Cancer Turnover at Old Age

Cancer Turnover at Old Age
A thesis presented
by
Francesco Pompei
to
The Division of Engineering and Applied Sciences
In partial fulfillment of the requirements
for the degree of
Doctor of Philosophy
in the subject of
Engineering Sciences
Harvard University
Cambridge, Massachusetts
May, 2002

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2002 by Francesco Pompei
All rights reserved

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Thesis advisor Author
Richard Wilson Francesco Pompei
Cancer Turnover at Old Age
Abstract
It has been commonly assumed for a half century that if a person lives long
enough, he or she will eventually develop cancer. Cancer age-specific incidence data
does not support that assumption, showing instead that incidence flattens at about age 80
and declines thereafter, approaching zero where there is data at about age 100. Previous
cancer models of long standing have been unable to explain the turnover in incidence
beyond age 80, and investigators have tended to ascribe under-reporting of cancers, or
that the oldest persons are somehow not susceptible, as explanations for the data. This
work presents the first model of cancer incidence incorporating the biological process of
cellular replicative senescence. The model provides good fits to human cancer age
distribution data for 40 organ sites from databases from the U.S., Holland, and Hong
Kong. Newly developed mice data from a 24,000 mice study has also been found to be
well fit by the model, confirming that cancers peak at about 80% of lifespan and actually
reach zero for the oldest mice. The model, mathematically a form of Beta function, is
derived by adding to standard multi-stage or clonal expansion models the observation
that in vitro data show aging cells lose their proliferative ability with age. Since
senescent cells cannot produce cancer, the pool of cells available to produce cancer
declines, thus lowering the incidence, reaching zero when all cells are senescent.
Further tests of the model performed against data on interventions that might alter

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senescence shows agreement in cancer rate and longevity changes, and also suggests that
longevity might be increased when cancers can be treated. The results also suggest that
studies of cancer associations with various dietary or environmental factors should
include the effect on longevity, since both results depend on senescence.
The most desirable intervention both reduces cancer by reducing cellular damage
causes of carcinogenesis, and reduces cellular damage causes of senescence, thus
achieving both cancer reduction and longer life. This combination is thus far known
only for dietary restriction, but others might be discovered from further research.

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Acknowledgements
This thesis, along with the Ph.D. program I was fortunate to be able to enter and
complete, created for me a higher sense of achievement and personal satisfaction than I
could possibly have anticipated. Coming so many years after being away from
academics since earning B.S. and M.S. degrees at MIT, made it all the more satisfying
both intellectually and emotionally. This was especially so, since I had an opportunity
to learn a new field and make an original contribution to the important study of cancer.
First and foremost I would like to thank my thesis advisor Professor Richard
Wilson for first introducing me to this field through his course, then accepting me as his
student and patiently providing guidance and continuous challenge to do my best work,
and finally to introduce me to the academic community to which this work would
contribute. The many hours over the past 7 years we have spent together on the research
leading to this thesis have been among most interesting and stimulating, as well as
instructive, that I have experienced.
I would like to thank the other members of my thesis committee, Professors Peter
Rogers, Richard Kronauer, and Dr. Lorenz Rhomberg: Professor Rogers for his steady
guidance and encouragement on my whole Ph.D. program, and the collegial friendship
we have had since our first meeting 10 years ago; Professor Kronauer for his valuable
guidance in applying the tools of engineering to the medical sciences; and Dr. Rhomberg
for his enthusiasm and guidance, particularly in the biological aspects of the research.