophysiological aging of the nervous tissues, these

alterations would signify aging-related impairment

and disorganization of electrical signals leading to

decrement in neurological functions (Singh and Shar-

ma 2005). Since information in the nervous system is

conducted and integrated as electrical signals, the

disorganization of electrophysiological activity would

result in derangement of neural functions. For exam-

ple, deficiency of, or absence of synchronous action

potential bursts may alter presynaptic neurotransmitter

release consequently influencing synaptic plasticity

and information processing (Apartis et al. 2000;

Lisman 1997). The decline in spontaneous multiple

unit activity with age can be considered as a measure of

neuronal impairment and thus as an important param-

eter of elctrophysiological aging.

The resting membrane potential of neurons is

generally not affected by normal aging (Frolkis et al.

1984; Potier et al. 1992, 1993; Chang et al. 2005) after it

has acquired its normal value during early postnatal days

(Zhang 2004). The synaptic resting membrane potential,

however, exhibits decrease with aging (Tanaka and

Ando 1990). A significantly increased input resistance

was found in aged monkey’s hippocampal granule cells

compared with cells from the young monkeys (Luebke

et al. 2004). Elevated input resistance was also observed

in aged monkey’s layer 2/3 pyramidal cells of the

prefrontal cortex (Chang et al. 2005).

The action potential is a membrane event consist-

ing of a series of sequential transient changes in the

membrane potential: threshold, a rising phase (spike),

a falling phase (overshoot-amplitude) and an after

hyperpolarization. These changes (components of the

action potential) occur over a small period of time that

constitute the duration of the action potential. Some

components of the action potential are affected by the

aging process. For instance, while the action potential

amplitude generally shows no age change, the spike

duration may be enhanced with aging (Barnes and Mc

Naughton 1980; Potier et al. 1992). After hyperpo-

larization following a single spike may not show an

age-related change, but the afterhyperpolarization

following a burst of spikes may exhibit age-related

changes (Potier et al. 1992): repetitive action potential

firing rates were significantly increased in aged cells,

which may be responsible for age-related prefrontal

cortex dysfunction. The rhythmic bursting activity

appears to be necessary for memory and attention

purposes. Interestingly, while the rhythmic bursting

activity is impaired by aging, the nonrhythmic activity

is not affected by aging (Apartis et al. 2000). Some

neurons are endowed with the ability to change their

pattern of firing action potentials during different

states of arousal. Those neurons, which fire nonrhyth-

mically during slow wave sleep, adopt burst-firing

patterns during waking and rapid eye movement

sleep. This functional plasticity (ability to shift from

one pattern of activity to the other), however, may

decrease with aging (Apartis et al. 2000).

Structural changes in synapses

and neurotransmitter sensitivity with age

Structural and neurochemical alterations in synapses

during aging, which may have profound effects on

synaptic transmission, are potential candidates for

age-related impairment of brain function and cogni-

tion (Monti et al. 2004; Marrone et al. 2004). The

synaptic resting membrane potential decreases with

aging (Tanaka and Ando 1990). Postsynaptic poten-

tials (both excitatory and inhibitory) which are

produced upon excitation of the postsynaptic mem-

brane by neurotransmitters may exhibit age-related

changes. Normal aging is likely to involve decreased

synaptic excitation and increased synaptic inhibitory

processes that may contribute to age-associated

cognitive impairment (Luebke et al. 2004), postsyn-

aptic potentials were decreased in aged rats.

Alterations in postsynaptic potentials (responses)

will depend on the presynaptic neurotransmitter

release mechanism, and on the number of binding

sites (receptor density). In age-associated synapse

elimination without pre and post synaptic death, there

is a loss of synaptic input in cells, and in such cases in

aged individuals there is an attenuation of EPSP

amplitude together with an attenuation of both the

amplitude and frequency of miniature excitatory

postsynaptic potentials (Coggen et al. 2004).

392 Biogerontology (2009) 10:377–413

123

The postsynaptic sensitivity to neurotransmitters

may be affected in aged subjects, and as a conse-

quence the inhibitory and excitatory postsynaptic

potentials (IPSP and EPSP) are likely to show age-

related alterations. Changes will depend upon the

number of binding sites (receptor density) available

and presynaptic release mechanisms (Shen and

Barnes 1996; Taylor and Griffith 1993). An age-

related decrease in the amplitude and duration of

c-amino butyric acid (GABA)-related IPSP was

found in CA1 neurons in three strains of rats although

glutamate-related EPSP’s were not significantly

altered in aged rats (Potier et al. 1993). Aged

synapses may also show deficient synaptic plasticity

(impaired long-term potentiation) (Almaguer et al.

2002).

Changes in excitability and molecular mechanism

of aged neuron

Molecular mechanisms of electrogenesis are complex

and involve ion movements through membrane

channels and pumps. At synaptic junctions interac-

tion of neurotransmitter molecules with their recep-

tors precedes generation of postsynaptic potentials.

The membrane pumps, channels, receptors and

protein molecular entities are a part of the biological

structure and functional organization. Therefore,

alteration in molecular functions resulting from

changes in genetic expression/genes may be causal

to changes in electrophysiological signals. Because

channel currents contribute to action potential gener-

ation, age-related alterations in the genetic expression

of channels (number of channels) and their subunit

composition (Murchison and Griffith 1995) may

affect action potential signaling. Molecular changes

are well documented in cholinergic, glycinergic and

GABA-ergic channels and receptors (Murchison and

Griffith 1995).

