Accelerated Aging Syndromes

Approximately 35% of the factors that influence life expectancy are inherited. Accelerated aging is therefore usually associated with genetic abnormalities. None of the accelerated aging syndromes, however, leads to a uniform, systematic “speeding up” of the aging process. A number of genetic disorders can lead to premature or accelerated aging (also referred to as progerias), including Down syndrome, Hutchinson–Gilford syndrome, and Werner's syndrome. Down syndrome, by far the most common, is caused by three copies of chromosome 21. Yet we usually do not consider this genetic disorder to be a disorder of accelerated aging because the focus is on the mild mental retardation, characteristic physical features, and “pleasant personality” associated with the syndrome. Nevertheless, people who experience Down syndrome demonstrate a number of findings associated with premature aging such as the early appearance of changes in the brain (specifically the accumulation of senile plaques and neurofibrillary tangles) that we find in the brains of nearly all very old people and more frequently (and in a somewhat different distribution) in Alzheimer's disease. The life expectancy of Down syndrome patients is significantly shortened as well.

Hutchinson–Gilford syndrome, a very rare condition, is the earliest onset accelerated aging syndrome. It is associated with dwarfism, physical immaturity, and pseudosenility. People who are affected look like very old, wizened, and diminutive adults with distorted features (due to bone abnormalities that include diminished growth of the lower jaw and generalized osteoporosis). Their heads are large when compared with their faces, whereas the ears and noses are small. Intense progressive atherosclerosis occurs during childhood and is the primary cause of death. The syndrome appears to be a rare autosomal recessive condition but also may be autosomal dominant with incomplete penetrance (an inherited trait that does not manifest itself universally). Death usually occurs during the teens.

Werner's syndrome, which is also very rare but has typically been considered the prototypical accelerated aging syndrome, usually appears later than the previous conditions. Once the condition manifests itself, however, those affected look 20 to 30 years older than their actual ages and their life spans are shortened. The disease usually has its onset before the affected people reach full maturity, usually during or after puberty, so those affected have thin limbs and are smaller in stature and less developed in other adult characteristics than would be expected. Their appearance is striking. Werner's patients have tightly drawn faces, pinched expressions, and protruding eyes. They exhibit beaked noses, protuberant teeth, and recessive chins. Many age-related characteristics appear early, including cataracts, hypogonadism (with lowering of testosterone in males), atherosclerosis, and early onset of diabetes. Cancers frequently appear before death. As would be expected, the life spans of Werner's patients are shortened significantly. A specific genetic mutation [Page 2]has been associated with Werner's syndrome, namely the WRN on chromosome 8. When the protein encoded by this gene loses function, the result is a genomic instability that appears to hasten the aging process.