Rejuvenation strategies share gene expression programs of reduced inflammation and downstream restored fatty acid metabolism

Abstract Understanding the mechanism of rejuvenation is central to aging research. No study has compared the effects of the four major rejuvenation strategies: senolytics(definition), caloric restriction(definition), in vivo partial cellular reprogramming and young/old blood factor exchange, which operate via different modalities. We use mice transcriptional data to compare them to each other and to normal aging. We find a shared gene expression program common to all rejuvenation strategies, in which inflammation declines and metabolism, especially of fatty acids, increases. An inverse signature occurs in normal aging. To test whether inflammation is upstream of the metabolic signature, we studied chronic inflammation in three different organs in young mice. Chronic inflammation was associated with a similar decline in metabolism, suggesting that inflammation is upstream of the metabolic signature. We find that inflammation may also underlie human transcriptional age calculator. We conclude that a core mechanism of rejuvenation acts through reduction of inflammation with downstream effects that enhance metabolism, attenuating the most robust age-related changes. This supports a notion of directly targeting genes associated with these pathways to mitigate age-related deterioration.