Glucose, glycation and aging

[Guest guest]

Hi All,

Glucose, glycation and aging may be related

and affected by our CR diets.

Good in my eyes was:

" CR acts is by

bringing about mild hypoglycemia and increased

insulin sensitivity. "

Also, there was:

" Certain diets and dietary factors are found to

affeect AGE formation.One study in which the

levels of AGE in two different nutritional groups

were compared suggests that vegetarians have a

signi & #64257;cantly higher AGE values in plasma than

omnivorous subjects (Krajcovicova-Kudlackova

et al.2002).Although vegetarians consume less

proteins and saccharides,intake of vegetables and

fruit with predominance of fructose is signi & #64257;cantly

higher in them.Fructose induced AGE formation

is greater in the plasma of these subjects due to its

higher reactivity.Neutraceuticals like thiamine

and pyridoxamine of the B-complex vitamins have

been shown to possess antiAGE properties.Both

green tea and vitamins C and E were highly effective

in blocking age-related increase in tendon

breaking time in mice.Green tea also blocked the

age-related increase in collagen associated & #64258;uo-

rescence without decreasing glycemia (Monnier

et al.2002).Thus it has the ability of uncoupling

collagen aging from other endocrine factors and is

found to be rich in the antioxidant catechin,am-

inoacids and other ingredients that may contribute

to its antiaging effects. It may probably act by

inhibiting oxidant stress since a combination of

vitamins C and E can duplicate the effects shown

by green tea. "

Why the pdf-available below fails to be located

in Medline with a " caloric restriction " search of the

abstract is unclear to me.

Suji G, Sivakami S.

Glucose, glycation and aging.

Biogerontology. 2004;5(6):365-73.

PMID: 15609100 [PubMed - in process]

Glycation, a deleterious form of post-translational modification of

macromolecules has been linked to diseases such as diabetes, cataract,

Alzheimer's, dialysis related amyloidosis (DRA), atherosclerosis and

Parkinson's

as well as physiological aging. This review attempts to summarize the

data on

glycation in relation to its chemistry, role in macromolecular damage

and

disease, dietary sources and its intervention. Macromolecular damage

and

biochemical changes that occur in aging and age-related disorders

point to the

process of glycation as the common event in all of them. This is

supported by

the fact that several age-related diseases show symptoms manifested by

hyperglycemia. Free radical mediated oxidative stress is also known

to arise

from hyperglycemia. There is evidence to indicate that controlling

hyperglycemia

by antidiabetic biguanides prolongs life span in experimental

animals. Caloric

restriction, which appears to prolong life span by bringing about mild

hypoglycemia and increased insulin sensitivity further strengthens

the idea that

glucose via glycation is the primary damaging molecule.

Abbreviations:

AGEs –advanced glycation end products;

CR –caloric restriction;

CML –N e -(carb-oxymethyl)lysine;

HNE –4-hydroxy-2-nonenal,

IRS –insulin receptor substrate;

MRPs –maillard reaction products;

MGO –methyl glyoxal;

NEG –nonenzymatic glycation;

RAGE –receptor for advanced gly-cation end products;

ROS –reactive oxygen species

Introduction

All organisms have a physiological or potential

longevity which is the age upto which they can live

under ideal conditions without stress or disease

and death occurs purely due to aging or senes-

cence.Beckman and Ames (1998)have de & #64257;ned

aging as a multifaceted phenomenon associated

with decrements in cellular and physiological

functions,increases in the incidence of numerous

degenerative diseases and diminished capacity for

responding to stress.With the advent of modern

medical science and technology,the human life

span has increased,the consequences of which are

an array of age-related diseases like diabetes,cat-

aract,Alzheimer 's,to name a few.Understanding

the molecular mechanisms involved in aging would

thus help in developing effective strategies in con-

trolling age-related diseases thereby enhancing the

quality of life of the elderly.Since aging cannot be

totally prevented,it is desirable to evolve methods

to delay the onset of age-related disorders and

their symptoms.Many studies have shown varia-

tions in cellular functions,anatomical structures,

and molecular level changes in aging.The current

review focuses on the post-translational modi & #64257;ca-

tion of proteins called as nonenzymatic glycation

(NEG),which appears to be the common factor

for the pathophysiology of a number of age-re-

lated disorders.

