Strain-specific metabolic responses to long-term caloric restriction in female ILSXISS recombinant inbred mice

Abstract

The role that genetic background may play in the responsiveness of organisms to interventions such as caloric restriction (CR) is underappreciated but potentially important. We investigated the impact of genetic background on a suite of metabolic parameters in female recombinant inbred ILSXISS mouse strains previously reported to show divergent lifespan responses to 40% CR (TejJ89-lifespan extension; TejJ48-lifespan unaffected; TejJ114-lifespan shortening). Body mass was reduced across all strains following 10 months of 40% CR, although this loss (relative to ad libitum controls) was greater in TejJ114 relative to the other strains. Gonadal white adipose tissue (gWAT) mass was similarly reduced across all strains following 40% CR, but brown adipose tissue (BAT) mass increased only in strains TejJ89 and TejJ48. Surprisingly, glucose tolerance was improved most notably by CR in TejJ114, while both strains TejJ89 and TejJ114 were hyperinsulinemic following CR relative to their AL controls. We subsequently undertook an unbiased metabolomic approach in gWAT and BAT tissue derived from strains TejJ89 and TejJ114 mice under AL and 40% CR. In gWAT from TejJ89 a significant reduction in several long chain unsaturated fatty acids was observed following 40% CR, but gWAT from TejJ114 appeared relatively unresponsive to CR with far fewer metabolites changing. Phosphatidylethanoloamine lipids within the BAT were typically elevated in TejJ89 following CR, while some phosphatidylglycerol lipids were decreased. However, BAT from strain TejJ114 again appeared unresponsive to CR. These data highlight strain-specific metabolic differences exist in ILSXISS mice following 40% CR. We suggest that precisely how different fat depots respond dynamically to CR may be an important factor in the variable longevity under 40% CR reported in these mice.

Molecular mechanisms of genotype-dependent lifespan variation mediated by caloric restriction: insight from wild yeast isolates

“…However, our study only tested a single CR condition (0.05% glucose) that different levels of CR may interact with genotype in different ways. In particular, each genotype may have a different optimal (for longevity) level of nutrient availability, or the activity of metabolic pathways might differ significantly depending on genetic background under CR condition, as it was shown in mice previously ( Mitchell et al, 2016 ; Wilkie et al, 2020 ; Mulvey et al, 2021 ). Further understanding of how gene-environment interaction modulates genotype-dependent conserved molecular responses to various level of nutrition availability may open new therapeutic applications to slow aging and age-related diseases through diet, lifestyle, or pharmacological interventions.…”

Molecular Mechanisms of Genotype-Dependent Lifespan Variation Mediated by Caloric Restriction: Insight from Wild Yeast Isolates

“…However, our study only tested a single CR condition (0.05% glucose) that different levels of CR may interact with genotype in different ways. In particular, each genotype may have a different optimal (for longevity) level of nutrient availability, or the activity of metabolic pathways might differ significantly depending on genetic background under CR condition, as it was shown in mice previously [13,96,97]. Further understanding of how gene-environment interaction modulates genotype-dependent conserved molecular responses to various level of nutrition availability may open new therapeutic applications to slow aging and age-related diseases through diet, lifestyle, or pharmacological interventions.…”

The Effects of Graded Levels of Calorie Restriction: XX. Impact of Long-Term Graded Calorie Restriction on Survival and Body Mass Dynamics in Male C57BL/6J Mice

“…The response of the different fat depots to CR may be an important factor in the variable longevity under 40% CR in 3 of the ILSXISS mouse strains ( 73 ). Fat mass can be separated into distinct depots, visceral or subcutaneous, also regarded as “bad” and “good” fat.…”