CR and advanced glycation endproduct restriction: ~ benefit?

[Guest guest]

Hi All,

The pdf-available below paper is mainly on the benefits of reducing

the level of our advanced glycation end product (AGE) formation, but

the comparisons made with the effects of CR, which also reduces our

advanced glycation end product (AGE) formation, appears to be

informatative. See:

" These findings are in support of clinical evidence from subjects

with diabetes or vascular or kidney disease. Most recently, evidence

from animal studies points to AGE restriction as an effective means

for extending median life span, similar to that previously shown by

marked caloric restriction. "

Vlassara H.

Advanced glycation in health and disease: role of the modern

environment.

Ann N Y Acad Sci. 2005 Jun;1043:452-60.

PMID: 16037266

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=16037266 & query_hl=2

INTRODUCTION

A major problem in public health today is the increasing incidence of

age-related chronic diseases, most prominently obesity, diabetes, and

cardiovascular and renal disorders. These have in common elevated

oxidant stress (OS) linked to a subinflammatory state.1-4 Among the

many mechanisms implicated in these disorders associated with normal

aging, an emerging one is OS-influencing gene expression.

Oligo-based microarrays and differential display analysis of gene

expression in mice have clearly indicated that age-related changes

are not simply the result of changes in gene expression, but rather

that of significant functional changes that are related to genes

controlling stress response.5,6 In mammals, the only major

intervention shown to effectively slow the age-related processes is

caloric restriction (CR); reduced caloric intake is indeed found to

modulate multiple intrinsic processes, prominent among these being a

reduction in oxidant stress.7-10

Increasing evidence points to links between intrinsic regulation of

oxidative pathways and stress response,9,10 and a general activation

in OS-related processes has been tied to chronic subinflammatory

states6 of diverse etiologies among healthy adult populations.5,11

Among those processes, lifelong, cumulative glycoxidation or advanced

glycation end product (AGE) formation is an important contributor to

OS, to cellular redox-sensitive transcription factor overactivity

and, ultimately, to inflammatory response or injury.12-14 Neither the

magnitude nor the origin of this elevated prooxidant state has been

completely understood.

A familiar subject that has provoked endless debate is human food and

eating habits. The modern dietary culture, aside of encouraging gross

overnutrition, has been recently found to be a major source for AGEs,

generated during standard exposure of food components to heat, and to

a lesser extent to irradiation and ionization, means intended to

render foods safer, more flavorful, and colorful.15-17 Human studies

have recently revealed significant correlations between ingested

AGEs, circulating AGEs (Fig. 1),18 and several markers of

inflammation,19,20 whereas animal studies seem to suggest that the

injurious impact of diet-derived AGEs on tissues, such as vascular

wall or kidney, could equal and even exceed that due to elevated

metabolites such as glucose or lipids per se.21-23 In this context,

restriction of AGEs in diet is found to exert a range of " protective "

