SIRT3 Upregulation as a Treatment for Lung Fibrosis

Fibrosis is a malfunction of tissue maintenance in which excessive scar-like collagen deposits disrupt tissue structure and function. This may be one of the consequences of the chronic inflammation of aging, and senescent cell accumulation is implicated in the progression of fibrosis. Researchers here show that upregulation of SIRT3 can reverse some of the disruption of cell function that causes fibrosis, resulting in improvements to health in aged mice. The approach they take is to deliver SIRT3 plasmids into the airway, where they are taken up by macrophage cells. Altered macrophage behavior as a result of increased SIRT3 expression then produces further signaling and cell behavior changes that lead to a reduction in fibrosis.

Fibrotic disorders span across multiple organ systems. A consistent pathological finding in these disorders is the accumulation of activated myofibroblasts and deposition of mature extracellular matrix in association with impaired capacity for epithelial cell regeneration. In most species and across organs in humans, regeneration and fibrosis are antagonistically and inversely related. While impaired regeneration leads to fibrosis, a skewing of the tissue repair response to fibrosis may reciprocally dampen latent regenerative capacity. Aging is known to be associated with impaired regenerative capacity, and it is also an established risk factor for human fibrotic disorders.

The biology of aging has advanced in recent years and, in addition to the identification of molecular and cellular hallmarks, several genes have been linked to life span. Multiple studies have implicated two genes, sirtuin 3 (SIRT3) and the forkhead box (FOX) transcription factor FOXO3A, with longevity. SIRT3 is localized to mitochondri1. SIRT3 ablation leads to accelerated aging, cancer, and age-related neurodegenerative disease.

We propose that aging biology can be leveraged to develop novel therapeutic strategies that target cellular plasticity and fate in established fibrosis. In this study, we report that SIRT3 is downregulated in fibroblasts from individuals with idiopathic pulmonary fibrosis and following bleomycin-induced injury in the lungs of aged mice with persistent, non-resolving fibrosis; restoring SIRT3 expression in the late reparative phase reverses established lung fibrosis. Furthermore, this study reveals that the pro-resolution effect of SIRT3 is mediated by macrophage-derived paracrine signaling that activates FOXO3A in fibroblasts, upregulates pro-apoptotic BCL2 family proteins and induces apoptotic cell death essential for fibrosis resolution.