Date Published: January 20, 2012
Publisher: Impact Journals LLC
Author(s): Michael C. Velarde, James M. Flynn, Nicholas U. Day, Simon Melov, Judith Campisi.
Cellular senescence arrests the proliferation of mammalian cells at risk for neoplastic transformation, and is also associated with aging. However, the factors that cause cellular senescence during aging are unclear. Excessive reactive oxygen species (ROS) have been shown to cause cellular senescence in culture, and accumulated molecular damage due to mitochondrial ROS has long been thought to drive aging phenotypes in vivo. Here, we test the hypothesis that mitochondrial oxidative stress can promote cellular senescence in vivo and contribute to aging phenotypes in vivo, specifically in the skin. We show that the number of senescent cells, as well as impaired mitochondrial (complex II) activity increase in naturally aged mouse skin. Using a mouse model of genetic Sod2 deficiency, we show that failure to express this important mitochondrial anti-oxidant enzyme also impairs mitochondrial complex II activity, causes nuclear DNA damage, and induces cellular senescence but not apoptosis in the epidermis. Sod2 deficiency also reduced the number of cells and thickness of the epidermis, while increasing terminal differentiation. Our results support the idea that mitochondrial oxidative stress and cellular senescence contribute to aging skin phenotypes in vivo.
Cellular senescence is an important anti-cancer mechanism that arrests the proliferation of cells in the face of potentially oncogenic stress . Cellular senescence has also been implicated in mammalian aging and age-related diseases in numerous tissues [2-5]. In mice and humans, cells that express senescence markers increase in number during aging in both the dermal and epidermal layers of the skin [6-9]. Mitochondrial dysfunction is known to be both a cause and a consequence of cellular senescence in cultured cells [10-17]. Mitochondria continuously generate potentially damaging reactive oxygen species (ROS) during oxidative phosphorylation [18,19]. These ROS are continuously detoxified by cellular antioxidants and antioxidant defense enzymes. However, when ROS are excessive the resulting cellular damage can drive cellular senescence . Despite numerous studies on mitochondrial function and senescence in cultured cells, little is known about the contribution of mitochondrial oxidative damage to cellular senescence in vivo.
Here, we show how natural aging is accompanied by decreased mitochondrial activity and increased cellular senescence in mouse skin. Consistent with the idea that these events are causally linked, constitutive Sod2 deficiency resulted in mitochondrial dysfunction and cellular senescence in the epidermis, as well as epidermal thinning, a known feature of aging skin.