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INTRODUCTION 3

through which hidden process flows to observable outcome. In this
book, I address the following kinds of questions, which illustrate the
link between disease processes and age-related outcomes.
Faulty DNA repair accelerates disease onset—that is easy enough to
guess—but does poor repair accelerate disease a little or a lot, early in
life or late in life, in some tissues but not in others?
Carcinogenic chemicals shift incidence to earlier ages: one may rea-
sonably measure whether a particular dosage is carcinogenic by whether
it causes a shift in age-specific incidence, and measure potency by the
degree of shift in the age-incidence curve. Why do some carcinogens
cause a greater increase in disease if applied early in life, whereas other
carcinogens cause a greater increase if applied late in life? Why do many
cancers accelerate rapidly with increasing time of carcinogenic expo-
sure, but accelerate more slowly with increasing dosage of exposure?
What processes of disease progression do the chemicals affect, and how
do changes in those biochemical aspects of cells and tissues translate
into disease progression?
Inherited mutations sometimes abrogate key processes of cell cycle
control or DNA repair, leading to a strong predisposition for cancer.
Why do such mutations shift incidence to earlier ages, but reduce the
rate at which cancer increases (accelerates) with age?
Why do the incidences of most diseases, including cancer, accelerate
more slowly later in life? What cellular, physiological, and genetic pro-
cesses of disease progression inevitably cause the curves of death to
flatten in old age?
Inherited mutations shift incidence to earlier ages. How do the par-
ticular changes in age-specific incidence caused by a mutation affect the
frequency of that mutation in the population?
How do patterns of cell division, tissue organization, and tissue re-
newal via stem cells affect the accumulation of somatic mutations in cell
lineages? How do the rates of cell lineage evolution affect disease pro-
gression? How do alternative types of heritable cellular changes, such
as DNA methylation and histone modification, affect progression? How
can one measure cell lineage evolution within individuals?
I will not answer all of these questions, but I will provide a compre-
hensive framework within which to study these problems.
Above all, this book is about biological reliability and biological fail-
ure. I present a full, largely novel development of reliability theory that