CR and its mimetics review

[Guest guest]

Hi All,

See the not pdf-available paper below. CR and its mimetics are reviewed.

J Am Geriatr Soc. 2005 Sep;53(9 Suppl):S280-3.

Caloric restriction and caloric restriction mimetics: current status and promise

for

the future.

Roth GS.

Dietary caloric restriction is the most reproducible means of extending

longevity

and maintaining health and vitality. It has been shown to be relevant to a wide

rage

of species, including primates. Examination of key markers of the calorically

restricted phenotype, such as plasma insulin, dehydroepiandrosterone sulfate,

and

body temperature, suggest that they may predict longevity in humans as well.

However, most people would be unwilling or unable to adopt the 30% to 40%

reduction

in food intake necessary to achieve optimal health and longevity benefits. For

this

reason, a number of laboratories are pursuing caloric restriction mimetics: ways

to

achieve the benefits of restriction without eating less. This approach will

undoubtedly remain a major focus of biogerontolgy for the foreseeable future.

PMID:

16131352

Humans are, by far, the longest lived of mammalian species. Some controversial

data

for whales and a few other species suggest that they may live a bit longer, but

compared to our next closest cousin, the chimpanzee (which is genetically about

99%

the same as us), we live almost twice as long.1 It is not clear why that is so.

Is

there an upper limit on human life span? Interestingly, if one examines various

populations, the maximum life span is still probably somewhere between 100 and

120

years. It is important to realize that, if the top 10 or 15 causes of death were

eliminated (including cardiovascular and renal diseases and various types of

cancer), we probably would not obtain more than another 20 years of life

expectancy.2

To increase maximal life span requires something more fundamental. One

intervention

that is commonly employed is exercise. Exercise is good, of course, and can help

to

avoid many of the diseases of aging, but, interestingly, exercise does not seem

to

intervene in the fundamental underlying aging process itself. For example, in a

classic study,3 the effects of exercise and caloric restriction were compared in

rats, whose maximum life span is about 1,200 days and median life span is about

900

days. If rats were allowed access to voluntary running wheels, median life span

was

extended by about 100 or 200 days, but maximum life span was not significantly

affected.3 That is important because exercise seems to help us avoid many of the

age-related diseases that might get us before we reach age 75 or 80, but it does

not

seem to be able to extend the maximum life span.

Caloric restriction, to my knowledge, is the only intervention that has

reproducibly

been shown to be able to do that, at least in animal models. For example, in

typical

studies, when rats were given 40% less food than they would choose to eat if

allowed

to take all they wanted, median and maximum life spans were increased by another

couple hundred days.4 In the study mentioned above, animals that were

calorically

restricted were given access to the run wheels, but the exercise did not add to

the

life-extending effects of the caloric reduction.3 Nevertheless, recent data

suggest

that, with moderate caloric restriction (10%), exercise may add to the

life-extending benefit of the caloric reduction.5

A classical caloric restriction experiment4 is depicted in Figure 1. Mice whose

caloric intake was reduced about 10% (so these controls were not too fat) were

compared with mice whose caloric intake was restricted 40% beyond that (50% from

baseline), resulting in substantial extension of the median and the maximum life

spans.

In addition to quantity of life, the quality of life is equally important. Few

of us

would want an extra 20 or 30 years of life if, throughout this period of time,

we

were sick, institutionalized, or markedly dysfunctional. One of the good things

about caloric restriction is that, in addition to extending the quantity of

life, it

appears to improve the quality of life, at least in animals.4 Although many of

the

age-related diseases occur, they do so to a less-severe degree and begin later

in

life. Even functional abilities, such as ability to learn how to navigate a

maze,

are maintained much later in life in calorically restricted animals.4

Most of the caloric restriction work over the last 70 years has been conducted

in

rats and mice. Restriction has also been studied in lower animals (invertebrates

and

insects, spiders, fish, and round worms), with similar results,4 but until 1987,

this intervention had never been tested in an animal that lived longer than

about 3

years. At that time, a study with rhesus and squirrel monkeys was started at the

National Institute on Aging.6 The reason for using monkeys was that they are so

close to humans, and the question to answer was whether human life span can be

extended quantitatively and qualitatively using caloric restriction

intervention.

