Current Aging Science - Volume 1, Issue 1, 2008

Fascinating biological questions cluster around the phenomenon of development and aging. Does every species age in the same way as the human? Is there a fundamental process of “aging” common to all organisms? How does aging occur in plants? How does the aging process deviate from the “normal” to cause aging-related disorders in long-lived species? Can one prevent and/or modify the aging process? How do environment and genes play a part in this process? Can we learn something from various human lifestyles, diets, cultures, environments and even from other species in order to enhance healthy aging? Indeed, the quest to maintain healthy, long life by mankind has been going on from time immemorial. We are just beginning to answer some of these questions from current research work. The major characteristics of aging are the deteriorative changes with time during postmaturational life and progressive inability to withstand stresses, making the organism vulnerable to disease and increasing the risk of death [1]. Various lines of research are helping us to understand the mechanisms of aging. First, the metabolically-based “Free radical damage theory” may explain some aspects of aging [2]. Studies on the biology of aging suggest that it results from normal processes that living cells employ to “burn fuel” supplying life's most important necessity, energy. Paradoxically, this indirectly results in much of the disease and disability that characterizes aging in humans and other animals. Indeed, free oxygen radicals, which are chemically unstable by-products of cellular oxidation, can start and propagate the deterioration of cell membranes and macromolecules [2,3]. Such accumulation of small “hits” causing cellular injury has far-reaching results ranging from uncorrected mutations and cancers to Alzheimer's disease and vascular pathology [3]. Alzheimer's disease, heart disease, stroke and diabetes are now among the leading causes of aging-related death in the United States [4], and they are increasing as the median age of US residents increases. These diseases are a major focus of current biomedical research, and their pathology is related to the aging process in complex ways. From the point of view of evolutionary biology, it is proposed that increases in brain size and the human life span over the past million years were happening along with changes in nutritional priorities and slower developmental rates [5]. These changes were accompanied by resistance for inflammation during the extreme prehistoric environments [5]. Findings from a wide range of disciplines point toward reduced levels of inflammation as a key factor in the recent increase in human life-spans. From the dietary perspective, the inclusion of more meat into the human diet supplied protein needed for larger brains but involved new physiological and genetic trade-offs between fitness and risk for long-term damage [6]. This scenario provides an adequate rationale for why variants of some genes for metabolizing animal fat (such as those of the ApoE gene family), which are linked to a human predisposition for atherosclerosis, some cancers, and the amyloid plaques of Alzheimer's disease, are not shared by our closest primate relatives [6]. Similarly, a diet too rich in animal fat may result in increasing exposure to pathogenic microbes and exacerbating inflammation and may accelerate aging. In the same topic of diet, current research in calorie restriction is another important line of aging research. Indeed, dietary restriction affects life-span and spontaneous cancer incidence [7]. From the point of reproductive physiology, the recent study of reproductive aging in female birds is quite fruitful and birds serve as a good model to study oxidative damage [8]. Regarding the role of hormones, measurements of serum levels of a number of potential steroidal and peptidic neuroendocrine aging markers have recently shed some important light into the human male aging progression [9]............

Accumulation of oxidatively altered cell components may play a role in the age-related cell deterioration and associated diseases. Caloric restriction is the most robust anti-aging intervention that extends lifespan and retards the appearance of age-associated diseases. Autophagy is a highly conserved cell-repair process in which the cytoplasm, including excess or aberrant organelles, is sequestered into double-membrane vesicles and delivered to the degradative vacuoles. Autophagy has an essential role in adaptation to fasting and changing environmental conditions. Several pieces of evidence show that autophagy may be an essential part in the anti-aging mechanism of caloric restriction: 1. The function of autophagy declines with increasing age; 2. The temporal pattern of the decline parallels the changes in biomarkers of membrane aging and in amino acid and hormone signalling. 3. These age-dependent changes in autophagy are prevented by calorie restriction. 4. The prevention of the changes in autophagy and biomarkers of aging co-varies with the effects of calorie restriction on life-span. 5. A long-lasting inhibition of autophagy accelerates the process of aging. 6. A long-lasting stimulation of autophagy retards the process of aging in rats. 7. Stimulation of autophagy may rescue older cells from accumulation of altered mtDNA. 8. Stimulation of autophagy counteracts the age-related hypercholesterolemia in rodents. It is suggested that the pharmacological intensification of suppression of aging (P.I.S.A. treatment) by the stimulation of autophagy might prove to be a big step towards retardation of aging and prevention of age-associated diseases in humans.

