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.
Moderate regular exercise is thought to be good for health, to help to retard aging and reduce incidence of age-related diseases in aged animals and elderly people. Mechanisms of these beneficial influences are not fully understood. We have investigated effects of regular exercise on oxidative modifications of proteins and DNA, and proteasome activities that can degrade oxidatively modified proteins as well as oxidative status and NF-kB in aging rat tissues.Keywords: regular exercise, oxidative stress, adaptation, proteasome, NF-kB
Intra- and extra-cellular proteins are subjected to numerous forms of post-translational modifications. While most of them are physiological as in phosphorylation and glycosylation, some of them are unphysiological and potentially harmful as in oxidation and glycation. Biological aging is defined as physiological decline with time that is likely caused by alteration of proteins. Altered proteins are mostly generated by post-translational modifications.Keywords: aging, histone, carbonylation, acetylation, dietary restriction
Dementia is prevalent in the aging population. Several studies have suggested a possible link between, limbic system anomalies and reward circuitry impairment in several forms of dementia. There are several difficulties in performing behavioral tasks with some patients due to the presence of the test administrator. Human interactions may alter patients' behavior. Thus, we have built and designed an Automated Memory Evaluation System (AMES) that measures the ability to remember geometric shapes of different colors and rewards positive patient responses as well as records response timings.Keywords: dementia, neuropsychology, gustatory, reward, automated
Insulin-like growth factor I (IGF-I) is a powerful neurotrophic molecule which appears to be part of the physiologic self-repair mechanisms of the adult brain. Using the aging female rat as a model of age-related dopaminergic (DA) neurodegeneration, we have implemented short-term restorative IGF-I gene therapy in the hypothalamus and cerebral ventricles.Keywords: Brain aging, IGF-I, Gene therapy, Magnetic nanoparticles, Magnetofection
Abnormal or inadequate vasculogenesis, local inflammation, and severe epithelial damage are common features of both inflammatory bowel disease (IBD) and radiation-induced injury resulting from pelvic or abdominal cancer treatment. Several studies have shown that adult bone marrow-derived stem cells, such as mesenchymal stem cells (MSC), upon transplantation, home to the damaged digestive tissue and facilitate mucosal repair in both IBD and radiation injury.Keywords: Endothelial Progenitor Cells, Mesenchymal Stem cells, EphB2, Intestine, Inflamatory Bowel Disease
Dedifferentiation signifies the capacity of somatic cells to acquire stem cell-like properties. This process characterizes the transition of differentiated plant cells to protoplasts (plant cells devoid of cell walls), a transition accompanied by widespread chromatin decondensation. Transcriptome profiling of dedifferentiating cells revealed striking similarities with senescing cells; both display a large increase in the expression of genes of specific transcription factor (TF) families including ANAC, WRKY, bZIP and C2H2.Keywords: Dedifferentiation, stem cell, senescence, chromatin, plants
A Cell-Based, High Throughput Screening Assay to Identify Small Molecule Compounds that Derepress Endogenous hTERT Expression Using Toxic hTR Template Mutants
Human telomerase is the subject of intense research because of its critical function in cellular immortality via telomere length maintenance. Presence of telomerase activity is strongly associated with immortality of embryonic stem and cancer cells. The human telomerase complex is composed of the human Telomerase Reverse Transcriptase protein (hTERT) and the human Telomerase RNA (hTR). Expression of telomerase activity is controlled, mainly at the level of hTERT transcription. However, the specific mechanisms of repression or silencing of the hTERT promoter region remain unclear.
