Aging-reversing properties of thyrotropin-releasing hormone.

Thyrotropin-releasing hormone (TRH) aroused our interest when we were engaged in related experiments, so we decided to study its effects on organs, tissues, and aging-related metabolic and hormonal markers when administered in acute or chronic (oral) doses at various time points in its cyclic circadian pattern. We also wanted to determine what effects, if any, it had on aging processes in two essential systems, namely gonadal-reproductive and kidney-urinary. Our results show positive changes as a result of short-term acute and long-term chronic oral administration of TRH to old mice that included rapid correction to more juvenile levels of most typical aging-related hormonal and metabolic measurements. Remarkably, testes function was maintained by means of a 4-month oral treatment with TRH in aging mice. As we suspected upon seeing a significant increase in testes weight, TRH resulted in maintenance or even reconstitution of testes structure and function when administered in the drinking water. This was demonstrated by the active formation and proliferation of mature spermatogonia and the intensive spermatogenesis in the follicles. The same TRH treatment led to protection for the kidneys from amyloid and hyalin infiltration of tubuli and glomeruli, which typically occurs in aging mice. In fact, we observed massive deposits of amyloid and hyalin material infiltrating the shrunken glomeruli and negatively affecting filtration capacity of the untreated mice, whereas this was barely present in the TRH-treated mice. Advanced hyalin degeneration could also be observed in the tubular vessels of the untreated control mice. These experiments with TRH supplementation show clear aging-delaying and apparently even aging-reversing effects of the neuropeptide, whether it was administered parenterally or orally. TRH, like melatonin, is an anti-aging agent with a broad spectrum of activities that, because of their actions, suggest that TRH has a fundamental role in the regulation of metabolic and hormonal functions.

Cancer and the endogenous "pineal clock": a means of early diagnosis and successful treatment as well as prevention of cancers.

The majority of chronic diseases, most notably those accompanying aging, result from progressive deterioration of central neuroimmunoendocrine control, often referred to as immunological surveillance. This is as true of cancer as it is of the development of cardiovascular, autoimmune, and neurodegenerative disease, in all of these immunological surveillance break downs, leading to an unraveling of the neuroimmunoendocrine process that inhibits proliferation of preneoplastic and neoplastic cells already existing in the body. The onset of cancer is anticipated by changes in the hormonalimmune coordination resulting in chronic quantitative alterations in the synthesis and release of hormones and the loss of the natural synchronicity of that release, which occurs according to circadian rhythms in the healthy organism, principally under the control of the pineal network. Periodic circadian hormonal release is the source of immune system regulation, thus altering hormone rhythms impairs the immune system's ability to maintain control over emerging tumor cells, not necessarily to eliminate them, but to inhibit proliferation. Malignancy, then, is the result of suppression of or interference with the regular release of hormones that maintain strict regulation of the thymo-lymphatic immune system's maturation and activity. This understanding means that we can act to prevent cancer by means of efficiently monitoring and maintenance of physiological hormonal values. For the cyclic synthesis of malignancies that are metastasized, a means of xenogeneic bone marrow transplantation is proposed as an alternative therapeutic approach.

Biological baseline of joint self-repair procedures.

Gel-Repairer is a biomaterial composed of Polydeoxyribonucleotides (Pdrn), Heat Shock Proteins (Hsps) and a thickening substance. It works as a local mesenchymal stem cells (MSCs) stimulator, finally generating connective tissue renewal. Our research is within the field of regenerative medicine and has historically built its foundation from the studies carried out on non-vital amnion and placental membranes. Our end point is the activation and stimulation of the local mesenchymal stem cells (MSCs) for the structural recovery of the joint involved in the degenerative process. Since 2003, we have been applying the Gel Repairer over more than 1200 patients, most of them elderly, affected by Degenerative Joint Disease (DJD). After 10 years of clinical experience, the results are really impressive, including the absence of toxicity, adverse reactions or side effects. Our clinical findings allowed the presentation of a clinical preliminary study performed on a large group of patients from 2003 to 2009 and recently published [1]. The following article is aimed at looking into the mechanism of action of the Joint Self-Repair procedure; furthermore some new technical opportunities are presented on tissue engineering advances in this fast evolving sector.

