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CHAPTER 9 dysregulated inflammatory pathways and coagulation. In balance, advancing

HEMATOLOGY IN OLDER age is associated with a procoagulant profile that may be of clinical impor-
tance in the presence of underlying atherosclerotic vascular disease.
PERSONS

William B. Ershler, Andrew S. Artz, and Bindu Kanapuru A PRIMER ON AGING

The world’s population is aging at an unprecedented rate and the impli-
1–4
SUMMARY cations for health care delivery are profound. Over the next several
decades, the percentage of the population older than age 65 years will
nearly double. In anticipation, an increased research effort is being
5
This chapter presents a current appraisal of our understanding of aging fol- made to better understand the basic biology of aging and the mecha-
lowed by a more detailed description of age-associated changes in hemato- nisms whereby individuals become susceptible to disease. 6,7
poiesis and their clinical consequences. Those who are older than the age of A central dogma of gerontology is that aging is not a disease. Yet,
75 years comprise a rapidly growing segment of the population. Marrow, like intrinsic biologic aging is the major risk factor for virtually all major
other organs, undergoes characteristic changes with advancing age, and many diseases of developed societies, including cancer, diabetes, atheroscle-
of these changes are evident by standard examination. For example, within the rotic cardiovascular and cerebrovascular disease, diabetes, neurode-
marrow space, hematopoietic cells occupy approximately one-half the volume generative diseases (e.g., Alzheimer and Parkinson), osteoporosis and
at mid-life, with adipose tissue making up the difference. Yet, in the absence infection. Examination of the mechanisms by which biologic aging
of disease, blood counts are generally maintained within a range established contributes to the pathogenesis of these diseases has now become
as normal for younger individuals. This is possible because hematopoietic stem recognized in the mainstream of scientific inquiry over a broad range
7
cells increase in number with age and are of sufficient functional capacity to of disciplines. However, from a biogerontologist’s perspective, there
remain certain features of aging that transcend the more discipline-
respond to homeostatic signals. Older people are more likely to have chronic focused investigations.
diseases that may produce additional stress on marrow reserve. Anemia, for One of these common features of aging is heterogeneity. For
example, is present in just over 10 percent of community-dwelling individu- example, for any measureable variable, the range of values among nor-
als older than age 65 years; for those residing in nursing homes, the preva- mal older individuals is much wider than the range of normal among
lence is closer to 50 percent. One distinction between anemias in older people younger individuals. This variation is particularly relevant for hema-
8,9
compared with younger people is that for approximately one-third of older tologists consulted to examine older, but otherwise healthy, individuals
anemic patients, a specific cause for the anemia cannot be determined. This with laboratory values outside the “normal range.”
“unexplained anemia” is likely the result of multiple factors, including inappro- Although functional declines that accompany normal aging have
priately low erythropoietin response, inflammatory cytokines, androgen defi- been well characterized, 10,11 in general these are not of sufficient mag-
ciency, and, in some persons, incipient myelodysplasia. Platelet and neutrophil nitude to account for symptoms or be mistaken for disease. For exam-
12,13
changes with age have been incompletely characterized but are likely to be ple, that kidney function declines with age is well recognized, and,
in fact, has proven to be a useful biologic marker of aging. Yet, clin-
subtle and of little clinical consequence. There is a well-characterized, age- ical consequences of this change in renal function, in the absence of
associated involution of the thymus gland that precedes the histologic changes a disease or the exposure to an exogenous nephrotoxic agent, do not
within the marrow, and marrow-derived T- and B-cell precursors are affected. occur commonly. Similarly, the marrow changes with age. Marrow
Older people have fewer naïve, reactive T cells and an increase in relatively stem cells increase in number and proliferative capacity, yet the in vitro
inert memory T cells. Thus, the capacity to react to new antigenic challenges is proliferative potential of progenitor cells is less. 14–16 Although clinically
reduced and there is an increased susceptibility to certain infections and vac- significant cytopenias do not occur in the absence of disease, mild to
cines. Also evident are deficient regulatory functions, which may explain the moderate anemia that has not been fully characterized occurs with
observed increase in autoantibody, paraproteins, and inflammatory cytokines increasing frequency, especially in the frail elderly. 17–20 Furthermore, in
in those of advanced age. In the absence of disease, however, these alterations frail individuals even a mild reduction in hemoglobin level is associated
19,21,22
are of little consequence. In the presence of chronic debilitating disease, they with untoward clinical outcomes. 23–25
Certain immune functions decrease with age,
but these may be
are likely to become more pronounced and as such, contribute to an exagger- of only marginal clinical significance. For example, whether the labora-
ated decline in overall function. Similar conclusions can be drawn regarding tory-observed declines in immune function contribute to a heightened
susceptibility to infection is a subject of debate, but data support an
association of age-associated qualitative change in lymphocyte function
and susceptibility to reactivation of tuberculosis 26,27 or herpes zoster 28,29
and diminished response to influenza vaccine. 30–33 There is compelling
evidence that a profound decline in immunity is causally related to cer-
34
Acronyms and Abbreviations: EPESE, Established Populations for the Epidemi- tain malignancies, but there remains debate over whether the more
ological Study of the Elderly; HSCs, hematopoietic stem cells; IADL, independent modest decline associated with normal aging is sufficient to account for
activities of daily living; IL, interleukin; NHANES III, National Health and Nutrition the observed increased rate of cancer in the elderly. 35,36 In fact, there
37
Examination Survey III; PAI-1, plasminogen activating inhibitor-I; TNF, tumor necrosis is some evidence that cancer incidence is even lower in frail elderly,
factor; UA, unexplained anemia; WHO, World Health Organization. a population known to be functionally immunodeficient. Similarly,
38
development of autoantibodies appear with increasing frequency

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