Ai posteri l'ardua sentenza

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Hi All,

The below pertains to whether CR is effective in humans.

" Ai posteri l'ardua sentenza " is translated at the bottom of the message.

MedGenMed Hematology-Oncology

Dec 2004

Caloric Restriction and Life Expectancy

- Tell me what you eat, and I'll tell you how long you'll live.

Highlights of the 5th European Molecular Biology Organization Interdisciplinary

Conference on Science and Society -- Time & Aging: Mechanisms and Meanings;

November

5-6, 2004; Heidelberg, Germany

Posted 12/22/2004

Elena la, PhD

Introduction

Tell me what you eat, and I'll tell you how long you'll live...

These words may sound like the lines of a song, but they actually reflect one of

the

most debated issues in our current understanding of the biology of aging, as

presented at the European Molecular Biology Organization (EMBO) conference

recently

held in Heidelberg, Germany, on " Time & Aging: Mechanisms and Meanings. "

Can diet help to prolong the expected lifespan of healthy individuals?

The experiments done in rodents and other short-lived species that link a

hypocaloric diet to a longer lifespan are well known. Can the information

obtained

in rodents be extrapolated to humans, and does it help to find " rules " that

would

lead to increased lifespans?

Caloric Restriction and Lifespan

L. Demetrius,[1] of Harvard University, Boston, Massachusetts, addressed the

applicability of the findings of a caloric restriction (CR) regimen from

short-lived

animal species to humans. The first evidence that CR could retard aging and

extend

lifespan was presented in the 1930s.[2] Since then, similar findings have been

confirmed in a variety of species, including mice, rats, fish, flies, worms, and

yeast.[3-5] Despite the extensive studies, however, the molecular basis for the

slowing of aging is still unclear, although the effects of CR on the physiology

of

an organism are well known.

One central question is whether CR will have the same life-prolonging effects in

humans.

According to Demetrius, to make any kind of prediction, we have to carefully

analyze

the similarities and differences between humans and the species in which the

studies

have been performed up to now. If we compare, for example, mice and humans, we

make

the hypothesis that mice are a miniaturized form of humans. Extrapolating the

data

about lifespan extension and CR obtained in mice to humans, we would predict

that

the mean lifespan could go from 75 to 90 years and the maximum lifespan from 120

to

150 years with CR. But is the initial assumption that mice are miniaturized

humans

valid?

" Mice are not small people, " argued Demetrius. Great differences exist in life

history and physiology, in cancer susceptibility, in the rate of senescence, and

several other factors. The metabolic rate is very different (16 kJ/day in mice

vs

7200 kJ/day in humans). The rate of senescence in mice follows a curve in which

mortality increases exponentially with age, in the absence of a mortality

plateau

that is, instead, seen in humans in whom mortality abates with age. There is

also a

difference in biological stability between mice and humans, exemplified by the

finding that mouse fibroblasts can convert to tumorigenic cells by the

perturbation

of just 2 signaling pathways. Conversely, in human fibroblasts the perturbation

of

at least 6 signaling pathways is necessary for tumorigenic conversion.

Mice and humans have been subjected to different ecologic and evolutionary

forces.

Mice (in the wild) are an opportunistic species, for which resources are

intermittently available, with alternating periods of population growth and

decrease

that occur rather quickly. On the other hand, humans are an equilibrium species

in

stable growth, for which resources are constant, although limited. If we look at

the

concept of Darwinian fitness (eg, the capacity of a population to survive and

reproduce under given environmental conditions), we find that the fitness of an

opportunistic species is based on demographic flexibility, whereas the fitness

of an

equilibrium species is based on demographic robustness.

In an opportunistic species, evolution will result in early sexual maturity,

large

litter size, and metabolic flexibility due to the high vulnerability to random

changes in metabolic networks. In an equilibrium species, evolution will result

in

late sexual maturity, small litter size, and metabolic robustness due to the

relative insensitivity of the system to random changes.