effects, for example, against impaired immune function, as in

autoimmune diabetes of nonobese diabetic (NOD) mice,24 or against

insulin resistance in db/db(+/+) mice,25 diabetic vasculopathy,23

nephropathy,21 and impaired diabetic wound healing.26 These findings

have provided significant support to the newly emerging clinical

evidence based on subjects with diabetes, vascular disease, or kidney

disease, who responded to a low-AGE diet by a considerable reduction

in markers of inflammation and vascular dysfunction.18,19

FIGURE 1. Serum AGE correlates with dietary AGE consumption in a

cross-section of patients with chronic renal failure.18

ADVANCED GLYCATION HOMEOSTASIS

It has been well understood that most NH2-containing lipids,

peptides, or nucleic acids can be spontaneously modified by reducing

sugars, causing bioreactive, prooxidant derivatives-AGEs-or

lipoxidation end products (ALEs).27-29 These substances are

ubiquitous (intracellularly and extracellularly) and form

spontaneously in the absence of hyperglycemia (Fig. 2) and thus

constitute important contributors to ROS production, which in the

presence of exogenous or endogenous AGE precursors can promote a

state of elevated oxidant or carbonyl stress. Indeed, under modern

lifestyle conditions, excessive consumption of foods rich in AGEs and

tobacco smoking30 are ideal avenues for acquiring large deposits of

tissue AGEs beyond those forming under conditions of hyperglycemia or

renal failure14,16,17 (Fig. 3). The resulting OS burden is likely to

overwhelm the natural anti-AGE defense mechanisms, including

antioxidant systems, yielding to a sustained state of elevated OS,

gradually substituting the OS-free homeostasis. However, the

magnitude of this AGE-driven prooxidant state has not been accurately

assessed as yet because all its causes may not have been accounted

for. Nonetheless, AGEs are found elevated consistently in chronic

diseases, typically associated with enhanced markers of OS, redox-

dependent transcription factor activity, and inappropriate

inflammatory responsiveness.27-29

FIGURE 2. Spontaneous AGE (N-carboxy-methyl-lysine [CML]-like)

formation in human endothelial cells (A) and in culture media

containing low serum (0.01%) (, as a function of time (48 h), in

the absence of hyperglycemia (glucose 5 mM), exogenous AGEs, or other

prooxidant substances. Note the linear increase in intracellular and

extracellular CML-like immunoepitopes.

FIGURE 3. Schematic depiction of the multiple sources of AGEs. Beyond

the known conditions associated with elevated circulating and tissue

AGEs, exogenous sources-namely, diet and tobacco-constitute

significant contributors.

It has long been speculated that a key defense system against AGE

accumulation should be the AGE receptor system.31,32 Current evidence

has revealed a more complex picture and suggests that the AGE

receptor system can be broadly divided into two arms: one associated

with increased OS and inflammatory effects, both of which enhance AGE

formation, best represented by RAGE,31,32 and the other, involving

AGE detoxification and suppression of OS and inflammation,

represented by AGE-R1,33 but also by AGE-R2, AGE-R3, scavenger

receptors class A, type II (MSR-AII), class B, type I (MSR-BI,

CD36).14,31,32

Given the complex properties of AGEs, of concern has been the

apparent failure of the AGE receptors, as a defense system, to

effectively counteract AGE accumulation and toxicity despite enhanced

expression of most of its components in high-AGE states, for example,

in diabetes. An apparent exception to this rule is AGE-R1, a 48-kD,

AGE-specific, type I transmembrane receptor protein: the expression

and function of this molecule was found suppressed in mesangial cells

(MCs) and in macrophages from NOD mice,34 as well as in mononuclear

cells from diabetic subjects with severe diabetic tissue injury,35

evidence that suggested a possible inverse relationship between

enhanced AGE toxicity and suppressed AGE-R1 expression. The reasons

for this paradox were not readily apparent. However, overexpression

of AGE-R1 in MCs, as well as in other cells normally lacking AGE

receptors (e.g., Chinese hamster ovary [CHO] cells), resulted in

enhanced AGE uptake and degradative activity, confirming the active

role of R1 in the turnover of AGEs.33 More importantly, findings from

MCs, CHO cells, and other cells helped distinguish AGE-R1 as a

receptor that can also actively suppress proinflammatory signals

triggered by AGEs, for example, via RAGE.33 On the basis of these

properties, AGE-R1 was termed SAGE (for suppressor of AGE) receptor.

Thus, in principle, R1/SAGE may serve to neutralize inappropriate AGE-

mediated cellular OS and activation. These properties of R1/SAGE are

likely to be beneficial, because they stand in direct opposition to

the predominantly proinflammatory properties of molecules such as

RAGE.29,31,32 The unique effects of R1/SAGE, however, could be

rendered ineffective under conditions of chronically elevated ambient

AGE levels: the total AGE pool may well exceed the receptor's

saturation limit, possibly resulting in cytoplasmic sequestration or

downregulation of this system. In this regard, exposure of NOD mice

to an AGE-poor diet for four consecutive generations resulted in a

linear increase in R1/SAGE expression by NOD splenocytes in a manner

inversely correlating with the reduction of serum AGE across

generations (Fig. 4).

