This searchable list includes the abstracts of all presentations given at a conference organised as part of the SENS series. We regret that the videos recorded at SENS3 and SENS4 are currently unavailable.
Cellular senescence irreversibly arrests proliferation in response to potentially oncogenic stress. Senescent cells also secrete inflammatory cytokines such as IL-6, which promote age-associated inflammation and pathology. HMGB1 (High Mobility Group Box 1) modulates gene expression in the nucleus, but certain immune cells secrete HMGB1 as an extracellular Alarmin to signal tissue damage. We show that nuclear HMGB1 relocalized to the extracellular milieu in senescent human and mouse cells in culture and in vivo.
Decline in proteasome and lon protease activity with age: transcriptional dysregulation or inhibitor accumulation?Audio: (Audio)
The Proteasome is an unusually large and complex proteinase found in the cytoplasm and nucleus of all eucaryotic cells. Proteasome has been shown to play several key roles in the appropriate turnover of normal proteins and the selective degradation of abnormal and damaged proteins. These activities give the Proteasome a vital place in cell cycle progression, protection from protein aggregation, antigen presentation, and maintenance of cellular homeostasis.Keywords: Oxidative stress, Proteasome, Lon protease, Mitochondria, Aging
Many people worry that life-extension will be available only to the prosperous. Does it follow that society should inhibit life-extension research and development, or does it follow instead that society should subsidize life-extension for the have-nots? I will briefly explain why subsidizing life-extension for the have-nots may be easier than it looks.Keywords: access, distribution, immortality, justice, life-extension
Investigation of the signalling pathways involved in the proliferative life span barriers in Werner Syndrome fibroblasts
Werner Syndrome (WS) fibroblasts enter replicative senescence after a reduced in vitro life span. Although this has been postulated as causal in the accelerated ageing seen in this disease, controversy remains as to whether WS is showing the acceleration of a normal cellular ageing mechanism, or instead the occurrence of a novel WS-specific process. To address this we analysed the signalling pathways responsible for senescence in WS fibroblasts. Cultured WS (AG05229) fibroblasts senesced after ~20 population doublings, with the majority of the cells having a 2N DNA content.Keywords: Cell cycle control, senescence, human ageing, telomeres, p53
Since Szilard's seminal 1959 article, the role of accumulating nuclear DNA (nDNA) damage - whether as mutations, i.e. changes to sequence, or as epimutations, i.e. adventitious but persistent alterations to methylation and other decorations of nDNA and histones - has been widely touted as likely to contribute substantially to the aging process throughout the animal kingdom. Such damage certainly accumulates with age and is central to one of the most prevalent age-related causes of death in mammals, namely cancer.Keywords: cancer, nuclear mutations, aging, pleiotropy,
Two years ago, at the first SENS conference (IABG 10), I presented a decidedly ambitious proposal for combating cancer much more thoroughly than can realistically be expected from any therapy currently existing or under development.Keywords: WILT, cancer, telomerase, ALT, gene targeting
Interspecies SCNT with ES cell mito-rescue: a proposed solution to some key ethical and logistical problems
Despite impressive advances, adult stem cells remain less promising than embryonic stem (ES) cells for treatment of numerous human conditions, including age-related ones. The pace of ES cell research has, however, been slowed by three critical difficulties. First, the embryo from which the ES cells are derived will not be totally immunocompatible with the recipient (even if HLA alleles are matched).Keywords: WILT, SCNT, mitochondrial DNA, mitochondrial biogenesis, oocyte availability
Despite enormous effort, progress in reducing mortality from cancer remains modest. Can a true cancer "cure" ever be developed, given the vast versatility that tumours derive from their genomic instability? Here we consider the efficacy, feasibility, and avoidability of side-effects of a therapy that, unlike any available or in development, could never be escaped by spontaneous changes of gene expression: the total elimination from the body of all genetic potential for telomere elongation, combined with stem cell therapies to maintain proliferative tissues despite this handicap.Keywords: cancer, replicative capacity, telomeres, stem cells, gene targeting
Aging is not popular with the general public, and they look to the scientists with the most detailed understanding of aging to provide credible information on how much longer humanity must endure it. Biogerontologists are acutely aware of their consequent responsibility not to suggest unrealistically optimistic timescales for the defeat of aging. However, they seem mostly to be unaware of their converse responsibility -- not to suggest or imply unrealistically pessimistic timescales.Keywords: real anti-aging medicine, public debate, timescales , ,
Human ageing is characterised by multiple changes at different levels of biological organisation. It is still not clear which (if any) molecular, cellular or physiological changes are more important drivers of the process of ageing or how they influence each other. One difficulty in understanding how different processes at different scales relate to ageing as a whole is the lack of integrative, holistic views of ageing.
