Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue

Abstract

SummaryThe free radical theory of aging postulates that the production of mitochondrial reactive oxygen species is the major determinant of aging and lifespan. Its role in aging of the connective tissue has not yet been established, even though the incidence of aging-related disorders in connective tissue-rich organs is high, causing major disability in the elderly. We have now addressed this question experimentally by creating mice with conditional deficiency of the mitochondrial manganese superoxide dismutase in fibroblasts and other mesenchymederived cells of connective tissues in all organs. Here, we have shown for the first time that the connective tissuespecific lack of superoxide anion detoxification in the mitochondria results in reduced lifespan and premature onset of aging-related phenotypes such as weight loss, skin atrophy, kyphosis (curvature of the spine), osteoporosis and muscle degeneration in mutant mice. Increase in p16 INK4a , a robust in vivo marker for fibroblast aging, may contribute to the observed phenotype. This novel model is particularly suited to decipher the underlying mechanisms and to develop hopefully novel connective tissuespecific anti-aging strategies.

Brain-Skin Connection: Stress, Inflammation and Skin Aging

“…It was also discovered that in the brain, stress leads to increased oxidative stress and mitochondria dysfunction [202, 203]. Considering ROS production in the mitochondria is the major determinant of aging and life span [204], stress can have a major impact on skin aging through the ROS pathway.…”

Exercise‐stimulated interleukin‐15 is controlled byAMPKand regulates skin metabolism and aging

“…These pathophysiological changes are thought to be driven by aged and senescent cells that exhibit reduced energy metabolism, higher mitochondrial oxidative stress, and pronounced mitochondrial DNA (mtDNA) deletions (Isobe et al ., 1998; Lu et al ., 1999), reflecting characteristics of the mitochondrial free radical theory of aging (Harman, 1972). In agreement, the deletion of a free radical scavenger within the mitochondria, superoxide dismutase 2, from connective tissue results in premature skin aging (Treiber et al ., 2011; Velarde et al ., 2012) and depleting mtDNA in dermal fibroblasts mimics the gene profile of photoaging (Schroeder et al ., 2008). Conversely, treatment with PPAR agonists that stimulate mitochondrial metabolism and cell proliferation improves skin wound healing (Ham et al ., 2010) and retards age-related tissue degeneration (Dillon et al ., 2012).…”

Unique quadruple immunofluorescence assay demonstrates mitochondrial respiratory chain dysfunction in osteoblasts of aged and PolgA−/− mice

“…There is further evidence for potential mitochondrial involvement in osteoporosis, for example in mice with mitochondrial transcription factor A (TFAM) deficient osteoclasts, increased resorption is observed, tipping the net balance in favour of bone resorption rather than formation23. In addition, mouse models with either a complete or osteocyte specific knockout of superoxide dismutase (Sod2), an enzyme involved in limiting oxidative stress in mitochondria, develop osteoporosis prematurely2425.…”