bluuebunny/crossref_metadata_2025 huggingface dataset:
Thrombophilic abnormalities, oral contraceptives, and risk of cerebral vein thrombosis: a meta-analysis
Authors: Dentali Francesco , Crowther Mark , Ageno Walter
Published: January 2006

Recent studies suggest that thrombophilic abnormalities and the use of oral contraceptives (OCs) are the leading causes of cerebral vein thrombosis (CVT). The purpose of this study was to assess the association between CVT and thrombophilic states, OCs, and their interaction. For data sources, we used the MEDLINE, EMBASE, and Cochrane Library databases (January 1994 to March 2005), reference lists of retrieved articles, and contact with content experts. We selected studies comparing the prevalence of OC use and the prevalence of prothrombitic abnormalities in patients with CVT compared with healthy controls. Two reviewers independently selected studies and extracted study characteristics, quality, and outcomes. Odds ratios (ORs) were calculated for each trial and pooled using the Mantel-Haenszel method. Seventeen studies were included. There was an increased risk of CVT in patients using OCs (OR 5.59; 95% confidence interval [CI] 3.95 to 7.91; P < .001), and in patients with factor V Leiden (OR 3.38; 95% CI 2.27 to 5.05; P < .001), with mutation G20 210A of prothrombin (OR 9.27; 95% CI 5.85 to 14.67; P < .001) and with hyperhomocysteinemia (OR 4.07; 95% CI 2.54 to 6.52; P < .001). We concluded that OC users, and patients with factor V Leiden, the prothrombin G20 120A mutation, and hyperhomocysteinemia are at a significantly increased risk of CVT.
Characterization of Siglec-H as a novel endocytic receptor expressed on murine plasmacytoid dendritic cell precursors
Authors: Zhang Jiquan , Raper Anna , Sugita Noriko , Hingorani Ravi , Salio Mariolina , Palmowski Michael J. , Cerundolo Vincenzo , Crocker Paul R.
Published: January 2006

We describe the cloning and characterization of Siglec-H, a novel murine CD33-related siglec-like molecule with 2 immunoglobulin domains. Unlike other CD33-related siglecs, Siglec-H lacks tyrosine-based signaling motifs in its cytoplasmic tail. Although Siglec-H has the typical structural features required for sialic acid binding, no evidence for carbohydrate recognition was obtained. Specific monoclonal and polyclonal antibodies (Abs) were raised to Siglec-H and used to define its cellular expression pattern and functional properties. By flow cytometry, Siglec-H was expressed specifically on plasmacytoid dendritic cell (pDC) precursors in bone marrow, spleen, blood, and lymph nodes. Staining of tissue sections showed that Siglec-H was also expressed in a subset of marginal zone macrophages in the spleen and in medullary macrophages in lymph nodes. Using bone marrow-derived pDC precursors that express Siglec-H, addition of Abs did not influence cytokine production, either in the presence or absence of synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG). In comparison, Siglec-H functioned as an endocytic receptor and mediated efficient internalization of anti–Siglec-H Abs. By immunizing mice with ovalbumin-conjugated anti–Siglec-H Ab in the presence of CpG, we demonstrate generation of antigen-specific CD8 T cells in vivo. Targeting Siglec-H may therefore be a useful way of delivering antigens to pDC precursors for cross-presentation.
Vasoactive intestinal peptide generates human tolerogenic dendritic cells that induce CD4 and CD8 regulatory T cells
Authors: Gonzalez-Rey Elena , Chorny Alejo , Fernandez-Martin Amelia , Ganea Doina , Delgado Mario
Published: January 2006

Induction of antigen-specific tolerance is critical for autoimmunity prevention and immune tolerance maintenance. In addition to their classical role as sentinels of the immune response, dendritic cells (DCs) play important roles in maintaining peripheral tolerance through the induction/activation of regulatory T (Treg) cells. The possibility of generating tolerogenic DCs opens new therapeutic perspectives in autoimmune/inflammatory diseases. Characterizing endogenous factors that contribute to the development of tolerogenic DCs is highly relevant. We here report that the immunosuppressive neuropeptide vasoactive intestinal peptide (VIP) induces the generation of human tolerogenic DCs with the capacity to generate CD4 and CD8 Treg cells from their respective naive subsets. The presence of VIP during the early stages of DC differentiation from blood monocytes generates a population of IL-10-producing DCs unable to fully mature after the effects of inflammatory stimuli. CD4 Treg cells generated with VIP-differentiated DCs resemble the previously described Tr1 cells in terms of phenotype and cytokine profile. CD8 Treg cells generated with tolerogenic VIP DCs have increased numbers of IL-10-producing CD8+CD28--CTLA4+ T cells. CD4 and CD8 Treg cells primarily suppress antigen-specific TH1-mediated responses. Therefore, the possibility of generating or expanding ex vivo tolerogenic DCVIPs opens new therapeutic perspectives for treating autoimmune diseases and graft-versus-host disease after allogeneic transplantation in humans.
Multiple Longevity Phenotypes and the Transition from Health to Senescence
Authors: ARKING ROBERT
Published: January 2006

