fig2

Figure 2. DNA damage response in aging. The genome is not only affected by the mutations but also by various endogenous, such as reactive oxygen species, and exogenous, such as ultraviolet light, resulting in various forms of DNA damage, most notably double-stranded DNA breaks (DSBs). The red color staining depicts the cardia myocyte LMNA protein, which resides in the inner nuclear membrane close to the chromatin. LMNA is involved in induction as well as repair of the DSBs and has a crucial role in nuclear membrane integrity. In the presence of LMNA mutations or deficiency, DSBs are increased and released into the cytoplasm, which is then sensed by the cyclic GMP-AMP synthase (CGAS) followed by activation of stimulator of interferon genes protein 1 (STING1) and TANK binding kinase 1 (TBK1). STING1 activates the nuclear factor kappa B (NFκB) components p65 and p50, whereas TBK1 phosphorylates interferon regulatory factor 3 (IFR3) which translocates into the nucleus and induces the expression of pro-inflammatory genes. Several proteins are recruited to the site of the DSBs, including the ataxia-telangiectasia mutated (ATM), which phosphorylates H2 histone family member X (H2AFX) and the tumor suppressor protein 53 (TP53). Activated TP53 translocates into the nucleus and induces the expression of genes involved in senescence-associated secretory phenotype (SASP), which collectively mediates molecular and cellular phenotypes of aging such as cell cycle arrest, senescence, fibrosis, apoptosis, and others.