The Mitochondrial Free Radical Theory of Aging (MFRTA) proposes that mitochondrial free radicals, produced as by-products during normal metabolism, cause oxidative damage. According to MFRTA, the accumulation of this oxidative damage is the main driving force in the aging process. Although widely accepted, this theory remains unproven, because the evidence supporting it is largely correlative. For example, long-lived animals produce fewer free radicals and have lower oxidative damage levels in their tissues. However, this does not prove that free radical generation determines life span. In fact, the longest-living rodent -Heterocephalus glaber- produces high levels of free radicals and has significant oxidative damage levels in proteins, lipids and DNA. At its most orthodox MFRTA proposes that these free radicals damage mitochondrial DNA (mtDNA) and in turn provoke mutations that alter mitochondrial function (e.g. ATP production). According to this, oxidative damage to mtDNA negatively correlates with maximum life span in mammals. However, in contrast to MFRTA predictions, high levels of oxidative damage in mtDNA do not decrease longevity in mice. Moreover, mice with alterations in polymerase gamma (the mitochondrial DNA polymerase) accumulate 500 times higher levels of point mutations in mtDNA without suffering from accelerated aging. Dietary restriction (DR) is the only non-genetic treatment that clearly increases mean and maximum life span. According to MFRTA caloric restricted animals produce fewer mitochondrial reactive oxygen species (mtROS). However, DR alters more than free radical production (e.g. it decreases insulin signalling) and therefore the increase in longevity cannot be exclusively attributed to a decrease in mtROS generation. Thus, moderate exercise produces similar changes in free radical production and oxidative damage without increasing maximum life span. In summary, available data concerning the role of free radicals in longevity control are contradictory, and do not prove MFRTA. In fact, the only way to test this theory is by specifically decreasing mitochondrial free radical production without altering other physiological parameters (e.g. insulin signalling). If MFRTA is true animals producing fewer mtROS must have the ability to live much longer than their experimental controls.

Clinical and experimental data point to existence of disturbances of adaptive ability of aged organism to extreme impacts. However mechanisms of these disturbances are not clear yet. The purpose of the investigation was to study age-related changes in reaction of erythrocyte antioxidant enzyme system in response to acute psycho-emotional stress and a possible role of these changes in age-related alterations of oxygen blood transport in nonhuman primates. Ten young (6-8 years) and ten old (20-26 years) healthy female rhesus monkeys were subjected to acute moderate psychoemotional stress (two hours squeeze cage restraint) at 1500h. Plasma cortisol, lipid peroxidation products (TBARS) and activities of superoxide dismutase (SOD), glutathione peroxidase, gluthatione reductase (GR), and gluthatione-Stransferase in erythrocytes were measured before stress and at 30, 60, 120, 240 min and 24 hours after beginning of the stress. We have found for the first time that SOD activity decreased in response to the stress in young monkeys while it increased in the half of old monkeys. Young animals also demonstrated essentially higher increase in GR activity and plasma cortisol level in response to the restraint in comparison with old monkeys. Level of TBARS did not practically change in response to the stress in young animals and significantly increased in old monkeys. The study demonstrated that the age-related alterations in SOD and GR stress responsiveness lead to activation of peroxide oxidation of lipids that may be considered as an important factor of aging damage of erythrocyte functioning and reliability of oxygen transport to tissues under stress conditions.

Inflammation plays a role in the development of Alzheimer's disease (AD). Several cytokines and chemokines have been detected both immunohistochemically and in cerebrospinal fluid from patients. Some of them, including Tumor Necrosis Factor-α, Interferon-γ-inducible Protein-10, Monocyte Chemotactic Protein-1 and Interleukin-8, are increased in AD and in Mild Cognitive Impairment (MCI), considered the prodromal stage of AD, suggesting that these modifications occur very early during the development of the disease, possibly explaining the failure of trials with anti-inflammatory agents in patients with severe AD. Further evidence suggests that cytokines and chemokines could have a role in other neurodegenerative disorders, such as Frontotemporal Lobar Degeneration and Amyothrophic Lateral Sclerosis. In this regard, analogies and differences among these neurodegenerative disorders will be discussed. Neurodegenerative disorders are considered multifactorial diseases, and genetic factors influence pathological events and contribute to change the disease phenotype from patient to patient. Gene polymorphisms in crucial molecules, including cytokines, chemokines and molecules related to oxidative stress, may act as susceptibility factors, increasing the risk of disease development, or may operate as regulatory factors, modulating the severity of pathogenic processes or the response to drug treatment. With these premises, genetic studies recently carried out will be described and discussed in detail.

