Professor Björn Schumacher

Innate immune responses to DNA damage in ageing and disease

DNA damage accumulation is thought to causally contribute to the functional decline in aging (Schumacher et al, 2008a). Cellular DNA damage responses (DDR) evoke cell cycle arrest, apoptosis, and cellular senescence that are essential for tumour suppression (Reinhardt & Schumacher, 2012). It has been suggested that inflammatory responses to DNA damage accumulation comprise a causal factor for tissue degeneration with aging. We aim to gain insight into how the innate immune system mediates systemic responses to DNA damage accumulation with aging. Understanding the mechanistic links between DNA damage and innate immune responses might reveal new therapeutic strategies to counteract chronic inflammation in aging-associated disease.

We aim to determine the mechanisms through which the innate immune response is mediated upon DNA damage. To achieve this we will employ the powerful experimental system of C. elegans and use the synergisms of the CCRC to explore functional conservation of innate immune responses to DNA damage and assess their role in vascular remodeling.

 

 

 

Non-cell autonomous consequences of p53 signaling in aging (grey) and cancer (red) associated processes. p53 induces several negative regulators of the cell intrinsic Insulin-like growth factor (IGF)-1 receptor signaling pathway as well as systemically acting IGF-BP3, the major antagonistic IGF-1 carrier in the circulation. IGF-1 signaling induces cell proliferation, while reduced IGF-1 signaling is associated with extended lifespan in species ranging from nematode worms to mammals. p53-mediated cellular senescence, in contrast, promotes cellular aging, while senescent cells modify their tissue environment through the senescence associated secretory phenotype (SASP) resulting in cytokine secretion that activates the innate immune system. The innate immune system in turn can act tumor suppressive (blue) by clearing cells that have become senescent as result of oncogene activation or chronic DNA damage. However, SASP might also have tumor promoting consequences on surrounding cells as cytokine signaling and chronic inflammation can promote proliferation of tumor cells. In addition, chronic inflammation is also associated with tissue aging.