New Applications in Aging Research

Related Articles:
a Hamilton’s Forces of Natural Selection after forty years. Evolution 61: 1265-1276.
a Do longevity mutants always show trade-offs? Experimental Gerontology 41: 1055-1058.
a Why dietary restriction substantially increases longevity in animal models but won’t in humans. Aging Research Reviews 4: 339-350.
a Evolution of late-life mortality in Drosophila melanogaster. Evolution 56: 1982-1991.



Session I: Defining and Measuring Aging

8:45

The Evolution of Late-Life Demography
Session Chair Laurence D. Mueller,
University of California, Irvine



Research on many different organisms has established that there is a general pattern of mortality rate deceleration in late life. The observation of more or less constant mortality at late ages is often referred to as a mortality plateau. Two very different theories have been offered to explain these observations: life-long heterogeneity of demographic rates and the evolution of mortality rates. Recent theories have been developed that expand the evolutionary theories to late-life female fecundity. Results from this theory suggest that fecundity is also expected to plateau in late-life. The timing of these late-life plateaus is intimately connected with the patterns of natural selection. Experiments with Drosophila populations subjected to different demographic selection confirm important predictions from this evolutionary theory.



Related Articles:
a Mutation Accumulation Affects Male Virility in Drosophila Selected for Later Reproduction
a An evolutionary heterogeneity model of late-life fecundity in Drosophila
a Lifelong heterogeneity in fecundity is insufficient to explain late-life fecundity plateaus in Drosophila melanogaster
a The Mueller Lab



9:10

Biological Age Measurement – Is it Possible?
Advisor: Chris Heward,
President
Kronos Science Laboratory



Aging can be defined as the decline in functional capacity of many vital physiological and biochemical systems leading to an increasing risk of morbidity and mortality over time. However, it cannot be measured by simply monitoring morbidity and/or mortality. Historically, some biogerontologists have attempted to develop methods to measure aging based upon the concept of “biological age” (BA). The rate of aging is expressed as the change in BA divided by the change in chronological age (CA). BA is determined by algorithmically combining multiple disparate biomarkers of functional capacity into a single number representing global biological functional capacity. The validity of this approach depends upon the degree to which the individual components of global aging are related (i.e. driven by a common fundamental underlying mechanism – the aging process). If disparate biomarkers of aging (BMA) are caused by the same underlying mechanism, they should not only correlate with CA, they should correlate with each other. Conversely, if no disparate BMAs can be found that correlate with each other, we must conclude that they are not caused by a common underlying mechanism. The Kronos Longitudinal Aging Study (KLAS) was initiated in 1999 to directly measure the age-related decline in human functional capacity over time and cross-sectional data has been collected from thousands of subjects, ranging in age from 15 to 103. To date, the KLAS cross-sectional database has been found to contain no examples of BMAs in different physiological systems which strongly correlate with each other. Thus, we must conclude that they are not valid predictors of global BA. Furthermore, since the KLAS database contains a large quantity of data on many of the best putative BMAs, we conclude that no common mechanism exists for these parameters and that no valid measures of global BA are likely to be discovered.



9:35
Enzymatic recognition of damaged biomolecules in aging – how do we prevent their accumulation?

Steven Clarke
Professor of Biochemistry
University of California, Los Angeles


We want to understand how aging organisms prevent the accumulation of degraded biomolecules that can increasingly interfere with physiological functions. There is now an enlarging family of enzymes that only recognize spontaneously degraded forms of DNA, proteins, and small molecules that participate in their repair or removal from cells. We propose that enzymatic methylation may be a general mechanism in the recognition of aged molecules. I will describe pathways for the enzymatic "repair" and replacement of damaged small molecules, especially a newly discovered pathway for the regeneration of age-damaged S-adenosyl-L-methionine (AdoMet). (S,S)AdoMet is the most widely used cofactor next to ATP, but it is subject to relatively rapid spontaneous degradation in cells leading to inactive (R,S) species. The major non-oxidative damage to proteins occurs at aspartyl and asparginyl residues and forms a variety of altered residues including L-isoaspartyl residues that introduce a kink in the polypeptide chain. L-isoaspartyl residues are recognized by a methyltransferase that can initiate their conversion to normal aspartyl residues. I will map out the relationships between protein isoaspartyl damage, oxidative damage, protein repair and proteolysis in aging mice, yeast, and worms. Finally, I will describe our search for new types of methyltransferases and other enzymes that can recognize age-damaged proteins and that may have roles in detoxification. The recent discovery of such enzymes suggests that we may be at only the beginning in identifying activities that cells utilize to prevent the build up of molecular "debris". Understanding these pathways may lead to therapeutic strategies to enhance their activities in humans and to minimize the detrimental effects of the aging process.