Hypopituitarism (HYPO) is a rare and under-investigated pathology in the elderly. Aim: to review our case records of patients ≥65 yrs with first diagnosis of anterior global hypopituitarism, in order to evaluate presentation symptoms, etiology, biochemical and hormonal pictures, pituitary morphology, and efficacy of therapy. Patients: 15 patients (65-82 yrs) were studied: in 11 (73%) HYPO was secondary to pituitary macroadenoma (nonsecreting in 10 and GH-secreting in 1); in 3 it was associated to empty sella, and in 1 to pituitary hypoplasia. Results: major presenting symptoms were visual-field defects and asthenia (40%) but also memory and/or gait impairment and nausea (30%) and depression (20%) were significantly observed. Dyslipidemia (73%), anemia (20%) and severe hyponatremia (13%) were found. After starting substitutive therapy and clinical improvement, 10 patients with macroadenoma underwent uneventful neurosurgery, which improved visual alterations but not pituitary function. Immunohistochemistry showed positivity for FSH in one patient and for GH in one patient. Six out of the eight patients with a postsurgical tumor remnant required treatment (surgery/radiotherapy/somatostatin analogue treatment in the acromegalic patient). Conclusions: The diagnosis of HYPO is often delayed in the elderly, since symptoms may be ascribed to aging and associated comorbidities. In our series, most of the aspecific symptoms were retrospectively addressed to HYPO since their resolution/improvement with replacement therapy. The prevalent cause of HYPO remains non-functioning pituitary macroadenomas. Hyponatremia can be a life-threatening presenting symptom. Symptoms considered apparently aspecific in the elderly should be investigated in order to possibly diagnose an important treatable disorder as HYPO.

Background: Diabetes is associated with a pro-inflammatory status characterized by an increased production of inflammatory molecules. Reactive Oxygen Species (ROS) and cAMP elevating agents represent two molecular systems, normally generated during inflammation. These molecules could be responsible for the alteration of signaling pathways. In the present paper we have studied the correlation between ROS generation and inositolpolyphosphates (InsP1, InsP2 InsP3 and InsP4) released by granulocytes from Type 1 diabetic patients (DM1) in the presence or in the absence of cyclic AMP-elevating agents. Methods: The effect of cAMP on ROS production was quantified in a chemoluminescence assay luminol-dependent (RLU/min). InsP1, InsP2 InsP3 and InsP4 were quantified by inositol-H3 in a Beta-counter and the results were expressed as count per minute (CPM). Results: The elevation of intracellular level of cAMP inhibited both InsP3 and ROS production in granulocytes from healthy subjects and activated in the cells from Type 1 diabetic patients. InsP1, InsP2 and InsP4 did not show significant alteration in both studied cells. There was a significant correlation between InsP3 and ROS in the presence of elevated content of cAMP. This correlation was observed in a 15 minutes reaction for healthy subjects and in 120 minutes for DM1. Conclusions: The importance of both InsP3 release and ROS production in an inflammatory process and tissue pathophysiology in Type 1 diabetic patients is still under debate because hyperglycemia accelerates generation of oxidative stress and may play an important role in the development of complications in diabetes. Thus, our results demonstrated alteration in metabolic response in granulocytes from Type 1 diabetic patients and it may be important for the development of therapeutic processes and drugs that interfere with signaling of ROS generation and may contribute to the improvement of the severe complications of diabetes.

The purpose of this work is to review the changes that take place in the microtubule associated protein tau during neuronal development, aging and neurodegeneration. Human tau protein is expressed from a single gene located on chromosome 17. The DNA is transcribed into nuclear RNA and this RNA, by alternative splicing, yields different mRNA species which are developmentally regulated. In aging, or in neurodegenerative disorders, post translational modifications of tau, such as phosphorylation, could take place, and new tau isoforms may appear. Thus, tau isoforms can be used as markers to follow neuronal development, aging or neurodegeneration.

Increases in both the age and the number of older adults in the United States will likely result in more people living with functional limitations and physical disabilities. The impact of this change in demographics will not only significantly impact older adult quality of life but may overwhelm existing health care services for this population. Resistance training with a strengthening component is currently recommended for older adults who wish to increase strength and overall health. However, muscle power has recently been found to contribute more to improvement in physical functioning than muscle strength and is becoming a focus of many resistance training studies in older adults. This review will discuss the current research supporting the implementation of traditional strength-enhancing resistance training, examine the contribution of muscle power to function, explore the rationale for implementing high velocity power training interventions, and review the recent literature on these novel power training interventions in older men and women. Recommendations for future research will be discussed.

The first goal of this article is to present nine Tai Chi Chuan training principles and incorporate them into a current model of motor control and motor learning theory. The second goal is to present a Tai Chi Chuan training model. The third goal is to construct a theory as to how Tai Chi Chuan principles may improve balance and motor skills in an aging population. Evidence from the areas of motor control, biomechanics, and human physiology are drawn upon to build a theory of motor skill learning and construct a Tai Chi Chuan training model.