- Email: [email protected]
Proceedings of the Seventh International Symposium on the Neurobiology and Neuroendocrinology of Aging, Bregenz, Austria, July 18–23, 2004
Experimental Gerontology 39 (2004) 1575–1578 www.elsevier.com/locate/expgero
Editorial
Proceedings of the Seventh International Symposium on the Neurobiology and Neuroendocrinology of Aging, Bregenz, Austria, July 18–23, 2004 1. Introduction This special issue of ‘Experimental Gerontology’ consists of the proceedings of the Seventh International Symposium on the Neurobiology and Neuroendocrinology of Aging [http://www.neurobiology-and-neuroendocrinology-of-aging.org/] held in Bregenz, Voralberg, Austria at the Kloster Mehrerau, July 18–23, 2004. The previous six Symposia in this series were held at the same site every other year since 1992 and the proceedings were published as a supplement to the Journal of Reproduction and Fertility [J. Reprod. Fertil. Suppl., 46, 1993); and as a series of special issues of Experimental Gerontology [Exp. Gerontol., 30 [3/4] 1995, 32 [4/5], 1997; 33 [7/8] 1988; 35 [9/10], 2000 and 38 [1/2], 2003. These Symposia attempt to integrate recent information derived from the study of neurobiology, neuroendocrinology, genetics, animal models, and degenerative CNS diseases with the fundamental issue of the nature of the aging process. The first article is by Dominique Toran–Allerand who was the Special Speaker. She presented her compiled data on the existence of a novel plasma membrane-associated estrogen receptor [ER], different from ERa and ERb which she has named ER-X. She also indicated that 17b-estradiol is a greatly under-appreciated neural growth and trophic factor for the mammalian brain at all ages. Similarly to other growth factors, such as the neurotrophins, 17b-estradiol influences neurogenesis, neuronal differentiation, and neuronal survival of its targets throughout life. ‘ER-X’ appears to work via the MAP Kinase system [mitogen-activated protein kinase (MAPK) and Extra-cellular signal-Regulated Kinase (ERK]. Her observations have far reaching implications into the understanding of prevention of age-related dementia and neurodegenerative diseases. The Keynote Speaker was Thomas Perls who discussed demographic data on centenarians. Centenarians are the fastest growing segment of our population. Among the centenarians in his study, 13% never experienced serious disease, while the remainder either survived a serious disease or experienced it at an unusually late age. 0531-5565/$ - see front matter q 2004 Published by Elsevier Inc. doi:10.1016/j.exger.2004.09.001
Many centenarians were relatively independent and approximately 20% were free of dementia. Among those who were demented, many had various rare CNS pathologies rather than Alzheimer’s disease. Studies of the children of centenarians indicate that exceptional longevity involves a strong genetic component. Nobuyoshi Hirose and Toshio Kojima reported findings in a large cohort of centenarians in Japan including a group of semi-super-centenarians (SSCs), i.e. individuals who are 105 years old or older. Among the centenarians, 23% were independent, 21% were cognitively intact, and 30% had no serious disease. The BMI was low and the incidence of diabetes was 2.1%, i.e. approximately 1/10 of the incidence in Japanese elders, and incidence of atherosclerotic plaques was also markedly lower than in octo- and nona- genarians. Serum albumin and cholesterol were reduced while several markers of inflammation were elevated. Among the SSCs, normal vision was maintained in 20%, hearing in 10%, and cognitive function in approximately 30%. Gene polymorphisms of APOE associated with the increased risk of Alzheimers disease were less frequent in centenarians that in the general population and still less frequent in SSCs. Studies of polymorphism of genes related to IGF-1 and insulin signaling revealed that centenarians had altered frequency of one IGF-1 receptor SNP and one Insulin receptor haplotype. In addition to identifying many interesting characteristics of exceptionally long-lived people, these studies provide very exciting evidence that IGF-1/-insulin signaling which is involved in the control of aging in organisms ranging from worms to mice is related also to human longevity. Alexander Bu¨rkle discussed the role of poly(ADPribosyl)ation in carcinogenesis and aging. Poly(ADPribosyl)ation is a DNA strand break-driven post-translational modification of proteins catalyzed by poly(ADP-ribose) polymerase-1 (PARP-1), with NADC serving as substrate. Poly(ADP-ribosyl)ation is triggered by DNA strand breaks and is functionally associated with DNA repair pathways and is a survival factor for cells under low to moderate levels of genotoxic stress. The work in his laboratory has shown a positive correlation between poly(ADP-ribosyl)ation with
1576
Editorial / Experimental Gerontology 39 (2004) 1575–1578