Cardiovascular disease and osteoporosis are leading health care problems in our aging population. Numerous studies have documented an association between these two multifactorial and degenerative diseases. Moreover, atherosclerosis is considered to be a chronic inflammatory disease such that the immune system actually modulates the atherogenic process. In addition, the immune system plays a key role in bone resorption through production by activated T lymphocytes of RANKL (receptor activator for NFkB ligand), a protein that stimulates the maturation and activity of osteoclasts.Keywords: Atherosclerosis, Osteoporosis, T cells
Advanced Glycation Endproducts (AGEs) form cross-links between proteins in the extracellular matrix (ECM) which are a major cause of the degradation of ECM function. AGEs accumulate with age in long-lived proteins such as collagen and elastin, significantly reducing tissue function. Removal of AGE cross-links is a potential route to reversing the disabilities of old age. AGE cross-links are however not the only AGEs in tissues. Conventionally, other AGEs have been used as markers of tissue glycation, in particular carboxymethyl lysine (CML).Keywords: Advanced Glycation Endproducts , Cross-links, Extracellular matrix
Age is the single most important risk factor for cancer and every strategy for postponing human senescence ultimately relies on developing efficient ways of eradicating neoplastically transformed cells from the body. Although conventional treatments have been improved against primary tumors, they are less effective against metastases. Indeed, most cancer patients do not die from the primary tumor, which can be effectively diagnosed and removed, but as a result of metastasis.
Age is the single most important risk factor for cancer and every strategy for postponing human senescence ultimately relies on developing efficient ways of eradicating neoplastically transformed cells from the body. Unfortunately, treatment outcomes for most common human cancers have only been incrementally improved over the last decades, which is mainly due to our inability to effectively deal with metastases. Indeed, most cancer patients do not die from the primary tumor, which can be effectively diagnosed and removed, but as a result of metastasis.Keywords: cancer vaccines, breast cancer, Mage-b, metastases ,
Recent data suggest that the epigenome is highly dynamic and serves as an interface between the environment and the inherited static genome. The large volume of epigenomic events and its continuous need of maintenance, i.e., after DNA repair or replication, suggest a high chance of errors. The question we wish to address is how unstable the epigenome really is. Do epimutations accumulate with age and do they occur in a random fashion, i.e., as ‘epigenomic drift’? Do they ever reach levels that are high enough to have functional consequences?
Recent data suggest that the epigenome is highly dynamic and serves as an interface between the environment and the inherited static genome. The large volume of epigenomic events and its continuous need of maintenance, i.e., after DNA repair or replication, suggests a high chance of errors. The question we wish to address is how unstable the epigenome really is. Do epimutations accumulate with age and do they occur in a random fashion, i.e., as ‘epigenomic drift’? Do they ever reach levels that are high enough to have functional consequences?Keywords: Epigenetic instability , Aging , Brain , Single-cells,
Epigenetic regulation is critically important in mammalian development. Changes in epigenetic regulation have also been shown to play a role in the etiology of human disease, for example, hypermethylation of tumor suppressor genes in cancer. Epigenetic changes in aging, which have been studied much less frequently, are a concern because once established epigenetic profiles are only partially stable and can vary substantially as compared with the more static DNA sequence code.Keywords: Aging, epigenetics, DNA methylation, ,
The ubiquitin/proteasome pathway (UPP) is responsible for elimination of damaged and misfolded proteins. In yeast it has been established that mutant isoforms of ubiquitin unable to participate in ubiquitin chain assembly exert a dominant negative effect on proteolysis (in the case of a K48R substitution) or on DNA repair (in the case of a K63R substitution). To explore the consequences of analogous mutations in the context of mammalian cells in vivo, we have created transgenic mouse strains in which wild type or mutant ubiquitin is expressed at high levels in most tissues.Keywords: ubiquitin, proteasome , transgenic , neurodegeneration ,
Little is known about how normal aging affects the brain. Recent evidence suggests that neuronal loss is not ubiquitous in aging neocortex. Instead, subtle and still controversial, region- and layer-specific alterations of neuron morphology and/or synapses are reported during aging, leading to the notion that discrete changes in neural circuitry may underlie age-related cognitive deficits. Although deficits in sensory function suggest that primary sensory cortices are affected by aging, our understanding of the age-related cellular and molecular changes is sparse.Keywords: Olfaction, Synapse, Mitral cells, Granule cells, Glomeruli
A Cell-Based, High Throughput Screen to Identify Small Molecule Compounds that Derepress the Telomerase Minimal Promoter in a Transient Luciferase Expression System
The presence of telomerase activity in human cells is strongly correlated to the expression of hTERT which is repressed in normal adult human cells. We are undertaking a screen for compounds that activate telomerase expression using a transient expression system similar to the one previously described by Won et al. The telomerase minimal promoter sequence was inserted into a promoter-reporter plasmid to drive expression of the luciferase coding sequence.
