SUN-044 - Effects of GH/IGF-1 Signaling on Cellular Senescence in Liver and Kidney of Growth Hormone Antagonist (GHA) Mice

Aging is associated with progressive tissue dysfunction and increased risk of chronic disease such as diabetes, cardiovascular disease, and neurodegeneration. Chronic cellular stress can cause cells to enter senescence, a state of irreversible growth arrest that becomes more prevalent with age and drives a pro-inflammatory state through the senescence-associated secretory phenotype (SASP). These factors disrupt tissue microenvironments and amplify tissue damage. Metabolic organs including adipose tissue, liver, and kidney are particularly vulnerable, and dysfunction in these tissues can contribute to systemic metabolic decline. Signaling through the growth hormone (GH) and insulin-like growth factor 1 (IGF-1) axis regulates growth, metabolism, and cellular stress responses. Prior work in mice with alterations in GH/IGF-1 action, such as bovine GH (bGH) transgenic mice and GH receptor knockout (GHR-/-) mice, reveal a strong positive correlation between GH/IGF-1 activity and cellular senescence in adipose tissue: bGH mice, with excessive GH action, exhibit elevated senescence whereas GHR-/- mice, with no GH action, exhibit reduced senescence. Growth hormone antagonist (GHA) mice, with reduced GH action, provide an intriguing exception. Despite extreme obesity - typically associated with increased senescence - GHA mice do not show an elevation in senescence in adipose tissue. However, they also do not show the pronounced reduction as seen in GHR-/- mice, suggesting that adipose tissue may behave uniquely in GHA mice due to its dramatic expansion and altered metabolic buffering capacity. In contrast, the liver and kidney do not undergo expansion and therefore avoid this confounding effect, making them ideal tissues for assessing GH/IGF-1 dependent regulation of senescence. Building on these findings, this study evaluated transcriptional markers of senescence and SASP in liver and kidney from GHA and wild-type mice. RNA was isolated and expression of p16, p21, IL-6, and TNF-α was quantified using real-time quantitative polymerase chain reaction (qPCR). Protein levels of p21 were also assessed. Analysis revealed tissue-specific patterns of senescence and SASP related gene expression in liver and kidney highlighting that these organs are especially responsive to GH/IGF-1 dependent regulation of cellular senescence providing insight into systemic aging mechanisms.

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