longevity in cells from different mammalian species. He suggested that increased poly(ADP-ribosyl)ation capacity in long-lived species might help retard the accumulation of DNA damage and mutations and thus slow down the rate of aging and carcinogenesis. The next paper authored by Min Jiang and Ilpo Huhtaniemi was presened by I. Huhtaniemi. After reviewing the information on inter-individual and age-related variation in sex hormone levels, he discussed genetic polymorphisms of androgen and estrogen receptors and their functional significance. For example, polymorphisms in androgen and estrogen receptor genes and genes for steroidogenic enzymes were shown to be associated with increased risk for dementia and prostate cancer. He also discussed recent evidence for geographic differences in testosterone levels in European men. This work contributes to the understanding how life-long exposure to the endocrine milieu of gonadal steroids may act as a determining factor to gender specific features of aging. Kay Lund presented data relating behavioral characteristics to genetic markers. Behavioral characterization distinguishes aged rats with impaired spatial learning and aged rats with unimpaired learning ability, mimicking the varied susceptibility of the human population to ageassociated learning impairments. Her studies are testing a hypothesis that hippocampal transcriptional mechanisms and gene expression profiles linked to activator protein-1 (AP-1) and glucocorticoid receptor (GR), mineralocorticoid receptor (MR) or cyclic AMP response element binding protein (CREB) families of transcription factors distinguish successful vs. unsuccessful aging in terms of cognitive abilities. Results of studies of the role of sex hormones in neuroprotection by S. Veiga, and colleagues were presented by Luis Garcia-Segura. Estrogens, including estradiol produced locally in the brain enhance production of insulin like growth factor-1 (IGF-1) which is neuroprotective. The central theme of their presentation was that brain steroidogenesis may be modified in adaptation to brain injury and neurodegenerative conditions. Local formation of estradiol in the brain, by the enzyme aromatase, can prevent neuronal loss and enhance the action of IGF-1. There were four lectures on Alzheimer’s disease. The first, presented by Eva Hogervorst addressed the issue of pituitary gonadotropins and free testosterone levels in a large cohort of men with Alzheimer’s Disease [AD]. The data showed that AD cases had significantly higher LH and FSH and lower free testosterone levels. Low free testosterone was an independent predictor for AD. Its variance was overall explained by high sex hormone binding globulin [SHBG]. In non-demented participants, subclinical hyperthyroid disease (a risk factor for AD) which can result in higher SHBG levels, was associated with low free testosterone. One of the conclusions was that the lowering SHBG and/or screening for subclinical thyroid disease may
prevent cognitive decline and/or wasting in men at risk for AD. The next paper authored by A. Dedeoglu et al., was presented by Xudong Huang. A growing body of evidence indicates that dysregulation of cerebral biometals (Fe, Cu, Zn) and their interactions with amyloid precursor protein and Ab amyloid may contribute to the Alzheimer’s amyloid pathology, and thus metal chelation could be a rational therapeutic approach for interdicting AD pathogenesis. He presented data concerning the development of the next generation of metal chelators, and described a newly designed and synthesized bifunctional molecule- XH1. He presented data that this lipophilic molecule has both amyloid-binding and metal-chelating moieties covalently connected by amide bonds. Their pilot data indicate that XH1 has no significant neurotoxicity or acute animal toxicity. These preliminary findings carry implication for XH1 being blood brain barrier permeable compound which could carry AD therapeutics targeting Alzheimer’s amyloidogenesis. Vladimir K. Patchev discussed the importance of androgen signaling in CNS function, ranging from sexspecific organization of neuroendocrine and behavioral circuits to adaptive capacity, resistance and repair. It was emphasized that the therapeutic use of androgens in neurological and mental disorders is far from being established. Critical issues which interfere with decisions on the suitability of androgens as therapeutic agents for CNS conditions were outlined. Analysis of the consequences of aging for the rat brain transcriptome and influence of androgens on differentially expressed genes with presumable significance in neuropathology were also discussed. Michael Rowan described studies on AD as a disease of misfolded protein. His presentation focused on the mechanisms of amyloid b-protein [Ab] inhibition of long-term potentiation at synapses in the rodent hippocampus. They concluded that their mechanistic approach implicated various oxidative /nitrosative stress-linked cascades and provide a possible explanation for the hippocampal memory impairment seen in preclinical states of AD. Two lectures dealt with reproductive hormones and receptors. Natalia Danilovich described the phenotype of FOllitropin Receptor KnockOut (FORKO) mice which lack the FSH receptor, FORKO female mice experience a chronic depletion of estrogen (E2) from early development, and exhibit characteristics similar to those of aging women, with ovarian failure, obesity, skeletal changes, and ovarian tumors. A variety of findings supports the conclusion that E2 deficiency in FORKO mice is responsible for their neural impairments associated with glial cell hypertrophy, regionspecific brain cells loss, and abnormal behavior. Findings from mice with FSH receptor haploinsufficiency (‘menomenopausal mice’) are also shedding light on the molecular basis of menopausal conditions that include degeneration of the hippocampus. Many phenotypes noted in the null
