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130 Part III: Epochal Hematology Chapter 9: Hematology in Older Persons 131

with advancing age, but these are considered markers of an acquired replicative limits of mammalian cells and it has been observed that “life
humoral immune dysregulation, and with regard to autoantibody, not span” is related to silencing large chromosomal regions. Mutations in
of clinical importance. In contrast, essential monoclonal gammopathy, these silencing genes lead to increased longevity. 48
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a clonal B lymphocyte expansion that increases in frequency with age Thus, if there are certain genes that regulate normal aging, or at least
and that stabilizes at a clone size that does not impair normal immuno- are associated with the development of an aged phenotype, it stands to
globulin synthesis or inhibit hematopoiesis, does have a probability of reason that acquired mutations of those genes might influence the rate
undergoing clonal evolution to a B-cell malignancy, such as myeloma, of aging. Over the years several theories have been proposed that relate
lymphoma, or monoclonal light-chain amyloidosis at a rate of 1 percent to this supposition. In general, they hypothesize a random or stochastic
per year (Chap. 106). 40 accumulation of damage, either to DNA or protein that leads eventu-
ally to dysfunctional cells, cell death and subsequent organ dysfunction,
THEORIES OF AGING and ultimately death. Prominent among these is the somatic mutation
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Providing a rational, unifying explanation for the aging process has been theory, which predicts that genetic damage from background radiation,
for example, accumulates and produces mutations that ultimately result
the subject of a great number of theoretical expositions. Yet, no single pro- in functional decline. A variety of refinements have been suggested to
posal suffices to account for the complexities observed (Table 9–1). this theory, invoking the importance of mutational interactions, trans-
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posable elements, and changes in DNA methylation status. 52
Genetic Effects A related hypothesis is Burnet’s intrinsic mutagenesis theory,
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That genetic controls are involved seems obvious when one considers which proposes that spontaneous or endogenous mutations occur at
that lifespan is highly species-specific. For example, mice generally live different rates in different species and that this accounts for the vari-
approximately 30 months and humans approximately 90 years. How- ability observed in life span. Closely related to this notion is the DNA
ever, the aging phenomenon is not necessarily a direct consequence of repair theory. Initially, there was great excitement about this idea as it
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primary DNA sequence. For example, mice and bats have 0.25 percent was found that long-lived animals had demonstrably more active DNA
difference in their primary DNA sequence, but bats live for 25 years, repair mechanisms than shorter-lived species. However, longitudinal
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10 times longer than mice. Thus, regulation of gene expression seems studies within a species have not revealed a consistent decline in repair
likely to be the major source of species longevity differences. mechanisms with age. This, of course, does not rule out the possibility
Progeria Syndromes Gerontologists have long been intrigued by that repair of certain specific and critical DNA lesions is altered with
the concept of accelerated aging and by examining those rare individ- advancing age. We now understand that there are multiple DNA repair
uals who are so affected. From work with invertebrate models a num- mechanisms, including base excision repair, transcription-coupled
ber of genes have been identified that associate with longevity. Yet, the repair, and even mitochondrial DNA repair mechanisms. Disorders
identification and functional analysis of analogous genes in humans involving one or a subset of repair mechanisms could lead to accumula-
remains elusive. With regard to genetic examples of accelerated aging, tion of DNA damage and dysfunction.
two syndromes have been well characterized: Hutchison-Guilford In yet another intrinsic/stochastic model, Orgel proposed the
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syndrome (early-onset progeria) and Werner syndrome (adult-onset error catastrophe theory in which he suggested that random errors
progeria). 41,42 Although neither these nor other progeria syndromes in protein synthesis occur and when the proteins involved are those
manifest a complete phenotype of advanced age, the identification of responsible for DNA or RNA synthesis, there is resultant DNA damage
the genes responsible for these particular syndromes is beginning to pay and the consequences thereof to daughter cells. Although this model has
dividends by providing clues to the molecular mechanisms involved in appeal, there has been no reported evidence for impaired or inaccurate
the aging process. For example, Werner syndrome is now defined by protein synthesis machinery with advancing age. However, a candidate
mutations in a single gene on chromosome 8 that encodes a protein protein that may eventually be shown to be so affected is telomerase.
containing a helicase-like domain. 43,44 The activity of the Werner protein This critical enzyme is necessary for maintaining telomere length and
helps to maintain telomere structure and homology-dependent recom- cell replicative potential. In vitro cellular senescence is associated with
bination. Similarly, a mutation in the lamin A (LMNA) gene localized diminished telomerase activity, but whether this relates to aging of the
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to chromosome 1 has been causally related to the Hutchison-Guilford organism as a whole remains controversial. 57
syndrome. The product of the mutated LMNA gene (termed progerin)
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accumulates, producing a variety of nuclear distortions of which telo- Posttranslational Effects
mere dysfunction and associated replicative senescence are notable. 47 Evidence that exogenous factors are involved in the acquisition of
Examination of aging in yeast has also been informative with regard age-associated damage to DNA and protein is derived from a number of
to the genetic controls of aging. These single-cell organisms follow the observations, many of which are circumstantial or correlative, but none-
theless provocative. It now appears that the accumulation of abnormal
TABLE 9–1. Theories of Aging protein within senescent cells, as predicted by the error catastrophe
theory, actually reflects posttranslational events, such as oxidation or
Intrinsic-stochastic Somatic mutation 50,51 glycation, and resultant crosslinking. There is theoretic appeal to the
Intrinsic mutagenesis 55 concept that key proteins, such as collagen or other extracellular matrix
Impaired DNA repair 56 proteins, and DNA become dysfunctional with age as a consequence of
Error catastrophe 58 the impairment produced by these crosslinks. 58–60
Glycation One mechanism producing crosslinks is called glyca-
Extrinsic-stochastic Ionizing radiation 50,51,53,58 tion, the nonenzymatic reaction of glucose with the amino groups of
Free radical 63,64 proteins. Presumably, glycation would occur more readily in the pres-
Genetically determined Neuroendocrine 298 ence of higher serum levels of glucose, and, thus, this theory fits well
Immune 77 with the observed, age-associated dysregulation of glucose metabolism
and prevalent hyperglycemia in geriatric populations. Of course, these

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