cTAGE5/MEA6 plays a pivotal role in COPII complex assembly, ER-to-Golgi trafficking, and secretion. However, whether cTAGE5/MEA6 is involved in other cellular functions remains unclear. Here, we show that conditional cTAGE5 knockout results in embryonic lethality during development and premature aging in adult mice. cTAGE5 deficiency leads to abnormal nuclear structure and disturbed cell proliferation in MEF cells. Further mechanistic studies reveal that cTAGE5 localizes not only to the ER exit sites but also to other ER structures, where it interacts with the lamin B receptor (LBR). Loss of cTAGE5 disrupts LBR's localization to the inner nuclear membrane, leading to its retention in the ER and instability. This results in abnormal nuclear (envelope) morphology and cellular senescence, likely driven by activation of the P53/P21 senescence pathway. Thus, our study uncovers cTAGE5's role in maintaining nuclear envelope integrity and highlights its function and potential mechanism in preventing cellular senescence and animal aging.