Morbidity and mortality of these animals, after 15 years on the study, are shown

in

Figure 2. There were fewer deaths in the calorically restricted group and fewer

chronic diseases, proliferative diseases, and cancers in the females. Although

none

of the differences have reached statistical significance yet, trends are clearly

emerging. Mortality has not reached the 50% point, so the study must continue

for

some years. However, current data suggest that the calorically restricted

monkeys

are likely to do better. Several other groups have also been conducting caloric

restriction studies in monkeys with similar results. There is now a consensus

that

caloric restriction is likely to be beneficial, if not from a quantitative

standpoint, at least from a qualitative health standpoint.7

How does it work? I believe that aging is the biological equivalent of the

second

law of thermodynamics and relates to entropy, which means going from an ordered

state to a disordered state. Calorically restricted organisms have better

protective

mechanisms against multiple and varied insults.4 Their oxygen radical protection

and

deoxyribonucleic acid repair capacities are better. In addition, they use energy

more slowly, so they can maintain more reserve capacity, and that is why they

" fall

apart " biologically at a later time.8 One piece of evidence that suggests that

this

is a thermodynamic process is the fact that, when organisms are calorically

restricted, their temperature drops. When monkeys are 30% caloric restricted for

3

months, each experiences a temperature drop of between 0.5°C and 1.0°C.9 Perhaps

this reflects a fundamental metabolic shift on the part of the organism from a

growth and reproductive strategy to a life-maintenance strategy with better

protective mechanisms. This is typical of most of the calorically restricted

phenotypes.4

What does this mean for people? It is difficult to study caloric restriction in

a

controlled way in humans, but some evidence has been noted in the course of a

remarkable study at the National Institute on Aging, conducted over 50 years;

approximately 900 men and 600 women are currently enrolled in the Baltimore

Longitudinal Study on Aging.

We were particularly interested in some biological endpoints in these people

that

are typical of calorically restricted animals: body temperature, insulin levels

(calorically restricted organisms have lower levels of insulin and greater

sensitivity to insulin, meaning that they are less likely to have diabetes

mellitus), and levels of dehydroepiandrosterone (DHEA or DHEAS, the major form),

a

good biomarker of aging. DHEAS levels drop with age in most people. Originally,

all

enrollees were men. There have been about 500 deaths in the population, so the

men

who died were divided in half with respect to temperature, insulin levels, and

DHEAS

levels. They were then compared with calorically restricted monkeys, which have

low

insulin levels and temperature but maintain high DHEAS levels. Figure 3 shows

that,

in humans, each of the three categories (lower temperature, lower insulin

levels,

higher DHEAS levels) was associated with a survival advantage.10 The interesting

thing is that these individuals were not calorically restricted. It is not known

why

some of the men had values of these three variables associated with a longevity

advantage. Nonetheless, these data provide three possible targets to develop

interventions that might affect longevity and survival.

Where is the field going? An article in Scientific American discussed the search

for

an antiaging pill.11 This would be a way to obtain the beneficial effects of

caloric

restriction without reducing food intake. These caloric restriction pills (or

related interventions) are called mimetics, because they mimic caloric

restriction.

The first one tried was the compound 2-deoxyglucose (2DG), a chemically modified

form of glucose. Some of the effects of 2DG are similar to those found with

caloric

restriction. Over a 6-month period, feeding rats 2DG, using three different

dosages,

all low enough not to suppress their appetite, resulted in lowering insulin

levels.

Also, there were slight reductions in the level of circulating glucose and a

lower

body temperature than in the control group.12 Thus, it was possible to achieve

some

of the biological endpoints that correlate with longer survival without reducing

food intake. The results were encouraging for 6 to 8 months. Unfortunately, a

3-year

experiment using doses that were nontoxic in the first experiment resulted in

lethal

drug toxicity (unpublished data).

There appears to be a narrow window between effective and toxic doses of 2DG.

Nevertheless, the data are interesting, and a number of companies are attempting

to

develop caloric restrictionmimicking drugs for animal and human use. Currently,

perhaps the most interesting, and most hyped, is resveratrol, which is present

in

red wine and in the skin of grapes. It is an antioxidant and protects against

free

radicals that are damaging to human macromolecules. Recently, investigators

studying

the yeast model of aging showed that it affected a particular gene (sir-2) that

they

feel may mediate the effects of caloric restriction and is linked to life

span.13

Serum from calorie-restricted rats also appears to activate this gene.14 So

resveratrol is now thought to have at least two effects, but much more testing

needs

to be conducted. The yeast represents a primitive model, but additional data

show

moderately increased longevity in somewhat higher organisms, including fruit

flies

and roundworms.15 As might be expected, entrepreneurs are currently hawking

resveratrol-containing wine extracts as the equivalent of the fountain of youth,

but

preliminary data on longevity in yeasts, fruit flies, and nematodes are, at

present,

all we have. Rodent longevity studies should be next in line. Currently, and

most

regrettably, there is not yet any evidence that resveratrol extends human life

span.

In sum, caloric restriction remains the most robust and reproducible

intervention

for life span extension. However, a more practical strategy for humans would be

the

development of caloric restriction mimetics that might extend quality and

quantity

of life without reducing food intake -- in essence, eating your cake and having

it

too. That is for the future, although, it is hoped, for the not-too-distant

future.

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

__________________________________________________