CR research update

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Hi All,

A highlight of the below pdf-availed paper may be: " In

our study, we have ... reported that the monkeys on CR

display ... an emerging survival advantage compared to

the age-matched controls (unpublished observations). "

RM, Weindruch R.

Calorie restriction: Progress during

mid-2005-mid-2006.

Exp Gerontol. 2006 Nov 22; [Epub ahead of print] No

abstract available.

PMID: 17125949

1. Overview

In keeping with the current trend, this year again has

seen a substantial volume of literature on the topic

of calorie restriction (CR). Work in widely diverse

species has contributed to our understanding of CR and

continues to provide important clues about the

mechanism of lifespan extension by CR. Let us

acknowledge at the outset that the scope of this

review permits only a handful of these studies to be

described, for this we apologize and list areas of

progress that we view as most important.

2. Towards a mechanistic understanding

A number of pathways originally identified in

longevity studies in invertebrates have come under

further scrutiny, requiring some revision of previous

models. The role of the Sirtuin family of NAD

dependent deacetylases in longevity and in the

mechanism of CR has drawn particular attention (Longo

and Kennedy, 2006). It remains to be seen if the

contribution of Sirtuins to the mechanism of CR is

conserved in yeast, worms and flies. As a result, data

from these organisms may not necessarily be predictive

of a role for Sirtuins in the mechanism of lifespan

extension by CR in mammals. The role of mitochondrial

respiration in CR has also been brought into question

by a study that demonstrates lifespan extension with

CR in a respiratory deficient yeast strain (Kaeberlein

et al., 2005a). The fact that alternate pathways

promoting longevity are induced in strains lacking

respiratory capacity does not negate a role for

mitochondrial metabolism where the organelles are

functional. The important finding from these studies

on strain dependent differences is that CR may extend

lifespan by impacting multiple pathways and that there

may be a certain amount of mechanistic plasticity.

The TOR pathway has long been suspected of providing a

link between nutrition, metabolism and longevity, and

deficiency in TOR signaling extends lifespan in worms

and flies. A large-scale analysis of over 500 single

gene deletion strains in yeast has pointed to the

involvement of the nutrient sensing TOR pathway in the

mechanism of CR (Kaeberlein et al., 2005b). There is

also evidence for down-regulation of the mTOR pathway

in the long-lived Ames Dwarf mouse (Sharp and Bartke,

2005). The mammalian mTOR pathway has recently been

shown to be involved in determining resting oxygen

consumption and oxidative capacity in cultured cells

(Schieke et al., 2006). mTOR affects mitochondrial

function and the mitochondrial phosphoproteome

independent of the regulation of ribosomal gene

expression. The influence of TOR on mitochondrial

function is of particular interest in the context of

CR, because mammalian studies have demonstrated that

mitochondrial metabolism and ROS generation are

altered in tissues from restricted animals compared to

controls (see below).

A significant challenge in the study of the mechanism

of CR in invertebrates is presented by the lack of

consensus in methodological approach. In worms,

differences in the implementation of CR (bacterial

dilution/anexic media/use of “genetic mimic”) cause

complications in determining key factors involved. As

a result, the extent of crosstalk between the insulin

signaling pathway and CR is controversial, and the

involvement of TOR and SIR-2.1 is still under

investigation (Houthoofd et al., 2005). Nonetheless,

the use of RNAi screens proves invaluable in the

identification of factors that influence longevity and

continues to provide new and exciting leads (Hansen et

al., 2005). An important issue relating to methodology

has been resolved in Drosophila studies where the

standard CR regimens reduce calories by dilution of

either the yeast or sugar component of the diet. By

direct comparison of isocaloric diet in terms of

lifespan extension and reversibility of effect, it

appears that all calories are not created equal and

the yeast component is the key determinant of lifespan

in this organism (Mair et al., 2005).

The extent of overlap between established regimens

that influence lifespan in the mouse model is also

unclear. In rodents, CR extends the lifespan of the

Ames dwarf but does not further extend the lifespan of

the growth hormone receptor knockout (GHRKO) mouse

(Bonkowski et al., 2006). The inference is not that

the GHRKO mouse and CR extend lifespan by the same

mechanism, rather that elements required in the

mechanism of CR are absent in the GHRKO mouse. This is

based on differences in gene expression profiles in

tissues from GHRKO and CR animals that do not support

an equivalent mechanism of lifespan extension.

