The effect of caloric restriction on the transcriptome of dermal fibroblasts during aging

During aging, stromal functions are thought to be impaired, yet little is known whether this stems from molecular and cellular changes of fibroblasts, a major component of stroma. Using population- and single-cell whole transcriptomics, and long-term lineage tracing, we studied alterations in murine dermal fibroblasts during physiological aging under different dietary regimes known to affect longevity. We show that the identity of aged fibroblasts becomes undefined, with the distinct fibroblast states present in young skin no longer clearly demarcated. In addition, old fibroblasts not only reduce the expression of genes involved in the formation of the extracellular matrix, but intriguingly, also gain adipogenic traits, paradoxically becoming similar to neonatal pro-adipogenic fibroblasts. These age-related alterations are sensitive to systemic changes in metabolism: long-term caloric restriction prevents them in old fibroblasts in a reversible manner, whereas a high-fat diet potentiates them in young fibroblasts. Finally, inhibition of the master regulator of adipogenesis, PPARgamma, attenuates fibroblast aging in vivo, providing potential anti-aging therapeutic alternatives to caloric restriction. 9-months-old female mice were either fed a normal diet ad libitum for 9 months (Old ND group), a normal diet for 2 months followed by 30% caloric restriction for 7 months of (Old CR group), or a 30% caloric restriction for 7 months followed by a normal diet for 2 months (Old CR-ND group). Young mice (4-weeks-old) were fed ND ad libitum for 4 weeks (Young ND group). For sample collection three mice from different groups were sacrificed per day. n=5 (biological replicates)