Enzyme replacement therapy (ERT) is an established means of treating lysosomal storage diseases. Infused therapeutic enzymes are normally targeted to the lysosomes of affected cells by interactions with cell-surface receptors that recognize carbohydrate moieties, such as mannose and mannose 6-phosphate (M6P), on the enzymes. We have investigated alternative strategies to deliver lysosomal enzymes to lysosomes using the lysosomal enzyme B-glucuronidase (GUS) and the enzyme deficient Mucopolysaccharidosis Type VII (MPS VII) mouse model,Keywords: lysosomal storage disease, enzyme replacement therapy, MPS VII, ,
CD8+ CD28- T cell clonal expansions frequently occur in elderly persons who fail to produce specific antibodies following immunization. These clones express effector cell markers and are mostly CD45RA+. When isolated and put into culture they are unable to proliferate, but produce IFNgamma upon stimulation. Many of the clones specifically recognize cytomegalovirus (CMV). These CD8+ type 1 effector cells seem to trigger a Th1 polarization, as CD4+ T cells from elderly persons without in vivo antibody production produce Th1, but only low amounts of Th2 cytokines upon stimulation with PHA.Keywords: immunosenescence, CMV, genetics, T cells ,
The nematode worm Caenorhabditis elegans (C. elegans) is increasingly popular as a model organism for ageing studies as well as for testing antioxidants and other compounds for effects on longevity. Not surprisingly, new investigators in the field (including ourselves) have begun to use C. elegans in this way. However, results in the literature are often confusing and contradictory. Here we discuss aspects that make C.Keywords: Caenorhabditis elegans, antioxidant, screening, lifespan,
Accumulation of DNA damage due to failing repair with advancing age is one of the key molecular pathologies in aging. Lipid peroxidation is a main source of endogenous damage in tissue DNA and is linked to chronic inflammatory processes underlying numerous degenerative diseases. Polyunsaturated fatty acids (PUFAs) are the direct source of this damage. Various PUFAs with different oxidizability are present as basic building blocks in biological membranes and serve as precursors for local signaling molecules which modulate the strength of immune response, growth and tissue maintenance.Keywords: lipid peroxide, DNA damage, PUFA, ,
Field observations have suggested for quite some time that certain fish, turtles and invertebrates have extremely long maximum lifespan potential. Age validation techniques have since confirmed these observations. Negligible senescence is defined in part as no observable age-related increase in mortality rate or decrease in reproduction rate after maturity, and no observable age-related decline in physiological capacity or disease resistance.Keywords: , , , ,
Caleb Finch at USC coined the term "negligible senescence" in 1990; later he added the test criteria of no observable age-related increase in mortality rate or decrease in reproduction rate after maturity, and no observable age-related decline in physiological capacity or disease resistance. AgelessAnimals.org (a.k.a. Centenarian Species and Rockfish Project), has previously studied rockfish and turtles in 14 pilot studies, twelve in the U.S. and two in Europe.Keywords: Negligible senescence, Ageless, Whales, Rockfish
Decrease with age in total rates of protein degradation and in the activity of specific proteolytic systems is a common characteristic for almost all the old organisms analyzed. Inefficient removal of proteins prolongs their half-life inside cells and increases their probability of getting altered or damaged. This often leads to their accumulation as toxic non-functional protein aggregates inside cells.Keywords: , , , ,
Diminished immune function and chronic inflammation are hallmarks of aging. They are also the major cause of morbidity and mortality associated with increasing age. The underlying causes for the same are not well understood. Here we show the increased reactivity of dendritic cells from aged subjects to self antigens as a potential mechanism contributing to age-associated inflammation. Consistent with this, dendritic cells from aged subjects display increased reactivity to intracellular self DNA by secreting enhanced quantities of type I interferon and IL-6 compared to the young controls.Keywords: Dendritic cells, Self DNA, Inflammation