Effects of long-term intraperitoneal injection of thyrotropin-releasing hormone (TRH) on aging- and obesity-related changes in body weight, lipid metabolism, and thyroid functions.

Adult adipose mice, high fat diet-fed (HFD) mice, anterior hypothalamus-lesioned obese mice and genetically obese mice, were injected daily with thyrotropin releasing hormone (TRH). The treatment provoked a mobilization of triglycerides in the peripheral blood, a decrease of leptin and a loss of body weight. The weight loss did not depend on TSH-mediated stimulation of thyroid hormone secretion with consequent metabolic hyperthyroidism. The levels of blood cholesterol were not affected or even suppressed. Even at a very high dosage TRH did not affect the obesity of genetically obese mice. The ubiquitous tripeptide TRH may thus constitute a key element in the hormone-controlled regulation of body weight and fat stores in the adult and aging body.

The rotational origin and state of the whole: its relation to growth, fertility, aging, death, and diseases.

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.

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 "signals" 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.

Neurodegenerative diseases: a common etiology and a common therapy.

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 clock" 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.

Effects of melatonin in age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of severe visual loss in aged people. Melatonin has been shown to have the capacity to control eye pigmentation and thereby regulate the amount of light reaching the photoreceptors, to scavenge hydroxyradicals and to protect retinal pigment epithelium (RPE) cells from oxidative damage. Therefore, it is reasonable to think that the physiological decrease of melatonin in aged people may be an important factor in RPE dysfunction, which is a well known cause for initiation of AMD. Our purpose is to explore a new approach to prevent or treat AMD. We began case control study with a follow-up of 6 to 24 months. One hundred patients with AMD were diagnosed and 3 mg melatonin was given orally each night at bedtime for at least 3 months. Both dry and wet forms of AMD were included. Fifty-five patients were followed for more than 6 months. At 6 months of treatment, the visual acuity had been kept stable in general. Though the follow up time is not long, this result is already better than the otherwise estimated natural course.1,2 The change of the fundus picture was remarkable. Only 8 eyes showed more retinal bleeding and 6 eyes more retinal exudates. The majority had reduced pathologic macular changes. We conclude that the daily use of 3 mg melatonin seems to protect the retina and to delay macular degeneration. No significant side effects were observed.

Prevention of Fas-mediated hepatic failure by transferrin.

Recent studies in lymphohemopoietic cells show that transferrin (Tf), a pivotal component of iron transport and metabolism, also exerts cytoprotective functions. We show here in a murine model that Tf interferes with Fas-mediated hepatocyte death and liver failure. The mechanism involves the downregulation of apoptosis via BID, cytochrome c, caspase-3 and caspase-9, and upregulation of antiapoptotic signals via Bcl-xL. The results obtained with iron-saturated Tf, Apo-Tf and the iron-chelator salicylaldehyde isonicotinoyl hydrazone indicate that the observed antiapoptotic effect of Tf was not mediated by iron alone. In conclusion, the data suggest that Tf has broader functions than previously recognized and may serve as a cytoprotective agent.

The pineal neurohormone melatonin and its physiologic opiatergic immunoregulatory role

The pineal gland functions as a neuroendocrine transducer that coordinate the organism response to changing environmental stimuli such as light and temperature. The main and best known pineal neurohormone is melatonin that is synthesized and released in a circadian fashion with a peak during the night darkness hours. We have recently reported that melatonin exerts important immuno regulatory functions. Here we describe the astonishing property of exogenous melatonin which is able to counteract completely the depressive effect of anxiety-restraint stress and/or of corticosterone on thymus weight, andibody production and antiviral responses. This effect seems to be mediated by antigen-activated T cells via an opiatergic mechanism.