Editorial / Experimental Gerontology 39 (2004) 1575–1578
condition also occur in G females but in an age related manner. These animals provide excellent model to investigate mechanisms underlying age-related changes especially when these events are accelerated, as in menopausal women. Mary Ann Ottinger discussed the use of an avian model [Japanese quail] in the study of neuroendocrine and behavioral aspects of reproductive aging. The data showed age-related decreases in the gonadotropin releasing hormone (GnRH-I) concentration in the median eminence of aging animals of both sexes, whereas preoptic-lateral septal region GnRH-I concentrations declined only in aging males. In comparison to hypothalamic slices from young animals, hypothalamic tissue from old reproductively inactive birds had reduced baseline GnRH-I release and diminished response to norepinephrine (NE). Deteriorating fertility also correlated with decreased male sexual behavior and loss of aromatase immunoreactive (AROM-ir) neurons in the medial, but not lateral preoptic nucleus (POA). Sexual behavior and AROM-ir could be restored with exogenous testosterone, and this was associated with increased cell size in the medial POA. These studies indicate a neuroplasticity of specific neural systems and a critical role of estradiol in maintaining reproductive function. Two papers were concerned with neuroprotection and reproductive aging. Monique Valle´e described the role of neuroactive steroids and their physiological role in cognitive aging. Neuroactive steroids are proposed to be biomarkers of cognitive aging, however, their specific functions are not established. In order to address this lack of information, new sensitive, specific, and accurate mass spectrometry assays were developed to allow quantification of neuroactive steroids in discrete brain regions. Such data should enhance understanding the actions of neuroactive steroids and allow unraveling their role in age-related cognitive deficits. The next paper by N.F. Gonzalez-Cadavid and J. Rajfer was presented by Nestor Gonzalez-Cadavid. The paper centers on erectile dysfunction (ED) as a major public health problem that seriously affects the quality of life of many men and their partners. ED is mainly associated with vascular disease, diabetes, smoking, and radical prostatectomy, and its prevalence increases significantly with aging. Based on animal and cell studies, neurogenic ED is assumed to be caused mainly by: (a) an insufficient synthesis of nitric oxide (NO) due to a decrease in the levels of the penile neuronal nitric oxide synthase (PnNOS) or the impairment of its regulation by protein effectors (NMDA receptor, protein inhibitor of nNOS: PIN), or (b) a loss of the cells themselves by apoptosis caused by the induction of inducible NOS (iNOS) and the production of peroxynitrite. In contrast, vasculogenic ED, although it may involve endothelial damage and down-regulation of endothelial NOS (eNOS), appears to be mainly caused by the relative loss of smooth muscle cells and replacement by collagen fibers (fibrosis). Gene therapy involving local
1577
administration to the penile corpora cavernosa of cDNAs expressing PnNOS or eNOS, or counteracting PIN, has been effective in ameliorating ED in aging rats. cDNA constructs for other genes involved in the control of penile erection have also been successfully tested. Gene transfer into the penis may soon translate to the clinic as a therapy aimed to cure the underlying conditions in ED, as opposed to the facilitation of erection on demand offered by the current oral therapies. Pidder Jansen-Du¨rr described his studies of endothelial cells aging. Human umbilical vein endothelial cells (HUVEC) exhibit increases in both total and non-mitochondrial production of reactive oxygen species (ROS) and in the incidence of tetraploidy as they age. Although apoptoisis is usually considered as a protective mechanism leading to removal of senescent cells, in the endothelium it may be associated with atherogenesis. Michal Karasek discussed age-related alterations in the release of melatonin and summarized evidence for beneficial effects of melatonin treatment. The nocturnal peak of melatonin levels precipitously declines with age. Alzheimer disease and cancer may further suppress serum melatonin but circadian melatonin rhythm is preserved in centenarians. In a group of elderly women, six months of treatment with melatonin improved self-assessed well-being