The nucleus is encapsulated by the inner and outer nuclear membrane (INM, ONM). Cargo is shuttled between the nucleus and cytoplasm by nuclear pore complexes. LEM-domain proteins span the INM and connect it to A- and B-type lamins and peripheral heterochromatin. Progerin retains its farnesyl moiety and remains associated with the INM. Progerin expression results in nuclear abnormalities, heterochromatin decompaction, clustering of nuclear pore complexes, senescence-associated lamin B1 reduction and DNA damage. Center: A speculative model depicting a possible chain of events that commences with an expression of mutant lamin A (progerin), loss of heterochromatin, replication defects and an accumulation of telomeric DNA damage that results in premature cellular senescence.