The Questions of Developmental Biology

Genetic aging programs.
Several genes have been shown to affect
aging. In humans, Hutchinson-Gilford progeria
syndrome causes children to age rapidly and to die
(usually of heart failure) as early as 12 years (Figure
18.37). It is caused by a dominant mutant gene, and its
symptoms include thin skin with age spots, resorbed
bone mass, hair loss, and arteriosclerosis. A similar
syndrome is caused by mutations of the klotho gene in
mice (Kuro-o et al. 1997). The functions of the
products of these genes are not known, but they are
thought to be involved in suppressing the aging phenotypes. These proteins may be extremely
important in determining the timing of senescence.
In C. elegans, there appear to be at least two genetic pathways that affect aging.
The first pathway involves the decision to remain a larva or to continue growth. After hatching,
the C. elegans larva proceeds through four instar stages, after which it can become an adult or (if
the nematodes are overcrowded or if there is insufficient food) can enter a nonfeeding,
metabolically dormant dauer stage. It can remain a dauer larva for up to 6 months, rather than
becoming an adult that lives only a few weeks. When it comes out of the dauer stage, it will live
as long as if it had never been a dauer larva. In the dauer stage, adult development is suppressed,
and extra defenses against ROS are synthesized. If some of the genes involved in this pathway are
mutated, adult development is allowed, but the ROS defenses are still made. The resulting adults
live twice to four times as long as wild-type adults (Figure 18.38; Friedman and Johnson 1988).
The second pathway involves the gonads. Germ cells appear to inhibit longevity, while the
somatic cells of the gonads act to prolong the life of the nematode (Hsin and Kenyon 1999).
As human life expectancy increases due to our increased ability to prevent and cure
disease, we are still left with a general aging syndrome that is characteristic of our species. Unless
attention is paid to the general aging syndrome, we risk ending up like Tithonios, the miserable
wretch of Greek mythology to whom the gods awarded eternal life, but not eternal youth.