and tended to increase IGF-1 and reduce estradiol levels. Klaus Turnheim explained how age-related changes in body composition, renal function, receptor levels, and signal transduction pathways can alter responses to drugs and risk of undesirable side effects in the elderly. He also discussed the consequences of the decline in homeostatic mechanisms during aging and provided examples of adverse CNS effects of several classes of drugs in older patients. Pat Prinz described physiological consequences of sleep deprivation and sleep disturbances. Endocrine changes induced by sleep deprivation include suppression of prolactin and growth hormone release, and alterations in insulin control of glucose levels that resemble a prediabetic condition. Associated with these changes are numerous changes in immune function and in markers of inflammation. Marc Tatar discussed his most recent studies of the endocrine control of aging in Drosophila. To more closely delineate the role of insulin-like signaling pathway in the control of aging in this species, he produced transgenic flies with overexpression of d-FOXO specifically in the fat body. This increased longevity of the animals, reduced their age specific mortality rate and increased stress resistance. This was associated with reduced insulin-like signaling in abdominal organs. Overexpression of either d-FOXO or PTEN in the heart completely suppressed cardiac aging. Studies in wild type and in long-lived mutant flies provided evidence that cardiac aging measured by the employed novel procedure correlates with longevity. In addition to advancing the present understanding of the effects of insulin on longevity, these exciting results identify organs which
1578
Editorial / Experimental Gerontology 39 (2004) 1575–1578
mediate the action of insulin and the specific steps of the signaling pathway that are involved in the control of aging. Martin Holzenberger described the characteristics of mice heterozygous for the targeted disruption of the IGF-1 receptor which are fertile and phenotypically very similar to normal mice but exhibit enhanced stress resistance and prolonged longevity. These findings provide important direct evidence for the role of IGF-1 in the control of mammalian aging. He also described his ongoing studies in which Cre-Lox system is used to delete IGF1R gene in CNS only, or in specific CNS regions. Brain-specific IGF1 resistance was associated with an increase in median but not in maximal longevity. Exciting results can be expected from the study of these novel models. Norman Sharpless’ manuscript is included but due to an injury, he was not able to attend the Symposium. His place on the program was taken at the very last moment by Michel Hofman who spoke on Brain Evolution in primates. This paper does not appear in these proceedings. Following are the abstracts of the posters presented at the Symposium. The organizers would like to thank George Wick and Beatrix Grubeck-Loebenstein and selected members of the editorial board of Experimental Gerontology for their guidance and assistance in publications of these proceedings. The 2004 Symposium was organized by Richard E. Falvo [Chapel Hill, North Carolina, USA] and Andrzej Bartke [Springfield, Illinois, USA]. Members of the program committee are Brian Lockhart [Croissy-sur-Seine, France], Alexander Bu¨rkle [Konstanz, Germany], Jay A. Zimmerman [Jamaica, New York, USA], Geoffrey Bennett [Nottingham, UK], Michel A. Hofman [Amsterdam,The Netherlands], Roberto C. Melcangi [Milan, Italy], Eva Sykova´, [Prague,Czech Republic], Paola Timiras [Berkeley, California, USA], George S. Roth [Pylesville, MD, USA], Georg Wick, Innsbruck, Austria]. Thanks are also extended to the Scientific Secretary, Michael Ramek [Graz, Austria].
We extend our gratitude to the financial contributors to this Symposium: National Institute on Aging, Bethesda, Maryland, USA School of Medicine, Southern Illinois University, Springfield, Illinois, USA Land Vorarlberg and the Landeshauptstadt Bregenz Southern Illinois University, Carbondale, Illinois, USA Ernest Schering Research Foundation, Berlin, Germany Merck and Co., Inc., Rahway, New Jersey, USA Junifur Foundation, Chatham County, North Carolina, USA Servier, Recherche Interne et des Alliances Strategiques, Suresnes, France Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina, USA Orentreich Foundation for the Advancement of Science, Cold Spring-on-Hudson, New York, USA
Richard E. Falvoa,*, Andrzej Bartkeb,1 Department of Cell and Molecular Physiology, School of Medicine, University of North Carolina at Chapel Hill, 5200 Medical Biomolecular Research Building, 103 Mason Farm Road, Chapel Hill, NC 27599-7545, USA b Department of Physiology and Internal Medicine, School of Medicine, Southern Illinois University, P.O. Box 19628, (801 North Rutledge, Room 4389), Springfield, IL 62794-9628, USA E-mail addresses: [email protected], [email protected] a
Received 31 August 2004 Available online 6 October 2004
*Corresponding author. Tel.: C1 919 966 1099; fax: C1 919 966 6927. 1 Tel.: C1-217-545-7962; fax: C1 217 545 8006.