Three different longevity phenotypes exist in Drosophila and other model systems, but only two are known in humans. The “missin” phenotype is the delayed onset of senescence phenotype, which can be induced by various interventions, including pharmaceuticals. The lability of the onset of senescence indicates that the mechanisms involved are plastic and can be altered. Only interventions that involve the upregulation of stress resistance genes, probably via the JNK pathway and/or dFOXO3a transcription factor, seem capable of generating a delayed onset of senescence phenotype. The data suggest that the cellular mechanisms responsible for maintaining the cell in a healthy state are under constant attack by ROS and/or abnormal protein accumulation. A stochastic growth factor/signal transduction failure may be the proximal event responsible for the decreased efficiency of the cell's defenses, resulting in the onset of senescence, degradation of the gene interaction network, and continuing loss of function.
Genetic Contribution to Aging: Deleterious and Helpful Genes Define Life Expectancy
Authors: LAO J I , MONTORIOL C , MORER I , BEYER K
Published: January 2006

For the best understanding of aging, we must consider a genetic pool in which genes with negative effects (deleterious genes that shorten the life span) interact with genes with positive effects (helpful genes that promote longevity) in a constant epistatic relationship that results in a modulation of the final expression under particular environmental influences. Examples of deleterious genes affecting aging (predisposition to early‐life pathology and disease) are those that confer risk for developing vascular disease in the heart, brain, or peripheral vessels (APOE, ACE, MTFHR, and mutation at factor II and factor V genes), a gene associated with sporadic late‐onset Alzheimer's disease (APOE E4), a polymorphism (COLIA1 Sp1) associated with an increased fracture risk, and several genetic polymorphisms involved in hormonal metabolism that affect adverse reactions to estrogen replacement in postmenopausal women. In summary, the process of aging can be regarded as a multifactorial trait that results from an interaction between stochastic events and sets of epistatic alleles that have pleiotropic age‐dependent effects. Lacking those alleles that predispose to disease and having the longevity‐enabling genes (those beneficial genetic variants that confer disease resistance) are probably both important to such a remarkable survival advantage.
Immunoregulation of Cellular Life Span
Authors: KAY MARGUERITE
Published: January 2006

Our current studies focus on the molecular changes induced by aging. During aging, changes in proteins occur that alter their function and render them immunogenic. These “neoantigen” are recognized by physiologic autoantibodies. Physiologic autoantibodies and their corresponding antigens offer therapeutic strategies for disease intervention through the innate immune response. Early studies done in the 1970s showed humans and animals to have physiologic antibodies that bind to a neoantigen called senescent cell antigen (SCA), which appears on senescent and damaged cells and initiates their removal by macrophages. These studies led to the discovery that oxidation can generate a new antigen in situ. Oxidation accelerated aging of red cells, generated SCA and IgG binding, and triggered removal of red cells by macrophages. Since then, a number of laboratories have found that oxidation can generate other neoantigens. For example, oxidized LDL (OxLDL) induces antibodies that can modify the natural progression of atherosclerosis. Apoptotic cells express oxidatively modified moieties on their surfaces that are involved in macrophage recognition and phagocytosis. Physiologic autoantibodies were used to isolate SCA from brain tissue. HPLC and fast atom bombardment ionization mass spectrometry (FAB‐MS) of the isolated antigen suggested that the aging antigen is a subset of band 3, a family of proteins also called anion exchange proteins (AE1–3). FAB‐MS results indicate that residues matching all three band 3 isoforms (AE1, AE2, and AE3) are detected in aging antigen fractions. Among the fragments identified with FAB‐MS was a sequence corresponding to an aging epitope, human band 3 sequence LFKPPKYHPDVPYVKR, residue 812–830 in AE1; HHPDVTYVK, residue 1144–1152 in AE2; or HHPEQPYVTK, residue 1135–1144 in AE3. A residue that is close to that region was identified in mouse AE1 ASGPGAAAQIQEVK, residue 762–775. The potential for altering the natural progression of diseases using select peptide‐defined epitopes within or overlapping the aging antigenic site (547–553 and 824–829) is discussed using the innate immune response to band 3 in malaria as an example.
Lunasensor, Infradian Rhythms, Telomeres, and the Chronomere Program of Aging
Authors: OLOVNIKOV ALEXEY
Published: January 2006

According to the redusome hypothesis, the aging of an organism is determined by the shortening of chronomeres (small perichromosomal linear DNA molecules). In this paper, a presumptive role for infradian hormonal rhythms is considered. Endogenous infradian rhythms are supposed to actively interact with those hormonal shifts which are governed by an exogenous infradian gravitational lunar rhythm. As a result of this interaction, the so‐called T‐rhythm is formed. Peaks of T‐rhythms are used as the pacemaker signals to keep the life‐long “clockwork” of the brain running. The “ticking” of this clock is realized by the periodically repeated shortening of chronomeres in postmitotic neuroendocrine cells, which occurs just at the maxima of T‐rhythms. Shortening of telomeres in mitotic cells in vivo is a witness of the aging of the organism, but not the cause of aging. The primary cause of aging is shortening of chronomeres, the material carriers of a temporal program of development and aging. To recognize exogenous gravitational infradian rhythms, a special physiological system—the “lunasensor” system—evolved. It is assumed that it is a necessity to have a lunasensor as a particular variant of sensors of gravitation.
The Rotational Origin and State of the Whole: Its Relation to Growth, Fertility, Aging, Death, and Diseases
Authors: PIERPAOLI WALTER
Published: January 2006

