Dr. Craig Atwood is an Associate Professor of Medicine at the University of Wisconsin and an investigator with the Geriatric Research, Education and Clinical Center at the William S. Middleton memorial Veterans Administration Hospital in Madison. Dr. Atwood and a colleague (Dr. Richard Bowen) have proposed a novel theory of aging based on the modulation of cell cycle signaling by reproductive hormones. This theory ('The Reproductive-Cell Cycle Theory of Aging') introduces a new definition of aging that has facilitated the conceptualization of why and how we age at the evolutionary, physiological and molecular levels (Bowen and Atwood, 2004). 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 as illustrated below.
Dr. Atwood has diverse research interests (see Novel Theories). Below are some of the different research themes ongoing in the laboratory.
1. Hormonal Regulation of 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 it was 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-ß precursor (AßPP) 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 recent 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). 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). From these basic research observations and insights came the basis for the aging theory. Aside from these 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; Cell), i.e. FSH, and not estrogens are primarily responsible for osteoporosis. Moreover, we have recently demonstrated that elevated serum gonadotropins following reproductive senescence may be one possible cause of the loss of selective permeability of the BBB at this time (Wilson et al., 2008). These findings implicate serum gonadotropins in the cerebropathophysiology of age-related neurodegenerative diseases such as stroke and Alzheimer's disease. These 3 independent lines of evidence (LH/amyloid production, FSH/osteoclast proliferation and gonadotropins/blood-brain barrier integrity) suggest that the surge in gonadotropins following menopause and with andropause is the driving force behind senescent changes leading to disease in aging humans. This research is providing a major paradigm shift in our understanding of senescence.
2. Hormonal Regulation of Embryogenesis. The physiological signals that direct the division and differentiation of human embryonic stem cells (hESC) into a blastocyst (blastulation) and neural tube (neurulation) are unknown. We have found that trophoblastic secretion of human chorionic gonadotropin (hCG) promotes the division of epiblast-derived inner mass cells (hESC), and their differentiation during blastulation and neurulation (Gallego et al., 2008). hCG treatment rapidly upregulates steroidogenic acute regulatory protein-mediated cholesterol transport and the synthesis of progesterone (P4). hESC express P4 receptor A, and treatment of hESC colonies with P4 induces neurulation as demonstrated by the expression of nestin and the formation of columnar neuroectodermal cells that organize into neural tube-like rosettes. Suppression of P4 signaling nhibits the differentiation of hESC colonies into embryoid bodies (blastulation) and rosettes (neurulation) (Gallego et al., 2009). Collectively, these findings implicate trophoblastic hCG secretion and signaling via LHCGR on the adjacent epiblast in the induction of hESC proliferation and differentiation into the blastula and neurula. 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 (Atwood et al., in press).
3. Hormonal Regulation of Aging and Reproduction. A third 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. This finding was recently confirmed by the cloning of Ce-GnRHR and the identification of a GnRH/AKH like ligand that modulates reproduction (Lindemans et al. 2009).
4. Autocrine/Paracrine Mechanisms of LH and Neurosteroid Production in the Brain. This line of research is based on our recent findings that the production of steroids by neuronal cells in the brain (neurosteroids) is regulated by LH via the regulation of steroidogenic acute regulatory protein expression. This novel finding helps explain for the first time the regulation of steroid synthesis in the brain, important for normal brain function, and how neurosteroid production is altered throughout life and disease (Liu et al., 2007). In addition, we have determined that GnRH signals via GnRH receptors present on neurons for the production of LH (Wilson et al., 2006), thereby helping to explain the presence of LH in neurons and it's accumulation during AD (Bowen et al., 2002). Subsequently, we identified the existence of endocrine and autocrine/paracrine feedback loops that regulate neurosteroid synthesis. This is the first time that autocrine/paracrine mechanisms of brain hormone production (extra-hypothalamic) have been identified.
5. Amyloid Biology. Another line of research in my laboratory evolved from studies aimed at understanding the physiological function of the amyloid-ß protein that deposits in the Alzheimer's disease brain. This research identified the amyloid-ß protein as a cuproportein (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-ß is neurotoxic or neurotrophic. We have demonstrated that amyloid-ß is both; neurotrophic to undifferentiated neurons, but toxic to differentiated neurons via a Cdk5 dependent tau phosphorylation pathway (Liu et al., 2004). More recently, we have reported that the amyloid-ß protein regulates the proliferation and differentiation of human embryonic stem cells (hESC); amyloid-ß promotes hESC proliferation, while non-amyloidogneic processing of AßPP induces the differentiation of hESC into neural precursor cells (Porayette et al., 2007 and 2009). Further, the physiochemical properties of amyloid-ß 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-ß 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. This idea has been expounded upon by other AD researchers (Hardy and Cullen, 2006, Nat. Med. 12; 756-7).
6. Hypoxia, and the Metallobiochemistry of the Brain.
A sixth line of research in my laboratory focuses on the
metallobiochemistry of the brain. Our recent studies have indicated that
hypoxic conditions promote the redistribution of metal ions in the
brain, thereby providing an explanation for the accumulation of metal
ions (and the likely source of oxidant stress) in certain
neurodegenerative diseases (Bishop et al., 2007).
Future studies include identification of the metal ion transport
pathways responsible for regulating metal ion influx/efflux in the brain
during hypoxia. In this respect, we have shown via microarray analyses
that copper alters the expression of key transport proteins in neurons
(Chan et al., unpublished data) and that excess copper induces apoptosis
of neurons in both in vitro and in vivo models of Wilson's disease (Chan
et al., 2008).