46
U N I T 1
Cell and Tissue Function
associated with aging. The most prominent example of
the damage theory is the somatic mutation theory of
aging, which states that the longevity and function of
cells in various tissues of the body are determined by the
double-stranded DNA molecule and its specific repair
enzymes. Deoxyribonucleic acid undergoes continuous
change in response to both exogenous agents and intrin-
sic processes. It has been suggested that aging results
from conditions that produce mutations in DNA or defi-
cits in DNA repair mechanisms.
The oxidative free radical explanation of aging is
an error theory in which aging is thought to result
partially from oxidative stress and the effects of free
radical damage. The major by-products of oxidative
metabolism include superoxides that react with DNA,
ribonucleic acid, proteins, and lipids, leading to cellu-
lar damage and aging. Blood glucose is another suspect
in cellular deterioration. In a process called
nonenzy-
matic glycation
, glucose molecules attach to proteins,
setting in motion a chain of chemical reactions that
ends with proteins binding together or cross-linking,
thus altering their structure and function. Investigators
hypothesize that glycation and oxidation are interde-
pendent, since free radicals and cross-links seem to
accelerate the formation of one another. Cross-links,
also known as
advanced glycation end products
(AGEs),
tend to stiffen tissues and cause some of the
deterioration associated with aging.
2,35
For example,
AGEs may help trap low-density cholesterol in arte-
rial walls and thus contribute to atherosclerosis. They
also have been linked to cataract formation, reduced
kidney function, and neurologic disorders such as
Alzheimer disease.
Syndromes of Premature Aging
The syndromes of premature aging, or
progeria
, rep-
resent a range of phenotypes seen in usual aging, but
with much earlier ages of onset and more rapid rates of
progression.
1
Hutchinson-Gilford progeria syndrome is
a rare fatal genetic disorder characterized by acceler-
ated aging in children.
42
The disorder is caused by a
mutation in the
LMNA
gene, which codes for a pre-
cursor of lamin A—a scaffolding protein that lines the
nucleus. The mutant gene leads to abnormal nuclear
structure and altered gene regulation and DNA replica-
tion. Although they are born looking healthy, children
with the disorder begin to display many characteristics
of accelerated aging at around 18 to 24 months of age.
Progeria signs include growth failure, loss of body fat
and hair, aged-looking skin, cataracts, and coronary
artery disease and stroke (Fig. 2-11). Death occurs at
an early age of atherosclerotic heart disease (average
age 13 years).
Other progeroid syndromes include Werner syn-
drome, also known as adult progeria, which does not
have an onset until the late teens, with a life span into
the 40s and 50s.
1
The gene responsible for the disor-
der has been localized to chromosome 8 and appears to
code for an enzyme involved in unwinding DNA, a pro-
cess that is necessary for DNA repair and replication.
FIGURE 2-11.
A 5-year-girl with progeria. (From National
Human Genome Research Institute, National Institutes
of Health.)
SUMMARY CONCEPTS
■■
Cell injury can be caused by a number of agents,
including physical agents, chemicals, biologic
agents, and nutritional factors.
■■
Among the physical agents that generate cell
injury are mechanical forces that produce tissue
trauma, extremes of temperature, and electrical
forces. Ionizing radiation can directly break
chemical bonds, whereas nonionizing radiation
exerts its harmful effects by causing vibration
and rotation of atoms and molecules. Chemical
agents can block enzymatic pathways, cause
coagulation of tissues, or disrupt the osmotic or
ionic balance of the cell. Biologic agents differ
from other injurious agents in that they are able
to replicate and continue to produce injury.
Among the nutritional factors that contribute to
cell injury are excesses and deficiencies of total
energy, as well as individual nutrients.
■■
Injurious agents exert their effects largely through
generation of reactive oxygen species (ROS)
