Systemic sclerosis-associated fibrosis: an accelerated aging phenotype?

Abstract

Purpose of review: Systemic sclerosis (SSc) is an autoimmune disease with fibrosis seen in multiple organs. Although not traditionally regarded as a disease of aging, SSc-associated fibrosis shares many of the hallmarks of aging seen in other age-related fibrotic disorders. Here, we review the current literature of the potential role of aging and age-related cellular processes in the development of SSc and fibrosis.

Recent findings: Accumulating evidence supports a role for immune dysregulation, epigenetic modifications, cellular senescence, mitochondrial dysregulation and impaired autophagy in fibrosis that occurs in aging and SSc.

Summary: Cellular alterations linked to aging may promote the development and/or progression of SSc-associated fibrosis.

Figure 1

SSc-associated fibrosis, inflammation and vasculopathy may be perpetuated or accelerated by aging-associated phenotypes that include immune dysregulation, epigenetic modifications, cellular senescence, mitochondrial dysfunction and impaired autophagy. Immune dysfunction, specifically immune-senescence, may fail to clear the accumulation of senescent (myo)fibroblasts that acquire an apoptosis-resistant phenotype. The elaboration of pro-inflammatory cytokines, matrix metalloproteinases (MMPs) and reactive oxygen species (ROS) by the so-called senescence-associated secretory phenotype (SASP) of fibroblasts and immune cells promotes the apoptosis-susceptible phenotype of adjacent epithelial cells and endothelial cells, thus providing a feed-forward mechanism for aberrant tissue remodeling.