# Decreased Glucose Metabolism and Declined Chaperones Are Unique Features Required for the Survival of Senescent Fibroblasts and Pyruvate Dehydrogenase Is a Potent Senolytic Target

## TL;DR

This study identifies unique metabolic and chaperone features in senescent fibroblasts and shows that targeting pyruvate dehydrogenase can selectively kill these cells.

## Contribution

The study reveals pyruvate dehydrogenase as a novel and potent target for selectively eliminating senescent cells.

## Key findings

- Decreased glucose metabolism and reduced ATP and alpha-KG production are key features of senescent fibroblasts.
- Inhibiting pyruvate dehydrogenase or Hsp90 selectively kills senescent fibroblasts.
- Combining TCA cycle inhibition with Hsp90 inhibition enhances the elimination of senescent cells and improves physical function in aged mice.

## Abstract

Cellular senescence contributes to aging and age‐related diseases. Deep identifications of the senescence‐specific cellular features are crucial to the better understanding of the survival and maintenance of senescence and the development of novel senolytics against senescent cells. By a global proteomic profiling of senescent human BJ fibroblasts induced by ionizing radiation, 178 cellular proteins with at least 4‐fold or greater changes in abundance were identified, representing the cellular landscape of the senescent fibroblasts. Functional enrichments and biological experiments demonstrated that the decreased glucose metabolism, reduced ATP and alpha‐KG production, and declined chaperones are the most striking features associated with senescent fibroblasts. Moreover, these proteomic features are closely correlated with their transcription alterations confirmed by RT‐PCR. Respectively, inhibiting pyruvate dehydrogenase (critical enzyme to supply acetyl‐CoA to TCA cycle) or glutaminase GLS1 (crucial enzyme to supplement TCA cycle intermediate alpha‐KG) or inhibiting Hsp90 (important member of chaperones) led to the selective killing of senescent fibroblasts, indicating the essential roles of the TCA cycle or chaperones in the survival and maintenance of cellular senescence. Most importantly, co‐inhibiting the TCA cycle and Hsp90 gave rise to the enhanced selective killing of senescent fibroblasts as well as the therapy‐induced senescent cancer cells and the alleviation of physical dysfunctions in aged mice, suggesting the synergistic regulation of cellular senescence by the TCA cycle and chaperones. Thus, our profiling revealed key cellular features for the survival and maintenance in senescent normal cells, demonstrating that pyruvate dehydrogenase is a novel and potent senolytic target for the selective elimination of senescence.

By a global proteomic profiling of senescent human BJ fibroblasts induced by ionizing radiation, key cellular features required for the survival of senescent fibroblasts were revealed, and pyruvate dehydrogenase was demonstrated as a potent senolytic target for selectively eliminating senescent normal cells, particularly the therapy‐induced senescent tumor cells.