10:00:
Panel Discussion
Moderator, John Sterling
Editor in Chief
Genetic Engineering and Biotechnology News (GEN)



10:25 BREAK



Session II: Model Organisms in Aging Research: Drosophila


10:50


Coordinate Regulation of Drosophila Activity, Behavior and Life Span by MnSOD
Session Chair, John Tower,
Associate Professor
Molecular and Computational Biology Program
University of Southern California


aa The manganese-containing form of superoxide dismutase, MnSOD, resides in the inner mitochondrial space and plays a central role in mitochondrial and redox physiology in eukaryotes. We have previously reported that conditional over-expression of MnSOD in adult flies can extend life span. Using a doxycycline-regulated expression system, we now find that under appropriate conditions, over-expression of MnSOD in adult males can increase mean and maximum life span by decreasing initial mortality rate, while at the same time producing flies that are on average more active and faster-flying. Comparison of gene expression patterns between control and MnSOD over-expressing flies suggests that MnSOD acts through a mechanism related to reduced insulin/IGF1-like signaling. The data suggest a model in which a retrograde signal of hydrogen peroxide from mitochondria to nucleus promotes longevity.



Related Articles:
a Bacterial load and life span
a Sex-specific regulation of aging and apoptosis
a The Tower Lab


11:15


Stress Responsive Signal Transduction and the Control of Longevity

Dirk Bohmann, Ph.D., Professor of Genetics,
Department of Biomedical Genetics,
University of Rochester, Medical Center



Research conducted over the last decade in simple model organisms, such as yeast, C. elegans and Drosophila, has led to the suggestion that aging is not, as was widely presumed previously, the result of inevitable degeneration, but a process that can be regulated in response to internal and external signals. Aging research aims at understanding and ultimately manipulating the genetic mechanisms controlling the time course of organism senescence and longevity. Two major aspects of cell function appear especially relevant in this regard: mechanisms that defend against oxidative damage, and metabolic control.

The oxidative stress theory of aging predicts that bolstering the organism’s anti-oxidant defenses may retard the aging process and extend lifespan. This hypothesis has received considerable support in recent years, mainly by studies in model organisms showing that genetic manipulation of anti-oxidant genes can augment oxidative stress tolerance and promote longevity. By extension, the signaling pathways that regulate anti-oxidant responses are plausible regulators of the aging process. We have tested this notion using Drosophila genetics, concentrating on two stress-inducible signal transduction systems: the JNK and the Nrf2 pathways.

Our work has shown that JNK signaling defends Drosophila against acute oxidative stress, delays the accumulation of oxidative damage throughout life, and extends lifespan, without affecting development or reproduction. Interestingly, in the context of aging regulation, JNK acts by activating the transcription factor Foxo. Foxo had previously been shown to be down-regulated by insulin and to be required for the life extending effects of decreased insulin/IGF signaling, as it has been documented in several model organisms. One conclusion of our experiments is that JNK and insulin signaling antagonize each other in the regulation of lifespan.

The evolutionarily conserved Nrf-2 pathway is well known to protect organisms from adverse effects of pro-oxidants and electrophiles. Nrf2 (NF-E2-Related Factor 2) and its cytoplasmic inhibitor Keap1 (Kelch-like ECH-Associated Protein 1) regulate the basal and oxidative stress-induced activity of many anti-oxidant genes and detoxification enzymes. Furthermore, Nrf-2 activation has been found to have cancer preventive functions. We characterized the Drosophila homologues of Nrf-2 and Keap1, and found that they contribute to the regulation of oxidative stress resistance and lifespan.

Our studies demonstrate that oxidative stress and metabolic signals engage a complex signaling machinery that influences aging and senescence, but might also be relevant for a number of other maladies including cancer and diabetes. Studies in Drosophila will help to elucidate the complex interplay between signaling pathways that governs aging and health.


