A recent review paper on calorie restriction (CR) research makes the case that using smaller, short-lived animals has made it hard to see the detailed picture of CR biochemistry. Only now that larger animals - such as humans and other primates - are in longer-term CR studies is the biochemistry becoming clear.
Prolonged CR 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. The biological mechanisms of this lifespan extension via CR are not fully elucidated, but possibly involve significant alterations in energy metabolism, oxidative damage, insulin sensitivity and functional changes in both neuroendocrine and sympathetic nervous systems.
Most of the difficulty in characterizing the systemic endocrine and neuroendocrine changes with aging and CR is due to the limited capability to collect large and multiple blood samples from small animals, which are usually shorter lived, and hence the most studied.
Ongoing studies of prolonged CR in humans are now making it possible to analyze changes in the "biomarkers of aging" to unravel some of the mechanisms of its anti-aging phenomenon. With the incremental expansion of research endeavors in the area of energy restriction, data on the effects of CR in non-human primates and human subjects are becoming more accessible. Detailed analyses from controlled human trials involving long-term CR will allow investigators to link observed alterations from body composition and endocrine systems down to changes in molecular pathways and gene expression, with their possible effects on aging.
It is interesting to consider that some degree of advances in CR knowledge stem from increasing the size of laboratory animals (and slowing down the pace of data collection) rather than the rapid advances in the tools of biotechnology taking place across the past decade.