The bowhead whale (Balaena mysticetus) has not only been estimated to live over 200 years, making it the longest-lived mammal, but these animals remain disease-free until much more advanced ages than humans can. The mechanisms for the longevity and resistance to aging-related diseases of bowhead whales are unknown, but it is clear they must possess aging prevention mechanisms.
Transcriptomic study of H2O2-induced premature senescence of human diploid fibroblasts using a low-density cDNA array
Normal human diploid fibroblasts (HDFs) stop dividing after a certain number of population doublings (PDs) in vitro. Telomere shortening observed at each cell division eventually leads telomeres to critical lengths, which in turn trigger growth arrest. Telomerase elongates the telomeres can immortalize HDFs without transformation. Stress-induced premature senescence (SIPS) establishes several at 72 h after exposure of HDFs to subcytotoxic concentrations of oxidative stressors such as hydrogen peroxide (H2O2).Keywords: cellular senescence, fibroblasts, telomeres, gene expression ,
The key physiological characteristic of aging is a failure to maintain tissue integrity due to progressive deterioration, coupled to the apparent exhaustion of normal regenerative potential. This may be due to environmental factors, such as DNA damage, which eventually cannot be overcome, and/or genetic components may exist that enforce intrinsic processes within an individual. We are developing a new model organism to study aging in which both characteristics are present and can be experimentally manipulated: an ascidian, or sea squirt, called Botryllus schlosseri.
Organiser's Note: Dr. deGroof was unable to attend the meeting, and consequently his talk was given by Dr. Lakatta.Keywords: extracellular matrix, AGE, collagen, crosslink, ALT-711
The loss of a normal airway is devastating due to a lack of effective treatment methods for repairing large defects. However tissue engineering of an airway using a patient's own cells would create a complete, immunotolerant airway substitute. We therefore developed methods to bioengineer a tubular tracheal replacement and assessed the application of this technology in a patient with end-stage airway disease due to tuberculosis.Keywords: Trachea Transplantation, Stem Cells, Tissue Engineering, Cartilage, Bioreactor
The Well-Breast Massage Study is intended to be a long-range study of the effects of breast massage and self-care on breast health. The participants of the study are a non-randomized sample of women all over the world of all ages, ethnicities, and health backgrounds. The principal investigator of the study is Caryn Boyd Diel, the Director of White Cloud Institute in Santa Fe, a school and research center for Energy Medicine and Taoist studies and Chinese self-healing techniques such as Chi Gong and Chi Nei Tsang, Asian Body therapy.Keywords: Well Breast Massage Research Study, , , ,
Insulin/IGF-1 signaling (IIS) regulates the aging process in worms, flies and mice. In the nematode Caenorhabditis elegans, IIS regulates processes in addition to aging such as early developmental decisions and the reproductive status of the animal. We present evidence for the placement of the uncharacterized gene, smk-1, within the insulin/IGF-1 pathway. Genetic analysis indicates that loss of smk-1 specifically influences the aging related function of the DAF-2 (IIS) signaling pathway.Keywords: insulin/IGF-1, C. elegans, longevity, FOXO3a, DAF-16
Mitochondrial transcription factor A (TFAM) acetylation and age-related mtDNA and TFAM contents in several rat tissues
Replication and transcription of the mitochondrial genome depend exclusively on nuclear DNA-encoded products. One of these products, mitochondrial transcription factor A (TFAM), plays a complex role in the regulation of both processes: it is required for mtDNA mainteinance and together with two other factors, TFB1 and TFB2, stimulates mitochondrial transcription . Moreover homozygous disruption of TFAM gene and tissue-specific TFAM knockout cause severe respiratory chain deficiency and increased apoptosis in mice embryos .Keywords: aging rat, TFAM, acetylation, mtDNA content ,
Managing the process and changes that occur with aging is a complex challenge that will require much more than cutting edge research in biomedical sciences. It is only with an approach that marries different fields of science with environment and nutrition, that we will truly be able to alleviate the effects of aging.