Related Articles:
a JNK signaling confers tolerance to oxidative stress and extends lifespan in Drosophila
a JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling



11:40
Genetic Basis of Cardiac Aging
Rolf Bodmer, Ph.D.
Professor and Program Director
Burnham Institute for Medical Research

We are using the evolutionarily conserved Drosophila heart to study the molecular-genetic basis for how individual organ function declines with age and how this process is coordinated and executed during senescence. We have developped new measurements of cardiac physiology in Drosophila, in combination with genetic screens to unravel the mechanisms involved in controlling cardiac performance and its decline with age. The aim is to create a novel genetic model and prototype for elucidating the basis of organ-specific aging. Our studies are a first attempt to rigorously examine the genetic mechanisms involved in cardiac functional aging, thereby charting new territory elucidating the genetics of organ aging.

We have identified novel contributors to the normal cardiac rhythm and performance and its changes with age. We recently found that cardiac arrhythmias in wildtype flies progressively increase with age, and that in mutants of the KCNQ potassium channel, which is responsible for the cardiac repolarization ) is drastically aggravated, as is the stress-induced compromise of heart function. Manipulation of other cardiac ion channels also alters heart function in distinct ways, including Herg and other potassium channels in Drosophila, involved in repolarization of the cardiac action potential. Moreover, homologs of congenital heart disease genes, such as tinman and neuromancer, are also required in the adult fly for maintaining normal heart function and for preventing its premature degeneration.




12:05
Panel Discussion
Moderator, John Sterling
Editor in Chief
Genetic Engineering and Biotechnology News (GEN)



Interventions: Prospects and Problems


1:30



Screening Anti-Aging Compounds: Rules of Investigation Session Chair, Mahtab Jafari
Assistant Professor -- Associate Director,
Program in Pharmaceutical Sciences,
University of California, Irvine

aaaa The use of animal models for screening and evaluating anti-aging compounds is a promising approach for drug discovery. While screening and evaluating anti-aging compounds using the premier animal genetic systems, Drosophila melanogaster and Caenorhabditis elegans, has already started, the fundamental biological issues involved in such screening have not been systematically formulated. As a result, after selecting potential compounds to be tested, we need appropriate methodologies to study the pharmacology of aging in model species. Once these methodologies or rules of investigation are developed, we may consider extrapolating these experimental findings with such systems to higher vertebrate model systems and eventually to the treatment of human aging. However, there are a number of potential artifacts, confounds, and errors that can arise in such research programs. In order to minimize these problems, I have developed a few rules of investigation and applied them to a number of potential anti-aging compounds. In my presentation, I will present my proposed rules of investigation and our initial positive results.



Related Articles:
a The Pharmacology of Aging in Drosophila
a Pioglitazone: an anti-diabetic compound with anti-aging
properties
a Rules for the use of model organisms in antiaging pharmacology


1:55


TBA
Ivan LaBat,
Sr. Director, Research and Product Development
Biomarker Pharmaceuticals, Inc

2:20

TBA
Calvin Harley
Chief Scientific Officer,
Geron Inc.



2:45
Panel Discussion
Moderator, John Sterling
Editor in Chief
Genetic Engineering and Biotechnology News (GEN)



3:10 Refreshment Break and Networking



Corporate Strategies for Therapeutic Development


3:35

Why is Longevity a Hard Sell?
Damian Crowe
Ayusya LLC for Long Tomorrow Inc


aa Potential investors in this nascent market have been sold snake-oil solutions to the ailments of old age to such an extent that the industry’s credibility has been seriously damaged. Although aging is a system-level process, many biologists have chosen to attack individual health problems by seeking out therapeutics which affect the proliferation of cells in culture and other reductive phenotypes. The interdependent multiple pathologies of aging and their effects on functional health, cannot be successfully addressed using this reductive paradigm. Astute investors know there is no magic bullet to “cure” aging. Biotech start-ups employing emerging technologies claim to be on the path leading to the elusive fountain of youth, and these will be surveyed.