Editorial
Proceedings of the Seventh International Symposium on the Neurobiology and Neuroendocrinology of Aging, Bregenz, Austria, July 18–23, 2004 1. Introduction This special issue of ‘Experimental Gerontology’ consists of the proceedings of the Seventh International Symposium on the Neurobiology and Neuroendocrinology of Aging [http://www.neurobiology-and-neuroendocrinology-of-aging.org/] held in Bregenz, Voralberg, Austria at the Kloster Mehrerau, July 18–23, 2004. The previous six Symposia in this series were held at the same site every other year since 1992 and the proceedings were published as a supplement to the Journal of Reproduction and Fertility [J. Reprod. Fertil. Suppl., 46, 1993); and as a series of special issues of Experimental Gerontology [Exp. Gerontol., 30 [3/4] 1995, 32 [4/5], 1997; 33 [7/8] 1988; 35 [9/10], 2000 and 38 [1/2], 2003. These Symposia attempt to integrate recent information derived from the study of neurobiology, neuroendocrinology, genetics, animal models, and degenerative CNS diseases with the fundamental issue of the nature of the aging process. The first article is by Dominique Toran–Allerand who was the Special Speaker. She presented her compiled data on the existence of a novel plasma membrane-associated estrogen receptor [ER], different from ERa and ERb which she has named ER-X. She also indicated that 17b-estradiol is a greatly under-appreciated neural growth and trophic factor for the mammalian brain at all ages. Similarly to other growth factors, such as the neurotrophins, 17b-estradiol influences neurogenesis, neuronal differentiation, and neuronal survival of its targets throughout life. ‘ER-X’ appears to work via the MAP Kinase system [mitogen-activated protein kinase (MAPK) and Extra-cellular signal-Regulated Kinase (ERK]. Her observations have far reaching implications into the understanding of prevention of age-related dementia and neurodegenerative diseases. The Keynote Speaker was Thomas Perls who discussed demographic data on centenarians. Centenarians are the fastest growing segment of our population. Among the centenarians in his study, 13% never experienced serious disease, while the remainder either survived a serious disease or experienced it at an unusually late age. 0531-5565/$ - see front matter q 2004 Published by Elsevier Inc. doi:10.1016/j.exger.2004.09.001
Many centenarians were relatively independent and approximately 20% were free of dementia. Among those who were demented, many had various rare CNS pathologies rather than Alzheimer’s disease. Studies of the children of centenarians indicate that exceptional longevity involves a strong genetic component. Nobuyoshi Hirose and Toshio Kojima reported findings in a large cohort of centenarians in Japan including a group of semi-super-centenarians (SSCs), i.e. individuals who are 105 years old or older. Among the centenarians, 23% were independent, 21% were cognitively intact, and 30% had no serious disease. The BMI was low and the incidence of diabetes was 2.1%, i.e. approximately 1/10 of the incidence in Japanese elders, and incidence of atherosclerotic plaques was also markedly lower than in octo- and nona- genarians. Serum albumin and cholesterol were reduced while several markers of inflammation were elevated. Among the SSCs, normal vision was maintained in 20%, hearing in 10%, and cognitive function in approximately 30%. Gene polymorphisms of APOE associated with the increased risk of Alzheimers disease were less frequent in centenarians that in the general population and still less frequent in SSCs. Studies of polymorphism of genes related to IGF-1 and insulin signaling revealed that centenarians had altered frequency of one IGF-1 receptor SNP and one Insulin receptor haplotype. In addition to identifying many interesting characteristics of exceptionally long-lived people, these studies provide very exciting evidence that IGF-1/-insulin signaling which is involved in the control of aging in organisms ranging from worms to mice is related also to human longevity. Alexander Bu¨rkle discussed the role of poly(ADPribosyl)ation in carcinogenesis and aging. Poly(ADPribosyl)ation is a DNA strand break-driven post-translational modification of proteins catalyzed by poly(ADP-ribose) polymerase-1 (PARP-1), with NADC serving as substrate. Poly(ADP-ribosyl)ation is triggered by DNA strand breaks and is functionally associated with DNA repair pathways and is a survival factor for cells under low to moderate levels of genotoxic stress. The work in his laboratory has shown a positive correlation between poly(ADP-ribosyl)ation with
1576
Editorial / Experimental Gerontology 39 (2004) 1575–1578
