Experimental Models of Caloric Restriction and Applicability to Humans

The lifespan-extending and other beneficial effects of CR, such as anti-tumor effects and the maintenance of more youthful physiology, have been reported in many hundreds of experiments over the past 70 yr. Nonetheless, the question of relevance to humans remains and will go unanswered until definitive human data are obtained (2). There are, however, data from a number of sources that suggest that CR may be relevant to human aging. For example, based on his study of Spanish nursing home residents, Vallejo (3) concluded that reduced caloric intake was associated with a significant reduction in morbidity and that mortality also tended to be lower in the group provided the fewest calories. Caloric intake in residents of the Japanese island of Okinawa differs by 20-40% in adults and children, respectively, compared to the national average (4). Interestingly, Okinawa has a greater proportion of centenarians, a lower overall death rate, and fewer deaths due to vascular disease and cancer. Although these were largely uncontrolled studies, they do suggest a possible link between calorie intake, disease, and perhaps even longevity.

More controlled studies of CR are ongoing using nonhuman primates, mostly Rhesus monkeys. Given the phylogenetic proximity between Rhesus monkeys and humans, these studies will shed some light on the question of CR relevance to man. Data from the primate studies have been reviewed elsewhere (5) and will not be discussed in detail here. Briefly, monkeys on CR exhibit many physiological responses consistent with those observed in rodents such as reductions in body weight and adiposity, fasting glucose and insulin, body temperature, and changes in serum lipids (e.g., cholesterol and triglycerides), among others (see Table 1). Emerging data suggest that CR may also favorably impact age-related diseases and associated morbidity and perhaps even mortality (5,6).

Another link between CR and human aging comes from studies of men in the Baltimore Longitudinal Study of Aging. Along with other National Institute on Agin (NIA) colleagues, we investigated whether three of the most robust physiological markers of CR in animals were related to survival in men in this

Table 1

Effects of Calorie Restriction on Selected Parameters of Morphology, Physiology, Aging and Disease in Rhesus Monkeys*

Category/parameter

Decrease Increase No change

Body Composition

Body weight Fat and lean mass Trunk: leg fat ratio Height

Development

Time to sexual maturity Time to skeletal maturity Metabolism

Metabolic rate (short-term) Metabolic rate (long-term) Metabolic rate (long-term:nighttime) Body temperature Thriiodothyronine (T3) Thyroxin (T4)

Thyroid Stimulating Hormone (TSH) Leptin

Endocrinology

Fasting glucose/insulin IGF-1/Growth Hormone Insulin sensitivity

Age-Related Maintenance of Melatonin and DHEAs Testosterone; Estradiol Cardiovascular Parameters

Systolic blood pressure Heart rate Serum triglycerides Serum HDL2B

LDL interaction with proteoglycans Lipoprotein(a)

Immunological Parameters

IL-6 IL-10

Interferon-Y Oxidative Stress

Oxidative damage to skeletal muscle Cell Biology

Proliferative capacity of fibroblasts Glycation products

Functional Measures

Locomotor activity Acoustic responses

*"X" notes whether caloric restriction has been shown to decrease, increase, or produce no change in the selected parameters.

ongoing study. In a non-CR cohort of normal men, reduced fasting insulin and body temperature and maintenance of higher levels of the adrenal steroid, dehy-droepiandrosterone-sulfate (DHEAS), were associated with greater survival (7). Finally, short-term studies in humans show that two of these three markers (reductions in fasting insulin and body temperature) are observed in response to short-term CR (8). Taken together, these findings bode well for the possibility that CR may indeed extend lifespan and retard many of the pathological processes associated with advancing age.

To achieve the maximum benefit from CR, presuming its applicability, humans would need to reduce their caloric intake by about 30% or from approx 2500 calories per day to 1750 (in men). The tremendous popularity of diet books, pills, and associated weight-loss products illustrates the challenge that use of such a regimen on a wide scale would present. Thus, to achieve the potential benefits of CR, an alternative approach is needed. In considering possible biological mechanisms of CR, we hypothesized that, by targeting alteration of cellular energy metabolism, it might be possible to "trick" the body into shifting to a CR-like survival mode (9) without actually reducing food intake, and in this way "mimic" the effects of CR.

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