The effect of CR on the 2 species will then be different. If we make the

hypothesis

that CR increases the stability or robustness of the metabolic network by

increasing

the metabolic efficiency and enhancement of homeostatic regulation in cells, we

can

predict that CR will induce large changes in an opportunistic species by

increasing

its robustness, whereas it will have weaker effects on an equilibrium species,

in

which robustness is already achieved. From this, Dr. Demetrius predicted that

the

response to CR with an increase in lifespan will be marginal in humans owing to

the

robustness or stability of their metabolic networks and the evolutionary history

of

the species.

CR in Primates

It seems important at this point to confront this theory with the data available

on

CR in humans or primates. Is there any evidence in favor or against this

hypothesis? The evidence on the effects of CR on long-lived organisms (eg,

primates)

is scanty, although some studies have been conducted in monkeys.[6-8] In these

studies, researchers administered a regimen associated with an approximate CR of

30%

to 35%.

The results of the physiological findings in the monkeys showed great

consistency

with the rodent data. However, none of the ongoing non-human primate studies

have

experienced sufficient mortality to allow the determination of whether CR does

indeed extent lifespan in these primates. Of note, preliminary data suggest that

deaths due to cardiovascular disease and cancer may be reduced in the CR groups.

These findings, however, are preliminary and based only on a small number of

animals.

It is clear that performing studies on CR in humans presents methodological and

ethical problems. For these reasons, the amount of data in humans is even

scarcer.

In some parts of the world, human populations have been naturally exposed to CR.

Most of these populations, however, are exposed to energy-restricted diets,

lacking

in proteins and micronutrients. In these populations, CR is usually associated

with

substantial, adverse physiological effects.

The effects of prolonged CR on health and longevity in the context of an

equilibrated diet have been examined in Japan.[9] A study compared data from

Okinawa

(where the number of centenarians is several-fold higher than in the rest of

Japan)

with the rest of the population. The researchers found that the total energy

consumed by school children in Okinawa was only 62% of the " recommended intake "

for

Japan as a whole. In the adults, energy intake was 20% less than in the rest of

Japan, although protein and lipid intake was about the same. The rates of death

from

vascular disease, malignancies, and heart disease were only 59%, 69%, and 59%,

respectively, of those of the rest of Japan. The study, however, concluded that

besides CR, other factors, such as genetic and environmental factors, were

important

in explaining these differences.

Another study was conducted to investigate the effects of long-term CR (with a

good

quality diet) on health and longevity in nonobese humans.[10,11] The study was

conducted in 120 men of whom half were randomly assigned to the control group

and

the other half to the CR group. The control group was fed about 9600 kJ/day,

whereas

the CR group was fed about 6300 kJ/day (corresponding to a 35% restriction vs

controls). The regimen was maintained for 3 years. The data showed less time in

the

infirmary (123 days vs 219 days) and a nonsignificant difference in the death

rate

(6 vs 13 deaths) in the CR group vs controls. This gives a hint that CR may

affect

lifespan in humans.

In all studies, the physiological effects of CR seen in short-lived animals seem

to

be present also in primates. For example, CR improved glucose metabolism and

altered

insulin sensitivity, and influenced the secretion of many hormones and the

activity

of the sympathetic nervous system. CR also appears to alter the gene-expression

profile of cells in the muscle, heart, and brain.

CR is hypothesized to reduce oxidative damage by reducing energy flux and

metabolism. The role of oxidative stress in aging is suggested by several

observations: First, lifespan is inversely correlated with metabolic rate in a

variety of animals, and it is directly correlated to the amount of reactive

oxygen

species produced; second, overexpression of antioxidative enzymes or activation

of

defensive mechanisms against oxidative stress retards aging and extends lifespan

in

some organisms; and third, CR reduces oxidative stress in various species,

including

mammals.