There may be an alteration in the excitability of

aged neurons. For example, aged neurons may show a

decrease in excitability, hippocampal CA1 pyramidal

neurons from aged animals have enhanced voltage-

gated Ca2? entry and post-burst after hyperpolariza-

tion, and as a result there is a decrease in their

intrinsic excitability (Hemond and Jaffe 2005; Cingo-

lani et al. 2002; Disterhoft and Mathew 2006) which

leads to age-associated impairments in cognitive

functioning (such as learning) and modulation of

firing properties of neurons (Cingolani et al. 2002).

The axonal excitability also shows age-related alter-

ations and could be due to changes in nodal and

internodal ion channels, nodal width, electrical iso-

lation between the internodal and nodal compart-

ments, altered myelination, and membrane potential

(Nodera et al. 2004).

Sensory stimulus-evoked responses consisting of

averaged short train of waves (representing changes in

EEG recorded from the scalp and corresponding to

dendritic actions in the cerebral cortex, called evoked

potentials) provide a picture of information (impulse)

flow through synaptic tracts of the brain. This

involves: sensory processing, axonal conduction,

synaptic transmission, and cognitive processing

(Crowley and Colrain 2004). The components of

evoked potentials (event related potentials both audi-

tory and visual) reveal both early and late electrical

brain processes associated with behavioral/physiolog-

ical functions. With increasing age there is likely to be

a decline in the performance of tasks and there are

multiple and varying effects of age on both auditory

and visual responses. Advancing age thus may be

associated with an elevated amplitude of early positive

waves (P100-auditory and p145-visual) and there may

be significant delays of the major late positive wave in

the old subjects (Pelosi and Blumhardt 1999). The

components of evoked potentials can thus be used as

process-specific time markers in young adult and aged

subjects (Pfutz et al. 2002; Boutros et al. 2000). The

alcohol use-related accelerated aging caused changes

in P300 latency and amplitude similar to those of

normally-aging human subjects (Boutros et al. 2000).

Parkinson disease patients showed lower N400 ampli-

tudes than normal elderly subjects showing impaired

delayed recognition memory in aging and Parkinson’s

disease patients (Minamoto et al. 2001). In normally-

aging demented patients, Vaney et al. (2002) did not

find age-related changes in the latency and amplitude

of P3. However, in this study Vitamin E supplemen-

tation appeared to lower the latency of the P3

amplitude but increase its amplitude indicating that

antioxidant therapy by decreasing the oxidative stress

may lead to improvement in cognitive pool of

generator neurons of P3. However, in several human

studies vitamin E has not been found to provide

cognitive benefits (Kang et al. 2006; Dunn et al. 2007).

In the aged striatum of Fisher 344 rats, there is an

increase in the activity of non-locomotor-related

Biogerontology (2009) 10:377–413 393

123

neurons (Standford and Gerhardt 2004). This

increased activity because of its influence on basal

ganglion output nuclei may contribute to age-related

or Parkinson’s disease-related hypokinesia and move-

ment disorders (Standford and Gerhardt 2004). The

suprachiasmatic nucleus of mice is subject to marked

electrophysiological changes (Nygard et al. 2005), in

old animals for example, there were more silent cells

(i.e., not rhythmically firing cells) than in young

animals.

Electrical changes in the cortex and synapse

plasticity

Electrical changes of the brain cerebral cortex are

recorded as the surface or cortical electroencephalo-

gram (EEG). The EEG is made up of a compounded

wave form consisting of multiple frequencies, and is

derived from summation of the synaptic activity in

cerebral cortex pyramidal cells (Salek-Haddadi et al.

2003). Spectral content of the EEG do reflect changes

occurring in the brain subcortical structures, and

several electrophysiological measures appear geneti-

cally heritable (Winterer and Goldman 2003). The

human EEG may undergo significant age-correlated

changes (Duffy et al. 1984) as the human EEG tends to

show reduced alpha activity with age; increased

dyscronization with age consisting of reduction in

slow activity and augmentation of fast activity.

Topographically the greatest change was found to

occur in the temporal lobes, and the right hemisphere

seemed to differ from the left (nonsymmetrical nature

of the aging process). Furthermore, topographically

temporal correlations were found to be stronger in

alpha than in beta oscillations and were largely

unaffected by age (Nikulin and Brismar 2005). In

general, the effect of age on the EEG may be frequency

specific and topographically variable (Landolt and

Borbely 2001).

Long-term potentiation (LTP) is considered a form

of synaptic plasticity and has been indicated as a

cellular mechanism of learning and memory. Aging

appears to be associated with an impaired ability to

maintain LTP, and alterations in the balance of

protein kinase/phosphatase activities may be respon-

sible for these impairments (Hsu et al. 2002). LTP is

a Ca2?-dependant process and is altered with age

(Isomura and Koto 1999; Foster and Kumar 2002).

Ca2? dysregulation with age and consequent changes

in Ca2? signaling pathways underlie the impairment

of LTP with age (Biessels et al. 2002b). Studies

concerning LTP have mostly focused on the hippo-

campus and particularly CA1 cells, as hippocampus-

dependant memory appears to be age-sensitive

(Foster and Kumar 2002). The age-related cognitive

decline is also associated with disruption of Ca2?

homeostasis. The aged CA3 cells were also found to

fail to rapidly encode new spatial information com-

pared with young CA3 cells (Wilson et al. 2005).

Electrophysiology changes in aging

Electrophysiological changes in the aging brain can

also be assessed by measuring cellular-level electro-

physiological activity i.e., unit and multiple-unit

action potentials. Multiple-unit activity (MUA) i.e.,

action potentials simultaneously derived from many

neurons represents an electrophysiological marker of

cellular firing activity of the concerned neuronal

population. Its alterations may reflect the biochem-

ical, physiological and behavioural changes of the

neurons (Mizumori et al. 1996; Barnes et al. 1987;

Malmo and Malmo 1982). Therefore, age-related

change in spontaneous (basal) neuronal firing is of

interest as one of the neuroelectric indicator of

electrophysiological functional alteration in the brain.