The purpose of my report is to synthetically summarize the concept of the rotatory essence of the Whole and to bring evidence that while aging responds to a precise inner “program” of the mammalian and any other species' “brain,” acceleration of aging and all diseases are simply the direct outcome of a desynchronization of our inner “clock” with respect to the precise periodicity and hormone‐integrated rhythmicity of the solar system. Those neuroendocrine, hormonal derangements of our inner clock are easily detectable and inevitably anticipate even by decades the onset of all diseases (autoimmune, cardiovascular, neurodegenerative, neoplastic). I will introduce those interventions capable of detecting early alterations and of restoring hormonal rhythmicity, which will consequently restore immunological surveillance in a positive cascade sequence.
The Pineal Aging and Death Program: Life Prolongation in Pre‐aging Pinealectomized Mice
Authors: PIERPAOLI WALTER , BULIAN DANIELE
Published: January 2006

A precise temporal program for growth, fertility, aging, and death exists in the “pineal complex” of the brain. It tracks, like a “clock,” the ontogenetic phases of our life program. Transplantation of a very old pineal gland into the thymus or under the kidney capsule of a young mouse produces acceleration of aging and early death. We investigated the existence of such an inner biological clock on the assumption that a time exists in the pineal program when the pineal gland actively starts to deliver aging and death “signal” to the body, thus accomplishing its genetically inscribed sequence. Groups of BALB/c male or female mice were surgically pinealectomized (PX) at the age of 3, 5, 7, 9, 14, and 18 months, and their life span was evaluated. Periodical measurements of blood and hormonal and metabolic parameters were taken. Results showed that while PX at the age of 3 and 5 months promotes acceleration of aging, no relevant effect of PX is observed in mice PX at 7 or 9 months of age. On the contrary, a remarkable life prolongation was observed when mice were PX at the age of 14 months. No effects were seen when the mice were PX at 18 months of age. The same aging‐promoting or ‐delaying effects were confirmed in the hematological and hormonal‐metabolic values measured. The findings demonstrate the existence of an evolutionary‐developmental role for the pineal complex during growth, fertility, and aging. The dominant role of the pineal in the initiation and progression of aging as a death signal is clear, but its nature and mechanism are totally unknown. In fact new experiments showed that an additional pineal gland from a young donor, when grafted into a young mouse, induces acceleration of aging. The significance of these intriguing findings is discussed.
Aging as a Mitochondria‐Mediated Atavistic Program: Can Aging Be Switched Off?
Authors: SKULACHEV VLADIMIR P. , LONGO VALTER D.
Published: January 2006

Programmed death phenomena have been demonstrated on subcellular (mitoptosis), cellular (apoptosis), and supracellular (collective apoptosis) levels. There are numerous examples of suicide mechanisms at the organismal level (phenoptosis). In yeast, it was recently shown that the death of aging cells is programmed. Many of the steps of programmed cell death are shown to be common for yeast and animals, including mammals. In particular, generation of the mitochondrial reactive oxygen species (ROS) is involved in the suicide programs. Aging of higher animals is accompanied by an increase in damage induced by mitochondrial ROS. Perhaps prevention of such damage by scavenging of mitochondrial ROS might slow down or even switch off the aging programs.
The Myth and Reality of Reversal of Aging by Hormesis
Authors: SONNEBORN JOAN SMITH
Published: January 2006

Hormesis is an adaptive response to low doses of otherwise harmful agents by triggering a cascade of stress‐specific resistance pathways. Evidence from protozoa, nematodes, flies, rodents, and primates indicate that stress‐induced tolerance modulates survival and longevity. “Realit” is that hormesis can prolong the healthy life span. Genetic background provides the potential for longevity duration induced by stress. Senesence, or aging, is generally thought to be due to a different impact of selection for alleles positive for reproduction during early life but harmful in later life, a process called antagonistic pleiotropy (multiple phenotypic changes by a single gene). After reproduction, life span is “invisible” to selection. I propose the revision that mutations selected for survival until reproduction in early life may also extend later life (protagonistic pleiotropy). The protagonist candidate genes for extended life span are hormetic response genes, which activate the protective effect in both early and later life. My revision of the earlier evolutionary theory implies that natural selection of genes critical for early survival (life span until reproduction) can also be beneficial for extended longevity in old age, tipping the evolutionary balance in favor of a latent inducible life span extension unless excess stressor challenge exceeds the protection capacity. Mimetic triggers of the stress response promise the option of tricking the induction of metabolic pathways that confer resistance to environmental challenges, increased healthy life span, rejuvenation, and disease intervention without the danger of overwhelmiong damage by the stressor. Public policy should anticipate an increase in healthy life span.
Protein Kinase C Signal Transduction Regulation in Physiological and Pathological Aging
Authors: BATTAINI FIORENZO , PASCALE ALESSIA
Published: January 2006