FIGURE 4. Effect of long-term exposure to a low-AGE food environment

on AGE-R1 (SAGE) expression and circulating AGE levels in four

generations of NOD mice (F0-F4). (A) Western analysis of NOD

splenocytes; ( serum AGE levels from the same donors (F0-F4). Note

the transgenerational inverse correlation between R1/SAGE expression

and AGE levels.

In this context, ample evidence suggests that diabetes,

cardiovascular disease, and other aging-related disorders may serve

as examples of such conditions. Both AGEs and OS are significantly

increased in diabetic and aging organisms, possibly together

rendering ineffective native antioxidant systems, scavengers, and AGE

receptors. Reconciling these phenomena has been the focus of our

investigation over many years.

ROLE OF THE ENVIRONMENT ON ADVANCED GLYCATION HOMEOSTASIS

Human or animal foods constitute major donors of AGEs and ROS.14-17

To assess whether exogenous AGEs constitute an excessively large

source of pathogenic AGE substances, we undertook several in vitro

and in vivo studies that yielded interesting findings. Food-derived

AGEs, like endogenous AGEs, were found to display potent protein-

protein crosslinking activity, ROS induction, suppression of

antioxidant reserves (e.g., GSH/GSSG ratio), and induction of

cytokines in cultured endothelial cells.36 More importantly, these

properties were found to be " transportable " into the blood stream.

Thus, low-density lipoprotein (LDL) obtained from diabetic subjects

preexposed to a regular AGE-rich diet proved capable of markedly

increasing NF-B activity and VCAM-1 secretion by endothelial cells

(consistent with vascular cell injury), whereas LDL from diabetic

subjects fed an AGE-poor diet did not acquire these toxic

properties.37 These findings supported the hypothesis that exogenous

reactive AGE precursors can induce significant molecular

transformation (or transglycation) of endogenous macromolecules, such

as LDL, rendering them toxic to target cells. The findings also imply

that such structural/functional changes can occur independently of

conditions such as diabetes.

Likewise, while diabetic animals fed regular diets consisting of the

standard AGE-rich mixtures developed the expected diabetic vascular23

or renal21 pathology, age-matched cohorts that were fed low-AGE diets

remained nearly free of such pathology, despite the presence of

diabetes.

Of interest, db/db(+/+) mice exposed to a low-AGE diet for 5 months

showed a significant reduction in fasting plasma insulin compared

with the group fed the regular food.24 Despite similar food

consumption, in the former group responses to glucose and insulin

tolerance tests were markedly improved, whereas the typically severe

islet damage due to spontaneous, type 2 diabetes in these mice was

largely prevented.25

In further studies, taking into consideration the links between

insulin resistance and vascular disease, the effects of an AGE-

restricted diet were tested on chronically fat-fed mice. Female

C57BL6 mice were subjected to prolonged, high-fat diets, but with

either high or low AGE content. At the end of 6 months, the degree of

visceral adiposity (including AGE-modified visceral fat) and of

insulin sensitivity correlated far better with the AGE content,

rather than the high-fat in the diet.38 After 6 months on the low-AGE

but still high-in-fat regimen, mice showed significantly lower

fasting insulin levels and close to normal responses to glucose and

insulin tolerance tests, compared with the high-fat, high-AGE-fed

controls.38 In addition, using euglycemic and hyperglycemic clamps,

both glucose infusion and plasma insulin levels in the low-AGE-fed

mice remained close to those of the normally fed control mice, as did

levels of circulating lipid peroxidation derivatives, 8-isoprostanes,

and plasma adiponectin.38

As a result of the above findings on the potential benefits of an AGE-

poor (but not calorically restricted) diet and given the well-

established effects of CR on aging,1,7,8 a comparative study was

conducted between low-AGE (AGE, 50% below standard diet) and

calorically restricted (CR, by 40% of ad lib) diet in normal C57BL6

mice, 4 mo, n = 22/group, over a period of 34 months.39 AGE

restriction in this series was found to be as effective as CR in

extending median life span, but without the need for restricting

caloric intake (low AGE vs. ad lib: 15%, P < 0.001, CR vs. ad lib:

13%, P < 0.001).