Age-related declines in spontaneous neuronal firing

have been found to occur in several brain areas:

inferior and superior colliculi of rat (Malmo and

Malmo 1982), locus coeruleus neurons of rat (Olpe

and Steinmann 1982), forebrain neurons of rat (Jones

and Olpe 1984), the cerebral cortex of rat (Roy and

Singh 1988; Abdulla et al. 1995), the hippocampus,

thalamus, and striatum of rat (Kaur et al. 1998, 2001,

2003; Sharma et al. 1993). Age related decline in

MUA in four brain regions of rats during aging from

6 to 24 months of age is shown in Fig. 5.

Diabetic brain features symptoms like

accelerated brain aging

Diabetes mellitus (DM) is a heterogeneous metabolic

disorder characterized by hyperglycemia resulting

from defective insulin secretion, resistance to insulin

action or both (Gavin et al. 1997). Type 1 diabetes is

the consequence of an autoimmune destruction of

pancreatic beta cells, leading to insulin deficiency.

394 Biogerontology (2009) 10:377–413

123

Insulin administration is required for survival. Type 2

diabetes is characterized by insulin resistance, and

relative, rather than absolute insulin deficiency. DM

is associated with moderate cognitive deficits and

neurophysiologic and structural changes in the brain,

a condition that may be referred to as diabetic

encephalopathy, diabetes increases the risk of demen-

tia especially in elderly. The emerging view is that

the diabetic brain features many symptoms that are

best described as accelerated brain aging. Animal

models can make a substantial contribution to the

understanding of the pathogenesis, which shares

many features with the mechanisms underlying brain

aging. By unraveling the pathogenesis, targets for

pharmacology can be identified. This may allow

treatment or prevention of the diabetic complications.

The effect of experimental diabetes on cerebral

enzymes has been evaluated by many authors (Kaur

and Lakhman 1994; Lakhman and Kaur 1997;

Khandkar et al. 1995; Siddiqui et al. 2005; Azam

et al. 1990a, b). Table 4 shows the changes in these

enzymes and effect of insulin. Khandkar et al. (1995)

had measured the activity of AChE from brain of

alloxan diabetic rats. The results suggested that

membrane binding and membrane alteration in dia-

betes can significantly influence the kinetic properties

of AChE. The results show that Km and Vmax of the

membrane bound enzyme, but not the soluble AChE

increased in the diabetic state, and is possibly related

to the delayed nerve transmission and impaired brain

function in the diabetic brain. Lakhman and Kaur

(1994, 1997) showed that acute hyperglycemia

Fig. 5 Electroencephalograms

and multiple unit action

potentials (MUA) showing age-

related changes. Figure adapted

from Sharma et al. (1993).

Derived from Rehman and

Masson (2001)

Biogerontology (2009) 10:377–413 395

123

caused an increase in the activity of AChE suggesting

that the dysfunction of the cholinergic system may be

involved in diabetes associated CNS complications;

they also showed an increase in MAO, with reversal

of the activity after insulin administration. Na?K?

ATPase also showed a decrease in activity in the

brain which was normalized after insulin administra-

tion (Kaur and Lakhman 1994).Changes in brain

Na?K? ATPase and MAO have been earlier reported

from diabetic brain by Mayanil et al. 1982b and

latter, i.e., MAO more recently also (Siddiqui et al.

2005) Reversal of the enzyme activity was shown by

insulin administration (Table 4).

The study of receptor subtypes, second messenger

system, and protein kinase may account for the

alteration in synaptic plasticity, together with the

possible role of cerebrovascular changes, oxidative

stress, non-enzymatic protein glycation, insulin and

alteration in neuronal calcium homeostasis are some of

the parameters that have been recently discussed in a

review by (Biessels et al. 2002a, b; Biessels and Gispen

2002). DM is often associated with complications such

as cardiovascular disease, kidney failure, retinopathy

and peripheral and autoimmune neuropathy. Proper

metabolic control, especially the hyperglycemia,

reduces the development of these complications.

Deficient signaling by insulin, as occurs in diabetes

is associated with impaired brain function, and diabe-

tes is associated with an increased prevalence of

AD. Alteration in the insulin receptor signal transduc-

tion pathway found in aging and AD are shown in

Fig. 6.

One of the hallmark and pathological characteris-

tics of AD is the presence of neurofibrillary tangle

containing hyperphosphylated tau, a microtubule

associated protein. Recently Clodfelder-Miller et al.

(2006) have demonstrated a massive and wide spread

increase in the phosphorylation of the microtubule

binding protein tau in mouse brain after depletion of

insulin by administration of streptozotocin. Tau

phosphorylation is a key regulator of the ability to

bind and stabilize microtubules (Johnson and Stoot-

hoff 2004), suggesting that this function is impaired

by insulin insufficiency, actually tau hyperphoryla-

tion is a key early event in the pathogenesis of AD

raising the possibility that the reported association

between diabetic and AD could in point be due to

increased phosphorlation of tau caused by insulin

deficiency. This hyperphosphorylation may sensitise

neurons to subsequent or concomitant insults associ-

ated with AD to promote progressive neurodegener-

ation. Authors also show that streptozocin induced

Fig. 6 Alteration in the

insulin receptor signal

transduction pathways

found in aging and

Alzheimer’s disease

showing the diverse roles

and functions that insulin

receptor plays, showing

insulin receptor

desensitization effects on

neuronal metabolism and on

the development of

Alzheimer’s disease. Figure

adapted from Fulop et al.

