Project Details
Projekt
Adipose tissue-lung axis: Early life obesity drives lung stem cell aging and predisposes to the development of idiopathic pulmonary fibrosis (IPF)
Subject Area
Biogerontology and Geriatric Medicine
Pneumology, Thoracic Surgery
Pneumology, Thoracic Surgery
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 542102810
Idiopathic pulmonary fibrosis (IPF) is a debilitating chronic lung disease (CLD) of unknown origin that is characterized by progressive remodeling of the lung parenchyma with a decline of lung function and extremely poor prognosis. IPF is associated with aging, and both incidence and prevalence are closely associated with an increasingly aging population worldwide, indicating an age-associated loss of lung-intrinsic defense and regenerative mechanisms. Accumulating evidence demonstrate that life-style factors, e.g., obesity are important risk factors for the development of IPF. Aging is multifactorial and characterized by genomic instability, cellular senescence and stem cell depletion, processes that are triggered and accelerated by inflammation (inflamm-aging). Adverse environmental influences especially early in life could disturb the balance of aging- and anti-aging mechanisms. Obesity is a condition with chronic subacute inflammation. Individuals that are overweight or obese share aging-related features. Prior studies and preliminary data from our group showed that early-life obesity causes aberrant lung structural maturation with risk for CLD through low-grade adipose tissue-related inflammation. Since obesity and aging processes converge in similar molecular mechanisms, we now hypothesize that obesity with overactive adipose tissue accelerates aging with increased susceptibility to pulmonary diseases through an adipose-tissue-lung interplay. To address these research question we defined four specific aims: (i) First, we will investigate the impact of diet-induced obesity in a murine model in early-life and in adulthood on lung epithelial metabolic and aging signatures using a multi-omics approach. (ii) Second we will study the effect of adipose tissue mediators on stem cell capacity and aging of alveolar epithelial cells by employing ex vivo lung models including precision-cut lung slices (PCLS) and organoid models. (iii) Third, we will test if early-life obesity and obesity in adulthood accelerate the senescent phenotype and aggravates bleomycin-induced pulmonary fibrosis in mice. Finally, (iva) we will study if serum from volunteers with obesity promotes aging processes and susceptibility to fibrotic stimuli in PCLS, and (ivb) to harness the obtained pathomechanistic insights to derive/test preventive and therapeutic strategies for IPF associated with obesity. This project proposal is a collaborative approach between metabolism and lung aging research. Completion of our joint project will thus provide new global mechanistic insights into the interplay between accelerated aging related to obesity as well as overactive adipose tissue that applies to the susceptibility to IPF and identify potential molecular switches to interfere with this mechanism therapeutically.
DFG Programme
Research Grants
