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G Living and Dying For Sex D M A Fill box to show platform used: PC Macintosh 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 Alt. Contact (Last, First): 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 Email: ABSTRACT Email: Voyager Pharmaceutical Corporation, Raleigh, N.C. and *Department of Medicine, University of Wisconsin, Madison, WI. On your proof: check one box & return to ITAC: OK Changes marked on proof; a disk with corrections is being submitted