In the last decade, we have seen increasing evidence of the importance of 
structural nuclear proteins such as lamins in nuclear architecture and 
compartmentalization of genome function and in the maintenance of mechanical 
stability and genome integrity. With over 400 mutations identified in the LMNA 
gene (encoding for A-type lamins) associated with more than ten distinct 
degenerative disorders, the role of lamins as genome caretakers and the 
contribution of lamins dysfunction to disease are unarguable. However, the 
molecular mechanisms whereby lamins mutations cause pathologies remain less 
understood. Here, we review pathways and mechanisms recently identified as 
playing a role in the pathophysiology of laminopathies, with special emphasis in 
Hutchinson Gilford Progeria Syndrome (HGPS). This devastating incurable 
accelerated aging disease is caused by a silent mutation in the LMNA gene that 
generates a truncated lamin A protein "progerin" that exerts profound cellular 
toxicity and organismal decline. Patients usually die in their teens due to 
cardiovascular complications such as myocardial infarction or stroke. To date, 
there are no efficient therapies that ameliorate disease progression, stressing 
the need to understand molecularly disease mechanisms that can be targeted 
therapeutically. We will summarize data supporting that replication stress is a 
major cause of genomic instability in laminopathies, which contributes to the 
activation of innate immune responses to self-DNA that in turn accelerate the 
aging process.