The p53 tumor suppressor is critical for protecting the cell against the deleterious effects of an array of stresses, including damage induced by reactive oxygen species. Stress-activated p53 can effect one of several antiproliferative outcomes, including apoptosis, cell cycle arrest, or cell senescence.Keywords: p53, mouse aging model, stem cells, cancer, accelerated aging
Observation of Preventive and Therapeutic Effects of Antithrombin-Ⅲ on Experimental Disseminated Intravascular Coagulation
Objective: To observe the preventive and therapeutic effects of antithrombin-III (AT-III) on experimental disseminated intravascular coagulation (DIC) in rabbits. Methods: Rabbits were at random divided into the control and AT-III plus lipopolysaccharide (LPS) or AT-III plus thromboplastin (Tp) groups. Experimental DIC was induced by injection of LPS or Tp. AT-III was intravenously injected after the injection of LPS or Tp. 2.5 hours later, blood sample were drawn and the concentration of fibrinogen, prothrombin time (PT), 3P test, platelet count, AST and CK was measured.Keywords: Antithrombin-III, Lipopolysaccharide, Disseminated intravascular coagulation, Throm-boplastin, Rabbit
... Elegant elegans, Black-Scholes, alchemists and flat earthers...! Biology, longevity risk and their economic effects...
In recent years developmental advances in biology at the molecular level have given rise to improving mortality and increasing longevity in the human species. As a consequence there has been a significant and growing risk affecting a number of financial institutions who have traditionally insured human life or provided financial provision for retirement. These institutions can no longer warehouse this risk or successfully fund it. This has raised a serious economic spectre.Keywords: insurance, longevity, risk, retirement,
A number of genes and molecular pathways have been linked to the aging process in lower organisms such as fruit flies, worms, and mammals. Common among these observations is the idea that oxidative stress and altered handling of reactive oxygen species (ROS) may be critical components of aging. Reactive oxygen species (ROS), generated by normal metabolism of oxygen in cells, are clearly important for normal cellular function and physiology, but can also be toxic, a two-faced ÒJanusÓ of cell biology.Keywords: , , , ,
Accelerated protein aggregation and amyloid fibril formation of the prion protein in the presence of glycogen
Among protein misfolding diseases the transmissible spongiform encephalopathies like Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle or scrapie in sheep and goats, are unique neurodegenerative diseases: They can be of either sporadic, or genetic, or infectious origin. Independent of the underlying etiology they are always infectious. The infectious agents are composed primarily of a host protein, the so-called prion protein (PrP).Keywords: protein misfolding, amyloid, prion, glycogen, corpora amylacea
There is very little change in the quantity of antibodies produced, of any isotype, with age. There is, however, a change in the quality of the antibody response. Older people produce less antibodies that are specific for the activating pathogen or vaccine. At the same time, the number of non-specific antibodies increases. Quite often these antibodies have self reactivity (such as anti-dsDNA). The appearance of these antibodies is not associated with pathogenic autoimmune disease, although it is true that the incidence of some autoimmune diseases increases with age.Keywords: immunity, antibody, affinity maturation, ,
Reduced function of T lymphocytes has been implicated in the age-associated increased morbidity and mortality due to infections as well as in the enhanced risk of cancer. Like other normal human cells, T lymphocytes are limited in their proliferative potential. Cell culture studies of repeatedly stimulated T cells have identified a variety of phenotypic, genetic and functional changes associated with the end stage of replicative senescence.