Calcium/phospholipid‐regulated protein kinase C (PKC) signalling is known to be involved in cellular functions relevant to brain health and disease, including ion channel modulation, receptor regulation, neurotransmitter release, synaptic plasticity, and survival. Brain aging is characterized by altered neuronal molecular cascades and interneuronal communication in response to various stimuli. In the last few years we have provided evidence that in rodents, despite no changes in PKC isoform levels (both calcium dependent and calcium independent), the activation/translocation process of the calcium‐dependent and ‐independent kinases and the content of the adaptor protein RACK1 (receptor for activated C kinase‐1) are deficient in physiological brain aging. Moreover, human studies have shown that PKC and its adaptor protein RACK1 are also interdependent in pathological brain aging (e.g., Alzheimer's disease); in fact, calcium‐dependent PKC translocation and RACK1 levels are both deficient in an area‐selective manner. These data point to the notion that, in addition to a well‐described lipid environment alteration, changes in protein‐protein interactions may impair the mechanisms of PKC activation in aging. It is interesting to note that interventions to counteract the age‐related functional loss also restore PKC activation and the adaptor protein machinery expression. A better insight into the factors controlling PKC activation may be important not only to elucidate the molecular basis of signal transmission, but also to identify new strategies to correct or even to prevent age‐dependent alterations in cell‐to‐cell communication.
Protection of Proteins from Oxidative Stress: A New Illusion or a Novel Strategy?
Authors: BOLDYREV ALEXANDER A.
Published: January 2006

Proteins damaged by oxidative stress have the most dangerous consequences. Oxidized protein derivatives inveigle lipids and carbohydrates into metabolic transformations that result in loss of protein functions and accumulation of glycated proteins and advanced glycated end products, which are difficult to remove from living tissues. Hydrophobic antioxidants are not very effective in protecting proteins from oxidative modification. At the same time, the natural hydrophilic antioxidant and anti‐glycating agent carnosine efficiently prevents oxidative modification of proteins and increases the life span of experimental animals under unfavorable conditions. It can be considered a potent natural geroprotector.
The Role of Hsp70 in Age‐Related Diseases and the Prevention of Cancer
Authors: PIERPAOLI EZRA V.
Published: January 2006

This article focuses on the structure, function, mode of action of one of the major heat shock proteins, Hsp70, and its implication in age‐related diseases and cancer.
Central and Peripheral Effects of Insulin/IGF‐1 Signaling in Aging and Cancer: Antidiabetic Drugs as Geroprotectors and Anticarcinogens
Authors: ANISIMOV VLADIMIR N. , BERSTEIN LEV M. , POPOVICH IRINA G. , ZABEZHINSKI MARK A. , EGORMIN PETER A. , TYNDYK MARGARITA L. , ANIKIN IVAN V. , SEMENCHENKO ANNA V. , YASHIN ANATOLI I.
Published: January 2006

Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. Insulin/insulin‐like growth factor 1 (IGF‐1) signaling molecules linked to longevity include DAF‐2 and insulin receptor (InR) and their homologues in mammals and to inactivation of the corresponding genes followed by increased life span in nematodes, fruit flies, and mice. It is possible that the life‐prolonging effect of caloric restriction are due to decreasing IGF‐1 levels. A search of pharmacological modulators of life span‐extending mutations in the insulin/IGF‐1 signaling pathway and mimetics of effects of caloric restriction could be a direction in the regulation of longevity. Some literature and our own observations suggest that antidiabetic drugs could be promising candidates for both life span extension and prevention of cancer.
The Phenomenon of the Switching of Estrogen Effects and Joker Function of Glucose: Similarities and Relation to Age‐Associated Pathology and Approaches to Correction
Authors: BERSTEIN LEV M. , TSYRLINA EVGENIA V. , VASILYEV DMITRY A. , POROSHINA TATJANA E. , KOVALENKO RINA G.
Published: January 2006

Estrogens and glucose are characterized by a myriad of functions that can be reduced to a small number of principal actions. In aging there is a simultaneous increase in the prevalence of diseases connected with estrogen deficiency as well as with estrogenic excess and associated with the phenomenon of the switching of estrogen effects (PSEE). Estrogens possess hormonal and genotoxic properties. An increase in genotoxic effect (isolated or combined with a decrease in hormonal effect) can influence the course of age‐associated diseases that, contrary to the situation with adaptive hypersensitivity to estrogens, may become less favorable or more aggressive. Inductors of PSEE include smoking, irradiation, and aging. Yet with “glycemic load” and the endocrine effect of glucose (the stimulation of insulin secretion), reactive oxygen species are formed in multiple sites, including adipose tissue. The ratio between hormonal and genotoxic effects reflects a “joke” function of glucose and can be conditioned by endogenous (perhaps including genetic) and exogenous factors. The shift in this glucose‐associated ratio may selectively encourage some chronic non‐communicable diseases. Several groups of treatments can be distinguished including alleviators of PSEE and insulin resistance syndrome (biguanides, glitazones, statins, modifiers of adipocytokines secretion, etc.) as well as other compounds aimed to optimally orchestrate the balance between endocrine and DNA‐damaging effects of estrogens and glucose.
Immunomodulation by Immunopeptides and Autoantibodies in Aging, Autoimmunity, and Infection
Authors: MARCHALONIS J J , SCHLUTER S F , SEPULVEDA R T , WATSON R R , LARSON D F
Published: January 2006

The operation of the immune system is a complex orchestration of specific self and non‐self‐recognition capacities mediated by cells of the innate system acting in coordination with T and B lymphocytes in a series of processes modulated by cytokines. We provide evidence for a natural immunomodulatory system involving autoantibodies directed against a controlling segment of T cell receptor Vβ chains that downregulate production of stimulatory cytokines balanced by the peptides which in turn upregulate inflammatory activities mediated by TH1‐type helper cells. TCR Vβ‐derived peptides effective in retrovirally induced immunosupression could also reverse the effects of immunosenescence in aged mice by restoring the balance of TH1‐ and TH2‐type immunity and the resistance of the animals to cardiac pathology caused by infection with coxsackievirus. An unexpected finding was an adaptive role of the T cells from peptide‐treated mice in remodeling damaged hearts by increasing net collagen synthesis by cardiac fibroblasts.
The Neuronal and Immune Memory Systems as Supervisors of Neural Plasticity and Aging of the Brain: From Phenomenology to Coding of Information
Authors: JOVANOVA‐NESIC KATICA D. , JANKOVIC BRANISLAV D.
Published: January 2006

