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A Theory of Aging Based on the Modulation of Cell Cycle Signaling by Reproductive Hormones
Richard L. Bowen and Craig S. Atwood*
HPG Hormones Drive Cell Proliferation and Differentiation
A mechanistic understanding of aging has yet to be described; this
paper puts forth a new theory that has the potential to explain aging in
all sexually reproductive life forms. The theory also puts forth a new
definition of aging - any change in an organism over time. This definition
includes not only the changes associated with the loss of function (i.e.
senescence, the commonly accepted definition of aging), but also the
changes associated with the gain of function (growth and development).
Using this definition, the rate of aging would be synonymous with the
rate of change. The rate of change/aging is most rapid during the fetal
period when organisms develop from a single cell at conception to a
multicellular organism at birth. Therefore, “fetal aging” would be
determined by factors regulating the rate of mitogenesis, differentiation,
and cell death. We suggest these factors also are responsible for
regulating aging throughout life. Thus, whatever controls mitogenesis
and differentiation must also control aging. Since life-extending
modalities consistently affect reproduction, and reproductive hormones
are known to regulate mitogenesis and differentiation, we propose that
aging is primarily regulated by the hormones that control reproduction
(hence, the Reproductive-Cell Cycle Theory of Aging). In mammals,
reproduction is controlled by hypothalamic-pituitary-gonadal (HPG) axis
hormones. Longevity inducing interventions, including caloric
restriction, decrease fertility by suppressing HPG axis hormones and
HPG axis hormones are known to affect signaling through the welldocumented longevity regulating GH/IGF-1/PI3K/Akt/forkhead pathway.
This is exemplified by genetic alterations in C. elegans where
homologues of the HPG axis pathways, as well as the daf-2 and daf-9
pathways, all converge on daf-16, the homologue of human Forkhead
that functions in the regulation of cell cycle events.
 LH (and its fetal counterpart hCG), FSH and GnRH drive
proliferation in many tissues (El-Hefnawy and Zeleznik, 2001)
LH (adult female)
LH (male and female)
LH (adult male)
mitogenicity index
Ruby Throated
Hummingbird
Cold exposed rats live slightly longer (Holloszy and Smith,
1986) than controls despite evidence that cold exposure in
rats significantly increases oxidative stress (Kaushik and
Kaur, 2003).
MDA Content [mol/mg protein]
Naked Mole Rat
2.5
% Survival
Box Turtle
Controls
Cold Exposure
100
2.0
1.5
40
1.0
Controls
Cold Exposure
20
GestationInfancy Childhood Puberty Adult-reproductive
period
Senescence
The Cost of Reproduction
Longevity is inversely correlated with reproduction (Williams, 1966) i.e.
animals that produce few offspring live longer (human) than those that
produce many (mouse). Hence, the “cost of reproduction”.
Reproductive Friendly vs Reproductive Hostile Environment
The hypothalamus acts as a sensor of the environment, receiving
and processing information,
to appropriately
regulate
reproductive function.
Metabolic and Reproductive Cost of Predator Avoidance
 We propose that some predation avoidance strategies require
increased energy expenditure which the animal perceives as a
hostile reproductive environment.
 This chronic hostile environment (caloric restriction) decreases
fertility by suppressing reproductive-cell cycle signaling factors.
This preserves fertility and slows aging – awaiting a more friendly
environment.
 However predator avoidance strategies that are not associated
with an increased metabolic cost (hostile reproductive
environment) are not associated with increased longevity.
Flying Fish
34 cm
0
Food
Deprived
Cold
Exercise
Estrous Cycle



GnRH



Lordosis



1
2 3 4 5 6
Lifespan (years)
Poison Dart Frog
7
Conversely, in an environment of limited food resources, of high stress
or of non-optimal temperature (cold or hot), the HPG axis is
downregulated to preserve reproductive resources for a sunny day.
24
28
32
36
40
44
Age (months)
0
Brain Heart Kidney Liver Small
Intestine
SUMMARY
The Reproductive-Cell Cycle Theory of Aging is able to
explain:
 Why and how aging occurs in all sexually reproductive life
forms including plants and unicellular organisms.
 The simultaneous regulation of the rate of aging and
reproduction.
 How differing rates of reproduction between species is
associated with differences in their lifespan.
 Why fasting extends longevity even though overall caloric
intake is unchanged.
 We
Hamilton’s Frog
5 cm
0
5
10
15
20
Lifespan (years)
THERAPEUTIC IMPLICATIONS
8
3-4 cm
Reviewed in
Wade et al., 1996
20
 The apparent paradox that size is directly proportional to
lifespan and inversely proportional to fertility between
species but vice versa within a species.
30 cm
Response
16
 Two phenomena that are closely related to species lifespan
- the rate of growth and development and the ultimate size of
the animal.
Atlantic Herring
For example in an environment with plentiful food, low stress and
moderate temperature, HPG axis hormones signal for reproduction.
0.5
0
Dept:
5 years, 10 cm, 3 grams,
Flying
40 years, 16 cm, 60 grams
Carrying a Shell
28 years, 13 cm, 750 grams
Digging
Phone:
60
Phone:
80
25
propose that dysregulation of the HPG axis following
menopause and during andropause drives senescence via altered
cell cycle signaling (dyosis).
 The
age-related
hormonal
mileau
associated
with
andropause/menopause is similar to that of the fetus. During fetal
life this is likely important for normal brain growth and
development. However, when adult terminally differentiated
neurons are exposed to this environment, it may result in the
aberrant re-entry of neurons into the cell cycle.
 This dyotic signaling leads to the biochemical, neuropathological
and cognitive changes characteristic of Alzheimer’s disease.
 Clinical trials using anti-gonadotropins are currently underway for
the treatment of mild to moderate Alzheimer’s disease.
Printed for Research ShowCASE by Instructional Technology & Academic Computing (ITAC), 368-3777
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HPG AXIS
fetal hCG
Birds, turtles and the naked mole rat display exceptional longevity
for their size. Based on this it has been proposed that avoidance of
predation selects for a slower aging phenotype.
Shortcomings in the Free Radical Theory of Aging
Name (Last, First):
In summary, we propose that the hormones that regulate reproduction
act in an antagonistic pleiotrophic manner to control aging via cell cycle
signaling; promoting growth and development early in life in order to
achieve reproduction, but later in life, in a futile attempt to maintain
reproduction, become dysregulated and drive senescence.
 Activins are primarily responsible for differentiative processes
during development and in adult life (Jones et al., 2002)
Working for Food Decreases Reproduction and Extends
Longevity
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ABSTRACT
Email:
Voyager Pharmaceutical Corporation, Raleigh, N.C. and *Department of Medicine, University of Wisconsin, Madison, WI.
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