Longevity Of Animals Research Articles

Curiosity Is Addictive, and This Is Not an Entirely Good Thing

Rejuvenation ResearchVol. 11, No. 1 EDITORIALCuriosity Is Addictive, and This Is Not an Entirely Good ThingAubrey D.N.J. de GreyAubrey D.N.J. de GreySearch for more papers by this authorPublished Online:15 Feb 2008https://doi.org/10.1089/rej.2008.0692AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byPolyunsaturated fats, membrane lipids and animal longevity16 October 2013 | Journal of Comparative Physiology B, Vol. 184, No. 2Interview with Jonathan Weiner12 January 2011 | Rejuvenation Research, Vol. 13, No. 6European Council of Art: A New Initiative to Combine Both Fields and Cultures in the Pursuit of Visionary Goals Aubrey D.N.J. de Grey12 January 2011 | Rejuvenation Research, Vol. 13, No. 6Metabolism and longevity: Is there a role for membrane fatty acids?15 March 2010 | Integrative and Comparative Biology, Vol. 50, No. 5Interview with Jan Vijg, Ph.D.9 December 2010 | Rejuvenation Research, Vol. 13, No. 5Interview with Prof. Dr. Augustinus Bader24 August 2010 | Rejuvenation Research, Vol. 13, No. 4Reaping the Longevity Dividend in Time: Biogerontology Heavyweights Advocate Seeking Late-Onset Interventions Against Aging Aubrey D.N.J. de Grey24 August 2010 | Rejuvenation Research, Vol. 13, No. 4Interview with David Kekich President and CEO, Maximum Life Foundation15 March 2010 | Rejuvenation Research, Vol. 13, No. 1The possible role of membrane lipids in the exceptionally long life of the short-beaked echidna, Tachyglossus aculeatus .Australian Zoologist, Vol. 35, No. 2Personal Profile: Interview with James Joseph, Ph.D.30 December 2009 | Rejuvenation Research, Vol. 12, No. 6Interview with Leonid A. Gavrilov, Ph.D. and Natalia Gavrilova, Ph.D.23 November 2009 | Rejuvenation Research, Vol. 12, No. 5Interview with Thomas Okarma, M.D., Ph.D.; CEO, Geron14 October 2009 | Rejuvenation Research, Vol. 12, No. 4Interview with Nigel M. de S. Cameron, Ph.D.13 July 2009 | Rejuvenation Research, Vol. 12, No. 3American Federation for Aging Research: Interview with Stephanie Lederman Vicki Glaser6 May 2009 | Rejuvenation Research, Vol. 12, No. 2The Curiously Misunderstood Role of Evidence in Designing New Technology Aubrey D.N.J. de Grey6 May 2009 | Rejuvenation Research, Vol. 12, No. 2Interview with John Vincent, Ph.D. Vicki Glaser10 March 2009 | Rejuvenation Research, Vol. 12, No. 1Explaining longevity of different animals: is membrane fatty acid composition the missing link?31 May 2008 | AGE, Vol. 30, No. 2-3Premature senescence of human endothelial cells induced by inhibition of glutaminase4 March 2008 | Biogerontology, Vol. 9, No. 4 Volume 11Issue 1Feb 2008 Information© 2008 Mary Ann Liebert, Inc.To cite this article:Aubrey D.N.J. de Grey.Curiosity Is Addictive, and This Is Not an Entirely Good Thing.Rejuvenation Research.Feb 2008.1-3.http://doi.org/10.1089/rej.2008.0692Published in Volume: 11 Issue 1: February 15, 2008PDF download

The GH-IGF1 axis and longevity. The paradigm of IGF1 deficiency

Primary or secondary IGF1 deficiency has been implicated in shortening of lifespan. This paper reviews available data on the influence of IGF1 deficiency on lifespan and longevity in animals and man. It has been shown that inactivation of the IGF1 gene or of the GH receptor in both invertebrates (C-elegans, flies-Drosphila) and rodents (mice and rats), leading to IGF1 deficiency, prolong life, particularly in females. In man, evaluation of the 2 largest cohorts of patients with Laron syndrome (inactive GH receptor resulting in IGF1 deficiency) in Israel and Ecuador revealed that despite their dwarfism and marked obesity, patients are alive at the ages of 75-78 years, with some having reached even more advanced ages. It is assumed that a major contributing factor is their protection from cancer, a major cause of death in the general population.