The accumulation of non-enzymatic advanced glycation endproducts (AGEs) in tissues and organs as a normal part of the aging process is accelerated by hyperglycemia. These AGEs provoke inflammatory, angiogenic and sclerotic cytokines that ultimately cause dysfunctional tissue pathology. AGEs also quench available nitric oxide, a potent vasodilator and are a potent stimulant for oxidative stress through generation of reactive oxidant species.Keywords: Glycation, Heart failure, Erectile Dysfunction, diabetes ,
Despite a variety of therapeutic strategies, HCC remains a significant cause of cancer death. Therefore ,to study the HCC pathogenesis is of the utmost importance for the prevention and treatment of this disease. In the present study markers known of regeneration(HGF/c -met system) and cell proliferation(c-myc oncogene) were studied in a series of 20 HCC cases. HGF concentration was estimated in serum by ELISA &in tumor tissues by immunohistochemistry, c-myc & c-met mRNA were detected by RT-PCR.Keywords: c-met, c-myc, hepatocellular carcinoma, hepatocyte growth factor ,
The mitochondria are constantly translocated along microtubule chains to locations in the cytoplasm where nutrients (triglyceride droplets, puryvate) are available. How the mitochondrion is directed is not known. A hypothesis is that it is transported by fluid movements to locations with a higher osmotic pressure. When a mitochondrion has absorbed puryvate and phosphate ions, the local osmotic pressure in the cytosol around the mitochondrion is decreased.Keywords: Aging, Mitochondria, , ,
In a surplus of nutrition baker´s yeast cells (Saccharomyces cerevisiae) propagate parthenogenetically by budding off daughter cells. Propagation of old mother cells leads to daughter lines with exaggerated signs of aging (Lansing effect). The age of the mother cell depends mainly on the number of cell divisions (maximum about 20 buds), but to a small degree also on the chronological age (metabolic time). It is proposed that the aging may be ascribed to an accumulation of insoluble cross-linked protein, formed as a side product of protein metabolism.Keywords: Aging, Insoluble protein, Lansing effect, ,
The increase in human lifespan encountered in modern time may not be ascribed to a decrease in aging rate, but to improvements in living conditions with a less hostile environment. This is implied by a decrease in the contribution to the mortality rate (Rm) by the age-independent Makeham parameter (A), whereas the Gompertz function (Ro exp(at)) has remained unchanged (Gavrilov and Gavrilova 1991). Our challenge is to increase lifespan and decrease Rm by decreasing the aging rate, i.e.Keywords: aging, Gompertz slope, insoluble protein , ,
Phase I study of Seneca Valley Virus (SVV-001), a replication competent oncolytic virus, in patients with neuroendocrine (NE) cancers
SVV-001 is a native non-pathogenic picornavirus that has exquisite tumor selectivity and therapeutic potential for cancers with neuroendocrine features, such as small cell lung cancer, carcinoid cancer, and most solid pediatric oncologies (Reddy et al., 2007; Wadhwa et al., 2007; Hales et al., 2008; Venkatraman et al., 2008). NTX-010 has many of the ideal properties of an oncolytic virus, including the lack of neutralizing activity by human blood, small size enabling efficient penetration and spread in tumors, stability, and ease of manufacturing.Keywords: lung, cancer, oncolytic, seneca, pediatric
There is now abundant experimental evidence in multiple human cell types in culture for the causal relationships between telomere loss and replicative senescence on one hand, and telomerase activation and cellular immortalization on the other. These relationships are supported by correlative data in human aging, chronic diseases, cancer, experiments in telomerase knock-out mice, and human genetic conditions of telomerase insufficiency.Keywords: telomerase, cancer, degenerative disease, telomere ,