Elderly persons have been exposed to a myriad of pathogens over their lifespan. This life-long immunological history leads, in many cases, to the generation of expanded populations of memory T cells that have reached the end stage of replicative senescence.Keywords: T cells, immune system, telomerase, replicative senescence ,
Telomerase is expressed in neonatal brains and also in distinct regions of adult brain. Telomerase was shown to protect developing neurons from apoptosis. Telomerase transgenic mice demonstrated significant resistance to ischemic brain injury and N-methyl-D-aspartic acid (NMDA) neurotoxicity. Hence, we and other hypothesized that increasing telomerase expression by pharmaceutical compounds may protect brain cells from death caused by damaging agents.Keywords: telomerase, ALS, neurodegeneretive, Neuroprotector,
The camelids - camels, llamas and their relatives - are unique in producing antibodies that have no light chain. These single polypeptide chain antibodies bind to antigens as strongly as conventional, multi-chain antibodies, but have lower molecular weights, are easier to engineer and produce, and more stable. They are attracting a lot of interest as potential therapeutics and diagnostics.Keywords: antibody, antibody engineering, camelid, ,
The intersection of nanotechnology and medicine is here. While nano biomedicine has led to wildly futuristic promises, it has also presented real breakthroughs in drug research, development and formulation. Two significant nanobiomedical advances will be discussed, each with the potential for great promise in treating human conditions in the very near future.Keywords: CNS regeneration, hemostasis, tissue repair, functional return of vision, nanomedicine
Contrary to previously held beliefs about the static nature of the adult mammalian brain, it is in fact capable of generating new neurons that can integrate into its complex circuitry. The recent development of new techniques has resulted in an explosion of research demonstrating that neurogenesis, the birth of new neurons, constitutively occurs in two specific regions of the adult mammalian brain (olfactory bulb and hippocampal dentate gyrus), and that there are significant numbers of multipotent neural precursors, or "stem cells," in many parts of the adult brain.Keywords: cortex, development, neural precursors, neurogenesis, stem cells
Expression of the 13 mtDNA-encoded proteins from nuclear transgenes (allotopic expression) might be the most effective gene-therapy strategy. However, there is an important difficulty, the extreme hydrophobicity of these proteins, which prevents their import into mitochondria from the cytosol.
The use of inteins (1), self-splicing "protein introns", might solve this problem: their insertion into such transgenes could greatly reduce the encoded proteins hydrophobicity, thus enabling import. The post-import spliced product would become the mature protein.Keywords: , , , ,
Telomere-initiated cellular senescence is triggered when telomeres, the ends of linear chromosomes, cannot fulfil their normal protective functions. Although changes in several cellular markers have been shown to be associated with senescence, the mechanisms that control it are largely unknown. In order to gain a better molecular understanding of this phenomenon, we studied the molecular markers associated with senescence in primary human MRC5 and BJ fibroblasts. Since their life span can be extended by the expression of telomerase, senescence is telomere-initiated in these cells.Keywords: Telomeres, senescence, DNA damage, checkpoints, human fibroblasts
Cryopreservation of Complex Living Systems: The Missing Link in the Regenerative Medicine Supply Chain
The current research effort in regenerative medicine has involved the expenditure of several billion US dollars to date, but relatively little attention has been paid to the fate of engineered tissue replacements between the time they are produced and the time they are used (inventory control and supply chain management). The problems of cryogenic banking of complex tissue replacements are much more serious than those involved in ordinary cell and tissue banking, and new technology will be required to overcome the limitations of current methods.Keywords: cryopreservation, transplantation, life extension, vitrification, freezing
Werner's syndrome (WS) is an inherited genetic disease in which individuals display the premature ageing of a selected subset of tissues. The disorder results from loss of function mutations in the wrn gene. Wrn codes for a member of the RecQ helicase family with a unique nuclease domain. There is significant evidence that the role of wrn is to assist in the repair and reinitiation of DNA replication forks that have stalled.Keywords: Werner's syndrome, drug sensitivity, COMET assay , ,
Angiogenesis in vitro: vascular tube formation from the differentiation of murine embryonic stem cells
Introduction: In this investigation murine embryonic stem (ES) cells were used to study endothelial cell development.
