Accelerated Aging: Human Progeroid Syndromes

Werner syndrome is known as adult progeria because affected individuals appear relatively normal until adolescence and develop aging characteristics thereafter. It is an autosomal recessive disorder that afflicts fewer than ten out of a million persons, with the highest incidences in Japan and Sardinia. Werner syndrome patients have accelerated development of many aging characteristics (including graying and loss of hair, wrinkling and ulceration of skin, cataracts, atherosclerosis, and osteoporosis) and increased incidence of certain age-related diseases (such as cancer, diabetes, and hypertension). They do not have increased neurodegenerative problems such as Alzheimer's, Parkinson's, or Huntington's disease, although some dementia has been reported. Werner syndrome patients invariably die before age fifty, usually from cancer or complications due to severe atherosclerosis.

Amazingly, all of the characteristics of Werner syndrome result from mutations in one gene, known as WRN. Biochemical study of the WRN protein demonstrated its DNA unwinding (helicase) and DNA degradation (exonuclease) activities. Although the exact function of WRN remains unknown, its catalytic activities and reported interactions with proteins involved in DNA metabolism point to possible roles in DNA replication, repair, or recombination. The loss of WRN function in Werner syndrome causes DNA metabolic errors that result in elevated deletions, insertions, and translocations of chromosomal DNA. Cells lacking WRN also shorten their telomeres (the protective DNA sequences at each chromosome end) much faster than normal cells, suggesting a direct role for WRN in telomere maintenance. In somatic cells, telomere shortening occurs during each round of replication, and thus is a biomarker of cellular aging. Critically short telomeres prevent cell division, suggesting a relationship between cellular senescence and aging of organisms. Cells from individuals with Werner syndrome undergo rapid cellular senescence, probably caused by accelerated telomere loss, supporting the proposed relationship between short telomeres, cellular senescence, and certain aging characteristics. In general, the Werner syndrome phenotype points to a connection between the accumulation of genetic changes, cellular senescence, and aging.