C h a p t e r 2
Cellular Responses to Stress, Injury, and Aging
45
infection involving a limb. Hyperbaric oxygen therapy
has been used, but clinical data supporting its efficacy
has not been rigorously assessed.
Cellular Aging
Aging is a complex natural process in which there are
physiologic and structural alterations in almost all organ
systems.
1,2,34–38
Even in the absence of disease, beginning
in the fourth decade of life, there is a progressive decline
in muscle strength, cardiac reserve, vital capacity, nerve
conduction time, and glomerular filtration rate. Although
the biologic basis of aging is poorly understood, there is
general consensus that its elucidation should be sought
at the cellular level. Many cell functions decline with
age. Oxidative phosphorylation by the mitochondria is
reduced, as is synthesis of nucleic acids and transcription
factors, cell receptors, and cell proteins.
A number of theories have been proposed to explain
the cause of aging. The main theories are based on sci-
entific observations at the molecular, cellular, organ,
and system levels. In general, these theories can be
divided into either programmed or error theories. The
programmed theories
propose that the changes that
occur with aging are genetically programmed, whereas
the
damage
or
error theories
maintain that the changes
result from an accumulation of random events or envi-
ronmental agents or influences that are associated with
DNA damage.
35–39
Evidence suggests that the process of
aging and longevity is multifaceted, with both genetic
and environmental factors playing a role. In animal
studies, genetics accounted for less than 35% of the
effects of aging, whereas environmental influences
accounted for over 65%.
36
In humans, long life appears
to have a stronger genetic basis, which explains why
centenarians and near centenarians tend to cluster in
families.
40
Replicative Senescence
Replicative senescence implies that cells have a limited
capacity for replication. At the cellular level, Hayflick
and Moorhead observed more than 40 years ago that
cultured human fibroblasts have a limited ability to rep-
licate (approximately 50 population doublings) and then
die.
41
Before achieving this maximum, they slow their
rate of division and manifest identifiable and predictable
morphologic changes characteristic of senescent cells.
One explanation of replicative senescence is related
to the length of the outermost regions of each chro-
mosome, called
telomeres,
that contain short repeat
sequences of DNA bases.
1,2,35
During mitosis, the molec-
ular machinery that replicates DNA cannot copy the
extreme ends of the chromosome. Thus, with each cell
division, a small segment of telomeric DNA is lost. Over
time, it is theorized that as the telomeres become pro-
gressively shorter, the DNA at the ends of the chromo-
somes cannot be protected, resulting in inhibition of cell
replication. The lengths of the telomeres are normally
maintained by an enzyme called
telomerase
, which is
present in low levels in stem cells, but is usually absent
in most adult cells. Therefore, as cells age, their telo-
meres become shorter and they lose their ability to rep-
licate and replace damaged or senescent cells. Moreover,
oxidative stress induces single-stranded damage to
telomeric DNA, and this defect cannot be repaired in
telomeres. In theory, such mechanisms could also pro-
vide a safeguard against uncontrolled cell proliferation
of abnormal cells. It has been shown that telomerase is
reactivated and telomeres are not shortened in immortal
cancer cells, suggesting that telomere elongation may be
important in tumor formation.
Genetic Influences
There is ongoing interest in genes that determine longev-
ity. Longevity genes have been found in fruit flies and
roundworms, organisms that have attracted consider-
able attention from scientists because of their short life
span and their well-characterized genomes. One exam-
ple is the mutation of the
Indy
(I’m Not Dead Yet) gene
in the fruit fly, which can double the length of its life.
35
Scientists have also found genetic clues to the aging pro-
cess in the tiny roundworm,
Caenorhabditis elegans
. By
altering one of its
daf-2
genes, which codes for a pro-
tein that is similar to insulin and insulin growth factor
(IGF)-1 receptors found in humans, researchers can
substantially extend the longevity of these worms.
1,35
Pathways related to the
daf-2
gene, for example, may be
responsible for relationships between caloric restriction
and prolonged life span in rodents and other animals.
Whether human counterparts of genes found in these
laboratory organisms exist and whether they have simi-
lar effects remain an ongoing area of inquiry.
However, many genes that are associated with
human life span are not intrinsically “longevity genes,”
per se. For example, because mutations in the tumor-
suppressor genes BRAC1 and BRAC2 increase mortal-
ity associated with breast and ovarian cancer, they are
rare among long-lived women.
40
Conversely, genes that
reduce the risk of atherosclerosis may be more common
in long-lived individuals. Genetic studies of biologic
aging have also explored the involvement of variants of
genes encoding apolipoproteins (proteins that bind lip-
ids for transport in the circulatory system), in particular,
the APOE gene encoding the synthesis of apolipoprotein
E. The presence of the variant apoE4 is associated with
an increased incidence of cardiovascular and neurode-
generative diseases, thereby shortening life span.
37,41
Accumulation of Environmental and
Genetic Damage
In addition to the importance of timing and a genetic
clock, cellular life span may be determined by a balance
between cellular damage resulting frommetabolic events
occurring within the cell and molecular responses that
repair the damage. The damage eventually accumulates
to a level sufficient to result in the physiologic decline
