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132 Part III: Epochal Hematology Chapter 9: Hematology in Older Persons 133

acquisition of age-related diseases (including cancer) and a reduction There are a multitude of oncogenic stimuli that may result in
in the rate of achieving certain established biomarkers of aging (i.e., a either cancerous transformation or cellular senescence. 105,106 Epigenetic
retardation in primary aging). The critical questions remain: What is the changes within chromatin, histones, or nucleic acids may be caused
mechanism of the effect of dietary restriction, and will it be applicable to by pharmacologic agents or altered expression of proteins. 107–109 Such
higher species? With regard to the latter, there are now comprehensive changes can alter the expression of protooncogenes or tumor-suppres-
and interactive studies within the United States in which dietary restric- sor genes and are a frequent occurrence among malignant tumors. Thus
tion is being examined in nonhuman primates 86,87 and human studies the senescence response aborts the uncontrolled proliferative response
are also underway. 88,89 Although it appears that the calorie restricted an assortment of potentially oncogenic stimuli.
monkeys in these studies are assuming a more youthful phenotype in Although diverse stimuli can induce a senescence response, they
a variety of physiologic measures, 86,90,91 it remains too early to predict appear to converge on one or both of the two pathways that establish
whether maximum survival will be affected. and maintain the senescence growth arrest. These pathways are gov-
erned by the gatekeeper tumor-suppressor proteins p53 and pRB. 104,110,111
CELLULAR SENESCENCE AND ORGANISMAL Furthermore, the senescence response to dysfunctional telomeres
requires the integrity of the p53 pathway.
112,113
Overexpression of the
AGING RAS gene may also trigger a p53-dependent damage response by pro-
After a finite number of divisions, normal somatic cells invariably enter ducing high levels of reactive oxygen species. 113–115 However, oncogenic
a state of irreversibly arrested growth, a process termed replicative RAS can also induce p16, an activator of the pRB pathways, which pro-
senescence. In fact, it has been proposed that escape from the regula- vides a second barrier to the proliferation of potentially oncogenic cells.
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tors of senescence is what oncologists term malignant transformation. There is an emerging consensus that senescence occurs through one
However, the role of replicative senescence as an explanation of organ- pathway or the other, with the p53 pathway mediating senescence pri-
ismal aging remains the subject of vigorous debate (for review, see refer- marily as a result of telomere dysfunction and DNA damage and p16/
ences 93 and 94). The controversy relates, in part, to the fact that certain pRB pathway–mediating senescence primarily as a result of oncogenes,
organisms (e.g., Drosophila, Cunninghamella elegans) undergo an aging chromatin disruption, and various stresses.
process, yet all of their adult cells are postreplicative. A more speculative, but potentially important consequence of cellu-
116
What is clear is that the loss of proliferative capacity of human cells lar senescence may be its impact on stem cells. Embryonic stem cells,
in culture is intrinsic to the cells and not dependent on environmental whether human or rodent, express a high level of telomerase and thus are
factors or even culture conditions. Unless transformation occurs, cells considered resistant to replicative senescence. 117,118 However, mammalian
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age with each successive division. The number of divisions turns out to adult stem cells or progenitor cells do not proliferate indefinitely. 119–122 The
be more important than the actual amount of time passed. Thus, cells ability of stem cells to undergo senescence and apoptosis is likely to be an
held in a quiescent state for months, when allowed back into a prolif- important mechanism for preventing cancer. 123,124
erative environment, will continue approximately the same number of
divisions as those that were allowed to proliferate without a quiescent AGING AND HEMATOPOIESIS
period. The question remains whether this in vitro phenomenon is
95
95
relevant to animal aging. Although when various species are compared, rep- Aging is a universal phenomenon that affects all normal cells, tissues,
licative potential is directly and significantly related to life span, within an organ systems, and organisms. Accordingly, the marrow undergoes
96
organism there is great variability in proliferative capacity from tissue to tis- changes with age. Age-related hematologic changes are reflected by a
sue and organ to organ. As such, age-associated changes in the marrow or gut decline in marrow cellularity, an increased risk of clonal myeloid neo-
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might relate to replicative senescence, whereas in muscle or brain other pro- plams and anemia, 17,126–130 and a decline in adaptive immunity. 131–134
cesses most certainly are involved. But, added to this heterogeneity within an
individual, is that fact that certain commonly employed models of aging (e.g., MARROW: ANATOMIC CHANGES
Drosophila, C. elegans) undergo an aging process despite a long held belief The percentage of marrow space occupied by the hematopoietic tissue
that all of their adult cells were post replicative. 94,97,98 However, this notion declines from 90 percent at birth to a level of approximately 50 percent
has been countered by the demonstration of multipotent intestinal stem cells at age 30 years and 30 percent at age 70 years. 135,136 A similar change
within the midgut near the intestinal basement membrane of Drosophila. occurs in the thymus, where involution begins at an earlier age and is
99
Unlike intestinal stem cells in vertebrates that interact with stromal cells reflected anatomically by a reduction in lymphoid mass with an increase
within a niche, analogous cells within Drosophila reside on the surface of the in fat and functionally by a steady decrease in the production of naïve
137
basement membrane and interact directly with daughter cells. Nevertheless, T cells. 80,138 Fat infiltration into the marrow and thymus results in a
the presence of such cells has rekindled an interest in Drosophila as a model diminished volume of hematopoietic tissue.
for stem cell biology, cancer, and whole-animal aging. 100,101 Although age-related change in the marrow is well described, the exact
mechanisms that regulate these changes remains speculative. For exam-
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CELLULAR SENESCENCE AND CANCER ple, it remains unclear whether the age-associated expansion of marrow fat
A feature of cellular senescence is diminished proliferative capacity. is a cause or an effect of aging and whether the changes seen in marrow and
histologically similar changes within the thymus are intrinsically related.
In fact, it is now understood that genes considered tumor suppressors Because of the intricate association of hematologic and immune functions
(e.g., p53, RB [retinoblastoma gene]) prevent cancer by inducing pro- and these common histologic patterns of change with age, both changes in
grammed cell death (apoptosis), particularly in cells at risk for neoplas- blood and innate immunity are discussed below in the sections on Blood
tic transformation. Alternatively, they can prevent potential cancer cells Cell Changes with Age and Aging and Immunity.
from proliferating by inducing permanent withdrawal from the cell
cycle (cellular senescence). Although little is known about how cells
choose between apoptotic and senescence responses, both are crucial MARROW: STEM CELLS
for suppressing cancer 102,103 and both are highly relevant to functional The ontogeny of hematopoietic stem cells is the focus of much atten-
decline and longevity. 104 tion. 140,141 In fetal development the manufacture of blood cells occurs

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