A number of studies have demonstrated an

anti-inflammatory effect of CR in rodents. In rats, CR

and exercise have beneficial effects on circulating

levels of C reactive protein, a marker of inflammatory

tone (Kalani et al., 2006). Transcriptional profiling

of mouse adipose tissue reveals a marked reduction in

the expression of genes involved in inflammation with

long term CR (Higami et al., 2006). While we do not

yet know how CR brings about the anti-inflammatory

effect, this phenotype may be an important contributor

to the delay in onset of age-associated diseases.

3. Mitochondria

The role of mitochondria in the mechanism of CR

continues to be an area of active research.

Differences in experimental approach have yielded

interesting and sometimes apparently contradicting

data. In flies, CR does not appear to affect

mitochondrial numbers in muscle but does appear to

alter mitochondrial morphology and in vitro enzyme

activities (Magwere et al., 2006). In mammalian cells

grown in serum derived from CR rats, mitochondrial

biogenesis is increased and bioenergetic efficiency is

improved with concomitant reduction in reactive oxygen

species (ROS) generation (-Lluch et al., 2006). A

separate study reports increased mitochondrial

biogenesis with CR based on increased transcription

levels of nuclear encoded mitochondrial genes and

increased mitochondrial DNA content in tissues from

restricted mice compared to controls (Nisoli et al.,

2005). A role for nitric oxide in CR is suggested by

the finding that endothelial nitric oxide synthase

(eNOS) is induced by CR, and the effect of CR on

mitochondrial markers is reduced in eNOS null mutant

mice. It will be interesting to see if reactive

species in general play a signaling role in the

mechanism of CR.

Studies in isolated mitochondria from rat skeletal

muscle reveal a reduction in ROS production with CR

that is not due to changes in proton leak (Bevilacqua

et al., 2005). Separate studies demonstrate that CR

opposes the decline in oxidative capacity of skeletal

muscle mitochondria. This effect is independent of

mitochondrial DNA integrity suggesting that there is a

difference in mitochondrial function with CR that

cannot be simply explained by differences in

mitochondrial DNA damage (Baker et al., 2006). This

same study demonstrated reduced activities of both

citrate synthase and Complex IV of the electron

transport system in extracts from CR muscle, however;

activities were maintained with age in CR tissues but

declined below the CR levels in tissues from Control

animals with age. Analysis of Complex IV activity in

skeletal muscle in situ provides evidence that

mitochondrial from CR animals have a higher affinity

for oxygen (Hepple et al., 2005). This raises the

possibility that data from isolated mitochondria may

not reveal key differences in mitochondrial function

with CR.

4. Studies in primates

A major goal of the field is to determine the

potential of CR in humans. On route to this is to

understand whether CR can slow the aging process in

nonhuman primates that share close genetic makeup to

humans. There are two studies (one at the USA’s

National Institute on Aging; the other at the

University of Wisconsin) in rhesus monkeys that began

in the late 1980s, which are examining the effects of

CR on aging. In our study, we have previously reported

that the monkeys on CR display signs of improved

health (e.g. 70% less body fat, higher insulin

sensitivity, favorable changes in circulating lipids).

Further, CR imparts a complete protection from Type 2

diabetes and an emerging survival advantage compared

to the age-matched controls (unpublished

observations). As the rhesus monkeys at our Primate

Center have an average lifespan of 27 years and a

maximum lifespan 40 years, it may be another 25 years

before we obtain full survival data from this

population.

Significant progress has also been made on the effects

of long-term CR in humans. Direct evidence comes from

studies of cardiovascular aging in long-term

practitioners of CR who were reported in 2004 to

display markedly improved risk factor profiles for

protection against developing cardiovascular disease,

including core features of CR (e.g., reductions in

circulating insulin and glucose levels). These

individuals also display fewer signs of aging in heart

(diastolic) function (Meyer et al., 2006). Additional

progress in human CR is occurring as result of the

USA’s National Institute on Aging funding to conduct

CR investigations in people. CR lowers body

temperature and insulin levels (both of which happen

in rodents on CR) in overweight subjects (Heilbronn et

al., 2006). In addition, CR (as well as exercise)

lowers adipocyte size and some negative outcomes such

as lipid deposition in visceral and hepatic tissues

and insulin resistance linked to large adipocytes

(Larson-Meyer et al., 2006).

5. Final comment

Clearly, significant advances in understanding the

biology of CR were gained over the period reviewed. A

glimpse at the publications appearing subsequent to

this period suggests that next year’s review will

convey even greater insights.

-- Al Pater, alpater@...

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