Date Published: April 29, 2018
Publisher: Impact Journals
Author(s): William R. Swindell, Edward O. List, Darlene E. Berryman, John J. Kopchick.
Caloric restriction (CR) has been extensively studied in rodents as an intervention to improve lifespan and healthspan. However, effects of CR can be strain- and species-specific. This study used publically available microarray data to analyze expression responses to CR in males from 7 mouse strains (C57BL/6J, BALB/c, C3H, 129, CBA, DBA, B6C3F1) and 4 tissues (epididymal white adipose tissue (eWAT), muscle, heart, cortex). In each tissue, the largest number of strain-specific CR responses was identified with respect to the C57BL/6 strain. In heart and cortex, CR responses in C57BL/6 mice were negatively correlated with responses in other strains. Strain-specific CR responses involved genes associated with olfactory receptors (Olfr1184, Olfr910) and insulin/IGF-1 signaling (Igf1, Irs2). In each strain, CR responses in eWAT were negatively correlated with those in human subcutaneous WAT (scWAT). In human scWAT, CR increased expression of genes associated with stem cell maintenance and vascularization. However, orthologous genes linked to these processes were down-regulated in mouse. These results identify strain-specific CR responses limiting generalization across mouse strains. Differential CR responses in mouse versus human WAT may be due to differences in the depots examined and/or the presence of “thrifty genes” in humans that resist adipose breakdown despite caloric deficit.
Caloric restriction (CR) has been extensively studied as an intervention hypothesized to lengthen healthspan, delay age-related disease and promote longevity. These effects have been supported by observations from a broad range of invertebrate and vertebrate organisms , although foundational experiments demonstrating favorable effects of CR on aging were performed using rodents [2,3]. The idea that CR improves mouse lifespan has for decades served as a guiding assumption in experimental aging research . In recent years, however, an increasingly nuanced CR paradigm has emerged with greater recognition of murine genetic factors , based upon the accretion of evidence demonstrating diverse responses to CR across inbred mouse strains , failure of CR to improve mean lifespan of wild-derived mice , and variable effects of CR on the lifespan of mice from recombinant inbred strain panels . These observations have challenged longstanding ideas regarding CR and its effects on aging, but are not unexpected considering the extensive genetic diversity among inbred mouse strains  and corresponding phenotypic differences related to disease propensity , body composition  and circulating hormone levels . Nonetheless, mouse strain differences complicate studies in aging and other fields of experimental medicine because mechanistic conclusions established from one strain may not be generalizable [13,14]. This diminishes repeatability of research results and challenges efforts to translate findings [15,16], since it is unclear which mouse strains can most faithfully represent the physiology of aging in primate species such as humans [17,18].
Mouse CR studies have frequently been limited to one strain (e.g., C57BL/6) and it has often been unclear whether conclusions should be generalized to other strains or translated to humans [13,14,17]. This study analyzed publically available microarray data (GSE75574) to compare short-term (14 week) CR responses in males from 7 mouse strains to distinguish shared and strain-specific CR responses in 4 tissues. The largest number of strain-specific CR responses was identified with respect to the C57BL/6 strain, indicating that responses in this strain may not be replicated in other genotypes. Such strain-specific responses can contribute to discrepant findings among laboratories, diminishing the apparent repeatability of preclinical research [13–15]. Our findings demonstrate this possibility and we expect that strain-specific effects identified here can inform the selection of background strain for studies targeting WAT, heart, muscle or neocortex . To facilitate translation of mouse findings, we attempted to identify a mouse strain for which CR responses in eWAT best matched those of human scWAT, but unexpectedly responses in all strains were negatively correlated with those from human experiments (Figures 6A and 6B). This surprising outcome may be explained by differences in the WAT depots examined for each species [54,55], or alternatively may reflect genuine species differences related to WAT metabolism in response to caloric deficit [56,57]. In either case, our findings raise the concern that the most commonly studied WAT depots from mice (epididymal) and humans (subcutaneous) are poorly analogous. This has implications regarding the interpretation and design of studies that aim to understand WAT responses to dietary interventions in mice.