longevity in cells from different mammalian species. He suggested that increased poly(ADP-ribosyl)ation capacity in long-lived species might help retard the accumulation of DNA damage and mutations and thus slow down the rate of aging and carcinogenesis. The next paper authored by Min Jiang and Ilpo Huhtaniemi was presened by I. Huhtaniemi. After reviewing the information on inter-individual and age-related variation in sex hormone levels, he discussed genetic polymorphisms of androgen and estrogen receptors and their functional significance. For example, polymorphisms in androgen and estrogen receptor genes and genes for steroidogenic enzymes were shown to be associated with increased risk for dementia and prostate cancer. He also discussed recent evidence for geographic differences in testosterone levels in European men. This work contributes to the understanding how life-long exposure to the endocrine milieu of gonadal steroids may act as a determining factor to gender specific features of aging. Kay Lund presented data relating behavioral characteristics to genetic markers. Behavioral characterization distinguishes aged rats with impaired spatial learning and aged rats with unimpaired learning ability, mimicking the varied susceptibility of the human population to ageassociated learning impairments. Her studies are testing a hypothesis that hippocampal transcriptional mechanisms and gene expression profiles linked to activator protein-1 (AP-1) and glucocorticoid receptor (GR), mineralocorticoid receptor (MR) or cyclic AMP response element binding protein (CREB) families of transcription factors distinguish successful vs. unsuccessful aging in terms of cognitive abilities. Results of studies of the role of sex hormones in neuroprotection by S. Veiga, and colleagues were presented by Luis Garcia-Segura. Estrogens, including estradiol produced locally in the brain enhance production of insulin like growth factor-1 (IGF-1) which is neuroprotective. The central theme of their presentation was that brain steroidogenesis may be modified in adaptation to brain injury and neurodegenerative conditions. Local formation of estradiol in the brain, by the enzyme aromatase, can prevent neuronal loss and enhance the action of IGF-1. There were four lectures on Alzheimer’s disease. The first, presented by Eva Hogervorst addressed the issue of pituitary gonadotropins and free testosterone levels in a large cohort of men with Alzheimer’s Disease [AD]. The data showed that AD cases had significantly higher LH and FSH and lower free testosterone levels. Low free testosterone was an independent predictor for AD. Its variance was overall explained by high sex hormone binding globulin [SHBG]. In non-demented participants, subclinical hyperthyroid disease (a risk factor for AD) which can result in higher SHBG levels, was associated with low free testosterone. One of the conclusions was that the lowering SHBG and/or screening for subclinical thyroid disease may
prevent cognitive decline and/or wasting in men at risk for AD. The next paper authored by A. Dedeoglu et al., was presented by Xudong Huang. A growing body of evidence indicates that dysregulation of cerebral biometals (Fe, Cu, Zn) and their interactions with amyloid precursor protein and Ab amyloid may contribute to the Alzheimer’s amyloid pathology, and thus metal chelation could be a rational therapeutic approach for interdicting AD pathogenesis. He presented data concerning the development of the next generation of metal chelators, and described a newly designed and synthesized bifunctional molecule- XH1. He presented data that this lipophilic molecule has both amyloid-binding and metal-chelating moieties covalently connected by amide bonds. Their pilot data indicate that XH1 has no significant neurotoxicity or acute animal toxicity. These preliminary findings carry implication for XH1 being blood brain barrier permeable compound which could carry AD therapeutics targeting Alzheimer’s amyloidogenesis. Vladimir K. Patchev discussed the importance of androgen signaling in CNS function, ranging from sexspecific organization of neuroendocrine and behavioral circuits to adaptive capacity, resistance and repair. It was emphasized that the therapeutic use of androgens in neurological and mental disorders is far from being established. Critical issues which interfere with decisions on the suitability of androgens as therapeutic agents for CNS conditions were outlined. Analysis of the consequences of aging for the rat brain transcriptome and influence of androgens on differentially expressed genes with presumable significance in neuropathology were also discussed. Michael Rowan described studies on AD as a disease of misfolded protein. His presentation focused on the mechanisms of amyloid b-protein [Ab] inhibition of long-term potentiation at synapses in the rodent hippocampus. They concluded that their mechanistic approach implicated various oxidative /nitrosative stress-linked cascades and provide a possible explanation for the hippocampal memory impairment seen in preclinical states of AD. Two lectures dealt with reproductive hormones and receptors. Natalia Danilovich described the phenotype of FOllitropin Receptor KnockOut (FORKO) mice which lack the FSH receptor, FORKO female mice experience a chronic depletion of estrogen (E2) from early development, and exhibit characteristics similar to those of aging women, with ovarian failure, obesity, skeletal changes, and ovarian tumors. A variety of findings supports the conclusion that E2 deficiency in FORKO mice is responsible for their neural impairments associated with glial cell hypertrophy, regionspecific brain cells loss, and abnormal behavior. Findings from mice with FSH receptor haploinsufficiency (‘menomenopausal mice’) are also shedding light on the molecular basis of menopausal conditions that include degeneration of the hippocampus. Many phenotypes noted in the null
