Progerin expression in humans: Implications for natural ageing

Progerin, a truncated lamin A isoform generated by cryptic LMNA splicing, is the pathogenic driver of Hutchinson–Gilford Progeria Syndrome (HGPS) and has been implicated as a putative marker in natural ageing. Low-level progerin arises in normal tissues, particularly skin, vasculature, and blood-derived cells, where it contributes to nuclear deformation, chromatin disorganization, DNA damage, telomere attrition, mitochondrial stress, stem cell exhaustion, and premature senescence. These cellular effects align with damage accumulation and senescence-based theories of ageing, while HGPS illustrates accelerated convergence of these mechanisms. Endogenous suppressors, including WRN helicase and telomere-protective factors, modulate progerin levels and mitigate its harmful consequences, highlighting the existence of regulatory pathways buffering nuclear lamina stress. Although its detection in normal ageing is constrained by low abundance and tissue specificity, progerin provides domain-rich information about vascular and dermal ageing, complementing systemic measures such as epigenetic clocks. Standardized ultrasensitive assays, longitudinal tissue-resolved studies, and interventional tests targeting upstream drivers or reinforcing endogenous inhibitors are key to validating progerin as part of multimodal biomarker panels. These insights may collectively position progerin as a mechanistic link between premature ageing and physiological ageing, positioning it as a potential component of biomarker strategies. • Progerin is a truncated lamin A isoform driving Hutchinson–Gilford Progeria Syndrome (HGPS) and is also produced at low levels during normal human aging. • Low-level progerin accumulates with age in skin, vascular smooth muscle, endothelial cells, and blood-related cell populations. • Telomere-protective factors (TRF2, hTERT) and the WRN helicase function as endogenous inhibitors of progerin, buffering nuclear stress and limiting progerin-mediated genomic instability. • HGPS recapitulates multiple hallmarks of aging (damage accumulation, programmed aging, metabolic, and evolutionary models). • Progerin shows promise as a tissue-specific biomarker of aging, particularly for vascular and dermal aging.