During the life span of a stable protein,various

post-translational modi & #64257;cations occur (Harding

et al.1989).These include deamidation,oxidation,

nitration,phosphorylation,racemization,isomer-

ization,ubiquitination,NEG,etc.NEG is a dele-

terious form of sugar –protein interaction in which

the carbonyl group of the sugar adds to the amino

group of a protein resulting in the formation of

glycosylamines,which undergo rearrangement to

form stable Amadori products.The formation of

Amadori products is an early reversible stage of

glycation and is dependent on concentration of the

compound and exposure time.This early stage of

glycation is further followed by the irreversible end

stage reaction in which the Amadori products

undergo dehydration,condensation,fragmenta-

tion,oxidation,cyclization,etc.,resulting in the

formation of a wide and heterogeneous class of

compounds called the Advanced Glycation End

products (AGEs).Structurally identi & #64257;ed AGE

molecules include pentosidine (Dyer et al.1991),

N e -(carboxymethyl)lysine (Ahmed et al.1986),

pyrraline (Njoroge et al.1987),imidazolone (Niwa

et al.1997),crossline (Obayashi et al.1996),etc.

There may be other AGE molecules which are yet

to be structurally characterized.Not only sugars,

but sugar intermediates in the glycolytic and the

polyol pathways are also capable of non-enzy-

matic modi & #64257;cation.In fact,certain intermediates

like dihydroxyacetone phosphate,glyceraldehyde-

3-phosphate and fructose-3-phosphate can form

AGEs faster than glucose (Hamada et al.1996;

Sharma et al.2002).Among sugars,glucose has

been shown to be the least reactive and the emer-

gence of glucose as the primary metabolic fuel has

been attributed to its ability to limit the potentially

deleterious NEG (Bunn and Higgins 1981).In

addition to the direct glycation involving sugar

and protein,monosaccharides can enolize and

thereby reduce molecular oxygen under physio-

logical conditions,yielding a ketoaldehyde (a dic-

arbonyl),H2 O2 and free radicals by a process

known as `glycoxidation '(Thornalley et al.1984).

The presence of two carbonyl groups in dicarbo-

nyls makes it highly reactive and more damaging

than sugars.Dicarbonyls like 1-,3-,4-deoxyg-

lucosones,glyoxal,and methyl glyoxal (MGO)

react with proteins and propagate intermolecular

as well as intramolecular crosslinks (Thornalley

et al.1999).A large amount of reactive oxygen

species (ROS)is produced at many steps of the

parallel and sequential glycation cascade.For

example,when the Amadori product takes on an

enaminol structure,the superoxide radical is gen-

erated.The amino acid peroxides formed during

glycoxidation can also become sources of ROS.

Recently evidence has been provided in clear cut

experiments with model systems that glycation

generates an active center which is a cross-linked

Schiffbased radical cation of the protein,that

mimics the characteristics of a metal-catalyzed

oxidation system.These active sites catalyze the

formation of free radicals (Yim et al.2001).Thus

NEG can also lead to oxidative stress and this can

in turn increase glycation by glycoxidation.Redox

metals like Cu2+which catalyze reactions involv-

ing glycation have also been shown to increase in

plasma with age (Harman 1965).This may explain

the role played by redox catalysts and substances

capable of free radical generation in tissue damage

associated with aging (Harman 1981).The `Gly-

cation theory of aging 'proposes that blood glu-

cose itself damages cellular constituents by

nonenzymatic modi & #64257;cations of macromolecules,

an event known to occur during physiological

aging and in a majority of age-related diseases

(Monnier 1989).