The ultimate goal of this report is to learn how to manipulate the level of memory T cells for more effective treatment of such neurological diseases as multiple sclerosis (MS), where certain T cell subsets recognize self‐antigens as opposed to pathogen antigens, and Alzheimer's disease (AD). Brain lesions (electrolitically, by kainic acid, with AlCl, and with 6‐OHDA); stimulations (electrical, magnetic, or pharmacological); or restoration of some neurological functions (thermoregulatory and behavioral) by fetal graft allotransplantations in bilaterally lesioned anterior hypothalamic area (AHA‐immune regulation) and nucleus basalis magnocellularis (NBM‐experimental AD) in our studies were designed to reproduce immune and cognitive deficits induced by lesions of these brain structures. To localize memory traces in the immune system and in the brain we used ethanol and drugs such as kainic acid and 6‐OHDA, which have been used very effectively to produce temporary lesions in the brain. Rats showed no learning and memory ability as well as inhibition of immune reactions.
Hormones Are Key Actors in Gene X Environment Interactions Programming the Vulnerability to Parkinson's Disease: Glia as a Common Final Pathway
Authors: MARCHETTI BIANCA , SERRA PIER ANDREA , L'EPISCOPO FRANCESCA , TIROLO CATALDO , CANIGLIA SALVO , TESTA NUCCIO , CIONI SERENA , GENNUSO FLORINDA , ROCCHITTA GAIA , DESOLE MARIA SPERANZA , MAZZARINO MARIA CLORINDA , MIELE EGIDIO , MORALE MARIA CONCETTA
Published: January 2006

Alterations in developmental programming of neuroendocrine and immune system function may critically modulate vulnerability to various diseases. In particular, genetic factors, including gender, may interact with early life events such as exposure to hormones, endotoxins, or neurotoxins, thereby influencing disease predisposition and/or severity, but little is known about the role of the astroglial cell compartment and its mediators in this phenomenon. Indeed, in the context of innate inflammatory mechanisms, a dysfunction of the astroglial cell compartment is believed to contribute to the selective degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta in Parkinson's disease (PD) and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) model of PD. Hence, in response to brain injury the roles of astrocytes and microglia are very dynamic and cell type‐dependent, in that they may exert the known proinflammatory (harmful) effects, but in certain circumstances they can turn into highly protective cells and exert anti‐inflammatory (beneficial) functions, thereby facilitating neuronal recovery and repair. Here, we summarize our work suggesting a chief role of hormonal programming of glial response to inflammation and oxidative stress in MPTP‐induced loss of DA neuron functionality and demonstrate that endogenous glucocorticoids and the female hormone estrogen (E2) inhibit the aberrant neuroinflammatory cascade, protect astrocytes and microglia from programmed cell death, and stimulate recovery of DA neuron functionality, thereby triggering the repair process. The overall results highlight glia as a final common pathway directing neuroprotection versus neurodegeneration. Such recognition of endogenous glial protective pathways may provide a new insight and may contribute to the development of novel therapeutic treatment strategies for PD and possibly other neurodegenerative disorders.
Neurodegenerative Diseases: A Common Etiology and a Common Therapy
Authors: PIERPAOLI WALTER
Published: January 2006

The variety of names of neurodegenerative diseases (NDDs) does not indicate that there is a wide variety of causes and a multiple number of cures. In fact NDDs derive from a common and repetitive, almost monotonous multicausal origin. NDDs are initiated invariably by a sudden or silent insidious decrease in immunologic resistance of the T cell‐dependent or delayed type, produced by a large variety of psychological‐emotional and/or environmental “stressors” (e.g., social, family‐domestic, economic, alimentary, traumatic, and professional). These stressors increase the vulnerability of tissues (in this case, a section of the central or peripheral nervous system) to attack by a common virus (e.g., adenoviruses and herpesviruses). This attack creates a vicious circle leading to emergence of virus‐generated tissue autoantigens and then to formation of autoantibodies. Use of corticosteroids and immunosuppressive drugs dramatically worsen and “eternalize” the diseases with further immunosuppression. Invariably, onset of NDDs is anticipated by a clear‐cut alteration of the hormonal cyclicity, which closely controls immunity. My experience with patients in the last five years indicates a new approach to prevent and cure NDDs, based on a system totally divergent from present therapies. In fact “resetting the hormonal cyclicity cloc” results in restoration of hormone‐dependent antiviral immunity, arrest of disease progression, and at least partial recovery of neural functions, whatever the origin, anatomic location, and course of pathology.
Clinical Perspectives for the Use of Melatonin as a Chronobiotic and Cytoprotective Agent
Authors: CARDINALI DANIEL P. , FURIO ANALÍA M. , REYES MARÍA P.
Published: January 2006