Additional factors that, however, should not be underestimated can be found in

the

psychosocial environment. Such factors can have a strong influence on individual

well-being and can influence physiological parameters directly or indirectly

modified by an appropriate diet. The effects of such psychosocial influences are

more difficult to evaluate in research studies than CR and can be resistant to

modification through intervention programs.

One then is left to wonder whether the isolated implementation of CR in humans,

to

induce maximum beneficial effects as seen in animals, is indeed a realistic

possibility.

Life Expectancy: Facts and Predictions

The reality is that life expectancy has been steadily increasing in the last 160

years by about 3 months per year. Where will this trend lead us? Is there an

upper

limit?

Predictions of life expectancy have great socioeconomical implications.

Insurance

companies and health and social security agencies base their policies on such

predictions. An increase in life expectancy of a few years can produce large

changes

in the overall numbers of the old and very old. Analysis of the factors that may

have an influence on life expectancy is, therefore, of great importance.

Plotting

life expectancy vs time, starting in 1840, we obtain a straight line that does

not

seem to approach a maximum nor reach a plateau. Reason, however, tells us that

there

must be a limit, and this has always been the view of the experts in the field,

who

envision various biological barriers and practical impediments to the steady

rise in

life expectancy that we have seen so far.

Predictions of life expectancy were the topic of Jay Olshansky's[12]

presentation,

from the University of Illinois, Chicago, who stated his conclusions first and

then

presented the facts that had led him to it. His conclusion: There is sufficient

evidence to predict that in developed countries life expectancy will decline in

the

first 50 years of the 21st century.

Why do we live as long as we do? The increase in life expectancy seen in the

last

century occurred predominantly because we succeeded in saving young people who

would

have otherwise died. In the 21st century, we can produce a similar increase only

by

increasing the life expectancy of the old. But so far, the epidemiologic data

seem

to argue against this possibility. Since 1981, life expectancy at 65 years has

remained constant at 19 years, after a steep rise in the 1930s.

There are several constraints to the duration of life: biochemical, biological,

demographic, and stochastic. According to Olshansky, 2 factors that will have a

great influence on life expectancy in the next decades are infectious diseases

and

obesity. Unless suitable interventions are implemented, countries with high

incidence and prevalence rates of either factor are not expected to fare well in

terms of overall life expectancies. The percentage of the US population that can

be

defined as obese has risen from 10% in the 1960s to about 30% today. The

phenomenon

is particularly worrying in children, especially those belonging to minorities.

Today 25% of Hispanic children in the United States are obese vs 10% in the

1960s.

In other countries, the rate of obesity is also increasing, although the

absolute

percentage is lower: 3% in Japan, 7% in Switzerland, 9% in Italy, 10% in France,

and

13% in Spain.

With regard to infectious diseases, there are several factors from which

Olshansky

predicts that they will become an increasing concern: the increase in

antibiotic-resistant organisms, the more rapid and efficient transport across

the

world (eg, SARS), and the increase in the population of immunocompromised

subjects

(eg, due to aging, HIV, and chemotherapy). The overall mortality by infectious

diseases in the United States has risen by 39% since the beginning of the 1980s

(with a 4.5% increase per year between 1980 and 1995) -- by 25% in the

population

older than 65 years and by 6-fold in the population aged 25-44.

Hospital-acquired

infections are increasingly resistant to treatment. In addition, although about

20,000 influenza-related deaths have been observed in the United States between

1969

and 1996, they have increased to about 70,000 since 1996.

In conclusion, Olshansky is of the opinion that although advances in biomedical

technology and modifications in lifestyle will allow life expectancy to continue

its

slow rise in the short term, a repetition of the large and rapid gains in life

expectancy observed during the 20th century are unlikely, because this would

require

the ability of slowing the rate of aging -- something that we don't seem to be

able

to do today.

According to the novelist Alessandro Manzoni, " Ai posteri l'ardua sentenza " --

only

posterity will know whether these predictions turn out to be true.

Al Pater, PhD; email: old542000@...

__________________________________

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