Dr. Atwood has diverse research interests based around the "Reproductive-Cell Cycle Theory of Aging" (Bowen and Atwood, 2004; Atwood and Bowen, 2011). This theory introduces a new definition of aging that has facilitated the conceptualization of why and how we age at the evolutionary, physiological and molecular levels. The basic premise behind the research is that hormones that regulate reproduction in mammals 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. In essence, this theory proposes that reproductive hormones regulate our aging by modulating the life cycle of cells. Importantly, the theory is not simply a philosophical work; it has immediate and practical implications for extending longevity and delaying/preventing age-related diseases.
Below are some of the different research themes ongoing in the laboratory.
- Endocrine Dyscrasia and Alzheimer’s Disease. The aging theory evolved from research conducted on how the age-related dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis following menopause and during andropause promotes neurodegeneration. From these studies we found that one member of this axis, the gonadotropin luteinizing hormone (LH) which becomes elevated in serum with aging and which accumulates in pyramidal neurons in the AD brain (Bowen et al., 2002), alters amyloid-β precursor (AβPP) protein processing and increases amyloid-ß generation (Bowen et al., 2004), the major component of amyloid plaques that deposit in the brains of individuals with AD. Our and other research has confirmed this finding in a transgenic mouse model of AD, and additionally demonstrated that GnRH analogues can stabilize cognition (Casadesus et al., 2006; Lin et al., 2010). Moreover, neurons in the senescent brain develop other phenotypic characteristics of dividing/transformed cells, such as the expression of LH and osteopontin (Wilson et al., 2006; Wung et al., 2007). We have determined that the endocrine dyscrasia associated with aging also decreases the selective permeability of the blood-brain barrier, which may be a precursor to cerebrovascular diseases including stroke (Wilson et al., 2008). From these basic research observations and insights came the basis for the aging theory. Aside from my own research findings, strong support for the theory was recently published by another group in which they show that high levels of a second gonadotropin, follicle-stimulating hormone (FSH), promote osteoporosis, independent of low estrogen levels (Sun et al., 2006), i.e. FSH, and not estrogens are primarily responsible for osteoporosis. These 2 independent lines of evidence (LH/amyloid production and FSH/osteoclast proliferation) suggest that the surge in gonadotropins following menopause and with andropause is the driving force behind senescent changes seen in aging humans. This research is providing a major paradigm shift in our understanding of age-related diseases.
- Hormonal Regulation of Aging and Reproduction. A second line of research is aimed at defining the exact mechanisms by which reproduction and reproductive hormones regulate aging. In this respect, we recently identified a GnRH receptor orthologue in Caenorhabditis elegans, a model of longevity studies (Vadakkadath Meethal et al., 2006). This is the first report of an evolutionarily conserved GnRH receptor in C. elegans, a central component of the endocrine system that orchestrates reproduction. The identification of an evolutionarily conserved GnRH receptor opens the way to using C. elegans as a model system to study reproductive endocrinology and it’s affect on longevity.
- Autocrine/Paracrine Mechanisms of LH and Neurosteroid Production in the Brain. We have identified in the brain a ‘mini-HPG’ axis that regulates the synthesis of neurosteroids (Wilson et al., 2006; Liu et al., 2008; Vadakkadath Meethal et al., 2009). The identification of paracrine/autocrine mechanisms in the brain, linked with endocrine mechanisms, for the control of sex hormone synthesis and signaling is important for our understanding of the neuroendocrinology of aging and age-related diseases.
- Amyloid Biology. A fourth line of research in my laboratory developed during the last decade has resulted in important discoveries regarding the neurochemical factors that promote the deposition of the amyloid-β protein. This work includes identification of the copper binding sites of amyloid-β both in vivo (Dong et al., 2003) and how this metal ion interaction leads to the oxidative modification of the protein (Atwood et al., 2004). In related studies, we have shown the metal ion chelator/antioxidant, alpha-lipoic acid, stabilizes cognition in a mouse model of AD (Atwood et al., unpublished data), and in collaborative studies (Drs. Veurink and Martins) have demonstrated that the use of combination antioxidant therapies can reverse neurodegeneration in an animal model of protein deposition (Veurink et al., 2002), suggesting a novel antioxidant therapy for AD. Another line of research related to the function of amyloid focuses on the long-standing and very interesting question of whether amyloid-β is neurotoxic or neurotrophic. Since joining UW, we have demonstrated that amyloid-β is both; neurotrophic to undifferentiated neurons, but toxic to differentiated neurons via a Cdk5 dependent tau phosphorylation pathway (Liu et al., 2004). In addition, we have found that amyloid-β production is increased only when neurons commit to death (Verdile et al., in preparation). Further, the physiochemical properties of amyloid-β indicate it to be a novel vascular sealant that can seal vascular lesions without compromising blood supply to the brain (Atwood et al., 2002a, b; 2003). Thus, amyloid-β may have as a normal physiological function the repair and growth of neurons during times of neuronal restructuring, i.e. during development, following injury and during senescence.
- Hormonal Regulation of Embryogenesis. Using human embryonic stem cells as a model system for early human embryonic development, we have demonstrated that the pregnancy hormones progesterone and hCG have obligatory developmental functions during embryogenesis (Gallego et al., 2008, 2010). hCG signals hESC to divide and differentiate into an embryoid body, and subsequently into a neuroectodermal rosette. Differentiation of hESC into neural precursor cells is mediated by the upregulation of steroidogenesis by hCG signaling through the luteinizing hormone/hCG receptor. Although hCG and progestagens are often considered primarily reproductive hormones with maternal influences, it is now clear that paracrine/juxtacrine signaling of hCG (and opioids) for mobilization of cholesterol for progesterone production by the epiblast/ synctiotrophoblast following conception is essential for human blastulation and neurulation. This paracrine/juxtacrine signaling by extraembryonic tissues is the commencement of trophic support by placental tissues in the growth and development of the human embryo.