Aging changes in body composition and metabolism bear a striking resemblance to those seen in states of male and female sex hormone, thyroid, and growth hormone (GH) deficiencies and cortisol excess. This resemblance, plus observed decreases with age in testosterone in men, estrogen in women, and GH in both sexes have led some to conclude that aging is caused by hormonal alterations and to the use of hormone replacement as anti-aging therapy.Keywords: hormones, membrane fluidity, signal transduction , ,
This paper outlines the ethical issues involved in life extending therapies. The arguments against life extension are examined and found wanting. The consequences of life extension are explored and found challenging but not sufficiently daunting to warrant regulation or control. In short there is no doubt that immortality would be a mixed blessing, but we should be slow to reject cures for terrible diseases which may be an inextricable part of life extending procedures even if the price we have to pay for those cures is increasing life expectancy and even creating immortals.Keywords: Immortality, Justice, ethics, ,
Expression of anti-fibrogenic factor, 14-3-3 sigma in active and senescent skin cells, both in vitro and in vivo
Non-healing and chronic wounds affect 47 million patients each year in North America, a majority of whom are elderly. Wound healing is a complex and dynamic process that involves not only cell-cell communication in the form of signaling mediators, but also cell-matrix signaling. There is compelling evidence that an imbalance in any of these signaling events will lead to problematic healing.Keywords: Non-healing wounds, 14-3-3 sigma, HIF-1, extracellular matrix, scarring
Regenerative Medicine: Systematic Application of Biotechnology, Bioengineering, Nanotechnology and Information Sciences for the Improvement of Human HealthAudio: (Audio)
The human body is a self-assembling machine, comprised of trillions of tiny parts, that maintains itself in good working order for decades. Damage by disease, injury by trauma and wear by time degrades our body's function.Keywords: , , , ,
The evolution of senescence is thought to follow from the progressive decline in the force of natural selection after the onset of reproduction. Cellular senescence caused by telomere shortening has been suggested as one potential causal agent of aging. In some tissues, telomeres are maintained by telomerase. The presence of telomerase promotes tumor formation however, suggesting a trade-off between aging and cancer. Weinstein and Ciszek's reserve-capacity hypothesis (2002) suggests that the strategies organisms have evolved to cope with this trade-off may vary with lifespan.Keywords: bird, telomerase, telomere, aging, lifespan
To help older people in our country, the Albanian Association Gerontology-Geriatrics (A.A.G.G.) was established in October 1991. The Association represents Albania in the International Gerontology (I.A.G.) and in the other European and World organizations that advocate for problems of "third age". During this period, the Association has organised many activities for its members and the public at large. The tradition in Albania is that responsibility for parents' care lay firmly sons, while married daughters look afer their frail parents.Keywords: mondi, , , ,
Using our knowledge of tumour immunology and genetic technology to treat cancer is now a realistic possibility. There are a variety of potential approaches but adoptive transfer of tumour-specific T cells is currently the most effective and has been successful in treating advanced melanomas. To extend this to other cancers and to simplify the process for clinical use, Engineered T cells (gene modified T cells artificially endowed with anti-cancer specificity) have been developed.Keywords: cancer immunotherapy, T cells, retrovirus, autoimmunity,
Human embryonic stem (hES) cells are being studied as potential source of cells for the treatment for many diseases (e.g. diabetes, Parkinson's, leukemia, congestive heart failure). The successful integration of hES cells into such therapies will hinge upon three critical themes: stem cell expansion in number without differentiating (i.e., self-renewal); differentiation into a specific progenitor type or collection of cell types; and, promotion of their functional integration into existing tissue.