(2003) and Li and Holscher

(2007)

396 Biogerontology (2009) 10:377–413

123

insulin deficiency shares with AD two common

outcomes, reduced pp2A activity and increased tau

phosphorylation.

Recently a review by Nelson et al. (2009) included

a description of cerebral neuropathology of Type 2

diabetes mellitus (CNDM2) patients. It is believed

that in the absence of a known pathogenomic

anatomic substrate for cognitive dysfunction in

diabetic patients, there are no definitive histopathol-

ogical changes in diabetic brains. Many metabolic

disorders induce mental changes out of proportion to

known neuropathological changes. These disorders

may be induced by fluxes in blood levels of insulin,

glucose and other metabolic parameters in DM2.

Other diseases like hypoxia can produce brain

atrophy and cell death. Thus delirium or a disease

with entirely nonspecific pathology may partly con-

tribute to diabetic neuropathy. This clearly shows that

several associations between DM2 and brain pathol-

ogy appear to exist. Evidence has been described for

and against the link between (CNDM2) and AD

pathogenesis. The authors concluded that in diabetics,

cerebrovascular pathology was more frequent and

Alzheimer-type pathology was less frequent than in

non diabetics (Nelson et al. 2009).

Diabetic neuropathy-peripheral and central

nervous system

Peripheral neuropathy is a frequent complication of

DM. Kamal et al. (2000) studied the role of hippo-

campus in certain types of learning and memory

where the function and synaptic plasticity has been

studied as plastic changes in synaptic strength are

assumed to be involved in learning and memory (Bliss

and Collingridge 1993). Animal models have been

used to examine the relation between memory deficits

and changes in synaptic plasticity in diabetes (Shafrir

1997; Kumagai 1999). Like diabetic patients, STZ-

diabetic rats develop end organ damage affecting the

eyes, kidney, heart, blood vessels, and peripheral and

central nervous system.

Aging and diabetes both affect cognition, synaptic

plasticity and glutaminergic neurotransmission in

rats, hence the effects of diabetes and aging interact,

this was examined by Kamal et al. (1999), and the

results suggested that there was an interaction

between aging and diabetes cerebral dysfunction.

Kamal et al. (2000) and Hoyer (1998) put forward the

concept that hyperinsulinemic brain glucose utiliza-

tion and insulin signal transduction in the brain play

an interconnected role in the patho-physiology, also

suggesting that Sporadic AD may reflect the brains of

Type 2 diabetes mellitus. Clinical and experimental

studies indeed show that altered glucose regulation

impairs learning and memory (Messier and Gagnon

1996) and defects in insulin action both in peripheral

and brain, and these have recently been implicated in

the pathogenesis of sporadic AD. Ryan and Geckle

(2000) came to the conclusion that the increased risk

of cognition dysfunction in elderly Type 2 patients is

the consequence of a synergistic interaction between

diabetic related metabolic derangements and struc-

tural and functional cerebral changes in normal aging

process due to changed insulin receptor function

(Fig. 6).

Regional cerebral blood flow changes occur in

response to alteration in metabolic demand of brain

regions. Kalaria (1996) has described the morpho-

logical and vascular changes with aging. Studies on

the effect of DM on cerebral blood flow has been

conflicting (Mankovsky et al. 1997; Sabri et al.

2000). Many uncertainties still exist about the patho-

physiologic mechanisms. It can be concluded, how-

ever, that both in aging and diabetes vascular changes

occur that may have consequences for the cerebral

circulation.

Aging, diabetes and Alzheimer’s disease,

age related disorders

A common theory for aging and for the pathogenesis

of AD relates cell death to oxidative stress mediated

by free radicals (Beckman and Ames 1998). Accu-

mulation of damaged, oxidized, dysfunctional protein

seems to result from a combination of age related

increase in the rate of oxygen free radical mediated

damage and a loss of the ability to degrade oxidized

protein (Facchini et al. 2000). Indeed increased levels

of oxidized protein and reduced activity of antioxi-

dant enzymes have been demonstrated in the brains

of aged individuals with and without AD (Gsell et al.

1995; Troni et al. 1984), and in diabetes (Table 4).

Diabetes is associated with increased oxidative

stress as reflected in an increased presence of lipid

peroxidation products (Jennings et al. 1987; Rosen

et al. 2001; Siddiqui et al. 2005; Genet et al. 2002).

Like in aging increased oxidative stress appears to be

Biogerontology (2009) 10:377–413 397

123

the result of increased formation of ROS, reduction in

ROS scavengers or both (Moorthy et al. 2005a, b;

Baquer et al. 1990). Increased ROS production in

diabetes is a consequence of the process of glucose

auto oxidation. This process in which glucose is

oxidized in the presence of free metal ion, leads to

superoxide and hydroxyl radical release, and finally

causes protein oxidation (Wolff et al. 1991; Wolff

and Dean 1987). The activity of ROS scavenger

compounds like glutathione, catalase and superoxide

dismutase may be affected by diabetes (Wohaieb and

Godin 1987; Genet et al. 2002). Decrease in ROS

scavenging compounds may be due to the direct

affect of diabetes and aging on scavenger production

or activity, like enhanced protein glycation may be

responsible for the reduced enzymatic anti-oxidant

activity of superoxide dismutase (Siddiqui et al.

2005; Mohamad et al. 2004). Alteration of glutathi-

one levels may be related to an increased polyol

pathway (Preet et al. 2005) activity as this leads to a

depletion of NADPH which is necessary for the

enzymatic reduction of oxidized glutathione (Fig. 2).

