The few formal studies of human calorie restriction continue to produce interesting data on the biochemistry of participants, and the degree to which the human response to lowered calorie intake lines up with the outcomes observed in mice. One of the puzzles to be solved is the way in which short-term effects that look very similar between humans and mice nonetheless lead to a radically different degree of enhanced life span. Mice can live up to 40% longer than normal when calorie restricted, which is certainly not the case for humans - it would be very surprising to find an effect much larger than five years for human life expectancy.
The authors of this paper choose to interpret the results as supportive of rate of living and oxidative theories of aging, which I have to think is a mistaken direction. There is so much evidence against those views of aging at this point that it is probably better to try to fit observations into newer and more robust views on how aging progresses at the detailed level of cellular biochemistry. In particular, the animal studies of longevity of the past twenty years include any number of cases in which sources of oxidative molecules are increased or decreased to produce longer life spans as a consequence - the systems of oxidative signaling and damage and repair are complex, and defy the imposition of any straightforward relationship.
For the past 40 years, aging research has focused on the mechanisms underlying the beneficial health impact of a sustained reduction in caloric intake below usual levels, while maintaining adequate intake of essential nutrients. Observations in a variety of laboratory animals indicate that calorie restriction (CR), beginning early or in mid-life and sustained for a substantial portion of the lifespan, increases longevity in a wide variety of, but not all, species. While the field of CR research eagerly awaits final lifespan data from the two remaining colonies of CR primates, despite differences in study designs, current data support the observation that sustained CR extends life without chronic disease and promotes a more youthful physical and mental functionality. In terms of CR in humans, few controlled clinical trials exist.
A variety of mechanisms have been proposed as mediators of the effects of CR on lifespan. An old but arguably a prevailing theory supporting lifespan extension with CR is a hybrid between two long-standing hypotheses of aging: the "rate of living" and the "oxidative damage" theories of aging. There are data from studies in rodents, non-human primates, and humans indicating that CR results in a decrease in metabolic rate that is greater than that expected on the basis of loss of tissue mass. This phenomenon, referred to as metabolic adaptation, was associated with less oxidative damage to DNA in our 6-month pilot study of CR in humans. The CR field has also focused on the ability for CR to attenuate age-related changes in physiological and endocrine factors that are known to change with age, such as core body temperature, plasma insulin, DHEAS, and thyroid hormones, as well as endocrine mediators of metabolic slowing such as plasma leptin.
Phase 1 CALERIE or the Comprehensive Assessment of the Long-Term Effects of Reducing Intake of Energy studies were the first randomized controlled trials to test the metabolic effects of CR in non-obese humans. Then, the phase 2 CALERIE study, a 2-year 25% CR prescription in non-obese volunteers, was shown to be safe and without any untoward effects on quality of life. Importantly, the study confirmed the presence of a CR-induced decrease in total daily energy expenditure (EE). However, in the CR group compared with the control group, resting metabolic rate adjusted for loss of fat-free and fat masses was only lower during the weight loss phase. Furthermore, reductions in core body temperature were noted in the CR group, but were not different from the controls, and changes in oxidative damage were not assessed.
We hypothesized a reduction in oxidative damage after 1 and 2 years of CR. Taken together with lower EE, such results would speak in favor of the long-standing hypotheses of biological aging stating that prolonged CR enhances energy efficiency at rest and therefore results in less reactive oxygen species production and reduced oxidative damage to tissues and organs, thus a combination of the rate of living and the oxidative damage theories of aging. To test this hypothesis, we delivered a highly controlled and intensive behavioral intervention targeting a 25% CR diet over 2 years and obtained reliable measurements of the most robust component of daily sedentary EE, i.e., energy metabolism during sleep, measured in a room calorimeter. Hormonal mediators of metabolism were measured along with urinary F2-isoprostane excretion as an index of oxidative damage.
According to the rate of living theory, those individuals who are the most efficient at utilizing energy should experience the greatest longevity. Observational studies of human aging have shown higher mass-adjusted metabolic rate (24hEE or resting EE) is associated with disease burden and is a predictor of early mortality. Interventions with the capacity to induce a sustained slowing of energy metabolism such as CR should remain a focus of longevity research because randomized clinical trials and cohort studies are lacking. With careful phenotyping of energy metabolism, biomarkers of aging, and oxidative stress, this modest, 2-year study of human CR identified a reduction in the rate of living along with a reduction in systemic oxidative stress. The duration of imposed CR being for only 2 years clearly limits any extrapolation or speculation of the impact of CR on longevity in humans.
Notably, many biomarkers of aging (that could be a consequence of the overall improved metabolic profile commensurate with adipose tissue loss) were also improved in these young, healthy individuals. There is a clear need for continued investigations of CR in humans, since the non-human primate data are not entirely conclusive on the extension in the average and maximal lifespan but provide strong evidence for extensive health benefits including improved quality of life.