CR human implication?

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Hi All,

The below paper seems related for those of us who may be interested in studying

CR

and those who are interested in the effects of our psychology in CR.

Not previously presented in the archives for its text, is:

Hadley EC, Dutta C, Finkelstein J, TB, Lane MA, Roth GS, Sherman SS,

Starke- PE.

Human implications of caloric restriction's effects on aging in laboratory

animals:

an overview of opportunities for research.

J Gerontol A Biol Sci Med Sci. 2001 Mar;56 Spec No 1:5-6. No abstract available.

PMID: 12088212

FOR more than 60 years it has been known that restricting caloric intake below

ad

libitum levels in several species of experimental animals extends life span and

slows numerous aging changes. Descriptive research on these effects continues to

expand and is being extended to nonhuman primates. However, there has been

little

research to explore the implications of these findings for the development of

interventions to affect human age-related changes and diseases.

In 1999, the National Institute on Aging, in collaboration with the National

Institute of Diabetes, Digestive, and Kidney Diseases, convened the Caloric

Restriction Clinical Implications (CRCI) Advisory Group to consider

opportunities

for such research. The group included expertise in gerontology, epidemiology,

clinical trials, nutrition, metabolism, endocrinology, neuroendocrinology,

genetics,

pharmacology, and behavioral medicine. It was composed of six panels, whose

reports

follow this overview. In brief, the six panel topics were:

• Current epidemiologic and intervention data

• Metabolic interventions

• Anorexiants and neuroendocrine manipulations

• Physical activity and body composition changes

• Genetic variability in responses to caloric restriction

• Effects of lowering caloric intake in nonobese persons.

These panel reports were developed before the CRCI Advisory Group's March 1999

meeting, discussed in its plenary session, and modified thereafter. Three

members of

the group (Barbara Hansen, Leo Lutwack, and Greenberg) served as " at

large "

members and contributed substantially to several panel reports. The reports

follow a

standard format, including background information and recommendations for

studies in

nonprimates, studies in nonhuman primates, studies in humans, recommendations on

methodologic approaches, and recommendations regarding resources and

infrastructure.

The following discussion of some of the main themes running through the Advisory

Group's considerations and recommendations emphasizes themes that cut across

contributions of several panels. Numerous equally important ideas appear in the

individual panel reports.

In regard to identifying interventions with potential human application, Panels

2

and 3 focused on an approach that complements the increasing interest in

learning

the mechanisms responsible for the effects of caloric restriction (CR) on aging

in

experimental animals. One way to probe these mechanisms in experimental animals

is

to examine how interventions that produce one or more of CR's physiologic or

biochemical effects (e.g., lowering circulating glucose levels) affect life span

or

age-related changes. Such interventions are referred to in the following reports

as

" CR-mimetic " interventions. If a CR-mimetic with a known mechanism of action

produces effects on life span and aging similar to those of CR, this would

implicate

this mechanism as a likely mediator of CR's effects.

Testing effects of CR-mimetic interventions in animals also provides an

experimental

therapeutic strategy to explore potential human interventions: Examining how

they

affect life span and aging in experimental animals can indicate potential

endocrine

or pharmacologic agents that might be used in humans to produce some or all of

CR's

beneficial effects in delaying or preventing age-related diseases. Some

CR-mimetics

(e.g., oral hypoglycemic agents) have been studied extensively in humans as

agents

to treat or prevent specific diseases. In such cases there may be opportunities

for

human studies to examine other effects on age-related changes.

The amount of information derivable from studies of CR-mimetic interventions has

increased greatly with the development of array technologies to determine

effects on

expression of a large number of genes. Using such techniques, effects of

CR-mimetics

could be compared with effects of CR itself, which have recently been studied

with

such methods (1). As evidenced by the opportunities discussed by Panel 5,

possibilities for testing CR-mimetic strategies also have been expanded greatly

by

techniques to produce transgenic animals. Transgenic strains that on ad libitum

diets have physiologic features similar to those seen in CR wild-type strains

can be

used to probe the mechanisms for CR's effects on aging, analogous to

pharmacologic

or endocrine manipulations noted above. In addition, the role of physiological

responses hypothesized to regulate CR's effects can be probed by examining

differences among effects of CR on aging in transgenic strains that differ in

these

responses.