Glucose metabolism in aging

Studies on the contribution of glycation to diseases

have focused primarily on its relationship to dia-

betes and its complications.But one should not

ignore the signi & #64257;cance of glycation in the context

of cellular metabolism since it affects all funda-

mental processes.Sugar induced damage is not

limited to diabetes.Even at normal glucose levels,

some degree of glycation occurs and the damage

caused thereby accumulates slowly over time.In

aged animals,NEG will be higher not only due to

hyperglycemia but also due to long-term exposure

of macromolecules to normoglycemic conditions.

AGEs like pentosidine and CML,which are con-

sidered as biomarkers of aging,have been shown

to increase & #64257;ve-fold from infancy to old age (Dyer

et al.1993).However the levels of these biomar-

kers are not uniformly increased in all the tissues

but have been shown to be higher in renal collagen

with pentosidine levels speci & #64257;cally higher in carti-

lage compared to skin collagen in human.It has

also been shown that the rate of accumulation of

CML on collagen is linear,while the increase in

collagen is nonlinear (Baynes 2000).However the

accumulation of AGEs is slower during biological

aging compared to that in diseases like diabetes.

Several studies have demonstrated an age-re-

lated glucose intolerance in humans.In a normal

individual,there is a slight age-related increase in

fasting glucose levels and a delay in returning to

normal after an oral glucose tolerance test (Fulop

et al.2003).One explanation for this is a reduction

in insulin sensitivity with age.Several lines of

evidences now suggest that with aging,insulin

resistance increases primarily due to changes in

insulin receptor signal transduction.Changes in

receptor number may also play a role.One cannot

overlook the part played by AGEs and oxidative

stress in this process.AGEs as well as free radicals

may directly in & #64258;uence or interfere with the insulin

receptor functioning and signal transduction by

diminishing the tyrosine phosphorylation of the

insulin receptor substrate (IRS).This in turn re-

sults in decreased protein kinase B activity altering

glucose and glycogen metabolism (Fulop et al.

2003).

Glycation in macromolecular damage

A universal feature of all aging cells is the

appearance of lipofuscin,nondegradable & #64258;uores-

cent intracellular granules of aggregated proteins.

A variety of inclusions such as lipofuscin granules,

corpora amylacca,Hirano bodies,granulovacuo-

lar degenerations and ubiquitin-positive granular

structures have been found in the aged human

brain (Kimura et al.1998).Evidences suggest the

presence of glycation end products like CML and

lipid peroxidation products like 4-hydroxy-2-non-

enal (HNE)in lipofuscin,which lead to protein

cross-linking, & #64258;uorescence and enzyme inactiva-

tion (Szweda et al.2003).

A major source of stress associated with aging

and age-related diseases are mitochondrial damage

and modi & #64257;ed protein accumulation.Accumulation

of AGEs like CML have been seen in mitochon-

dria of aged animals.Hyperglycemia can result in

overproduction of mitochondrial ROS,leading to

in formation of more AGEs primarily by forming

the intermediate MGO.MGO can inhibit respi-

ratory rate and has a suppressive effect on the

complex I of the respiratory chain which is a major

source of superoxide radicals in vitro (Bakala et al.

2003).Tanaka et al.(2000)have shown that nearly

two thirds of Japanese centenarians have a mito-

chondrial gene variant which codes for a subunit

of NADH dehydrogenase at complex I of the

respiratory chain.That this variant is associated

with low leakage of free radicals is supported by

the report that women with this variant have fewer

mitochondrial DNA mutations.

Among the potentially relevant targets of sug-

ars,collagen is the & #64257;rst matrix protein that was

used to demonstrate that glucose derived AGEs

can form intermolecular bonds (Kent et al.1985).