New findings in gene knockout, mutant and transgenic mice

During the past year, some novel genetic modifications were shown to alter the lifespan of mice, thus expanding the list of genes and physiological processes that influence mammalian aging. Considerable progress was also made in identifying putative mechanisms of extended longevity in previously described gene knockouts, mutants and transgenics. In addition, new leads concerning mechanisms of aging were derived from studies of gene knockout mice in which aging is accelerated. Among the important findings from the period July 2006 to July 2007: Core body temperature was shown to influence longevity in homeothermic animals; a Surf1 gene knockout extended lifespan in mice; separate studies using Little and Snell dwarf mice found stress resistance enhancements correlated with longevity gains; and mice heterozygous for deletion of insulin receptor substrate 2 (IRS-2) lived longer than normal animals, while animals with homozygous or heterozygous deletion of IRS-2 selectively in the brain exhibited comparable extension of lifespan and various symptoms of delayed aging.

Highly resistant macromolecular components and low rate of generation of endogenous damage: Two key traits of longevity

Key characteristics relating oxidative damage to aging and longevity are reviewed. Available information indicates that the specific composition of tissue macromolecules (proteins, lipids and mitochondrial DNA) in long-lived animal species gives them an intrinsically high resistance to modification that likely contributes to the superior longevity of these species. This is obtained in the case of lipids by decreasing fatty acid unsaturation, and in the proteins by lowering their methionine content. Long-lived animals also show low rates of reactive oxygen species (ROS) generation and oxidative damage at their mitochondria. On the other hand, dietary restriction decreases mitochondrial ROS production and oxidative damage to mitochondrial DNA and proteins. These changes are due to the decreased intake of dietary proteins (not of lipids or carbohydrates) of the dietary restricted animals. In turn, these effects of protein restriction seem to be specifically due to the lowered methionine intake of the protein and dietary restricted animals. It is emphasized that both a low rate of generation of endogenous damage and an intrinsically high resistance to modification of tissue macromolecules are key traits of animal longevity.

From Dioxin to Drug Lead—The Development of 2,3,7,8‐Tetrachlorophenothiazine

Polychlorinated dibenzo-p-dioxins are persistent environmental pollutants. The most potent congener, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), causes a wasting syndrome and is a potent carcinogen and immunosuppressant in the rat at high doses. However, low doses cause opposite effects to some of those observed at higher doses, resulting in chemoprevention, stimulation of the immune system, and longevity in experimental animals. The new TCDD analogue, 2,3,7,8-tetrachlorophenothiazine (TCPT), was developed to take advantage of the low-dose effects of dioxins that have potential application as therapeutics. Its development marked a deviation from the traditional scope of phenothiazine drug design by deriving biological effects from aryl substituents. TCPT was synthesized in three steps. The key ring-closing step was performed utilizing a Buchwald-Hartwig amination to provide TCPT in 37% yield. Its potency to induce CYP1A1 activity over 24 h was 370 times lower than that of TCDD in vitro. The elimination half-life of the parent compound in serum was 5.4 h in the rat and 2.7 h in the guinea pig, compared to 11 and 30 days, respectively, for TCDD. These initial findings clearly differentiate TCPT from TCDD and provide the basis for further studies of its potential as a drug lead.