Materials & Methods: Murine ES cells (CCE cell line) exposed to Alpha-MEM medium containing 10% FBS for 4 days and then cultured in endothelial basal-2 medium containing vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF), and epidermal growth factor (EGF) and 5% FBS.Keywords: embryonic stem cells, endothelial cells, tube formation, differentiation ,
Unlimited self renewal and potential capacity of embryonic stem cells (ESC) in differentiating into a wide variety of cell types has made the cells an attractive source of donor cells for developmental studies and cell therapy. Blocking the differentiation of ES cells in culture and using them in clinical applications requires some genetic manipulations of the cells. The aim of the present study is to transfect CCE ES cells by EGFP and BDNF Genes. For this purpose pIRES2-EGFP and pcDNA3-hBDNF-v5 plasmids were used.Keywords: Embryonic Stem Cells, Transfection, Electroporation, GFP, BDNF
Current literature reports that physical exercise confers health protective benefits for both cardiovascular disease and atherosclerosis, as well as several neurological pathologies including Alzheimer's and Parkinson's diseases. However, the salutary effect of physical exercise on neuronal function remains elusive in its underlying mechanisms. In this work we sought for possible structural changes induced by moderate physical exercise (MPE) in the aging brain. Adult (12 months of age), old (27 months of age) and old-MPE (27 months of age) mice were used.Keywords: physical exercise, synaptic morphology, synaptic plasticity, hormesis, oxidative stress
Mitochondrial dynamics in distal dendrites of hippocampal CA1 neurons of aged rats correlates with good performance in passive avoidance test
A progressive decline of the mitochondrial metabolic competence is associated with aging. In the brain, this phenomenon particularly affects high energy-requiring processes that take place during neuronal stimulation. Aim of the present work was to verify whether activity-dependent changes in mitochondrial parameters in distal dendrites of CA1 hippocampal neurons of aged (26-27 month old) female Wistar rats might correlate with performance differences in the passive inhibitory avoidance task.Keywords: mitochondrial morphology, mitochondrial structural dynamics, successful aging, hippocampus, inhibitory avoidance
Chronic aluminum administration to old rats results in increased levels of brain metal ions and enlarged hippocampal mossy fibres
The effect of chronic aluminium intake has been investigated in the central nervous system of aged male Wistar rats to assess the potential role of the accumulation of this metal ion on the development of neurodegenerative features observed Alzheimer's disease. Aluminum dichloride hexahydrate (2g/L) was administered for 6 months in the drinking water.Keywords: Aluminum administration, brain metal ions, hippocampus, Timm's reaction, Alzheimer's disease
Geroprotector is a therapetics aiming at root causes of age-related diseases and as such capable of extending the life span of model animals and ultimately humans. The causes of aging are very ancient and evolutionary conservative. This means that the targets for the small molecule intervention can be identified using bio-informatics tools as the most conservative proteins in the pathways containing the largest number of genes responsible for the life span control.Keywords: , , , ,
The expression of SMP30 having multifunctions is decreased with ageing in almost all organs. The amino acid sequence of SMP30 is highly conserved among various species. Intracellular localization of SMP30 is both in cytoplasm and nucleus. Since a part of SMP30 is phosphorylated , we determined phosphorylation sites by proteomic analysis. In addition SMP30 catabolizes organophosphates in the presence of cationic ions except calcium ion. Although SMP30 has been thought to be a calcium-binding protein, our study showed no eveidence on its binding to calcium ion.Keywords: SMP30, phosphorylation, organophosphatase , ,
Cellular “functional replacement” with a “cell-free strategy” in early Alzheimer's and Parkinson's diseases: evidences from related animal models
Background. Current evidence suggests that bone marrow stem cells (BMSC) contribute to lesioned/degenerated brain tissue repair by both secretion of trophic paracrine factors and functional incorporation into affected regions. Hypothesis. In vitro generated conditioned medium from cultured BMSC (CM-BMSC) replaces the stem cell grafting benefits in early Alzheimer’s and Parkinson’s diseases models respectively. Methods. BMSC-derived conditioned medium (BMSC-CM) was obtained from culture expanded BMSC (10 passages).Keywords: animal model, neurodegenerative disease, stem cells, mild cognitive impairment, preclinical parkinsonism