An accelerated aging of collagen is seen in diabetes

due to the accumulation of biomarkers like CML,

pentosidine and other AGEs.Collagen aging in

diabetes is apparent not only by increase in these

biomarkers,but also by increases in browning and

& #64258;uorescence,and a decreased solubility and elas-

ticity.Biomarkers of oxidative stress such as

o -tyrosine and methionine sulphoxide do not

change in skin collagen during diabetes suggesting

that hyperglycemia rather than oxidative stress is

the cause of this damage in diabetes (Baynes 2000).

Impairment in the assembly and association of

type IV collagen molecules into normal network

occurs due to glycation.AGE modi & #64257;ed lamini

have a decreased capability for self assembly and

binding to collagen IV molecules and heparin

sulphate proteoglycan.According to Odetti et al.

(1992),the rate of accumulation of collagen AGE

& #64258;uorescence is 3.7%per year.AGEs have also

been shown to induce the hyper _expression of

adhesion molecules like V-CAM-1 and ICAM-1 in

the endothelium.AGEs formed in the skin vessels

and skin extra cellular matrix have the ability to

activate the microin & #64258;ammatory cycle by upregu-

lating the synthesis of ICAM-1 which plays an

important role in skin aging (Giacomoni and Rein

2001).

The toxicity of glycation is due to its ability to

inhibit speci & #64257;c functions of proteins through cross

linkage,aggregation and precipitation as well as to

produce ROS.Because of the accumulation of

modi & #64257;ed,glycated and misfolded proteins in aged

organisms,they require increased amounts of

chaperones to prevent their aggregation.Due to

their vulnerability for aggregation,modi & #64257;ed pro-

teins are excluded from the normal metabolic

pathway and accumulate in the aging cell.One

way to protect the cell is their elimination.Protein

degradation is mostly undertaken by the proteo-

lytic apparatus,the proteasome and aided by

various chaperones.Aging leads to the decline in

the activity of the proteasome (Conconi et al.

1996).Glycated,oxidized and aggregated proteins

are poorer substrates for and highly effective

inhibitors of the proteasome (Friguet et al.1994;

Bence et al.2001;Bulteau et al.2001).AGEs have

also been shown to contribute to the development

of apoptosis and _expression of apoptotic genes

(Chen et al.2003).Aging enhances apoptosis as

well as susceptibility to it in several types of intact

cells (Higami and Shimokawa 2000).Thus dysre-

gulation of the apoptotic process may be involved

in some aging processes.

AGE modi & #64257;ed proteins are not inherent to the

body and are recognized as foreign molecules to be

removed from the body.Since AGEs are con-

stantly formed under physiological conditions,

complex receptor systems have evolved to remove

glycation modi & #64257;ed molecules.It has been shown

that adverse effects caused by glycation are medi-

ated via AGE recognizing receptors like RAGE,

the AGE receptor complex and type 1 and type 2

scavenger receptors (Stitt 2001).RAGE is a

member of the immunoglobulin family and is ex-

pressed in a variety of cell types,including endo-

thelial cells,smooth muscle cells,mononuclear

cells and neurons.The degradation products of

AGEs are carried into the circulation to be cleared

by the kidney.In aging where there is a deterio-

ration of renal function,there is a pronounced

increase in AGE degradation products in circula-

tion.AGE peptides,which are low molecular

weight degradation products of AGEs in circula-

tion can further modify low density lipoprotein

(LDL),collagen and other biomolecules.Thus the

catabolic products of AGE if not eliminated from

the body by the kidney can irreversibly alter renal

and extra renal structures,producing `second 'and

`third 'generation AGEs (Vlassara 1996).

