Seymen, N. | Search bioRxiv

bioRxiv2024

Expression of Most Retrotransposons in Human Blood Correlates with Biological Aging

Retrotransposons (RTEs) have been postulated to reactivate with age and contribute to aging through activated innate immune response and inflammation. Here, we analyzed the relationship between RTE expression and aging using published transcriptomic and methylomic datasets of human blood. Despite no observed correlation between RTE activity and chronological age, the expression of most RTE classes and families except short interspersed nuclear elements (SINEs) correlated with biological age-associated gene signature scores. Strikingly, we found that the expression of SINEs was linked to upregulated DNA repair pathways in multiple cohorts. We also observed DNA hypomethylation with aging and significant increase in RTE expression level in hypomethylated RTEs except for SINEs. Additionally, our single-cell transcriptomic analysis suggested a role for plasma cells in aging mediated by RTEs. Altogether, our multi-omics analysis of large human cohorts highlights the role of RTEs in biological aging and suggests possible mechanisms and cell populations for future investigations.

genomics↗

bioRxiv2023

Beneficial effects of intermittent fasting in NASH and subsequent HCC development are executed by concerted PPAR alpha and PCK1 action in hepatocytes

The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen (two non-consecutive days of food deprivation per week), initiated in the active phase of mice, prevents/ameliorates NASH and fibrosis as well as reduces subsequent HCC development without affecting total calorie intake. The timing, length and number of fasting cycles as well as the type of NASH diet were all critical parameters determining the effectiveness of the fasting benefits. Combined proteomic, transcriptomic and metabolomic analyses identified that PPAR and glucocorticoid receptor (GR)-PCK1 act co-operatively as hepatic executors of the fasting response by promoting fatty acid catabolism and gluconeogenesis whilst suppressing anabolic lipogenesis. In line, PPAR targets and PCK1 were reduced in human NASH. Additionally, dynamic [18F]FDG-PET analysis in vivo revealed increased [18F]FDG uptake/retention and enhanced gluconeogenesis in the liver upon fasting (in accordance with PPAR and GR-PCK1 activation) when assessed by compartmental modelling. Hepatocyte-specific GR deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis, confirming their causal relationship in integrating systemic signalling in hepatocytes. Notably, PPAR agonist pemafibrate recapitulated key aspects of hepatic fasting signalling at a molecular level. Therefore, IF or pharmacological mimetics of the PPAR and/or GR-PCK1 axis could be a viable intervention against NASH and subsequent liver cancer. One-Sentence SummaryIntermittent fasting protects against fatty liver disease and liver cancer through concerted PPAR and GR-PCK1 action in hepatocytes.

cancer biology↗