Targeting the hypothalamic MC4 receptor: A novel approach to senolytic therapy?

The hypothalamus is a center of whole-body energy metabolism. With aging, its function decreases, leading to a higher chance of metabolic disorders. Conversely, overnutrition, such as in cases of type 2 diabetes and obesity, can also cause cellular senescence independent of age. Elevated glucose levels accelerate neuronal senescence by inducing oxidative stress and inflammatory responses, leading to cellular aging and neurodegeneration. Melanocortin receptor 4 (MC4R) neurons in the hypothalamus play a crucial role in energy homeostasis, and MC4R expression levels tend to decrease with aging. In our study, we exposed a mouse hypothalamic cell line (mHypoE-N46) to high glucose (50 mM) and observed an increase in the levels of the cellular senescence marker p21, along with a reduction in Mc4r levels. Additionally, we found an increase in Basic helix-loop-helix ARNT-like protein 1(Bmal1) expression, indicating a disruption of circadian rhythm in energy homeostasis regulated by the hypothalamus. Therefore, we hypothesize that: i) High glucose elevates Bmal1 in hypothalamic neurons, triggering senescence, which then downregulates MC4R. This leads to metabolic dysfunction and aging-independent metabolic abnormalities. ii) To ameliorate the senescence, agonizing MC4R signaling could be an option, potentially reducing p21 expression and normalizing Bmal1 expression rhythms in the hypothalamus. Besides, these agonists could also serve as senolytic therapeutics for correcting neuronal dysfunction in age-related metabolic regulation. Given the decreased levels of MC4R during aging, these agonists could be useful not only for senescence caused by overnutrition but also in natural aging processes. These hypotheses can be demonstrated using an animal model with high glucose or high-fat diet and hypothalamic-specific MC4R knockout mice. Understanding the mechanisms underlying biological age-independent senescence is crucial for identifying novel therapeutic targets and interventions to mitigate age-related diseases and promote healthy aging. The exploration of MC4R agonism as a senolytic approach could provide valuable insights into novel therapeutic avenues for combating age-related disorders and extending healthspan.