Notes

HUMAN PREMATURE AGING SYNDROMES
Some comparisons of the p53 and XPD mouse mutant phenotypes with those
of several segmental progeroid syndromes in humans are summarized in
Table 1. Two of the most well known human progeroid syndromes are
Hutchinson–Gilford syndrome (HGS), also referred to as progeria, and
Werner syndrome (WS). HGS patients appear normal at birth, but by the end
of their second year growth begins to slow and loss of hair and subcutaneous
fat begin (De Busk, 1972). Although their intellectual development is normal,
these children reach a height of only about 3 feet and a weight of about
35 pounds, and usually die of cardiovascular complications at an average
age of 13 years. The syndrome is very rare (about 1 per 10 million births),
and the genetic defect in HGS is not known, although it is usually assumed
that HGS is due to an autosomal dominant mutation, possibly arising
during germ cell production or development. The short stature and
musculoskeletal abnormalities are more consistent with developmental
abnormalities than premature aging, although fibroblasts taken from HGS
patients have short telomeres and little replicative potential remaining, suggesting the replicative life span of these cells may have been compromised
by excessive apoptosis and cell replacement early in life. The short stature
and developmental abnormalities might then be due to insufficient cell
replacement from the various stem cell reservoirs with increasing age.
However, other than short telomeres, there is no strong evidence for genetic
instability in HGS that might trigger such an early and continuing apoptotic
response.
WS patients also appear normal at birth, and a diagnosis of WS is usually
not made until puberty, when growth begins to slow down (Martin and
Oshima, 2000). This is followed by premature graying of hair, atrophy of
various tissues (particularly reproductive tissues and skin), type 2 diabetes,
atherosclerosis, and osteoporosis. Most striking, however, is the genetic instability that accompanies WS, so WS patients are at high risk for neoplasia. This
is consistent with the discovery that the WRN gene codes for a protein with
DNA helicase (known as a recQ helicase) and 3¢ Æ 5¢ exonuclease activities
(Gray et al., 1997; Huang et al., 1998). Thus, this protein may be involved in
any one or all of the following: replication, repair, recombination, and transcription. Fibroblasts isolated from WS patients have short life spans, but
longer than that of HGS fibroblasts. WS patients usually die of either cancer
or myocardial infarction at a median age of about 47 to 48 years.
In contrast to HGS and WS, patients with Bloom syndrome (BS) do not
appear normal at birth, but are born small, and remain smaller than normal
throughout their short life, with death usually occurring in their twenties
due to cancer. The defective gene (BLM) associated with Bloom syndrome
also codes for an enzyme with a recQ-like DNA helicase activity, but not
exonuclease activity. Several speakers at the recent Keystone symposium on
“DNA Helicases, Cancer and Aging” (March 12–17, 2002) suggested that the
small stature of Bloom syndrome patients may result from excessive cell
death, even in the fetal stage of life. Because BS is characterized by genomic
instability, particularly sister chromatid exchanges, such cell death may be
triggered by the accumulation of replication intermediates (Bischof et al.,
2001) that either induce cell death or lead to illegitimate recombination. The
growth defects associated with these three human syndromes appear not to
be caused by growth hormone deficiency (Laron, 2002).
The preliminary results with Bloom syndrome raise the issue of
whether excessive cell death also contributes to the phenotype of Werner,
Hutchinson–Gilford, or Cockayne syndrome, all of which are characterized
by short stature, and/or to other segmental progeroid syndromes. On the
other hand, the increased susceptibility to cancer might indicate that
decreased apoptosis is occurring in WS patients (Campisi, 2002). These questions seem to deserve increased attention in future research on the roles of
cell death in aging and development of various aging phenotypes, and this
may also tell us something about p53 function and aging, as Yang et al. (2002)
have reported that p53 may also play a role in regulating the activity of the
DNA helicases associated with Werner and Bloom syndromes.