A Low Protein Diet Increases the Hypoxic Tolerance in Drosophila

Dietary restriction is well known to increase the life span of a variety of organisms from yeast to mammals, but the relationships between nutrition and the hypoxic tolerance have not yet been considered. Hypoxia is a major cause of cell death in myocardial infarction and stroke. Here we forced hypoxia-related death by exposing one-day-old male Drosophila to chronic hypoxia (5% O2) and analysed their survival. Chronic hypoxia reduced the average life span from 33.6 days to 6.3 days when flies were fed on a rich diet. A demographic analysis indicated that chronic hypoxia increased the slope of the mortality trajectory and not the short-term risk of death. Dietary restriction produced by food dilution, by yeast restriction, or by amino acid restriction partially reversed the deleterious action of hypoxia. It increased the life span of hypoxic flies up to seven days, which represented about 25% of the life time of an hypoxic fly. Maximum survival of hypoxic flies required only dietary sucrose, and it was insensitive to drugs such as rapamycin and resveratrol, which increase longevity of normoxic animals. The results thus uncover a new link between protein nutrition, nutrient signalling, and resistance to hypoxic stresses.

Animal physiotherapy

Animal physiotherapy is a field of growth in the UK due to factors including increasing client (owner) awareness and demand. Advances in veterinary diagnostic and treatment technology have lead to increasingly sophisticated and integrated veterinary management of both companion and performance animals, and overall increases in animal longevity. Using human physiotherapy techniques to manage similar problems in veterinary patients is not a new phenomenon however. Animal physiotherapy can trace its origins back to at least the early 20th century in the UK. Specific legislation citing the application of ‘Physiotherapy’ in veterinary medicine first appeared over 40 years ago (Veterinary Surgeons Exemptions Order, 1962). The Association of Chartered Physiotherapists in Animal Therapy (ACPAT) was founded as special interest group of the Chartered Society of Physiotherapists (CSP) in 1985, and has a growing membership (to date has over 150 fully qualified Category A members in the UK). In 2000, the first intake of students where enrolled on the M.Sc./Post-Graduate Diploma in Veterinary Physiotherapy at the Royal Veterinary College, London. This program of part time study was developed to provide chartered physiotherapists with the ability to apply their professional knowledge, experience and practical therapy skills to the treatment of animal patients. M.Sc. students are required to complete an original research project, contributing to the development of a much-needed scientific evidence base for veterinary physiotherapy. This article aims to provide an overview of the treatment of animals with physiotherapy from the perspective of an ACPAT physiotherapist. Some understanding of human manual therapy principles and nomenclature is assumed. Animal physiotherapy is a field of growth in the UK due to factors including increasing client (owner) awareness and demand. Advances in veterinary diagnostic and treatment technology have lead to increasingly sophisticated and integrated veterinary management of both companion and performance animals, and overall increases in animal longevity. Using human physiotherapy techniques to manage similar problems in veterinary patients is not a new phenomenon however. Animal physiotherapy can trace its origins back to at least the early 20th century in the UK. Specific legislation citing the application of ‘Physiotherapy’ in veterinary medicine first appeared over 40 years ago (Veterinary Surgeons Exemptions Order, 1962). The Association of Chartered Physiotherapists in Animal Therapy (ACPAT) was founded as special interest group of the Chartered Society of Physiotherapists (CSP) in 1985, and has a growing membership (to date has over 150 fully qualified Category A members in the UK). In 2000, the first intake of students where enrolled on the M.Sc./Post-Graduate Diploma in Veterinary Physiotherapy at the Royal Veterinary College, London. This program of part time study was developed to provide chartered physiotherapists with the ability to apply their professional knowledge, experience and practical therapy skills to the treatment of animal patients. M.Sc. students are required to complete an original research project, contributing to the development of a much-needed scientific evidence base for veterinary physiotherapy. This article aims to provide an overview of the treatment of animals with physiotherapy from the perspective of an ACPAT physiotherapist. Some understanding of human manual therapy principles and nomenclature is assumed.