A second general strategy for probing human implications of CR's effects in

animals

involves short- or medium-term human intervention studies. In recent years,

considerable knowledge has been gained from human studies of weight-loss

interventions lasting as long as several years. These interventions frequently

include increased physical activity as well as lowered caloric intake.

Nonetheless,

the targeted reduction in caloric intake has been as much as 25% (2). The

interventions have been designed for weight loss in overweight or obese persons,

but

recently, studies of obesity-prevention interventions have begun as well. The

outcomes addressed by these studies have been mainly metabolic and

cardiovascular

risk factors associated with overweight or obesity, some of which are modified

similarly to the effects of CR in experimental animals.

Thus, medium-term human intervention studies in nonobese persons, recommended by

Panel 6, may be viewed in one light as an extension of lines of research that

were

developed to test benefits of weight loss interventions against obesity. The

hypotheses to be tested are more specific in that the intervention is confined

to

reducing caloric intake (rather than changing both diet and physical activity,

as in

most earlier studies). On the other hand, the range of outcomes recommended for

these studies is broader than that in most human weight-control intervention

studies, including many age-related changes and risk factors affected by CR in

experimental animals, and potential adverse effects. It is also worth noting the

recommendations to study psychosocial and quality-of-life outcomes. These are

particularly important in view of the major cultural roles of eating and

associated

activities, as well as attitudes toward body shape and weight.

The distinction between " pure " caloric intake-reducing interventions and

alternative

weight-loss interventions relates to an issue of practical and mechanistic

importance addressed by Panel 4: Is CR's effect on weight the crucial mediator

of

its effects on aging in laboratory animals? If so, other interventions to

control

weight, such as physical activity, might be expected to produce the same

effects.

Panel 4's review of evidence from rodent studies suggests that, though weight

control through increased activity may increase average life span and diminish

age-related changes associated with overweight, it is not in itself sufficient

to

mimic CR's effects on maximum life span (and by inference at least some of the

pathologies that determine it). This difference could be caused either by a

failure

to produce all of CR's beneficial effects, or by other adverse effects. These

findings reinforce the need to clarify differences between the effects of

calorie

limitation and those of physical activity in human weight-control strategies, as

well as interactions between the two interventions.

As noted by Panel 1, one aspect of the laboratory animal paradigm of CR as

clearly

not applicable to human intervention studies: its involuntary nature. In

contrast to

calorically restricted laboratory animals, almost all humans have free access to

food, so that some degree of volition (either limiting intake below former

levels

through willpower or by taking anorexiants) must be involved in lowering calorie

intake. This has implications in regard to considerations discussed by Panel 3,

noting that neuroendocrine effects of long-term involuntary food restriction

could

be essential mediators of its delay of aging changes. These effects might not

occur

in conditions where voluntary intake was diminished either by self-restraint or

by

anorexiant administration. These considerations reinforce the need for better

understanding of the neuroendocrine effects of long-term involuntary CR,

voluntary

CR, and anorexiant administration, and their relevance to long-term human

studies of

anorexiants and other weight control agents.

The panel reports illustrate differences in how researchers on CR in humans and

in

laboratory animals customarily address its effects on mortality and disease

incidence. Researchers on humans generally have dealt with effects on rates over

a

small fraction of the life span – rarely longer than 5 years, generally in

middle

age or early old age. Researchers on CR's effects in laboratory animals

customarily

consider effects on survival curves over the entire life span after sexual

maturity

or early middle age, in particular the rates of rise in mortality and disease

incidence with age. Although the term " caloric restriction " has been applied to

both

human and animal studies, it is important to bear the distinction in mind,

particularly in regard to the lack of human data on the effects of CR that are

particularly important to aging researchers—the " rightward shift " of the

survival

curve and increased maximum life span. To show conclusively that a human

CR-mimetic

intervention mimicked CR's effects in laboratory animals, one would need to

determine its effects on survival curves into advanced age.

....

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

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