So the key question is: how can an investor filter out viable prospects from the background noise of charlatans and no-hopers? A substantial part of the answer can be found in the raw computing power of the most ancient of all of life`s processes … evolution itself. For the past thirty years, evolutionary biologists have been harnessing laboratory selection to dramatically increase the lifespans of short-lived laboratory animals. By combining experimental evolution with leading-edge genomic tools, the systemic complexity of aging that has baffled biologists for so long can be overcome. Finally, the industry has the tools needed to manage the complexity of this risky aging business.



4:00
Regenerative Medicine: Applications in Age-Related Degenerative Disease
Michael West,
Chairman, and Chief Scientific Officer
Advanced Cell Technology, Inc



4:25

SIRT1 Activation: A Novel Mechanism for Treating Diseases of Aging
Philip D. Lambert Ph.D.,
Senior Director, Pharmacology
Sirtris Pharmaceuticals


aa Caloric (food) restriction has been shown to enhance insulin sensitivity and extend lifespan in several animal species, and SIRT1, an NAD+-dependent protein deacetylase, seems to play an important role in these effects. SIRT1 modulates the activity of several intracellular transcription factors and coregulators, including PGC-1a, Foxo1, NF-kB, NCoR, p300 and p53. Functionally, SIRT1 seems to regulate mitochondrial biogenesis in certain tissues.
Through high-throughput screening and medicinal chemistry approaches, we have developed multiple novel, potent compounds with several distinct chemical scaffolds that activate SIRT1 by lowering the Km of SIRT1 for acetylated peptide substrates.
In rodent models of obesity and type 2 diabetes our SIRT1 activators lower blood glucose levels, improve insulin sensitivity and increase tissue mitochondrial capacity. Thus, SIRT1 activation shows great potential as novel approach for treating insulin resistance and type 2 diabetes.
* Identified multiple SIRT1 activators structurally distinct from resveratrol
* SIRT1 activators improve insulin sensitivity in obese, insulin-resistant rodents
* SRT501 first-in-class small molecule that activates SIRT1 in clinical trials



4:50 Panel Discussion
Moderator, John Sterling
Editor in Chief
Genetic Engineering and Biotechnology News (GEN)


Keynote


5:15

Sirtuins, Aging and Disease
Leonard Guarente,
Novartis Professor, MIT





SIR2 and related genes are NAD-dependent deacetylases that slow aging in yeast, C. elegans, and Drosophila. In yeast and flies, SIR2 genes are also involved in the longevity conferred by dietary or calorie restriction (CR). The mammalian SIRT homologs are involved in changes in stress resistance and metabolism known to be associated with CR. The CR diet not only extends life span in rodents, but also protects against many diseases of aging. In this talk, I will discuss a SIRT1 transgenic mouse that over-expresses this sirtuin and confers metabolic phenotypes associated with CR, I will describe studies to probe the response of these mice to diseases of aging, and detail relevant molecular pathways that connect SIRT1 to physiological processes linked to aging and disease. Finally. I will discuss the role of time itself as a risk factor for the major diseases cancer, cardiovascular disease, neurodegenerative disease and diabetes, and why and how approaches to slow aging are bound to also mitigate these diseases



Related Articles:
a SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Caloric Restriction in Pancreatic b Cells
a Unlocking the Secrets of Longevity Genes
a Two neurons mediate diet-restrictioninduced longevity in C. elegans



6:00 Cocktail Reception

End of Day 1

Tuesday, January 8, 2008



7:30 Registration & Breakfast



8:00

Opening Remarks
Michael R. Rose
Professor,
University of California, Irvine




Caloric Restriction



8:10

Gene Expression Profiling of Aging
Richard Weindruch
Professor of Medicine,
University of Wisconsin-Madison



From Academic Discoveries to Commercialization: In this presentation, I will describe our experiments representing the first use of microarrays to study the aging process and its retardation by caloric restriction (Lee et al., Science 285:1390-3, 1999). A patent application and subsequent experimentation led Dr. Tomas Prolla and I to establish LifeGen Technologies, LLC in 2001. This company has focused on the use of gene expression profiling to evaluate dietary interventions to slow the aging process. Current pursuits, both academic and commercial, will be described.