Genistein, a soy isoflavone, up‐regulates expression of antioxidant genes: involvement of estrogen receptors, ERK1/2, and NFκB

We have previously reported that estrogens up-regulate longevity-associated genes. As recent evidence has shown that estrogen replacement therapy is associated with an increased risk of cardiovascular disease, we have studied the effects of genistein, a soy isoflavone with a similar structure to estradiol, on the expression of antioxidant, longevity-related genes. MCF-7 cells (human mammary gland tumor cell line) were incubated for 48 h with 0.5 microM genistein, a concentration found in the plasma of populations consuming diets rich in soy protein. Peroxide levels were determined by fluorimetry, activation of extracellular-signal regulated kinase (ERK1/2), and nuclear factor kappaB (NFkappaB)-signaling pathways by Western blot analysis and ELISA, respectively, and mRNA expression of antioxidant genes by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Inhibition of basal peroxide levels in MCF-7 cells by genistein was prevented by pretreatment of cells with the estrogen receptor antagonist tamoxifen. Phosphorylation of extracellular regulated kinase (ERK)1/2 led to an activation of NFkappaB, as indicated by increased p50 subunit expression in nuclear extracts, and increased mRNA levels of the antioxidant enzyme manganese-superoxide dismutase (MnSOD). Inhibition of ERK1/2 abrogated genistein-mediated NFkappaB activation and elevated expression of MnSOD. Our molecular studies may provide a basis to determine the effects of genistein and other soy protein-derived products on longevity in both animals and the human population.

Hippocampal IGF-1 expression, neurogenesis and slowed aging: clues to longevity from mutant mice

Recent studies point out the important role of IGF and insulin-related signaling pathways in the control of longevity of laboratory animals. The Ames dwarf mouse is a murine model of circulating GH and IGF-1 deficiency that exhibits dwarf phenotype characteristics and significantly extends lifespan. It is interesting to know that Ames dwarf mice do not experience an age-related decline in cognitive function when compared to their young counterparts. In this study, the most recent works on local GH and IGF-1 expression in the hippocampus of Ames mice are briefly reviewed.

Durée de vie, génétique et axe somatotrope

Research on ageing made a big leap forward when genes regulating lifespan were discovered about a decade ago. First isolated by screening the genome of the nematode Caenorhabditis elegans, most of these genes belong to an essential signalling pathway that is highly conserved during animal evolution. Orthologous genes in vertebrate species are the families of genes coding for insulin, insulin-like growth factors (IGF) and related proteins. Intensively studied and well-known for their pivotal roles in proliferation, differentiation, survival and metabolism of most cells, we now discover their multiples functions with respect to the control of longevity and their ability to modulate the cell's responses to oxidative stress, a major cause of cellular and organismal ageing. The activity of IGF signalling in mammals depends on a complex interplay of endocrine signals that together constitute the somatotropic axis. Accordingly, several components of this hormone axis, like growth hormone or growth hormone releasing hormone receptors, regulate efficiently animal longevity, which has been elegantly demonstrated by studies performed in genetically modified mouse models. From this and other work, it becomes increasingly clear that the control of ageing is a question of hormonal regulations. We here present several of these models and discuss the respective contributions of insulin and IGF signalling to the regulation of lifespan. We review data on the Klotho gene that acts on lifespan via surprising and not yet fully understood molecular mechanisms, connecting this new, hormone-like substance to IGF and insulin signalling. We further report recent evidence showing that human lifespan might be controlled in similar ways. Finally, we shed some light on clinical GH treatment in humans, from an endocrinologist's point of view.

The Sirt1 Gene Promotes Insulin Secretion in Accord with Diet

Those seeking the fountain of youth would do well to watch their calories. Indeed, caloric restriction has been known for many years to increase longevity in laboratory animals. A simple explanation for this effect is that reducing food intake slows down the body's metabolism, which reduces the formation of toxic byproducts that cause tissue damage and aging.

