Accelerated Aging: Human Progeroid Syndromes

Cockayne syndrome is an autosomal recessive disease that also appears early in childhood, although the age of onset and severity of symptoms are variable. Individuals with this disorder have growth retardation and multiple degenerative problems, including central nervous system degeneration that often results in deafness, vision deficits, and motor problems. Other agerelated features are premature arteriosclerosis, progressive joint deformities, and loss of subcutaneous fat. Sun sensitivity is associated with Cockayne syndrome, although increased malignancy (including UV-related skin cancer) is not. Death usually occurs by early adolescence as a result of progressive neurodegeneration.

Cockayne syndrome is the result of mutations in one of five genes. Most affected individuals have defective CSA or CSB genes, although specific XPB, XPD, or XPG gene mutations result in Cockayne syndrome combined with another disease, xeroderma pigmentosum. This genetic complexity indicates that these five gene products impinge on a common pathway that is faulty in Cockayne syndrome. Extensive research has demonstrated that the problem lies in the complex coordination of transcription with DNA repair. In normal cells, certain types of DNA damage are removed faster from the template strand of transcribed genes than from the remainder of the genome. Individuals with Cockayne syndrome are deficient in this highly efficient repair of the transcribed strand of active genes and, consequently, have difficulty in resuming transcription following DNA damage. Persistent damage in the transcribed strand may sequester RNA polymerase, and the concomitant transcription deficits may explain many Cockayne syndrome abnormalities. Another hypothesis is that transcription blockage induces programmed cell death (apoptosis), and sufficient cell loss elicits aging signs and other characteristics of Cockayne syndrome. Inhibition of transcription or induction of apoptosis in neurons that contain increased endogenous oxidative DNA damage could explain the profound neurodegeneration associated with this disease. Ultimately, a failure in DNA metabolism is responsible for Cockayne syndrome.