A local decreases in endogenous ROS scavenging

compounds may be due to increased consumption by

ROS, like the generation of increased amount of

hydrogen peroxide (Hothersall et al. 1981; Ikebuchi

et al. 1993). Increased concentration of lipid perox-

idation byproducts have been demonstrated in the

brain of diabetic rats and in aging rat brain (Kumar

and Menon 1993; Mooradian and Smith 1992; Genet

et al. 2002; Siddiqui et al. 2005; Leutner et al. 2001;

Sinha et al. 2005; Kumar et al. 2008). The activity of

SOD and catalase, enzymes involved in antioxidant

defense of the brain, appears to be decreased in (STZ)

diabetic rats (Kumar and Menon 1993;Makar et al.

1995), whereas in Type 2 diabetic mice increased

brain superoxide dismutase activity has been reported

(Huang et al. 1999; Table 4).

In tissues affected by diabetes the amount of

AGE’s are generally increased, leading to structural

changes in the extracellular matrix, as well as to

modifications of cell membranes and intracellular

components (Brownlee 2000; Singh et al. 2001;

Siddiqui et al. 2005). Increased levels of AGE’s have

been reported in central and peripheral nervous tissue

from diabetic animals (Pekiner et al. 1993; Ryle et al.

1997; Vlassara et al. 1983).

Age related disorders, like AD and T2DM affect a

large number of people, AD and T2DM share several

molecular process that underline the respective

degenerative development. Disturbance in insulin

signaling appears to be the main common impairment

that affects cell growth and differentiation, cellular

repairs mechanisms, energy metabolism, and glucose

utilization. Insulin not only regulates blood sugar

levels but also act as growth factors on all cells

including neuron in the CNS. Impairment of insulin

signaling, therefore, not only affect blood glucose

levels but also causes numerous degenerative pro-

cess. Other growth factors signaling systems such as

insulin growth factors (IGFs) and transforming

growth factors (TGFs) also are affected in both

conditions. Also misfolding of protein plays an

important role in both diseases, as does the aggrega-

tion of amyloidal peptides and hyperphosphorylated

protein. More general physiological process such as

angiopathic and cytotoxic developments, the induc-

tion of apoptosis, or of non-apoptotic cell death via

production of free radicals, greatly influence the

progression of AD and T2DM. In a recent review Li

and Holscher (2007) have outlined and discussed in

details the two metabolic, diseases, T2Dm and AD

and showed similarity between the physiological

process, epidemiological links, similarities in forma-

tion of amyloid peptides in the brain. Other similar-

ities were discussed between NFTs (neurofibrillary

tangles) and growing evidence that impairments in

insulin signaling is partly responsible for the cogni-

tion decline in AD. One impairment that has been

described repeatedly is the observation that in AD,

insulin resistance in the CNS develops due to

alterations of insulin receptors sensitivity, affecting

the expression and metabolism of amyloid beta and

tau protein. Insulin receptor signal transduction

pathway in aging and Alzheimer’s brain is shown

in Fig. 6.

Recently Khan and Ballard (2008) have reviewed

the main mechanisms thought to underpin the devel-

opment of AD and the treatments that are being

developed based upon it. The hallmarks of AD are

mainly two fold, as discussed earlier in the review the

formation of extra-cellular b-amyloid plaques, intra-

cellular neurofirillary tangles and shrinkage of the

brain. Deficits Amyloid processing are the main

genetic predisposition leading to the amyloid hypoth-

esis. The authors have discussed a range of

approaches that are currently under investigation for

the disease modifying treatment of Alzheimer. These

398 Biogerontology (2009) 10:377–413

123

range in their targets from anti-amyloid treatment to

neuroprotective agent and neurogenerative therapies.

The anti-amyloid therapies are aimed at slowing

down or halting the production of the amyloid

peptide by together targeting the secretase enzymes

which cleave amyloid from APP presenting the

aggregation of the amyloid into plaques or using

immunotherapies to completely remove amyloid

from the brain.

Since aging and diabetes are also now included as

a neurodgenerative physiological phenomena, the

treatments used for AD may also be used for the

delaying of neuronal complication associated with

aging and diabetes. Mantha et al. (2006) have

recently shown the neurotoxic effect of synthetic

amyloid peptide in isolated synaptosomes from aging

rat brains together with changes in neuronal markers.

Kumar et al. 2008 have measured the lipofuscin

changes in aging brain and effect of DHEA on it

together with effects of diabetes and insulin treatment

of diabetic brains (latter unpublished).

Changes in neuronal markers, diabetes, aging

Lipofuscin is a morphological structural entity and

is mainly accumulated in post-mitotic cells of brain.

The accumulation of lipofuscin in cells occurs

because it is undegradable and cannot be removed

from the cells via exocytosis. As age progresses, the

lipofuscin content per neuron as well as the number

of pigmented neurons has been shown to increase in

a linear fashion in many regions of the brain

(Sharma et al. 1993; Drach et al. 1994; Moorthy

et al. 2005a, b). Intraneuronal accumulation of

lipofuscin is considered to be a marker of neuronal

aging, and its formation appears to be integrative

and proportional to the occurrence of lipid perox-

idation. In addition, an age-related increase in lipid

peroxidation has been shown to be directly corre-

lated with the gross level of lipofuscin accumulation

and thus, as reported by earlier workers, intraneu-

ronal accumulation of lipofuscin is considered to be

a marker of neuronal aging (Sohal and Brunk 1989;

Sharma et al. 1993).

Aging increases accumulation of fluorescent ‘‘lip-

ofuscin’’ or ‘‘wear and tear’’ pigments in post-mitotic

cells such as neurons and muscle cells (Terman and

Brunk 2006). DM is one of the diseased model for

aging (Cerami et al. 1987) and its complications

include peripheral neuropathies that exhibit axonal

degeneration, demyelination and impaired axonal

transport that would affect cell body functions.