ENERGY INTAKE, MEAL FREQUENCY, AND HEALTH: A Neurobiological Perspective

The size and frequency of meals are fundamental aspects of nutrition that can have profound effects on the health and longevity of laboratory animals. In humans, excessive energy intake is associated with increased incidence of cardiovascular disease, diabetes, and certain cancers and is a major cause of disability and death in industrialized countries. On the other hand, the influence of meal frequency on human health and longevity is unclear. Both caloric (energy) restriction (CR) and reduced meal frequency/intermittent fasting can suppress the development of various diseases and can increase life span in rodents by mechanisms involving reduced oxidative damage and increased stress resistance. Many of the beneficial effects of CR and fasting appear to be mediated by the nervous system. For example, intermittent fasting results in increased production of brain-derived neurotrophic factor (BDNF), which increases the resistance of neurons in the brain to dysfunction and degeneration in animal models of neurodegenerative disorders; BDNF signaling may also mediate beneficial effects of intermittent fasting on glucose regulation and cardiovascular function. A better understanding of the neurobiological mechanisms by which meal size and frequency affect human health may lead to novel approaches for disease prevention and treatment.

Minireview: The Role of Oxidative Stress in Relation to Caloric Restriction and Longevity

Reduction of caloric intake without malnutrition is one of the most consistent experimental interventions that increases mean and maximum life spans in different species. For over 70 yr, caloric restriction has been studied, and during the last years the number of investigations on such nutritional intervention and aging has dramatically increased. Because caloric restriction decreases the aging rate, it constitutes an excellent approach to better understand the mechanisms underlying the aging process. Various investigations have reported reductions in steady-state oxidative damage to proteins, lipids, and DNA in animals subjected to restricted caloric intake. Most interestingly, several investigations have reported that these decreases in oxidative damage are related to a lowering of mitochondrial free radical generation rate in various tissues of the restricted animals. Thus, similar to what has been described for long-lived animals in comparative studies, a decrease in mitochondrial free radical generation has been suggested to be one of the main determinants of the extended life span observed in restricted animals. In this study we review recent reports of caloric restriction and longevity, focusing on mitochondrial oxidative stress and the proposed mechanisms leading to an extended longevity in calorie-restricted animals.

Trichostatin A extends the lifespan of Drosophila melanogaster by elevating hsp22 expression.

The level of acetylation of histones in nucleosomes is related to the longevity of yeast and animals. However, the mechanisms by which acetylation and deacetylation affect longevity remain unclear. In present study, we investigated the influence of histone acetylation modification on the expression of hsp22 gene and the lifespan in Drosophila melanogaster using histone deacetylase (HDAC) inhibitor Trichostatin A (TSA). The results showed that TSA could extend the lifespan of Drosophila melanogaster. Furthermore, TSA significantly promoted the hsp22 gene transcription, and affected the chromatin morphology at the locus of hsp22 gene along the polytene chromosome. Present data implicate that TSA may affect the lifespan of Drosophila through changing the level of histone acetylation and influencing the expression of hsp22 gene that is related to aging.

942. Combinatorial Treatment with Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Gene and a Chemotherapeutic Agent Suppressed Hepatic Metastasis of Colon Carcinoma

