Hierarchical Homeostatic Failure in Hutchinson-Gilford Progeria Syndrome: From Nuclear Lesion to Systemic Decline

Hutchinson-Gilford progeria syndrome (HGPS) is a fatal laminopathy caused by an LMNA mutation that generates progerin, a permanently farnesylated, truncated form of prelamin A. Although progerin's structural effects are well established, prior reviews have largely cataloged its downstream consequences, genome instability, proteostasis failure, inflammation, stem-cell dysfunction and matrix remodeling, as parallel, largely independent processes. Here, two decades of mechanistic evidence are reorganized into a single evidence-ranked hierarchy spanning four interconnected levels of homeostasis, nuclear, cellular, tissue and organismal, that explicitly separates established mechanisms from inferred cross-scale links. Progerin perturbs post-mitotic nuclear reassembly, but several defining abnormalities emerge or intensify during interphase and across successive cell generations, indicating progressive maintenance failure rather than a purely static structural model. Nuclear dysfunction is associated with impaired proteostasis, stress adaptation and lineage competence; these cellular defects can be amplified by extracellular-matrix remodeling, chronic inflammation, and reduced regenerative capacity. Evidence is strongest for nuclear and cellular mechanisms, whereas a continuous nucleus-to-organism sequence remains an integrative, testable model. When fragmented mechanisms are ordered across biological scales, this framework helps explain disease latency, tissue selectivity, partial reversibility, and the rationale for combination therapy. Lonafarnib, proteostasis-directed interventions, JAK-STAT inhibition and genome-, RNA-, and progerin-directed strategies are therefore considered complementary approaches acting at distinct levels of the hierarchy. HGPS is not a replica of physiological aging, but a genetically defined system that reveals how persistent nuclear stress can progressively erode conserved adaptive networks.