Abstracts



[Back to top] [Full Text Article]
Towards an Understanding of the Anti-Aging Mechanism of Caloric Restriction, 2008, Vol: 1(1)
Gabriella Cavallini, Alessio Donati, Zina Gori and Ettore Bergamini

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.


[Back to top] [Full Text Article]
The Mitochondrial Free Radical Theory of Aging: A Critical View, 2008, Vol: 1(1)
Alberto Sanz and Rhoda K.A. Stefanatos

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.


[Back to top] [Full Text Article]
Stress, Aging and Reliability of Antioxidant Enzyme Defense, 2008, Vol: 1(1)
Nadezhda D. Goncharova, Victor Yu. Marenin and Tatiana N. Bogatyrenko

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 psycho-emotional 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-S-transferase 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.


[Back to top] [Full Text Article]
Inflammation in Neurodegenerative Disorders: Friend or Foe?, 2008, Vol: 1(1)
Daniela Galimberti, Chiara Fenoglio and Elio Scarpini

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.


[Back to top]
Editorial: A New Journal with an Integrated Approach in the Study of Aging and Longevity, 2008, Vol: 1(1)
Debomoy K. Lahiri

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 macro-molecules [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 re-search 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].

Environment’s role is not static, as recent work suggests that environmental factors, such as metals and dietary supplements, can modulate gene expression early in life and that this may manifest as an aging-related disorder many years later [10]. Indeed for such diseases, the second trigger is aging-dependent, which could be oxidative stress or inflammatory factors [11]. Thus, along with proper nutrition, appropriate body mass index, physical and mental exercise and healthy environment are important for longevity by slowing down or preventing aging-related disease mentioned above.

An increasing number of articles in the aging field are being published in the biomedical literature. A simple search of “Aging” in PubMed/Medline provides an awesome 8164 citations in just the last 12 months alone! Advances in aging research are contributed by worldwide researchers who cut across the disciplines. Importantly, for aging-related disorders, research work that bridges the gap between basic science discovery and translational studies is indispensable to develop novel diagnostic, preventive and therapeutic strategies. At this time it would be very useful for researchers and educators to integrate different aspects of aging research for communicating major research findings effectively to various scientists, educators, health science professionals, and policy makers. However, there are only a few journals devoted to the various aspects of aging research. As the aging field is large and dispersed in the literature, it is appropriate, therefore, to launch a new journal focusing on topics of major importance to the aging research field. Bentham Science Publishers, with the help of a strong team of members of the Editorial Board, is launching a new journal: Current Aging Science. The journal will publish cutting-edge reviews and original research papers on all aspects of age-related scientific research. Undoubtedly, this new international journal will not only advance the field but also effectively complement the existing excellent journals related to the field.

How can we effectively monitor the progress of research and what are the guidelines? What was said 125 years ago at the inaugural issue of the journal Science [12] is true again: “Science must be true to itself as well as in accord with its surroundings. It must maintain ever the highest tone and the most impartial accuracy. It must covet the scrutiny of every eye, and must be generous ever in the acknowledgment of its shortcomings. Higher than all, it must be devoted to the truth. It must cheerfully undertake the severest labor to secure it, and must deem no sacrifice too great in order to preserve it. It must have an unlimited capacity for work, and an unlimited enthusiasm in it, while at the same time a proper reserve in affirming the results of it. While striving itself for the highest attainable accuracy, it must be catholic and liberal toward others. It must not magnify differences, nor impute motives.”