In addition, in this series, long-term AGE restriction, although

isocaloric to the standard diet, prevented age-associated weight gain

and insulin resistance, based on glucose-to-insulin ratio, suggesting

that this dietary intervention may preserve mechanisms related to

glucose and energy utilization, which become impaired with aging.

CONCLUSION

The effects of an AGE-restricted but isocaloric diet could be

attributed to the reduction of cumulative glycoxidant burden, which

might have helped to " decompress " native antioxidant/anti-AGE defense

mechanisms. The molecular mechanisms of the above effects are

currently under active investigation.

In viewing together the available information from animal and human

studies, it is worth noting the marked and parallel changes in

circulating glycotoxins and inflammatory markers observed in human

subjects after a variable AGE dietary regimen.18,19 Such studies

currently expanded to healthy subjects (reviewed elsewhere in this

volume by J. Uribarri) are among the first to reveal a substantial

interaction between large pools of exogenous and native glycoxidant

substances in humans. This evidence also may pose significant

challenges, because the effects of a sustained glycoxidant burden

have not been widely distinguished from that which is assumed

as " physiological " or healthy.

We conclude that, under the modern dietary/social structure,

excessive consumption of AGEs/ALEs and related oxidants may represent

an independent factor for inappropriate chronic OS and inflammatory

factor surges during the healthy adult years, which over time may

facilitate the emergence of complex diseases, such as diabetes and

other disorders related to aging. Reconsidering the AGE content of

common foods may prove a feasible and broadly applicable intervention

in both health and disease, possibly resulting in an extended healthy

life span.

[Guest guest]

From Message 15110 10/04

From my personal view...

I point I made earlier is that some of this is " semantics " and how we

define acitivity, exercise and fitness. MET levels is one way as is

caloric expenditure and now we have total steps. METs tells intensity

but not total output, while caloric expenditure tells total output but

not intensity and total steps estimates output. And we have problems

in the way it is measured and/or collected.

The other point I tried to make is that there seems to be some level of

activity, including endurance, strength and range of motion (which I

think is more important than flexibility) that we need to have to

survive. Granted our modern day society has made it so we don't need

those as much to survive and can even get by without them.

I think both of the above add to the confusion in the data and the

apparent conflicts.

My own PERSONAL interpretation (and this is stictly personal) of all I

have read and discussed... (which could be individualized to anyone else

personal lifestyle) is we get the most benefit (without the

consequences of overdoing it) by

- the " equivalent " of a 30-60 minutes brisk walk most days of a week (brisk

means

walking as if you had somewhere to go and were running late)

- the equivalent of 2-3 strength training sessions a week of around

15-30 minutes

- the equivalent of some brief but very high intensity endurance

sessions (ie 5-10 fast sprints of 10-15 seconds each 1-3x a week)

- 5-15 minutes of ROM exercises daily if possible, which are basically

just simple calisthenics in which you move all your body parts through

their full Range-Of-Motion a few times each. Doing this will prevent

the loss of flexibility as we age.

All of this can be accomplished in 60 minutes or less a day.

If you get all this in the course of your normal life, than you don't

need to add in.

If you get some of it but not others, just formally add in the parts you

are missing.

Except for the brief sprints, none of this is strenous, most of it can

be fun, and can be fit in simply. And the brief sprints, are actually

invigorating as they are intense, but brief and not done often, so not

draining.

And I say " equivalent " cause for endurance, it can be walking, biking or

whatever. For strength it could be weights, machines, dumbells, body

weight exercises etc, Whatever you prefer.