PubMed · 17022513
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Osamu Ueda, Kenji Fujieda. 2006-09-28. [Down syndrome].. https://pubmed.ncbi.nlm.nih.gov/17022513/
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Cdc42 is a member of the Rho GTPase family known to regulate cell actin cytoskeleton organization, polarity, and growth, but its function in mammalian organismal physiology remains unclear. We found that natural aging of WT mice is marked with increased Cdc42 activity in various tissues. Among the negative regulators of Cdc42, gene targeting of Cdc42 GTPase-activating protein (Cdc42GAP) results in constitutively elevated Cdc42-GTP level in diverse tissues of adult mice; significantly shortened life span of the animals; and multiple premature aging-like phenotypes, including a reduction in body mass, a loss of subdermal adipose tissue, severe lordokyphosis, muscle atrophy, osteoporosis, and reduction of reepithelialization ability in wound-healing. Cdc42GAP-/- mouse embryonic fibroblasts and/or tissues display reduced population doubling, significantly dampened DNA damage repair activity after DNA-damaging agent treatment, accumulated genomic abnormalities, and induction of p53, p16Ink4a, p21Cip1, and senescence-associated beta-galactosidase expressions. Furthermore, Cdc42 activation is sufficient to promote a premature cellular senescence phenotype that depends on p53. These results suggest a role of Cdc42 activity in regulating mammalian genomic stability and aging-related physiology.
Guanidinosuccinic acid is an aberrant metabolite isolated 40 years ago in the blood and urine of uremic subjects and a suspect in the toxicity associated with renal failure. It plays a minor role in the bleeding diathesis of uremia, contributes to the methyl group deficiency of dialysis patients, and is a factor in the premature atherosclerosis of end stage renal disease through the induction of hyperhomocysteinemia. As a major player, however, in the diversity and severity of uremic symptoms, it is a disappointment. Recently its source has been identified. It results from the superoxidation of argininosuccinic acid, which leads, also, to the production of gamma glutamic semialdehyde, an advanced glycation end product (AGE), which normally results from from the Maillard reaction, the non-enzymatic browning of protein. AGEs stimulate cross-linkages in protein that lead ultimately to loss of function, phagocytosis, and removal, and are important elements in the premature aging characteristic of renal disease, and diabetes.