A nutritional memory impairs transcriptional, metabolic and survival response to dietary restriction in old mice

Dietary restriction (DR) during adulthood can greatly extend lifespan and improve metabolic health in diverse species. However, whether DR in mammals is still effective when applied for the first time at ¬old age remains elusive. Here, we conducted a late-life DR switch experiment employing 800 mice, by switching old animals from ad libitum (AL) to DR and vice versa. Strikingly, the switch from DR-to-AL acutely increased mortality, while the switch from AL-to-DR caused only a weak and gradual increase in survival, highlighting a memory of earlier nutrition. A significant association between fat preservation and survival response pointed to the adipose tissue as a potential memory source. Consistently, post-switch RNA-seq profiling in liver, brown (BAT) and white adipose tissue (WAT) demonstrated that the transcriptional and metabolic program of chronic DR remained largely refractory to the AL-to-DR switch in the two fat tissues, particularly in WAT. This loss of transcriptional flexibility coincides with a major proinflammatory signature in aged preadipocytes, which is prevented by chronic DR feeding. Integration of lipidomics confirmed impaired membrane lipogenesis and limited mitochondrial copy number increase under late-life DR as functional consequences of this memory effect. Together, our results provide evidence for a nutritional memory as a limiting factor for DR-induced longevity and metabolic remodeling of WAT in mammals. Overall design: Total RNA of liver and white adipose tissue extracted from 26 months (old), control-fed(AL), dietary-restricted (DR), AL-to-DR switched (ALDR) and DR-to-AL switched (DRAL) F1 hybrid mouse strain (C3B6F1) were generated by deep sequencing using Illumina sequencing. Total RNA of white adipose tissue extracted from 5 months young AL and AL-to-DR switched mice were additionally generated by deep sequencing using Illumina sequencing. Liver and WAT samples (total RNA) were sequenced in paired-end mode with 2x100bp reads. BAT samples (mRNA; polyA-enriched) were sequenced in single-end mode with 1x150bp reads.