Several studies have documented that oxidative

DNA lesions accumulate with aging and it appears

that the major site of this accumulation is mito-

chondrial.Not only proteins,but also amino

groups of nucleic acids are modi & #64257;ed in the pres-

ence of reducing sugars to form DNA-bound

AGEs.DNA modi & #64257;cations are more serious than

those on proteins,since they can become perma-

nent via mutations and other types of genomic

instability and a cell can pass on this information

to the next generation.Many studies have shown

that DNA structure and function are affected after

incubation with reducing sugars like fructose,

glucose,glucose-6-phosphate and reactive glycated

products formed from glyceraldehyde-3-phosphate

and lysine (Levi and Werman 2001).Enhanced

intracellular levels of glucose-6-phosphate were

also found to increase plasmid DNA mutation in

Escherichia coli (Lee and Cerami 1987).

Glycation in age-related diseases

The direct detection of AGEs in atherosclerotic

plaques as well as the amyloid plaques in patients

with dialysis related amyloidosis (DRA)and Alz-

heimer 's disease (AD)has con & #64257;rmed the role of

NEG in the pathogenesis and progression of these

age-related diseases (Thorpe and Baynes 1996).

Oxidative stress dependent formation of AGEs has

also been detected very early in the onset of Par-

kinson 's disease (Koutsilieri et al.2002).Using

antiAGE antibodies,AGEs have been found in the

b amyloid plaques and neuro & #64257;brillary tangles in

the brains of patients with Alzheimer 's disease.

The levels of AGE increased threefold in AD

brains.Glycation of these proteins promotes their

nucleation and precipitation,suggesting an addi-

tional mechanism by which NEG can aggravate

the progression of pathology in Alzheimer 's dis-

ease.In vitro glycation of amyloid and tau proteins

has shown that the seeding effect of amyloid does

increase after glycation (Kikuchi et al.2003).

Alterations in I/IR signaling and glucose metab-

olism in brain during aging and Alzheimer 's

resulting in inhibition at the S/G2/M phases of the

cell cycle with activation of the G1 phase have

been shown.This leads to accumulation of the b

amyloid protein and the hyperphosphorylation of

tau protein (Fulop et al.2003).Thus the initial

event of deposition of these proteins is followed by

the accumulation of AGEs on them,resulting in

in & #64258;ammation and tissue damage.An increase in

the levels of b microglobulin (b M)and AGE

b M in DRA initiates a local in & #64258;ammatory re-

sponse,a major cause of bone destruction and

connective tissue degeneration in DRA patients

(Thorpe and Baynes 1996).Age-related autoim-

mune diseases like rheumatoid arthritis and lupus

erythrematosus are characterized by enhanced

in & #64258;ammatory responses which accelerate the aging

of tissues.Rheumatoid arthritis patients show an

increase in the levels of pentosidine in plasma

indicating oxidative stress and damage to collagen

(- et al.1998).AGEs invoke

in & #64258;ammatory responses by binding to RAGE,

which are distributed on an array of cells including

those of monocytes and lymphocytes.

A defective vascular relaxation and hyperten-

sion associated with both diabetes and aging is

caused by collagen bound AGEs in the vascular

walls which directly react with nitric oxide and

inactivate it.LDL,a lipid carrier plays a crucial

role in atherogenesis (Thorpe and Baynes 1996).

AGE moieties were found to be present on both

the apoprotein as well as the lipid components.

Apart from oxidative modi & #64257;cation,advanced

glycation has been found responsible for limiting

the clearance of LDL and making it more ath-

erogenic.A very direct link between redox cat-

alysts like Cu2+and Fe2+and atherosclerosis

was established by showing the presence of these

metals in the atherosclerotic plaques of patients

who died of atherosclerosis (Halliwell 1997).

These transition metals released as a result of

tissue injury promote further oxidative stress,

which in turn can release more metal ions

(Halliwell 1997).Thus oxidative stress arising as

consequence of NEG can also contribute to

metal ion release.

The AGEs accumulating in the eye lens during

the aging process induce photosensitization of

some aminoacids like tryptophan contributing to

photodamage and cataract formation (Rochette

et al.2003).In vitro studies have shown that

a crystallin,a chaperon,prevents the aggregation

of lens crystallin and other unfolded proteins and

protects against glycation (Heath et al.1996).

