Work on the development of drugs to mimic portions of the response to calorie restriction is one of the most widespread of efforts to modestly slow the aging process. It is unlikely to produce enormous gains in human longevity, however, as while calorie restriction does produce striking improvements in human health, it certainly doesn't have the same impact on human longevity as it does in short-lived species. In mice, calorie restriction extends life by 40% or so, and such a large effect in humans attained only through diet would have been discovered long ago. Progress on a working calorie restriction mimetic therapy has been painfully slow and expensive, with little to show for it so far beyond increased knowledge of some areas of cellular metabolism and a handful of drug candidates that cannot be used in practice due to side-effects, unreliable results, or insignificant outcomes when they do work. Nonetheless, the efforts continues. Researchers here propose a greater level of detail when comparing the outcome of calorie restriction and drug candidates in order to better identify compounds that more accurately reproduce the calorie restriction response:
Calorie restriction (CR) without malnutrition of micronutrients has been known for decades to profoundly increase lifespan and healthspan in multiple strains of laboratory rodents. More recent studies in model organisms and nonhuman primates also provide support for increased survival or prevention of age-related pathology in these widely diverse animal models. There is interest in understanding if CR and genetic interventions that increase survival actually reduce rates of aging at the molecular level. Gene expression profiling studies of multiple tissues in aging mice have shown that CR initiated in early to mid-life delays age-related gene expression changes, suggesting a delay in aging at the molecular level. Analysis of age-dependent mortality rates suggests that CR delays aging at early ages, but is associated with a pattern that resembles a compression of the aging process in the late component of the lifespan. The mechanisms of action of CR remain unclear, and understanding how different tissues and strains of mice respond to this dietary intervention is likely to be useful in understanding how CR impacts the aging process.
Two major, interrelated CR research directions are the following: (i) the identification of mechanisms which underlie CR's favorable health outcomes and (ii) the discovery of agents which may mimic at least some of the desirable outcomes of CR in subjects fed a normal caloric intake. The development of CR mimetics (CRMs) is important because the widespread practice of CR itself is unlikely to be practical in humans. An early consideration of how to approach the identification of CRMs focused on metabolic interventions. This metabolic theme proved to be a productive avenue for the discovery of CRMs.
CRMs, in large part, are either drugs or phytochemicals. Regarding phytochemical compounds, the most widely studied compound shown to mimic CR is resveratrol. Interestingly, high-dose resveratrol does not appear to extend longevity of lean (genetically normal) mice. However, we reported that mice from a long-lived strain treated from 14 to 30 months of age with either a relatively low dose of resveratrol or CR showed fewer signs of cardiac aging than age-matched controls, implying positive effects on healthspan. Furthermore, there was striking mimicry of CR-induced transcriptional shifts by resveratrol in heart, muscle, and brain in old animals. These conflicting observations suggest that CRMs may have tissue-specific effects in aging and that a tissue-specific screening strategy may be useful in evaluating CRMs.
In this study, we utilized a gene expression profiling approach to identify robust tissue-specific transcriptional markers of CR that were significantly altered in expression in the majority of mouse strains tested. We focused on heart, gastrocnemius, white adipose tissue (WAT), and brain neocortex. Using quantitative PCR, we then screened seven candidate CRMs for their ability to influence the expression of some of the novel CR transcriptional markers in vivo. We also measured the effects of the candidate CRMs on previously characterized, nontranscriptional CR biomarkers.
Importantly, we have shown that a drug that has strong activity in modulating CR transcriptional markers (pioglitazone) also modulates physiological measures of CR, such as reduced adipocyte size and mitochondrial mass. However, pioglitazone increased the levels of the inflammatory marker TNF-α, a finding suggestive of drug side effects. The putative CR mimetic L-carnitine, an amino acid involved in lipid metabolism, exhibited even stronger effects on CR transcriptional markers while modulating adipocyte size in a manner consistent with CR mimicry. These findings support the use of tissue-specific, robust transcriptional markers of CR as an effective approach to screen and identify compounds that have the potential to mimic the beneficial effects of CR on lifespan and healthspan. We also note that based on the finding that different compounds display tissue-specific CRM activity, it appears likely that stronger CR mimicry at the organismal level may be achieved by combining different CRMs.