Current Aging Science is still very much a “work in progress”. In fact, the contents for the first issue of Current Aging Science represent a perfect mixed bag of both basic and applied sciences. Cavallini and colleagues present (pp. 4-9) a timely review towards an understanding of the antiaging mechanism of caloric restriction. This article is followed by two complementary articles on different dimensions of the hyperactive free radicals, collectively called reactive oxygen species (ROS). While Sanz and Stefanatos critically review (pp. 10-21) the mitochondrial free radical theory of aging, Goncharova and coworkers nicely elaborate (pp. 22-29) on the relationship of stress, aging and reliability of anti-oxidant enzyme defense. Following up discussion from ROS to another important area of research, Galimberti and colleagues well tackle (pp. 30-41) the controversial aspect of inflammation in neurodegenerative disorders. From mechanistic studies, we then move to two disease-related articles. Foppiani and collaborators present (pp. 42-50) a multifaceted clinical and biochemical investigation on hypopituitarism in the elderly. Chaves and colleagues elegantly describe (pp. 51-55) a correlation study between ROS production and InsP3 released by granulocytes from type 1 diabetic patients in a cAMP-dependent manner. For tracking down the molecular events of aging and aging-related disorders, Hernández and colleagues timely highlight (pp. 56-61) how tau protein could serve as a molecular marker of development, aging and neurodegenerative disorders. Two articles deal with subjects beyond biological mechanism but quite relevant in the context of older subjects. While Sayers elo-quently updates (pp. 62-67) us on high velocity power training in older adults, Gatts succinctly discusses (pp. 68-70) a Tai Chi training model that preserves or restores balance, mobility, sensory attention, and motor skills in older adults. This is just the beginning, and comments, advice and suggestions from the readers would definitely improve and broaden the scope of the journal.

Current Aging Science is a new vehicle run by aging-related investigators worldwide across a wide range of disciplines. The major aim of the journal is to publish frontier review and experimental articles on all areas of research that may influence longevity. This multidisciplinary journal will help in understanding the biology and mechanism of aging, genetics, pathogenesis, intervention of normal aging process and preventive strategies of aging-related disorders. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, clini-cal, molecular, and animal models, including lower organism models (e.g., yeast, Caenorhabditis elegans and Drosophila). In addition to the effect of aging on integrated systems, the journal also will include original articles on recent research in fast-emerging areas of adult stem cells, brain imaging, calorie restriction, immunosenescence, molecular diagnostics, pharmacology and clinical aspects of aging. We are also planning to report advances in areas related to developmental programming of aging and the synergistic mechanisms of aging with cardiovascular diseases, obesity and neurodegenerative disorders. We plan to discuss, debate, and challenge some of the aforementioned topics in the pages of Current Aging Science.

With great hope and optimism we undertake the great challenges and opportunities to unravel the biology of aging and understand the mechanism of aging-related disorders. With great humility and honor I take the responsibility as editor-in-chief of Current Aging Science. I sincerely appreciate the excellent cooperation from the members of the Editorial Advisory Board of the journal. I am grateful to Matthew Honan and colleagues of Bentham Science Publishers for their support and advice. I thank John Nurnberger, Jr. for his invaluable advice and also acknowledge the support of Indiana University School of Medicine, Department of Psychiatry and the members of my laboratory of Molecular Neurogenetics. Personally, I am deeply indebted to my late father, Benoy K. Lahiri, who enlightened and guided me through the path of knowledge and ignited in me the curiosity for knowing the unknowns. With continued support from the general public and the scientific community, and confidence that scientific progress will elucidate the key for longevity, Current Aging Science embarks upon a bright future. May this journal succeed by highlighting and advancing the progress in aging-related research and by changing and adapting to new challenges; at this moment, please join me in helping it push forward.

REFERENCES

[1] Masoro EJ. In: ‘Challenges of biological aging’. (Ed: Masoro EJ) Springer Publishing Co. New York, pp. 1-202 (1999).

[2] Harman DJ. Aging: A theory based on free radical and radiation chemistry. Gerontology 11: 298-300 (1956).

[3] Beckman KB and Ames BN. The free radical theory of aging matures. Physiol Rev 78: 547-581 (1998).

[4] Anderson RN and Smith BL. Natl Vital Stat Rep 53 (no. 17) (2005); www.cdc.gov/nchs/data/nvsr/nvsr53/nvsr53_17.pdf.

[5] Finch CE. The biology of human longevity: Inflammation, nutrition, and aging in the evolution of life-spans. Academic (Elsevier), Amsterdam, pp. 640 (2007).

[6] Holmes DJ. The fires of aging. Science 319: 1044-1045 (2008).

[7] Weindruch R and Walford RL. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science 215(4538): 1415-1418 (1982).