Top of pageAbstract As a therapeutic approach to eradicate highly malignant neoplasms including metastatic liver tumors, a powerful, specific and systemically applicable tool that directly destroys tumor cells is required. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various transformed cells, while most normal cells are unsusceptible to the TRAIL-mediated apoptosis induction. In the present study, we evaluated therapeutic efficacy of intravascular TRAIL gene therapy against multiple hepatic metastasis model in mice. A chemotherapeutic agent, actinomycin D, was also administered to assess whether the tumoricidal activity of the TRAIL is further improved by the combination therapy. First, recombinant human TRAIL (rTRAIL) was added to the CT-26 (murine colon carcinoma) in culture in the presence or absence of 10 ng/ml actinomycin D, and cell proliferation and apoptosis were assessed in vitro by means of the tetrazolium and flow cytometric analyses. The treatment with rTRAIL alone failed to affect viability of CT-26 cells, while rTRAIL plus actinomycin D treatment effectively induced apoptosis in a dose dependent fashion. Anti-tumor effect in vivo of the TRAIL plus actinomycin D treatments was then investigated. pGEG.TRAIL was constructed so that the plasmid encoding the 3′ extracellular domain of human TRAIL fused with a secretory signal sequence. When the vector construct was intravenously transfected into mice, a considerable concentration of TRAIL molecule was detected in the sera of the animals, whereas delivery of a wildtype TRAIL construct did not result in a significant elevation of the genetic product in the murine sera. To establish liver metastasis, CT-26 cells were injected into the spleen of syngenic BALB/c mice (day 0). On days 1 and 8, mice received intravascular transfection with pGEG.TRAIL or pGEG.4 (a control plasmid), while actinomycin D was intraperitoneally injected into some groups of mice. The mice were sacrificed on day 14, when the numbers of metastatic nodules were revealed to be 63.8±31.5 (untreated), 49.4±21.0 (pGEG.4 plus actinomycin D), 52.3±32.7 (pGEG.TRAIL alone) and 14.8±17.3 (pGEG.TRAIL plus actinomycin D). The statistical analyses demonstrated that combination treatment significantly suppressed the liver metastasis in comparison with the untreated and pGEG.4 plus actinomycin D groups (p=0.015 and 0.021, respectively). All of the mice given injections with either the pGEG.sTRAIL or actinomycin D died within 44 days, which was not significantly longer than the longevity of control animals. In drastic contrast, 18% of the mice treated with the both agents survived for more than 90 days without any evidence of tumor progression. These results strongly suggest that the soluble TRAIL gene transfer and the administration with a chemotherapeutic agent synergistically elicit anti-tumor activities in vivo, and the combinatorial chemo-gene therapy may become an efficient and feasible means to suppress metastatic liver tumors.

Ageing, repetitive genomes and DNA damage.

The mitochondrial production of reactive oxygen species is inversely proportional to longevity in animals. A key question now is, which molecules, among those that are oxidized, affect the lifespan of the organism most significantly?

The Production of Tumor Necrosis Factor in Cells of Tumor-Bearing Mice After Total-Body Microwave Irradiation and Antioxidant Diet

The effects of repeated treatment with weak microwaves (MW) (8.15–18 GHz, 1 µW/cm2, 1.5 h daily) and diet with antioxidants (AO) (β-carotene, α-tocopherol, and ubiquinone Q9) on production of tumor necrosis factor (TNF) in macrophages and T lymphocytes of healthy and tumor-bearing mice (TBM) were studied. Tumor size and mortality of TBM were also followed. Microwave radiation and antioxidant diet stimulated production of TNF in cells from healthy mice. At early stages, tumor growth induced TNF production in mouse cells; however, this effect decreased as tumors grew. In TBM exposed to MW, TNF production was higher than in unirradiated TBM. Oppositely, AO diet induced TNF production in healthy mice but did not affect TNF secretion in TBM. Accordingly, prolonged treatment of TBM to MW, but not to AO diet, decreased tumor growth rate and increased overall animal longevity. These results suggest that diminished tumor growth rate due to extremely low-level MW exposure of mice carrying tumors, at least in part, was caused by enhancement in TNF production and accumulation of plasma TNF.