Hellweg et al. (1994) also showed that autofluores-

cent pigments such as lipofuscin/ceroid could be

increased in neurons of rats that have experimentally

induced diabetes. Lipofuscin is well known to

increase during aging of neurons of humans and

some animals, and is an important bio-marker of

aging. It has been shown that DM significantly

increased the fluorescent pig-ments in the neurons of

experimentally induced DM, with the possibility that

the induction of DM makes some functional changes

due to the accumulation of the fluorescence materials

in neurons (Sugaya et al. 2004). The authors therefore

concluded that experimentally induced DM by

alloxan increases the production of autofluorescent

pigments ‘‘lipofuscin’’ in the neurons; that this

change is thought to correlate with aging. This result

suggests the possibility that the DM could make the

functional change in several types of neurons.

Phosphorylation and dephosphorylation of pro-

teins (enzymes and receptors), are known to regulate

numerous aspects of cell function and abnormal

phosphorylation is causual in many diseases and

aging. Pyruvate Dehydrogenase genome complex

(PDC) is central to the regulation of glucose homeo-

stasis. McLean et al. (2008) have recently presented

and discussed the regulation of pyruvate dehydroge-

nase (PDH). Their results showed that the putative

insulin mediator inositol phosphoglycan P type (IPG-

P) has a sigmoidal inhibitory action on the PD kinase,

together with a linear stimulation of PD phosphatase,

suggesting a powerful regulatory function, involving

phosphorylation (kinases) and dephosporylation

(phosphatase) thereby regulating the active and

inactive form of PDH. The IPG;s are released from

cell membranes by insulin, very significant in the

case of diabetes. Synthetic inositol hexose amine

analogues were shown to have similar effects as

natural IPG’s suggesting their potential for their use

in treatment of metabolic disorders including diabe-

tes. Unpublished observations by Baquer and

McLean’s from McLean laboratory on changes in

rat brain, IPG’s with age, also show results correlat-

ing with the diabetic data, reiterating the similarities

and complications occurring with diabetes, aging and

neurological disorders, contemplating the probable

use of synthetic IPG analogues for reversing some

Biogerontology (2009) 10:377–413 399

123

changes associated with neurological disease and

aging.

Insulin effect on brain

Recent data implicate insulin itself in the pathogen-

esis of age related memory decline and diabetic

encephalopathy (Gispen and Biessels 2000;

Schulingkamp et al. 2000). Insulin and its receptors

are known to be present in the brain (Havrankova

et al. 1978a, b; Azam et al. 1990a, b). Insulin

receptors are concentrated in specific brain region,

particularly abundant in the hypothalamus and olfac-

tory bulb. The physiological function of insulin in

brain region is still a controversy, and glucose uptake

by brain is considered to be mainly insulin insensitive

(Kumagai 1999). Insulin does affect cerebral glucose

utilization to some extent (Schulingkamp et al. 2000),

analogous to its role in the periphery. In addition

brain insulin does seem to play a role in the

regulation of food intake and body weight (Schwartz

et al. 1999), and it may act as a neuromodulator

influencing the release and reuptake of neurotrans-

mitters, and probably also learning and memory

(Zhao et al. 1999).

Impairment of insulin signaling pathway in the

periphery and brain have been implicated in AD,

diabetes and aging (Frolich et al. 1998). In AD the

age-related reduction in cerebral insulin levels

appears to be accompanied by functional disturbances

of the insulin receptor qualifying AD as an Insulin

Resistant Brain State. Chronic hyperinsulinemis is

associated with cognitive decline. Acute insulin

administration, in these individuals while keeping

glucose at fasting levels, actually improves memory

in individuals with AD, as well as in healthy controls

(Craft et al. 2000). Morever, the brain insulin/IR

signal transduction, beside the regulation of glucose

metabolism, delivers signals necessary for synaptic

activity and plasticity, of memory formation and for

memory storage as well as for cell differentiation

(Kremerskothen et al. 2002). Recently insulin levels

have been measured in aging and show a decrease

with age (Koricanac et al. 2004), insulin levels are

also decreased in DM as well as experimental

diabetes in animal models (Fulop et al. 2003; Biessels

et al. 2002b; Taha et al., unpublished).

Insulin degrading enzyme (IDE) has been mea-

sured in diabetic brain and diabetic treated with

insulin (Azam et al. 1990a, b; Table 4). IDE is a

metalloendopeptidase also involved in the degrada-

tion of amyloid beta protein (Qiu et al. 1998) the

latter is involved in the pathology of AD and has been

shown to induce apoptosis invitro (Forloni 1993;

Watt et al. 1994). It has been reported that invitro

insulin, inhibits insulin degrading enzyme (IDE)

activity and proteosomal function competitively

(Bennett et al. 2000; Hamel et al. 1998; Qiu et al.

1998) impairing protein turnover, thereby facilitating

the gradual accumulation of oxidized protein. Dia-

betes and its treatments with insulin are likely to

affect cerebral insulin levels and insulin signaling. It

is different, however, to separate the direct effect of

alterations in insulin homeostasis on the brain from

the consequence of the accompanying alteration in

peripheral and control glucose homeostasis, which in

themselves can affect the brain.

