Identification and validation of the pivotal role of MANF gene in pancreatic β-cell aging using bioinformatics

Pancreatic β-cells are essential for maintaining endocrine function, and their age-related decline is strongly associated with insulin resistance and an increased risk of developing diabetes. By integrating cross-species bioinformatics analyses (single-cell RNA-seq data from young and aged cynomolgus macaques and microarray data from young and old mouse pancreatic β-cells), we identified mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum (ER) stress-related gene, as a key regulator of β-cell aging. Using a d-galactose (D-gal)-induced aging mouse model (400 mg/kg/day for 10 weeks) and H₂O₂ (300 μM)-treated MIN6 cells, we demonstrated that MANF expression was downregulated in the aging models, which also exhibited elevated levels of cyclin-dependent kinase inhibitor P21, insulin resistance, impaired glucose tolerance, and decreased insulin secretion. Notably, administration of human recombinant MANF (hrMANF) (0.7 mg/kg, three times/week) reversed the insulin resistance, improved glucose tolerance and insulin secretion. Our study is the first to establish MANF as a guardian of β-cell proteostasis during aging, thus offering a novel therapeutic avenue for diabetes by targeting β-cell senescence. It's a finding with high clinical relevance for aging populations, as it directly addresses the critical reasons for age-related diabetes progression and provides a strategy to preserve β-cell function and reverse aging-related diabetes in older adults.