The circadian time system involves periodic gene expression at the cellular level, synchronized by a hierarchically superior structure located in the hypothalamic suprachiasmatic nuclei. Treatment of circadian rhythm disorders has led to the development of a new type of agent called “chronobiotics” among which melatonin is the prototype. In elderly insomniacs, melatonin treatment decreased sleep latency and increased sleep efficiency, particularly slow‐wave sleep. The effect of melatonin on sleep is the consequence of increasing sleep propensity (by augmenting the amplitude of circadian clock oscillation via MT1 receptors) and of synchronizing the circadian clock via MT2 receptors. Daily melatonin production decreases with age and in several pathologies, attaining its lowest values in Alzheimer's disease (AD) patients. About 45% of AD patients have disruptions in their sleep and “sundowning” agitation. Generally, melatonin treatment decreases sundowning in AD patients and reduced variability of sleep onset time. Both open and controlled studies have indicated a significant decrease of cognitive deterioration in AD patients treated with melatonin. The mechanisms accounting for the possible therapeutic effect of melatonin in AD patients may be manifold. On one hand, melatonin treatment promotes slow‐wave sleep in the elderly and could be beneficial by augmenting the restorative phases of sleep. On the other hand, melatonin protects neurons against β‐amyloid toxicity. By its combined chronobiotic and cytoprotective properties melatonin provides an innovative neuroprotective strategy to reduce the cost of lifetime treatment of some neuropsychiatric disorders.
Melatonin Influences on the Neuroendocrine‐Reproductive Axis
Authors: DÍAZ LÓPEZ BEATRIZ , RODRÍGUEZ E DÍAZ , URQUIJO COLMENERO , ÁLVAREZ C FERNÁNDEZ
Published: January 2006

The neuroendocrine‐reproductive axis designates the functional activity of the hypothalamus‐pituitary‐gonadal axis. A delicate synchronization of many inputs at these three different levels is vital for normal reproductive function. From the median basal hypothalamus, the median eminence releases gonadotrophin releasing hormone into the portal circulation to reach the anterior pituitary gland. Gonadotrophin releasing hormone is obviously a key hormone for the regulation of the secretion of gonadotrophins LH and FSH.
Caloric Restriction Mimetics: The Next Phase
Authors: ROTH GEORGE S. , LANE MARK A. , INGRAM DONALD K.
Published: January 2006

Calorie restriction (CR) mimetics are agents or strategies that can mimic the beneficial health‐promoting and anti‐aging effects of CR, the only intervention conclusively shown to slow aging and maintain health and vitality across the phylogenetic spectrum. Our lead compound, developed at the National Institute on Aging, was 2‐deoxyglucose, an analogue of the native sugar, that acted as a glycolytic inhibitor, having limited metabolism and actually reducing overall energy flow—analogous to CR. This agent reduced insulin levels and body temperature of rats, similar to the physiological effects of CR, but toxicity was noted in long‐term studies, which apparently prevented life‐span extension. We previously demonstrated that lower insulin and body temperature (as well as maintenance of dehydroepiandrosterone levels) correlate with longevity in non‐CR humans. The recent work of other investigators shows that humans subjected to short‐term CR also have lower insulin and body temperature. Obviously, longer‐term CR is extremely difficult to maintain; hence, the need for CR mimetics. The next phase of calorie restriction studies includes basic investigations as well as possible clinical trials of a number of candidate CR mimetics, ranging from glycolytic inhibitors to lipid‐regulating agents to antioxidants and specific gene modulators. The scope of these ongoing studies in various laboratories, as well as their practical implications, are reviewed and analyzed here.
Mechanisms Regulating Melatonin Synthesis in the Mammalian Pineal Organ
Authors: SCHOMERUS CHRISTOF , KORF HORST‐WERNER
Published: January 2006

The day/night rhythm in melatonin production is a characteristic feature in vertebrate physiology. This hormonal signal reliably reflects the environmental light conditions and is independent of behavioral aspects. In all mammalian species, melatonin production is regulated by norepinephrine, which is released from sympathetic nerve fibers exclusively at night. Norepinephrine elevates the intracellular cAMP concentration via β‐adrenergic receptors and activates the cAMP‐dependent protein kinase A. This pathway is crucial for regulation of the penultimate enzyme in melatonin biosynthesis, the arylalkylamine N‐acetyltransferase (AANAT); cAMP/protein kinase A may, however, act in different ways. In ungulates and primates, pinealocytes constantly synthesize AANAT protein from continually available Aanat mRNA. During the day—in the absence of noradrenergic stimulation—the protein is immediately destroyed by proteasomal proteolysis. At nighttime, elevated cAMP levels cause phosphorylation of AANAT by protein kinase A. This posttranslational modification leads to interaction of phosphorylated AANAT with regulatory 14–3–3 proteins, which protect AANAT from degradation. Increases in AANAT protein are paralleled by increases in enzyme activity. Stimulation of the cAMP/protein kinase A pathway may also activate pineal gene expression. In rodents, transcriptional activation of the Aanat gene is the primary mechanism for the induction of melatonin biosynthesis and results in marked day/night fluctuations in Aanat mRNA. It involves protein kinase A‐dependent phosphorylation of the transcription factor cyclic AMP response element‐binding protein (CREB) and binding of phosphorylated CREB in the promoter region of the Aanat gene. In conclusion, a common neuroendocrine principle, the nocturnal rise in melatonin, is controlled by strikingly diverse regulatory mechanisms. This diversity has emerged in the course of evolution and reflects the high adaptive plasticity of the melatonin‐generating pineal organ.
Modulatory Factors of Circadian Phagocytic Activity
Authors: HRISCU MONICA L.
Published: January 2006

