A nutritional memory impairs survival, transcriptional and metabolic 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 white adipose tissue (WAT) as a potential memory source. Consistently, post-switch RNA-seq profiling in liver and WAT demonstrated that the transcriptional and metabolic program of chronic DR remained largely refractory to the AL-to-DR switch specifically in adipose tissue. 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.