Link Between Aging and Fibrotic Pulmonary Disease Discovered

A study analyzing transcriptome biomarker data has shown evidence linking cellular senescence with idiopathic pulmonary fibrosis (IPF), suggesting that this fatal lung disease maybe involve a form of accelerated aging.

“IPF is a poorly understood disease, and its effects are devastating,” said study senior author Nathan LeBrasseur, PhD, of Mayo Clinic, “Individuals with IPF express difficulty completing routine activities. There are currently no effective treatment options, and the disease leads to a dramatic decrease in health span and life span, with life expectancy after diagnosis between 3 to 5 years.”

Dr. LeBrasseur and his team, which included experts across several departments at Mayo Clinic, as well as Newcastle University Institute for Ageing and The Scripps Research Institute, studied the lung tissue of healthy individuals and of persons with mild, moderate, and severe IPF. The tissue samples were made available from the Lung Tissue Research Consortium.

They found that the markers of cellular senescence were higher in individuals with IPF, and senescent cell burden increased with the progression of the disease. They then demonstrated that factors secreted by senescent cells could drive inflammation and aberrant tissue remodeling and fibrosis – hallmarks of IPF.

“We discovered that senescent cells, which accumulate in the IPF lung, are a viable source of multiple factors that drive fibrotic activation,” explained lead author Marissa Schafer, PhD, postdoctoral fellow in Dr. LeBrasseur’s lab. According to Dr. LeBrasseur, the findings represent a conceptual shift in the way researchers think about IPD: “Up to this point, research efforts have largely focused on understanding the unique elements that contribute to IPF. Here, we are considering whether the biology of aging is accelerated in this aggressive disease. What we’ve found is that senescent cells are prevalent, secreting toxic molecules that affect healthy cells in that environment and are essentially promoting tissue fibrosis.”

Equipped with the findings from their studies of human lung tissue, the team then investigated the process in mice. They found that, much like in humans, mice with clinical features of IPF also demonstrated increased amounts of senescent cells. They used a genetic model programmed to make senescent cells self-destruct and a drug combination of dasatinib and quercetin, which, in previous studies conducted by Mayo Clinic, was shown to eliminate senescent cells. Results showed that clearing senescent cells from unhealthy mice improved measures of lung function and physical health, such as in exercise capacity on a treadmill. This suggests that targeting senescent cells could be a viable treatment option.

“We are exploring whether senolytic drugs, or drugs that can selectively kill senescent cells, can be used for the treatment of aging-associated conditions, including IPF,” said Dr. LeBrasseur, “More research is needed to validate this, and our goal is to move quickly from discovery to translation to application, and, ultimately, meet the unmet needs of our patients.”

The study, by Schafer MJ et al, was published online February 23, 2017, in the journal Nature Communications.