Motor and cognitive recovery induced by bone marrow stem cells grafted to striatum and hippocampus of impaired aged rats: functional and therapeutical considerations
Impairments in motor coordination and cognition in normal and pathological aging are often accompanied by structural changes i.e. loss of synapses and neurons. Also, it has been recently shown that bone marrow stem cells can give origin to cells of different tissues, including neural cells. Given the therapeutic implications of increasing health and functional possibilities in the aged brain, we have tested the effects of rat femur bone marrow stem cells, rBMSCs, grafting to the striatum hippocampus of aged rats with motor or cognitive deficits respectively.Keywords: stem cells, aging, neural grafting, sensorimotor function, cognition
Background. Neurogenic events and associated behavioral improvements have been reported after housing under enrichment environment conditions (EE), demonstrating the presence of newborn cells from neurogenic niches. Previous studies have demonstrated the bone marrow stem cells (BMSC) possibilities as source of tissue in brain grafting studies. Objectives: To compare functional effects induced by EE (12 weeks, 6 hours/day) and/or hippocampal BMSC grafting (H-Graft) in an early Alzheimer´s disease rat model. Methods.Keywords: animal model , early Alzheimer's disease, stem cell grafting, cognitive impairment, environment enrichment
Environmental enrichment-behavior-oxidative stress interactions in the aged rat: issues for therapeutical approach in human aging
The effects of environment enrichment on motor activity, exploration and cognitive performances were studied in aged rats. Both, non-impaired (NI) and impaired (I) rats were submitted to daily training in complex-enriched environment (cEE) for 60 days. Animal were examined at spatial water maze task, passive avoidance test, open field test and sensorimotor coordination tasks (bridges test and Marshall scales). At the end of experiment animal were sacrificed for brain biochemical determinations (gluthatione content and specific-ChAT activity).Keywords: aging, environmental enrichment, cognition, motor function, neurorehabilitation
The future of human life spans, a demographic perspective Caleb E Finch,Andrus Gerontology Center, University of Southern California, Los Angeles CA 90089-0191 Since the 18th C, human life spans have increased globally from a life expectancy at birth (LE0) of 25-40y, to >80y in healthy countries; the LE70 has also more than doubled (1-3). In essence the J-shaped mortality curve has shifted to progressively lower levels with minor changes in the accelerating (Gompertz) phase of mortality during aging (1,3).Keywords: inflammation, Gompertz slope, minimum mortality , ,
We currently give absolute priority to medical interventions that save the life of individuals who are on the verge of death. Nobody in the UK is ever refused life-saving treatment unless it is unproven or ‘futile’. We do not take into account how much voluntary risk a person has taken on, their ability to pay, or even (in most cases) how expensive the therapies will be. If some curative intervention can provide a number of healthy additional years of life to a particular individual, it is provided.Keywords: Ethics, Resource Allocation, Clinical Policy, Justice,
Calorie Restriction (CR) without malnutrition slows aging and increases lifespan in simple model organisms and rodents. In Rhesus monkeys long-term CR reduces the incidence of type 2 diabetes, cardiovascular disease and cancer, and protects against age-associated sarcopenia and neurodegeneration. However, only in the Wisconsin, but not in the NIA monkey study, CR significantly increased average lifespan so far.Keywords: calorie restriction, human, lifespan
The general model of most tissue-engineering strategies rests on the use of exogenous biocompatible scaffolds in which cells can be seeded and matured in vitro or in vivo, to grow the tissue of interest. Scaffolds have been subject to prolific research and development over the last thirty years and, in general, offer the advantage of good biocompatibility, cell attachment and proliferation, while providing the biological, chemical, and mechanical clues to guide the eventual cell differentiation and assembly into a three-dimensional tissue construct.Keywords: tissue engineering, scaffold, bioprinting, vascular graft, nerve graft