Related Articles:
a Gene Expression Profile of Aging and Its Retardation by Caloric Restriction
a Transcriptional profiles associated with aging and middle age-onset caloric restriction in
mouse hearts
a Adipose tissue energy metabolism: altered gene expression profile of mice subjected to long-term caloric restriction
a Energy Restriction Lowers the Expression of Genes Linked to Inflammation, the Cytoskeleton, the Extracellular Matrix, and Angiogenesis in Mouse Adipose Tissue



8:35

Can Caloric Restriction Work in Humans?
Eric Ravussin
Chief, Division of Health and Performance Enhancement
Douglas L. Gordon Chair in Diabetes and Metabolism
Professor , Pennington Biomedical Research Center




Caloric restriction (CR) extends life span and retards age-related diseases in rodents and lower species. Several biomarkers of longevity (glucose, insulin, core body temperature and DHEAS) have been identified in rodents and monkeys but whether CR improves these in humans is unknown. Furthermore, the mechanism through which CR increases life span is unclear. One hypothesis is that metabolic rate is reduced beyond that expected for the reduction in metabolically active mass leading to reduced oxidative damage and possibly improvement in mitochondrial function. 48 healthy (36.8±1.0 y), nonsmoking, overweight (BMI 27.8±0.7) men and women were randomized into one of four groups for 6 months; Control = 100% of energy requirements; CR = 25% restriction; CR+EX = 12.5% CR +12.5% increase in energy expenditure by structured exercise; LCD = low calorie diet until 15% weight reduction followed by weight maintenance. Individual diets were provided to subjects for 2 weeks before baseline tests, during the first 3 months of intervention and again for 2 weeks before tests at month 6. At baseline and month 6, body composition was measured by DEXA, 12-h fasting blood samples were collected, sedentary 24h energy expenditure (24h-EE) and 24h core body temperature were determined in a metabolic chamber and a muscle biopsy was taken. Weight change at M6 was –1.0±1.1% (Control), –10.4±0.9% (CR), –10.0± 0.8% (CR+EX) and -13.9±0.8% (LCD). At M6, fasting insulin levels were significantly reduced from baseline in the CR, CR+EX and LCD groups (all, p<0.01), whereas DHEAS and glucose levels were unchanged. Core temperature was reduced in CR group by 0.2±0.05 ?C and by 0.3±0.08 ?C in the CR+EX group (both, p<0.05). At baseline, fat-free mass accounted for 86% of the variance in sedentary 24h-EE. After adjustment for changes in body composition, sedentary 24h-EE was unchanged in controls (-18±52 kcal/d; p>0.05), but decreased in the CR (-135±42 kcal/d), CR+EX (-117±52 kcal/d) and LCD (-125±35 kcal/d, groups (all, p<0.008). These “metabolic adaptations” (~6% more than expected based on loss of metabolic mass) were statistically different from controls (p<0.05). Serum protein carbonyl concentrations and urinary isoprostanes excretion rates were not changed from baseline to month 6 in any group, whereas DNA damage was reduced from baseline in the CR, CR+EX and LCD groups at month 6 (p? 0.005) but not in the Control group. CR and CR+EX was associated with an increase in the muscle expression of genes involved in mitochondrial biogenesis and mitochondrial fusion including PGC1-α , mitochondrial transcription factor A, endothelial nitric oxide, SIRT1 and PSARL (all, p<0.05). In parallel, mitochondrial content increased by 35±5% in the CR group (p<0.05) and 21±4% in the CR+EX group (p<0.05), with no change in the control group (2±2%). However, the activity of key mitochondrial enzyme of the TCA cycle (citrate synthase), β-oxidation (β-HAD) and electron transport chain (COX II) were all unchanged. This study suggests that 6 months of CR in non-obese humans was sufficient to improve biomarkers of aging and supports the theory that 24h-EE is reduced beyond that expected due to reduced metabolic size. Whether this metabolic adaptation translates into overall reduced oxidative damage remains to be determined. The increased mitochondrial content in association with a decrease in whole body DNA damage is however an important indication that CR improves mitochondrial function in human skeletal muscle.
Given the difficulties of practicing CR in our “obesogenic” environment, it is no wonder that a large amount of research in the gerontology field (and now pharmaceutical companies) is being geared toward identifying and testing compounds that mimic CR. Excitement is growing for resveratrol, a compound with antioxidant properties found in red wine, in the skin of grapes and berries and in peanuts. Already resveratrol has been shown to increase lifespan in yeast, fruit flies and recently by ~60% in fish. However, it is only in late 2006 that exciting data have shown that resveratrol increased the survival of mice even in conjunction with a high calorie diet. In another recent study, resveratrol was found to improve the efficiency of skeletal muscle metabolism by increasing mitochondrial biogenesis and function. Interestingly, besides being resistant to high-fat diet induced obesity and insulin resistance, mice fed large doses of resveratrol could run twice as long as the control mice before exhaustion. Some of these data will be presented in the session. There is no doubt that if compounds mimicking the beneficial effects of CR, individuals for the most part will opt to enjoy the effects of anti-aging via a ‘pill’ and not CR.
In the mean time, caloric restriction remains an anti-aging strategy for only a few self-selected people who are taking the chance that it will increase average and maximal lifespan in humans. Even if not true, there is no doubt that most of the people practicing seriously CR will be free from most if not all the chronic diseases of aging.