Aging leads to a compromise in the chaperone

function of a crystallin allowing the formation of

light scattering aggregates that can proceed to

form cataracts (Derham and Harding 1997).Also

the action of highly reactive dicarbonyls such as

glyoxal and MGO is increased in diabetes and

aging leading to increased AGE crosslinks on

a crystallins with resultant loss of chaperone

activity,increased ab crystallin content and dense

aggregate formation (Derham and Harding 1999;

Shamsi et al.2000).

Glycation and diet

The sources of AGEs can also be exogenic,for

example,food derived.The exogenic Maillard

reaction products (MRPs)are formed during heat

processing of food,which is done to enhance their

& #64258;avors.Many foods can form high levels of AGEs

during cooking which,upon digestion,release

reactive peptides into the circulation.These in turn

have the ability to form covalent crosslinks (Kos-

chinsky et al.1997).Tobacco curing also involves

glycation.Combustion of these adducts during

smoking can release reactive,toxic glycation

products which enter the blood stream and be-

come & #64257;xed in tissues due to their abilities to

crosslink (Cerami et al.1997;Nicholl et al.1998).

Low molecular weight peptides (MRPs)are ab-

sorbed partially into the circulation and excreted

in urine.However,during renal insu & #64259;ciency,their

removal is impaired.A recent hypothesis suggests

that glycated molecules in feed may have given rise

to bovine spongiform encephalopathy in cattle

(Boratynski and Gorski 2002 )

Certain diets and dietary factors are found to

affeect AGE formation.One study in which the

levels of AGE in two different nutritional groups

were compared suggests that vegetarians have a

signi & #64257;cantly higher AGE values in plasma than

omnivorous subjects (Krajcovicova-Kudlackova

et al.2002).Although vegetarians consume less

proteins and saccharides,intake of vegetables and

fruit with predominance of fructose is signi & #64257;cantly

higher in them.Fructose induced AGE formation

is greater in the plasma of these subjects due to its

higher reactivity.Neutraceuticals like thiamine

and pyridoxamine of the B-complex vitamins have

been shown to possess antiAGE properties.Both

green tea and vitamins C and E were highly effective

in blocking age-related increase in tendon

breaking time in mice.Green tea also blocked the

age-related increase in collagen associated & #64258;uo-

rescence without decreasing glycemia (Monnier

et al.2002).Thus it has the ability of uncoupling

collagen aging from other endocrine factors and is

found to be rich in the antioxidant catechin,am-

inoacids and other ingredients that may contribute

to its antiaging effects. It may probably act by

inhibiting oxidant stress since a combination of

vitamins C and E can duplicate the effects shown

by green tea.

Efforts are being made to identify molecules that

can arrest the formation of AGEs at the level of

Amadori products and post-Amadori conversion

to AGEs.An interesting & #64257;nding is that acetalde-

hyde forms a stable complex with Amadori prod-

ucts thus preventing them from further conversion

to AGEs.Since the alcohol consumed gives rise to

acetaldehyde in the body,this may be a possible

explanation for the cardio protection bestowed by

consumption of moderate amounts of ethanol in

the diet,the so called `French paradox '(Bucala

2002).A great deal of research is being conducted

in order to & #64257;nd therapeutically effective ways to

trap Amadori products,AGE molecules like CML

and dicarbonyl compounds,to inhibit signaling

pathways and & #64257;nally to trap free radicals directly

in order to control oxidative stress (Monnier et al.

2002).Since caloric restriction has been shown to

lower plasma glucose and/or insulin levels as well

as raise insulin sensitivity,a number of compounds

which can act as `CR mimetics 'have the potential

to increase longevity (Weindruch et al.2001).