Editorial / Experimental Gerontology 39 (2004) 1575–1578
condition also occur in G females but in an age related manner. These animals provide excellent model to investigate mechanisms underlying age-related changes especially when these events are accelerated, as in menopausal women. Mary Ann Ottinger discussed the use of an avian model [Japanese quail] in the study of neuroendocrine and behavioral aspects of reproductive aging. The data showed age-related decreases in the gonadotropin releasing hormone (GnRH-I) concentration in the median eminence of aging animals of both sexes, whereas preoptic-lateral septal region GnRH-I concentrations declined only in aging males. In comparison to hypothalamic slices from young animals, hypothalamic tissue from old reproductively inactive birds had reduced baseline GnRH-I release and diminished response to norepinephrine (NE). Deteriorating fertility also correlated with decreased male sexual behavior and loss of aromatase immunoreactive (AROM-ir) neurons in the medial, but not lateral preoptic nucleus (POA). Sexual behavior and AROM-ir could be restored with exogenous testosterone, and this was associated with increased cell size in the medial POA. These studies indicate a neuroplasticity of specific neural systems and a critical role of estradiol in maintaining reproductive function. Two papers were concerned with neuroprotection and reproductive aging. Monique Valle´e described the role of neuroactive steroids and their physiological role in cognitive aging. Neuroactive steroids are proposed to be biomarkers of cognitive aging, however, their specific functions are not established. In order to address this lack of information, new sensitive, specific, and accurate mass spectrometry assays were developed to allow quantification of neuroactive steroids in discrete brain regions. Such data should enhance understanding the actions of neuroactive steroids and allow unraveling their role in age-related cognitive deficits. The next paper by N.F. Gonzalez-Cadavid and J. Rajfer was presented by Nestor Gonzalez-Cadavid. The paper centers on erectile dysfunction (ED) as a major public health problem that seriously affects the quality of life of many men and their partners. ED is mainly associated with vascular disease, diabetes, smoking, and radical prostatectomy, and its prevalence increases significantly with aging. Based on animal and cell studies, neurogenic ED is assumed to be caused mainly by: (a) an insufficient synthesis of nitric oxide (NO) due to a decrease in the levels of the penile neuronal nitric oxide synthase (PnNOS) or the impairment of its regulation by protein effectors (NMDA receptor, protein inhibitor of nNOS: PIN), or (b) a loss of the cells themselves by apoptosis caused by the induction of inducible NOS (iNOS) and the production of peroxynitrite. In contrast, vasculogenic ED, although it may involve endothelial damage and down-regulation of endothelial NOS (eNOS), appears to be mainly caused by the relative loss of smooth muscle cells and replacement by collagen fibers (fibrosis). Gene therapy involving local
1577
administration to the penile corpora cavernosa of cDNAs expressing PnNOS or eNOS, or counteracting PIN, has been effective in ameliorating ED in aging rats. cDNA constructs for other genes involved in the control of penile erection have also been successfully tested. Gene transfer into the penis may soon translate to the clinic as a therapy aimed to cure the underlying conditions in ED, as opposed to the facilitation of erection on demand offered by the current oral therapies. Pidder Jansen-Du¨rr described his studies of endothelial cells aging. Human umbilical vein endothelial cells (HUVEC) exhibit increases in both total and non-mitochondrial production of reactive oxygen species (ROS) and in the incidence of tetraploidy as they age. Although apoptoisis is usually considered as a protective mechanism leading to removal of senescent cells, in the endothelium it may be associated with atherogenesis. Michal Karasek discussed age-related alterations in the release of melatonin and summarized evidence for beneficial effects of melatonin treatment. The nocturnal peak of melatonin levels precipitously declines with age. Alzheimer disease and cancer may further suppress serum melatonin but circadian melatonin rhythm is preserved in centenarians. In a group of elderly women, six months of treatment with melatonin improved self-assessed well-being and tended to increase IGF-1 and reduce estradiol levels. Klaus