Basal phagocytosis of neutrophils, a crucial component of non‐specific immunity, is an eminently circadian parameter. In mice and rats, rates of phagocytosis peak in the second half of the dark span. A lipopolysaccharide‐induced phagocytic response challenged in this period appears the most significant in amplitude and duration. Neonatal administration in rats of the neurotoxic agent monosodium glutamate, which induces massive destruction of the arcuate nucleus, suppresses the phagocytic response and moderately inhibits basal phagocytosis. Physiological phagocytosis in vivo appears to depend on the presence of the nocturnal melatonin surge. Functional pinealectomy, achieved in rats by a 2‐week exposure to constant light, lowered the average circadian level of phagocytosis, damped the characteristic rhythm of neutrophil adherence, and decreased the neutrophil count and the amplitude of its circadian oscillation. In an in vivo study, adult rats were given alcohol intraperitoneally (0.1 mL ethanol/kg body weight, 1:10 in saline solution), alone or co‐administered with melatonin (1 mg/kg body weight), for 16 days, once a day at 20:00 h. Alcohol‐treated animals displayed a drastically depressed and flattened phagocytic curve, a marked decline of the adherence ability, and a reduction of the mean circadian neutrophil and lymphocyte count. Addition of melatonin significantly increased circadian values of phagocytosis, restored adherence, and prevented the numeric depletion of lymphocytes induced by alcohol. In correlation with other experimental evidence, our data speak for a physiological role of melatonin in upkeep of neutrophil phagocytosis and hint towards the existence of several pineal‐hypothalamic pathways regulating different components of phagocytosis in vivo.
The Role of NF‐κB in Protein Breakdown in Immobilization, Aging, and Exercise: From Basic Processes to Promotion of Health
Authors: BAR‐SHAI MARINA , CARMELI ELI , REZNICK ABRAHAM Z.
Published: January 2006

Between the ages of 20 and 80 years, humans lose about 20–30% of their skeletal muscle weight. This phenomenon has been termed sarcopenia of old age and is directly involved in the well‐being of the aged. With aging, people tend to be less mobile and are frequently bedridden, which exacerbates the muscle weight loss. The molecular mechanisms responsible for the muscle protein breakdown during immobilization in aging have been studied in our laboratory in a model of 24‐month‐old Wistar rats, immobilized for 4 weeks. Subsequently we investigated the activation of the intracellular and extracellular proteolytic systems in the immobilized muscles. A similar group of young (6‐month‐old) rats was examined and compared to the older rats. The involvement of NF‐κB transcription factor in muscle atrophy was assessed in immobilized muscles of young and old animals. There were marked differences in the kinetics and the pattern of NF‐κB activation in young versus old muscles. It seems that in both young and old animals in the early stages of limb immobilization, an alternative pathway of NF‐κB activation can be observed. However, in late stages of immobilization, the canonic pathway of NF‐κB activation (p65/p50 complex with I‐κB α degradation) is predominant. Interestingly, the canonic activation pathway is more prominent in muscles from old animals compared to young ones. The activation of NF‐κB has been observed also in muscles subjected to acute and intense exercise, implying that inflammatory processes may take place under the conditions of intense exercise. This may cause muscle damage and protein breakdown. Therefore, using NF‐κB pathway inhibitors may prove beneficial in attenuating NF‐κB‐associated muscle damage in both disuse atrophy and strenuous exercise.
Stress‐Induced Hypocortisolemia Diagnosed as Psychiatric Disorders Responsive to Hydrocortisone Replacement
Authors: SCHUDER SUZIE E.
Published: January 2006

In patients of all ages, many disorders labeled as psychiatric may actually be due to hormonal insufficiencies. For example, cortisol deficiency is rarely taken into account in a medical or psychiatric work‐up, so persons with mild to moderate cortisol insufficiency are for the most part relegated to receiving a psychiatric diagnosis when, in fact, the same disorder is represented. However, the symptoms of cortisol insufficiency appear to closely parallel such psychiatric disorders as post traumatic stress disorder (PTSD) and addictions. There has been some question of whether substance abuse causes a hypocortisolemic state. In reviewing the literature and obtaining detailed histories of addicted patients, it appears that childhood trauma, also known as “early life stres” (ELS), instead may elicit a hypocortisolemic state. This leads some to self‐medicate with an addictive substance to quell the pain of a cortisol insufficiency, both physical and emotional. In fact, the literature supports the concept that addictive substances increase cortisol in predisposed patients. Patients with a variety of psychiatric disorders including addictions were found to have signs and symptoms of mild or moderate hypocortisolemia. Generally, an appropriate comprehensive examination supported a diagnosis of cortisol insuffiency. For the most part, these patients were succesfully treated with physiologic doses of bio‐equivalent hydrocortisone, along with replacement of any other deficient hormone. By correcting underlying hormonal insufficiencies, many patients improved, with some patients having a total reversal of psychiatric symptoms. It is therefore reasonable to evaluate and treat hormonal insufficiencies with hormones prior to using psychotropic medication.
Use of Telomerase to Create Bioengineered Tissues
Authors: SHAY JERRY W. , WRIGHT WOODRING E.
Published: January 2006