Aging brain, hyperglycemia and calcium

hypothesis

It is generally assured that aging is one of the most

important and consistent risk factors for AD. The

calcium hypothesis of brain aging and dementia has

been put forward to account for a number of the

phenomena in the pathogenesis of dementia (Khach-

aturian 1994). A cellular mechanism that regulates

the homeostasis of calcium plays a critical role in

brain aging. Small changes in free calcium (Ca2?)

sustained over a period of time results in cellular

damage. A close relation between Ca2? homeostasis,

the production of ROS, ischemia and brain cell death

has been reported (Finkel and Holbrook 2000;

Kristian and Siesjo 1996). Disturbed (Ca2?) regula-

tion and Ca2? channel activity have been described in

various diabetic tissues, like myocardium, arteries

and muscle and have been implicated as secondary

complications of diabetes (Levy et al. 1994). Con-

sidering the peripheral nerve as target for diabetic

damage, there are several direct and indirect mech-

anisms through which diabetes related disturbance in

Ca2? homeostasis may lead to impaired nerve

function (Biessels et al. 1996a, b).

It has been discussed in earlier section in this

review that diabetes appears to be an important risk

factors for significant cognitive decline and dementia

in aging. Preliminary studies in experimental models

of diabetes and aging provide evidence that

400 Biogerontology (2009) 10:377–413

123

treatments aimed at the pathogenesis factors may be

fruitful, for example with anti-oxidants or Ca2?

channels antagonist may restore defects in synaptic

plasticity in STZ diabetes rats (Biessels et al. 2002a,

b; Biessels and Gispen 2002). As shown recently,

treatments with antidiabetic agents, and hormones to

aging animals, reducing blood glucose levels in the

diabetic animals, ameliorate altered antioxidant status

and membrane linked function, like Na?K? ATPase

activity and membrane fluidly in alloxan diabetic and

aging rat brain, cause significant reversal of the aging

and diabetic induced effects (Moorthy et al. 2005a, b;

Siddiqiui et al. 2005).

Metabolic disorders associated with diabetes

and Alzheimer’s disease

Type 2 DM is one of the most common metabolic

disorders, and its prevalence increase with age. Insulin

resistance or T2DM is often associated with the most

common occurring metabolic and physiological prob-

lems, including elevated blood pressure, cardiovascu-

lar disease, dyslipidemia and high cholesterol levels,

this clustering of risk factors are known as the

metabolic syndrome (Ahmed and Goldstein 2006;

Levine 2006). Recent evidence has identified T2DM

as a risk factor for AD. AD a progressive neurode-

generative disorders of either unknown etiology

leading progressively to serve incapability and death,

has been described as the pandemic of the twenty-first

century (Jellinger 2006). Familial AD is caused by

mutations in the amyloid precursor protein (APP) and

presenelin genes, both linked to Amyloid beta

systems. The etiology of the sporadic form of AD is

common with an interaction of both genetic and

environment risk factors (Blennow et al. 2006). A key

event in AD pathogenesis is the conversion of

Amyloid beta from soluble monomeric form into

various aggregated forms in the brain. A therapeutic

strategy will be therefore to prevent aggregation of the

soluble form (Liu et al. 2006).

Using aging animals models of AD and T2DM

Lester-Coll et al. (2006) showed that Sporadic

Alzheimer’s disease (SAD) can be recognized as an

insulin resistant brain state. It was further shown that

the brains of STZ-injected rats were reduced in size

and exhibited neurodegeneration, associated with cell

loss, gliosis and other characteristics similar to AD

brain (Lester-Coll et al. 2006). Additionally STZ

injection produces oxidative stress in the brain of

treated rats (Sharma and Gupta 2001). The impair-

ment of insulin signaling in the brain results in the

development of neuropathy, rat model therefore can

be a valuable tool for basic research of the biochem-

ical process that underlines neurodegeneration (Grun-

blatt et al. 2006, 2007). While there were obvious

difference between the two conditions, the similar

signaling impairment and cytotoxic process are

important to obtain detailed knowledge about them.

Antiaging strategies

Possible antiaging strategies may involve reduction

of oxidative stress and prevention of lipofuscin

accumulation (Terman and Brunk 2006). Pharmaco-

logical intervention, besides many other types of

interventions, to reduce oxidative stress, and to

prevent lipofuscin formation is an interesting

approach to slow the aging process. There is

tremendous public interest in the development of

antiaging therapy and the idea that the aging process

can be reversed by approaches such as antiaging

medicine is emerging (de Grey 2003) although

limitations (Ohlansky et al. 2004) are there. A variety

of substances and drugs have been investigated for

their antiaging influences.

Chemical antiaging compounds therapy

Acetyl-L-Carnitine (ALC) is an ester of L-carnitine,

and is normally synthesized in tissues from the

reversible acetylation of carnitine (Shigenaga et al.

1994). In experimental studies it has been found to

reduce age-related cognitive and neural changes

(Markowska et al. 1990; Caprioli et al. 1995; Davis

et al. 1993). It has cholinergic and cholinoprotective

effects because of its ability to increase acetylcoen-

zyme A levels (Szutowiez et al. 2005). It reduces

lipofuscin accumulation and has antioxidative action

(Dowson et al. 1992; Kaur et al. 2001). Kaur et al.

(2001) have further shown that ALC treatment

activates glutathione-s-transferase and Na?K?-ATP-

ase, and reduces lipid peroxidation in the brain. It has

been proposed as a therapeutic agent for several

neurodegenerative disorders (Calabrese et al. 2006).

ALC activates EEG in elderly human patients

(Herrmann et al. 1990) and augments multiple unit

Biogerontology (2009) 10:377–413 401

123

activity in brain regions of aged experimental animals

(Kaur et al. 2001; Singh and Sharma 2005; Fig. 7).

ALC was,however, not found to show cognitive

benefits in Down syndrome (Pueschel 2006) Alzhei-

mer disease patients (Thal et al. 2000, 1996) and in

dementia (Hudson and Tabet 2003).