Diversity in growth and longevity in short-lived animals: squid of the suborder Oegopsina

This article is an overview of age and growth studies of squid belonging to the suborder Oegopsina, which includes the majority (~215) of squid species inhabiting offshore waters of the continental shelves and pelagic waters of the world ocean. Three main periods in the history of age and growth studies of oegopsin squid are identified. A brief history of the different methods applied to study oegopsin age and growth is presented. The lifespan of oegopsin squid varies from almost 3 months in small pelagic tropical species to 2 years in polar and deepwater species. Generally, the lifespan of similar-sized oegopsin squid increases with latitude. Growth of the majority of oegopsin squid is best described by one of the asymptotic growth functions, but some tropical squid are characterised by non-asymptotic growth. Many aspects of growth variability are discussed, such as ontogenetic, sexual, intra-specific, geographical, inter-annual and inter-specific variations. The fast growth rates of oegopsin squid give them the advantage of passing quickly through the most vulnerable first trophic levels of the oceanic food web, enabling them to compete successfully with nektonic fishes.

Genetic control of stem cells: implications for aging.

Stem cells are currently at the center of both controversy and notoriety. The harvest of human embryonic or fetal stem cells, at least with methods available now, necessarily involves the sacrifice of the embryo or fetus. This critical step in the procurement of stem cells has stimulated intense discussion at all levels of academia, government, and society in general. What societal benefits, if any, justify such a strategy for obtaining these stem cells? In other species it has been possible to generate virtually all cell types found in adult organs from embryonic stem cells. This ability has opened endless clinical possibilities for tissue and organ replacement through the transplantation of cells derived from embryonic stem cells. Luckily, there may be an alternative to this ethical dilemma. It is becoming increasingly clear that stem cells exist in many, if not all, adult tissues. Adult stem cells normally replenish tissue cells lost through the wear and tear of aging or damage from injury or disease. With the proper coaxing in tissue culture and when transplanted, these stem cells may regenerate the full repertoire of organotypic cells and thus may therapeutically regenerate tissues in vivo in much the same way as embryonic stem cells do. For several reasons, the best-studied stem cells are those of the blood-forming system. Mature blood cells generally have short functional life spans, usually measured in days, and therefore require replenishment at a steady pace throughout one's lifetime. Stem cells are intimately involved in this renewal and, because of the relative ease of access to the bone marrow, stem cells have been well studied. Second, bone marrow transplantation following radiation or high-dose chemotherapy in the treatment of cancer has fostered research on the basic biology and therapeutic uses of hematopoietic stem cells over the more than 30 years stem cell transplantation has been used clinically. It is my aim to review what is known about the genes controlling hematopoietic stem cell function. Identifying, and ultimately manipulating, the genes that regulate stem cell number, replication rate, and self-renewal capacity may have important clinical benefits. I discuss evidence suggesting that the characterization of least some of these stem cell genes will shed light on mechanisms important in the aging process. I advance the hypothesis that stem cells accumulate cellular damage during aging that diminishes their developmental potency and ability to replenish blood cells, particularly after hematopoietic stress. In this view, the impaired function of stem cells in hematopoietic and in other self-renewing tissues limits the longevity of animals, and perhaps of humans.

Effect of time of restriction on the decrease in mitochondrial H2O2 production and oxidative DNA damage in the heart of food-restricted rats.

In the present study, the question if medium-term (4 months) caloric restriction (40%) decreases mitochondrial H2O2 production and oxidative DNA damage was investigated. Caloric restriction (CR) is the only experimental manipulation that increases maximum life span. Previous long-term CR studies have showed that CR decreases the mitochondrial rate of free radical production in diverse tissues and species. Those studies agree with the idea that the superior longevity of the restricted animals can be partly due to their lower mitochondrial rate of free radical generation. However, caloric restriction effects strongly depend on implementation time. Previous studies have shown that the decrease induced by CR on oxygen radical generation and oxidative damage to mitochondrial DNA occurs after 1 year but not after 6 weeks of restriction. In the present investigation, mitochondrial H2O2 production did not change in medium-term (4 months) caloric restricted animals, and, in agreement with that, no differences were found in either mitochondrial or nuclear oxidative DNA damage between restricted and ad libitum-fed animals. These results confirm the importance of the time of CR implementation, and show that time longer than 4 months is needed to decrease the mitochondrial rate of free radical generation and the oxidative damage to mtDNA in the rat heart.