Turnheim explained how age-related changes in body composition, renal function, receptor levels, and signal transduction pathways can alter responses to drugs and risk of undesirable side effects in the elderly. He also discussed the consequences of the decline in homeostatic mechanisms during aging and provided examples of adverse CNS effects of several classes of drugs in older patients. Pat Prinz described physiological consequences of sleep deprivation and sleep disturbances. Endocrine changes induced by sleep deprivation include suppression of prolactin and growth hormone release, and alterations in insulin control of glucose levels that resemble a prediabetic condition. Associated with these changes are numerous changes in immune function and in markers of inflammation. Marc Tatar discussed his most recent studies of the endocrine control of aging in Drosophila. To more closely delineate the role of insulin-like signaling pathway in the control of aging in this species, he produced transgenic flies with overexpression of d-FOXO specifically in the fat body. This increased longevity of the animals, reduced their age specific mortality rate and increased stress resistance. This was associated with reduced insulin-like signaling in abdominal organs. Overexpression of either d-FOXO or PTEN in the heart completely suppressed cardiac aging. Studies in wild type and in long-lived mutant flies provided evidence that cardiac aging measured by the employed novel procedure correlates with longevity. In addition to advancing the present understanding of the effects of insulin on longevity, these exciting results identify organs which
1578
Editorial / Experimental Gerontology 39 (2004) 1575–1578
mediate the action of insulin and the specific steps of the signaling pathway that are involved in the control of aging. Martin Holzenberger described the characteristics of mice heterozygous for the targeted disruption of the IGF-1 receptor which are fertile and phenotypically very similar to normal mice but exhibit enhanced stress resistance and prolonged longevity. These findings provide important direct evidence for the role of IGF-1 in the control of mammalian aging. He also described his ongoing studies in which Cre-Lox system is used to delete IGF1R gene in CNS only, or in specific CNS regions. Brain-specific IGF1 resistance was associated with an increase in median but not in maximal longevity. Exciting results can be expected from the study of these novel models. Norman Sharpless’ manuscript is included but due to an injury, he was not able to attend the Symposium. His place on the program was taken at the very last moment by Michel Hofman who spoke on Brain Evolution in primates. This paper does not appear in these proceedings. Following are the abstracts of the posters presented at the Symposium. The organizers would like to thank George Wick and Beatrix Grubeck-Loebenstein and selected members of the editorial board of Experimental Gerontology for their guidance and assistance in publications of these proceedings. The 2004 Symposium was organized by Richard E. Falvo [Chapel Hill, North Carolina, USA] and Andrzej Bartke [Springfield, Illinois, USA]. Members of the program committee are Brian Lockhart [Croissy-sur-Seine, France], Alexander Bu¨rkle [Konstanz, Germany], Jay A. Zimmerman [Jamaica, New York, USA], Geoffrey Bennett [Nottingham, UK], Michel A. Hofman [Amsterdam,The Netherlands], Roberto C. Melcangi [Milan, Italy], Eva Sykova´, [Prague,Czech Republic], Paola Timiras [Berkeley, California, USA], George S. Roth [Pylesville, MD, USA], Georg Wick, Innsbruck, Austria]. Thanks are also extended to the Scientific Secretary, Michael Ramek [Graz, Austria].
We extend our gratitude to the financial contributors to this Symposium: National Institute on Aging, Bethesda, Maryland, USA School of Medicine, Southern Illinois University, Springfield, Illinois, USA Land Vorarlberg and the Landeshauptstadt Bregenz Southern Illinois University, Carbondale, Illinois, USA Ernest Schering Research Foundation, Berlin, Germany Merck and Co., Inc., Rahway, New Jersey, USA Junifur Foundation, Chatham County, North Carolina, USA Servier, Recherche Interne et des Alliances Strategiques, Suresnes, France Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina, USA Orentreich Foundation for the Advancement of Science, Cold Spring-on-Hudson, New York, USA
Richard E. Falvoa,*, Andrzej Bartkeb,1 Department of Cell and Molecular Physiology, School of Medicine, University of North Carolina at Chapel Hill, 5200 Medical Biomolecular Research Building, 103 Mason Farm Road, Chapel Hill, NC 27599-7545, USA b Department of Physiology and Internal Medicine, School of Medicine, Southern Illinois University, P.O. Box 19628, (801 North Rutledge, Room 4389), Springfield, IL 62794-9628, USA E-mail addresses: [email protected], [email protected] a
Received 31 August 2004 Available online 6 October 2004
*Corresponding author. Tel.: C1 919 966 1099; fax: C1 919 966 6927. 1 Tel.: C1-217-545-7962; fax: C1 217 545 8006.