Role of pro-oxidative connective tissue in skin aging – Molecular mechanisms and therapeutic strategies

• Applicant: Professorin Dr. Karin Scharffetter-Kochanek
• Subject Area: Dermatology ; Cell Biology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432048315

To understand the role of fibroblasts in organ aging and tissue decline, we will analyze our earlier generated connective tissue specific murine model depicting enhanced aging and compare it to intrinsically aged control mice. The previously established murine aging model with a connective tissue specific deletion of the manganese superoxide dismutase (SOD2) revealed concomitant up-regulation of p16INK4A, a cell cycle inhibitor promoting irreversible fibroblasts senescence, and a profound decline of Insulin-like Growth Factor 1 (IGF-1), an important growth and tissue maintenance factor. Suppressed release of IGF-1 constitutes a key hallmark of the senescence-associated secretory phenotype (SASP) of senescent fibroblasts. The installment of such an aging program enforces severe connective tissue aging and overall skin aging. Indirect evidence of our laboratory suggests that a redox-dependent transcription factor concomitantly induces p16INK4A, while suppressing IGF-1. We here will follow two main interconnected objectives: 1. to establish the role of the redox sensitive transcription factor JunB/AP1 in skin aging and to unravel its mode of action in tissue decline, and 2. to assess whether cells of the innate immune system with reduced removal capacity of senescent fibroblasts are responsible for further accumulation of senescent fibroblasts in the skin of aged mice. These two research foci are intimately interrelated, and both contribute to a better understanding of enhanced accumulation of senescent cells in connective tissue rich organs. Using connective tissue specific double Sod2/JunB deficient mice, we will dissect whether redox-dependent JunB is responsible for skin aging and whether this depends on selective translation with suppression of IGF-1. By means of genetically manipulated murine models which lack natural killer cells (NK cells) or macrophages, we will explore whether senescent cells accumulate in connective tissue rich organ like skin. In addition, we will employ strategies, like adoptive transfer of young NK cells/macrophages (bone marrow) and natural IgM to more efficiently remove senescent cells and will study the likely possibility that reprogramming of the SASP will attenuate or even restore delayed aging and skin homoeostasis including stem cell renewal and enhanced regenerative capacity. This project will help to define the central role of fibroblast senescence on skin aging, and on other connective tissue rich organs, such as bone and muscle. The expected results will hold unprecedented promise for the development of appropriate interventions for organ and organismal aging/tissue decline.

• DFG Programme: Research Grants