Studies in the MRL mouse have demonstrated a unique capacity to heal wounds through a process of regeneration. This has been shown in multiple tissue types including muscle, cartilage, and connective tissue and in organs such as the ear, heart, and digits. The concept that life extension may be mediated by regeneration and its associated processes is a reasonable proposal. We will present molecular and cellular evidence from the MRL which examines this possibility.Keywords: , , , ,
The cerebrum, as the substrate for our consciousness, memories, personality, and self-identity, presents unique challenges for regenerative medicine. Regenerative approaches must not only maintain general cerebral function, but also preserve as much as possible the details of the wiring and firing parameters that define each individual. A combination of molecular repair and gradual cellular replacement appears most likely to succeed.Keywords: neocortex, glutamatergic neurons, cell migration, cell dispersion, apoptosis
The neocortex is the seat of our highest cognitive functions. Neocortical projection neurons, the principle neurons of the neocortex, become dysfunctional with age and can be lost due to neurodegeneration or insults such as stroke or trauma. The highly plastic nature of neocortical neuronal networks suggests that they could in theory withstand a slow turnover of neurons over time without significantly compromising function or memory. Therefore cell replacement may be a viable approach to rejuvenating the neocortex.Keywords: neocortex, cell replacement, neurons
Why organisms age and the reasons for the differences in longevity between different species is a fundamental question in biology. Changes in aging rates can be induced, most notably by increasing or decreasing calorie intake: Organisms subjected to caloric restriction (CR) live longer compared to those fed ad libitum (AL). CR robustly affects the age-related changes of several pathways: gene expression, hormones, oxidative damage, immune system, etc. All these mechanisms have a remarkable effect on longevity.Keywords: Calorie Restriction, Ad libitum, Anti-Aging, ,
Thymic involution is one of many events that leads to the inefficient functioning of the elderly immune system, causing an increased susceptibility to numerous infectious diseases. This loss of immune function, can be in part characterized by the loss of the cytokine IL-7.Keywords: IL-7, CCR9, fusion protein, therapy, thymic involution
Aging is associated with impairment in mitochondrial function that has been implicated in tissue dysfunction particularly in post-mitotic tissues. We examine here the impact of long term caloric restriction (CR), begun in juvenile male Fischer 344 X Brown Norway F1-hybrid rats, on the age-associated decline in oxidative capacity and mitochondrial function across a range of metabolic and contractile phenotypes in skeletal muscles, and in the most highly aerobic muscle, heart.Keywords: mitochondria, caloric restriction, mitochondrial DNA, mitochondrial biogenesis ,
Cancer remains one of the greatest challenges in prolonging healthy life. Despite decades of effort, the strategies for treating cancer have changed relatively slowly. Modern molecular diagnostics have shown that each cancer is a unique instance of disease, and that cancers are capable of evolving within the host; how can this information be better applied to treatment? One possibility is to develop a synthetic oncolytic viruses. Oncolytic viruses selectively infect and replicate within cancer cells while leaving normal cells unaffected.Keywords: , , , ,
The importance of diet and nutrition in human health and disease is well established. Basic laboratory research, clinical trials, and epidemiological studies have all contributed to our understanding of the minimum daily requirements (MDR) for both micro- and macro-nutrients necessary for survival and disease prevention. Caloric restriction experiments in a variety of species have also suggested a connection between diet and aging.Keywords: nutrition, health, longevity, oxidative stress, phytochemicals
The bold assertion by proponents of SENS (namely Aubrey de Grey) that "SENS is a practical, foreseeable approach to curing aging" has stirred considerable controversy among gerontologists. The reformulation of this assertion into a testable hypothesis will not only require concise definitions for the somewhat subjective terms "practical", "foreseeable", and "curing", it will require a precise definition of the term "aging". To facilitate proper experimental design, this definition must focus on the nature of aging itself, not its causes or consequences.Keywords: Aging, functional capacity, biomarkers, longevity ,
Telomeres are chromosomal caps that prevent genomic instability and protect chromosomal integrity. When cells divide, telomeres shorten due to the "end replication problem". Decreased telomere length is associated with cellular senescence (aging), as older cells show markedly shorter telomeres. A predominant hypothesis between telomere length and aging is that the relationship is causative rather than correlative, i.e. decreased telomere length causes aging, or at least several of the main symptoms of it.