[8] Ogburn CE, Carlberg K, Ottinger MA, Holmes DJ, Martin GM, Austad SN. Exceptional cellular resistance to oxidative damage in long-lived birds requires active gene expression. J Gerontol A Biol Sci Med Sci 56(11): B468-74 (2001).

[9] Morley JE, Kaiser F, Raum WJ, Perry HM 3rd, Flood JF, Jensen J, et al. Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone. Proc Natl Acad Sci USA 94(14): 7537-7542 (1997).

[10] Lahiri DK and Maloney B. Genes are not our destiny: the somatic epitype bridges between the genotype and the phenotype. Nat Rev Neurosci 7:doi:10.1038/nrn2022-c1 (2006).

[11] Lahiri, DK, Maloney B, Basha MR, Ge Y-W and Zawia NH. How and when environmental agents and dietary factors affects the course of Alzheimer’s disease: the “LEARn” model (Latent Early-Life Associated Regulation) may explain the triggering of AD. Curr Alzheimers Res 4(2): 219-228 (2007).

[12] King M. Future of American science. Science 1(1): 1-3 (1883).


[Back to top] [Full Text Article]
Tau as a Molecular Marker of Development, Aging and Neurodegenerative Disorders, 2008, Vol: 1(1)
Félix Hernández, Mar Pérez, Elena Gómez de Barreda, Paloma Goñi-Oliver and Jesús Avila

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.


[Back to top] [Full Text Article]
Possible Links of Age Related Hypertension and Evolution Imposed Features of Heart and Aorta, 2008, Vol: 1(3)
Sven Kurbel

The left ventricle thickness is a limiting factor of optimal heart size and strength. Due to disappearance of all the features compromising left ventricular compliance, mammalian heart has decreased vascular density and coronary vessel diameter and it requires sufficient diastolic aortic pressure for the left ventricle perfusion. Atrial muscle and the right ventricle are perfused during the entire heart cycle. The systolic pressure in the left ventricle forces blood vessels in the muscle wall to collapse, particularly in the subendocardial muscle layer. This makes the most active part of the heart prone to hypoxia.

Optimal perfusion of the left ventricle wall requires sufficient aortic pressure during diastole, making individuals with higher diastolic pressures advantageous, in situations requiring combination of increased heart rate and output. Described mechanisms might have contributed to the hereditary quality of age-related hypertension in humans.


[Back to top] [Full Text Article]
High Velocity Power Training in Older Adults, 2008, Vol: 1(1)
Stephen P. Sayers

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.


[Back to top] [Full Text Article]
Is the Yeast a Relevant Model for Aging of Multicellular Organisms? An Insight from the Total Lifespan of Saccharomyces cerevisiae, 2008, Vol: 1(3)
Renata Zadrag, Grzegorz Bartosz and Tomasz Bilinski

The applicability of the free radical theory of aging to the yeast S. cerevisiae is a matter of debate. In order to get an insight into this question, we studied the reproductive potential (the number of buds produced), reproductive lifespan (the time during which a yeast cell is able to divide), postreproductive lifespan (duration of life of yeast cells which ceased to divide) and total lifespan (sum of reproductive lifespan and postreproductive lifespan) of three isogenic pairs of yeast strains. Each pair contained a parent strain and a disruptant of gene(s) coding for important antioxidant enzyme(s) (CuZn-superoxide dismutase, all five peroxiredoxins or glutaredoxin 5). Although the reproductive potential was decreased in all antioxidant enzyme-deficient mutants, the differences in the reproductive lifespan between the parent strains and the mutants were less pronounced while postreproductive lifespan and total lifespan were not diminished in the mutants. These results suggest that either the free-radical theory of aging is not applicable to S. cerevisiae or that this yeast is not a proper model organism for the study of aging of higher organisms. In our opinion the latter possibility is more apparent and the increase in cell volume (unavoidable for a cell propagating by budding) rather than accumulation of oxidative damage may be the main reason for the cessation of budding (and perhaps postreproductive death) in S. cerevisiae.


[Back to top] [Full Text Article]
A Tai Chi Chuan Training Model to Improve Balance Control in Older Adults, 2008, Vol: 1(1)
Strawberry Gatts

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.