Energy restriction and aging

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JV, Heilbronn LK, Ravussin E.

Energy restriction and aging.

Curr Opin Clin Nutr Metab Care. 2004 Nov;7(6):615-622.

PMID: 15534428 [PubMed - as supplied by publisher]

Purpose of review

The focus of this review is on current research involving long-term

calorie restriction and the resulting changes observed in

possible biomarkers of aging. Special emphasis will be given to

the basic and clinical science studies which are currently

investigating the effects of controlled, high-quality energy-

restricted

diets on both biomarkers of longevity and on the

development of chronic diseases related to age and obesity in

humans.

Recent findings

Prolonged calorie restriction has been shown to extend both the

median and maximal lifespan in a variety of lower species such

as yeast, worms, fish, rats, and mice. Mechanisms of this

lifespan extension via calorie restriction are not fully elucidated,

but possibly involve significant alterations in energy metabolism,

oxidative damage, insulin sensitivity, and functional changes in

both the neuroendocrine and sympathetic nervous systems.

Ongoing studies of prolonged energy restriction in humans are

now making it possible to analyze changes in these aging

biomarkers to unravel some of the mechanisms of its antiaging

phenomenon.

Summary

With the incremental expansion of research endeavors in the

area of energy or calorie restriction, data on the effects of

calorie restriction in animal models and humans are becoming

more accessible. Detailed analyses from controlled human trials

involving long-term calorie restriction will allow investigators to

link observed alterations in body composition down to changes

in molecular pathways and gene expression, with their possible

effects on the biomarkers of aging.

Naturally occurring energy restriction in

humans

Over the course of history, nonvolitional calorie restric-tion

has been imposed on human populations during

episodes of famine as well as by force of man. Notably,

these diets were associated with marked growth

deficiencies due to deficient levels of protein and

micronutrients. Historically, populations exposed to

severe energy restrictions are characteristically short in

stature, with late reproductive maturation [14] and

adverse psychological functioning. Physiological para-meters

affected by severe calorie restriction include

changes in resting pulse, temperature, blood pressure

and metabolic rate. Additionally, adults of these popula-tions

had lower baseline gonadal steroids and suppressed

ovarian function [15], impaired lactation [16], and poor

immune function [17].

In contrast, observational studies of Okinawans by

Kagawa [18] showed remarkable attributes of prolonged

calorie restriction in the context of a high-quality diet.

Analysis showed that the total energy consumption for

adults and school-aged children on the island of Okinawa

was approximately 20% and 38% less, respectively, than

the Japanese average. Relative to the rest of Japan,

however, the prevalence of centenarians on Okinawa

was found to be about 3.5 times higher than the

Japanese average; and there was a clear reduction in

mortality rates related to cerebral vascular disease (59%),

heart disease (59%) and malignancy (69%) [18].

... Controlled trials of prolonged energy

restriction in humans

In previous works, scientists compiled the effects of

chronic calorie restriction on biomarkers of aging in

animal models, and used these surrogate markers of

longevity as predictors of long-term calorie restriction

effects in humans [12]. Since then, clinical trials funded

by the National Institute on Aging named CALERIE

(Comprehensive Assessment of Long-Term Effects of

Reducing Intake of Energy) were initiated in 2002 to

address the effects and potential mechanisms of

prolonged calorie restriction in nonobese humans, and

to test the feasibility of using calorie restriction as a

therapeutic tool in humans to delay the onset of aging-related

comorbidities (Fig. 1). These randomized clinical

trials represent a collaborative effort between the

Pennington Biomedical Research Center in Baton

Rouge, Tufts University in Boston, and Washington

University in St Louis. The aim of CALERIE is to

determine the effects of prolonged calorie restriction on

metabolic rate, on diverse biomarkers of aging (e.g.

dehydroepiandrosterone, body temperature, oxidative

stress etc.) and on predictors of chronic age-related

diseases such as cardiovascular disease and type 2

diabetes.

Interventions of the CALERIE trial at the Pennington

Biomedical Research Center include randomization of

participants to one of four interventions for 6 months: (1)

25% restriction of baseline energy requirements; (2) a

combination of increased physical activity (12.5%) and

energy restriction (12.5%) resulting in an equivalent

energy deficit; (3) very low energy diet (HealthOne,

Health and Nutrition Technology, Carmel, California)

until 15% weight loss is achieved, followed by weight

clamping at the new lower body weight; and (4) a control

group prescribed a healthy energy balanced diet.

The following hypotheses are being investigated by the

Pennington Biomedical Research Center CALERIE

trial.

(1) Calorie restriction reduces metabolic rate and core

temperature, out of proportion to the reduction in

body weight (fat-free mass and fat mass) and is

associated with reduced oxidative damage.

(2) Calorie restriction improves biomarkers of aging and

risk factors for age-related metabolic diseases,

including cardiovascular disease and type 2 diabetes.

(3) Calorie restriction alters the neuroendocrine axes,

sympathetic nervous system activity.

(4) Calorie restriction alters the expression of genes

involved in aging, including those related to

oxidative stress and energy metabolism.

(5) Psychophysiologic outcomes (i.e. quality of life,

mood, cognitive function, and risk of developing an

eating disorder) are improved when the energy

deficit is achieved by combining physical activity

and calorie restriction compared with calorie restric-tion

alone.

Conclusion

Prolonged energy restriction has been proven to extend

the lifespan of various lower species. Although it remains

unknown if such an extension will apply to the longevity

of longer-lived species such as humans, the benefits of

prolonged calorie restriction appear to be numerous.

Many of the physiological changes observed with

prolonged calorie restriction are conducive to improved

health and quality of life, and may possibly delay the

onset of age-related diseases and morbidities in humans.

The benefits shown by studies of prolonged energy

restriction are diverse and include `healthier' body

composition, decreases in energy expenditure and

oxidative damage, improvements in insulin sensitivity

with concomitant decreased risk of type 2 diabetes, and

improvement of lipid profile and endothelial function

with decreased risk of cardiovascular disease.

Due to the pluripotent nature of energy restriction, the

exact mechanisms by which calorie restriction extend

lifespan are still being investigated, and will likely

remain a challenge. However, controlled human trials of

prolonged energy restriction, such as the multi-center

CALERIE study, are transforming this challenging

investigation into a modern scientific reality.