# Rapamycin Reverses the Hepatic Response to Diet‐Induced Metabolic Stress That Is Amplified by Aging

## TL;DR

Rapamycin can reverse age-related liver damage caused by a high-fat diet in mice, reducing inflammation and fat buildup.

## Contribution

This study shows that rapamycin reverses age-amplified metabolic and inflammatory liver changes caused by a high-fat diet.

## Key findings

- Older mice on a high-fat diet showed more severe liver inflammation and fat accumulation than younger mice.
- Rapamycin treatment reversed most of the harmful gene expression changes in the livers of older mice.
- Rapamycin reduced liver fat, body weight, and cancer-related gene activity in aged mice.

## Abstract

Aging is associated with increased susceptibility to metabolic stress and chronic liver disease, yet the interactions between age and metabolic stressors and the potential for ameliorating interventions remain incompletely understood. Here, we examined the hepatic response of young (7‐month‐old) and old (25‐month‐old) C57BL/6 male mice to a 9‐week high‐fat diet (HFD) and assessed whether rapamycin, a well‐established pro‐longevity intervention, could mitigate age‐exacerbated effects. While both age groups developed metabolic‐associated steatohepatitis (MASH), older mice displayed more severe hepatic steatosis, inflammation, and transcriptional dysregulation. Transcriptomic profiling of whole livers and purified hepatocytes revealed that aging amplifies HFD‐induced inflammatory and metabolic gene expression changes, including activation of immune pathways and suppression of metabolic pathways. Notably, treatment of aging mice with rapamycin reversed the majority of HFD‐driven transcriptional alterations, including upregulation of pro‐inflammatory regulators such as Stat1, and dysregulation of metabolic gene networks. Rapamycin also reduced hepatosteatosis, total body weight, and a tumorigenic transcriptomic signature associated with hepatocellular carcinoma risk. These findings demonstrate that aging intensifies hepatic sensitivity to dietary metabolic stress and identify rapamycin as a promising therapeutic to counteract age‐related liver dysfunction and metabolic dysfunction‐associated steatotic liver disease (MASLD) progression.

Aging exacerbates high‐fat diet (HFD) induced hepatic steatosis, and transcriptional dysregulation of pathways including inflammation, immune, and metabolic regulation in mouse liver and hepatocytes. The addition of rapamycin to HFD reversed most HFD‐driven gene‐expression changes in old mice, including those linked to metabolic dysfunction and inflammation, as well as hepatosteatosis and body weight gain in old mice.