Telomeres are repetitive DNA (TTAGGG) elements at the ends of chromosomes. Telomerase is a ribonucleoprotein complex that catalyzes the addition of telomeric sequences to the ends of chromosomes. The catalytic protein component of telomerase (hTERT) is expressed only in specific germ line cells, proliferative stem cells of renewal tissues, and cancer cells. The expression of hTERT in normal cells reconstitutes telomerase activity and circumvents the induction of senescence. Telomeres shorten with each cell division, eventually leading to senescence (aging), due to incomplete lagging DNA strand synthesis and end‐processing events, and because telomerase activity is not detected in most somatic tissues. There are specific tissues and locations in which replicative senescence likely contributes to the decline in human physiological function with increased age and with chronic illnesses. While expressing hTERT in cells results in the maintenance of telomere length and greatly extended life span, blocking replicative aging systemically would be predicted to increase the potential for tumor formation. However, there are many situations in which the transient rejuvenation of cells could be beneficial. Ectopic expression of hTERT has been shown to immortalize human skin keratinocytes, dermal fibroblasts, muscle satellite (stem), and vascular endothelial, myometrial, retinal‐pigmented, and breast epithelial cells. In addition, human bronchial, corneal and skin cells expressing hTERT can be used to form organotypic (3D) cultures (bioengineered tissues) that express differentiation‐specific proteins, demonstrating that hTERT by itself does not alter normal physiology. The production of hTERT‐engineered tissues offers the possibility of producing tissues to treat a variety of chronic diseases and age‐related medical conditions that are due to telomere‐based replicative senescence.
Bio‐Identical Steroid Hormone Replacement: Selected Observations from 23 Years of Clinical and Laboratory Practice
Authors: WRIGHT JONATHAN V.
Published: January 2006

To maximize the safety and efficacy of human hormone replacement therapy, it is suggested that exact molecular copies of human hormones (“bio‐identica” hormones) be administered in physiologic quantities and proportions, following physiologic timing and routes of administration. It is also suggested that physicians return to the practice of monitoring hormone therapy by precise laboratory measurement levels of the hormones administered. This paper also presents clinical and laboratory data concerning appropriate proportions of bio‐identical estrogens, the physiologic and supraphysiologic nature of commonly employed doses, estrogen levels achieved by varying routes of administration, and the significant effects of iodine on estrogen metabolism and cobalt on estrogen excretion.
Can We Delay Aging? The Biology and Science of Aging
Authors: ANTON B , VITETTA L , CORTIZO F , SALI A
Published: January 2006

Long before the fountain of youth, mankind has had an interest in staying young. As we move into the 21st century, that interest has not only continued, but it has become an obsession. While no one can really prevent normal, chronological aging, there are things we can do to slow down “pathological aging.” After all, aging is about accelerated inflammation, depletion, and wear and tear. With the marked increase in life expectancy and life span, clinicians need to be aware of the effects of aging on the provision of treatment modalities. Appropriate interventions individualized to the patient can help to “compress morbidity” by shortening the period of functional decline common in old age. Therefore, the “health span” will come closer to matching the life span. Disease and disuse are far more likely explanations for functional decline and the onset of common chronic conditions in older persons than is “tru” natural or normal aging. Regardless of your genetic inheritance, you can accelerate aging by lifestyle choices and environmental conditions to which you expose your genes. There are even ways to reverse the problems associated with aging. Getting older does not have to mean growing older. Welcome to the world of preventative gerontology, better known asanti‐aging medicine!
New Horizons for the Clinical Specialty of Anti‐aging Medicine: The Future with Biomedical Technologies
Authors: KLATZ RONALD
Published: January 2006

Anti‐aging medicine is a medical specialty founded on the application of advanced scientific and medical technologies for the early detection, prevention, treatment, and reversal of age‐related dysfunction, disorders, and diseases. It is a health care model promoting innovative science and research to prolong the healthy life span in humans. As such, anti‐aging medicine is based on principles of sound and responsible medical care consistent with those applied in other preventive health specialties. Because it embraces the use of biomedical technology, anti‐aging medicine offers a hopeful model of health care in which healthy human life spans of 120 years and longer may be achieved—if we employ anti‐aging therapeutics today, and encourage the continued expansion of biomedical technologies to prevent, treat, and cure diseases.
The Need for Anti‐aging Medicine: The Challenges Faced to Incorporate Preventative Medicine into the Clinic and into Society
Authors: MICANS PHILIP
Published: January 2006

The world's population is getting older and this fact is made clear by the aging demographics of both developed and developing countries. Projections estimate that there will be very sharp rises in the numbers of people over the age of 50, and very small increases expected in those under 15. From these facts, we judge that the costs of traditional health care based on the current “nationalistic” model will struggle to be met unless they undergo a radical alteration. A number of possible solutions are debated, ending in a conclusion that a liberal society is likely to choose preventative medicine as the next health care model for the twenty‐first century. To this end, the concept of anti‐aging preventative medicine is tackled, including some of the difficulties involved with bringing this new arm of medicine into the clinical environment. Also discussed is the challenge of biological age measurement, to assist in the determination of the actual level of health in a “health” person, with a view to an optimal health, rather than just normal health. Anti‐aging medicine is a new concept, one that enables individuals to work with health care professionals in a different way and to take better care of themselves. It is in everyone's interests to understand that there is a need for preventative medicine in our societies and that this information is conveyed effectively to the public.