Efffectively these compounds are antidiabetic drugs

like sulphonylureas,biguanides,thiazolidinedi-

ones,a glucosidase inhibitors,phlorizin and van-

adate (Weindruch et al.2001).The toxicity of

these molecules to humans will have to be rigor-

ously evaluated.It is also necessary to understand

the consequences of administering these drugs to

normal subjects as most available data are on the

blood glucose lowering effect of these molecules in

the diabetics rather than in control subjects.In this

context,it may be safer to use natural products

and botanicals with blood glucose lowering abili-

ties.Despite the availability of experimental data

on CR and longevity in rodents and nonhuman

primates,it is not clear what the effects of long-

term CR will be on human health,intellect and

well being.

Results from various studies overwhelmingly

indicate that caloric restriction (CR)is the single

most powerful intervention that can prolong life

span.CR in birds and rodents decrease collagen

glycation,glucose autoxidation and tendon colla-

gen cross-linking (Cefalu et al.1995;Sell et al.

2000).In primates,CR decreases glycemia but

glycated hemoglobin is only marginally decreased.

It is found that the magnitude and onset of these effects

are in part species dependent (Kemnitz

et al.1994).In primates CR possibly acts by

decreasing glycemia and lipidemia ( et al.

1998;Campisi 2000),the results of which are de-

creased oxidant stress (Gredilla et al.2001)and

carbonyl stress,respectively.

There is clear cut evidence that glycation is

responsible for cataract formation,secondary

complications accompanying diabetes,atheroscle-

rosis,Alzheimer 's and DRA among others.The

administration of blood glucose lowering agents,

like the antidiabetic biguanides,prolongs the

average life span in mice and rats (Anisimov et al.

2003).This shows a direct link between hypergly-

cemia,glycation,aging and life span.Since glyca-

tion brings about cellular damage and increased

free radical production and thereby oxidative

stress,glucose may be the primary trigger in aging.

Summary

The age-related increase in fasting glucose levels

and glucose intolerance in humans and a delay in

returning to normal after an oral glucose tolerance

point to the fact that in aged individuals there is a

diminished capacity to metabolize the damaging

sugars.Apparently the resultant hyperglycemia

would lead to the formation of more AGEs.The

ability of the AGEs to become resistant to prote-

olytic removal and invoke in & #64258;ammatory response

can bring about damage further.Thus the accu-

mulation of AGEs in aging tissues would be the

consequences of both hyperglycemia and impaired

removal of AGEs from the body.Many of the

symptoms manifested in natural aging bear

resemblance to those seen in the hyperglycemic

state (diabetes).Age-related diseases exihibit in-

creased levels of glycation and its end products,

further supporting the idea that sugars are the

damaging molecules.Lowering glucose levels di-

rectly by antidiabetics like biguanides prolongs life

span further pointing to glucose as the primary

cause of the changes observed in aging.In addition

free radicals arising from glucoxidation and other

sources like mitochondrial leakage further accel-

erate the aging process.Dietary sources of AGEs

can be as damaging as the endogenous AGEs.The

components of diet also accelerate the formation

of AGEs in the body.The accelerated formation of

AGEs in the vegetarians who consume foods rich

in fructose is an example of this.Although most of

the CR studies have been carried out on lower

animals,the results from such studies point out

that one of the mechanisms by which CR acts is by

bringing about mild hypoglycemia and increased

insulin sensitivity.

Thus in summary,glucose seems to be central to

the phenomenon of aging and age-related diseases

for the following reasons.(1)The symptoms

manifested in natural aging like cataract are simi-

lar to those resulting from hyperglycemia.(2)

Aging is accompanied by mild hyperglycemia and

glucose intolerance.(3)CR,which is known to

prolong life span,appears to act by bringing about

mild hypoglycemia and increased insulin sensitiv-

ity.(5)Lowering glucose levels directly by antidi-

abetics like biguanides prolongs life span.Free

radicals arising from glucoxidation and other

sources like mitochondrial leakage further pro-

mote the aging process.

Cheers, Alan Pater