The IGF/IGFR System During Chronic Liver Disease: Role in Neurocognitive Complications and Aging

Aging is associated with a significant functional impairment of different organs, including liver, and it increases sensitivity to the development of liver-related complications. In fact, advanced chronic liver disease is higher in aged populations and is associated with worse prognosis. These patients frequently show a dysfunctional liver-brain axis and exhibit mild neurocognitive dysfunction, which significantly impairs quality of life. The insulin-like growth factor system is the major endocrine system regulating energy and substrate metabolism, participating also in growth, proliferation and regulation of tissue-specific cell differentiation. Several studies have shown that the IGF1-IGF1R system is significantly altered in CLD contributing to CD4+ T cell activation and differentiation toward Th17, a main driver of the inflammatory microenvironment and liver tissue damage present in these patients. Recent studies highlight the involvement of Th17 cells in cognitive impairment. These cells can breach the blood-brain barrier and exacerbate brain injury in various neurological disorders. Neuroinflammation is also linked to the insulin-like growth factor system, as IGF is involved in the protein synthesis necessary for the growth and survival of different cell populations of the brain, such as neurons, astrocytes and microglia. Thus, an altered IGF/IGFR system is involved in cognitive decline and memory, and several studies have revealed its implication in aging and cell senescence. This narrative review summarizes the participation of the IGF/IGFR system in chronic liver disease, focusing on its multifactorial role on the liver-brain axis and its contribution to inflammatory and neurocognitive complications developed during aging in these patients.