L-Deprenyl (phenylisopropyl-N-methylpropynyl-

amine, also known as selegiline), a selective inhibitor

of monoamine oxidase B, is used as an adjunct to the

pharmacotherapy of Parkinson’s disease. L-deprenyl

is of interest to biogerontologists as it shows bene-

ficial effects against aging-related parameters (Kitani

et al. 2002; Kaur et al. 2003), and is considered as a

putative antiaging drug. The drug has antioxidative

effects (Kaur et al. 2003) and its effects on antiox-

idative enzymes are unrelated to the monoamine

oxidase and uptake of catecholamine effects of the

drug (Knoll 1998). A continuous administration of

deprenyl improves the performance of patients with

AD (Knoll 1993); it improves memory impairment

mediated by the cholinergic system (Takahata et al.

2005), reverses age-related deficits in long-term

memory (Kiray et al. 2004), protects against cogni-

tive impairment induced by neonatal administration

of iron and in cerebral ischemia (Maia et al. 2004).

Deprenyl augments multiple unit activity in brain

regions indicating that it reverses the aging-related

decline in brain electrophysiological activity (Kaur

et al. 2003).

Centrophenoxine has been widely studied for its

antiaging effects (Sharma et al. 1993; Fig. 8). It

augments the activity of antioxidant enzymes and

inhibits lipofuscin formation (Roy et al. 1983;

Sharma et al. 1993), also improves synaptic plastic-

ity. Centrophenoxine stimulates multiple unit activity

in aged rat brain cerebral cortex and hippocampus

(Roy and Singh 1988; Sharma et al. 1993).

Herbal antiaging neuroprotective compounds

Curcumin (a yellow pigment extracted from the

rhizome of the plant Curcuma longa (turmeric) is also

CORTEX HIPPOCAMPUS

STRIATUM THALAMUS

Fig. 7 Effect of acetyl-L-

carnitine and L-deprenyl on

electroencephalogram and

multiple unit action

potential (MUA). Figure

derived from Kaur et al.

(2001)

402 Biogerontology (2009) 10:377–413

123

of interest as an antiaging substance because of its

antilipidperoxidative, antilipofuscinogenic effects. It

also counters aging-related decrease in membrane-

linked Na?K? ATPase activity in aging rats (Bala

et al. 2006; Sharma et al. 2008; Goel et al. 2008).The

plant herb Bacopa monniera (called Brahmi in

Sanskrit) is also of interest for neuroprotective

antiaging properties and extract of the plant has

beneficial effects on cognitive functions (Singh and

Dhawan 1997). The extract also counteracts alumi-

num-induced oxidative stress in the hippocampus

(Jyoti and Sharma 2006; Jyoti et al. 2007). Curcumin

was, however, not found to have beneficial effects on

lipid profiles in humans (Baum et al. 2007). Further-

more, some studies indicated that other mechanisms

than the antioxidant activities could be involved in

the neuroprotective effects of ALC and curcumin

(Mancuso et al. 2007).

Steroids, as antiaging compounds

Dehydroepiendrosterone (DHEA) is a neuroactive

steroid and can regulate neural functions through its

influence on neurotransmitter-gated ion channel and

gene expression; DHEA is synthesized denovo in the

brain and accumulates in the nervous system (Racchi

et al. 2001). DHEA’s substantial fall with age has

been shown to be associated with neuronal vulnera-

bility to neurotoxicity process. Thus, DHEA is

considered to be a neuroactive pharmacological

substance with potential antiaging properties. Cal-

cium-phospholipid-dependant protein kinase C (PKC)

is involved in the induction and maintenance of long-

term potentiation of signal transduction and thus has a

key role in learning and memory. With brain aging

there is alteration (impairment) of mechanisms

involving the activity of PKC, and administration of

DHEA to aging male animals can modulate the age—

associated impairment of PKC signal transduction

(Racchi et al. 2001). DHEA may thus indirectly

restore age-associated impairment in cognitive func-

tions and has been received as a pharmacological

antiaging substance (Kumar et al. 2008; Sinha et al.

2005) Administration of DHEA to aging animals was

found to significantly decrease the increased mono-

amine oxidase activity, lipid peroxidation and lipo-

fuscin accumulations in the brain. DHEA was also

found to counter the age-related decline of superoxide

MUA

EEGold control

30-days centrophenoxine-treated

Fig. 8 Effect of

centrophenoxine on

hippocampal MUA and

electroencephalogram in 24

month-old rat. Figure

derived from Singh and

Sharma (2005)

Biogerontology (2009) 10:377–413 403

123

dismutase and Na?K? ATPase activity in the brains

of old rats (Sinha et al. 2008; Taha et al. 2008;

Table 6). The effect of estrogen on aging parameters

in animal models has been discussed in earlier section

(Table 3).

A controlled maintenance/achievement of normal

hormone levels, increasing the sensitivity of insulin

receptors, control of blood glucose levels to near

normal values, are some of the physiological param-

eters to be achieved after the above pharmacological

interventions, which can be tried, leading to a better

management of age related disorders and diabetic

complications, delaying their onset considerably.

Thus, by identifying and understanding functional

dimensions of these natural physiological conditions,

timely interventions will be effective in prevention of

complications to a healthier life span of the

individual.

Acknowledgments The authors gratefully acknowledge the

financial support in the form of projects from University Grants

Commission, and Indian Council of Medical Research, India.

Pardeep Kumar is the recipient of SRF from Council of

Scientific and Industrial Research, New Delhi, India. This work

was in part supported by a grant for International Scientific

Cooperation. This review is dedicated to late Prof. A. L.

Greenbaum, Professor of Biochemistry, University College of

London, UK for appreciation of his wide knowledge of

teaching biochemistry and excellent communications and

writing skills of scientific work to make it easily understood

by students, scholars and researchers.

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