Abstract
Understanding the mechanism of rejuvenation is central to aging research. No study has compared the effects of the four major rejuvenation strategies: senolytics, caloric restriction, 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Significant expansion of the findings by analysis of additional datasets and conditions prompted an extensive reframing and reorganization of the research.
Abbreviations
- TMS
- Tabula Muris Senis
- scRNA-seq
- Single-cell RNA sequencing
- DEG
- Differentially expressed gene
- RS
- Rejuvenation strategies
- ABT
- ABT-737 mediated senolytic treatment
- CR
- Caloric restriction
- IVPR
- in vivo partial reprogramming
- HP
- Heterochronic parabiosis
- HP ACC
- Heterochronic parabiosis-related accelerated aging
- CI
- Chronic inflammation.
- IPF
- Idiopathic pulmonary fibrosis NASH – Non-alcoholic steatohepatitis
- ON
- Obstructive nephropathy
- EC
- Endothelial cell
- DNAm
- DNA methylation