The decreased exclusion of nuclear eccDNA: From molecular and subcellular levels to human aging and age-related diseases

•DNA damage accumulation may be caused by reduced exclusion of nuclear eccDNA in aging and age-related diseases.•eccDNA originates from non-coding DNA during DNA damage repair.•Decrease of functional NPCs leads to reduced exclusion of nuclear eccDNA.•Deregulated nuclear F-actin affects exclusion of nuclear eccDNA.•NR formation shortens the distance between the nucleolus periphery and NPC. Extrachromosomal circular DNA (eccDNA) accumulates within the nucleus of eukaryotic cells during physiological aging and in age-related diseases (ARDs) and the accumulation could be caused by the declined exclusion of nuclear eccDNA in these states. This review focuses on the formation of eccDNA and the roles of some main factors, such as nuclear pore complexes (NPCs), nucleoplasmic reticulum (NR), and nuclear actin, in eccDNA exclusion. eccDNAs are mostly formed from non-coding DNA during DNA damage repair. They move to NPCs along nuclear actin and are excluded out of the nucleus through functional NPCs in young and healthy cells. However, it has been demonstrated that defective NPCs, abnormal NPC components and nuclear actin rods are increased in aged cells, various cancers and certain other ARDs such as cardiovascular diseases, premature aging, neurodegenerative diseases and myopathies. Therefore, mainly resulting from the increase of dysfunctional NPCs, the exclusion of nuclear eccDNAs may be reduced and eccDNAs thus accumulate within the nucleus in aging and the aforementioned ARDs. In addition, the protective function of non-coding DNA in tumorigenesis is further discussed.