9:00
The Search for Calorie Restriction Mimetics
Don Ingram
Professor and Head
Nutritional Neuroscience and Aging Laboratory
Pennington Biomedical Research Center
Louisiana State University System


When considering all possible aging interventions evaluated to date, it is clear that calorie restriction (CR) remains the most robust. Studies in numerous species have demonstrated that reduction of calories 30-50% below ad libitum levels of a nutritious diet can increase life span, reduce the incidence and delay the onset of age-related diseases, improve stress resistance, and decelerate functional decline. A current major focus of this research area is whether this nutritional intervention is relevant to human aging. Evidence emerging from studies in rhesus monkeys suggests that their response to CR parallels that observed in rodents. To assess CR effects in humans, investigations of individuals practicing CR as well as results from well controlled clinical trials have repeated many findings from the monkey studies indicating potential health benefits of this intervention. However, even if results from these studies could eventually substantiate CR as an effective anti-aging strategy for humans, the utility of this intervention would be hampered because of the degree and length of restriction required. As an alternative strategy, new research has focused on the development of "CR mimetics." The objective of this strategy is to identify compounds that mimic CR effects by targeting metabolic and stress response pathways affected by CR, but without actually restricting caloric intake. For example, drugs that inhibit glycolysis (2-deoxyglucose), enhance insulin action (metformin), affect stress response pathways (resveratrol), or fat metabolism (adiponectin) are being assessed as CR mimetics. Promising results have emerged from initial studies regarding physiological responses indicative of CR (reduced body temperature and plasma insulin) as well as protection against neurotoxicity, enhanced dopamine action, and upregulated neurotrophic factors. Ultimately life span analyses in addition to expanded toxicity studies must be accomplished to fully assess the potential of any CR mimetic. Nonetheless, this strategy clearly offers a very promising and expanding research endeavor



9:25
PANEL



Model Organisms in Aging: Sirtuins and Nematodes



9:50
SIRT1, Metabolism and Calorie Restriction.
ADVISOR Laura Bordone,
Principal Investigator
Novartis Institutes for BioMedical Research, Diabetes and Metabolism Disease Area

The NAD-dependent family of deacetylases (sirtuins) has been shown to mediate important diverse biological processes including extension of lifespan in multiple species including yeast, C. elegans, and Drosophila. Among the 7 mammalian sirtuins, SIRT1 regulates many important cellular processes, including cell survival, glucose homeostasis and fat metabolism. In particular, SIRT1 has been shown to mediate some of the effects of calorie restriction. In this talk I will discuss a mouse model that overexpresses SIRT1 that show phenotypes resembling calorie restriction. In addition, I will discuss the role that SIRT1 plays in metabolism, especially in the regulation of insulin secretion. These studies help to elucidate the major role that SIRT1 plays in metabolism and calorie restriction.



Related Articles:
a SIRT1 transgenic mice show phenotypes resembling calorie restriction
a Calorie Restriction, Sirt1 and Metabolism Understanding Longevity



10:15

Metabolism, Aging, and NAD World: Mammalian Sirt1 and Systemic NAD biosynthesis
Shin-ichiro Imai, M.D., Ph.D
Assistant Professor, Department of Molecular Biology and Pharmacology
Washington University School of Medicine



Biosynthesis: In our current society, achieving “productive aging”, which aims to maintain good health and spirit in our later life, will be important to promote a stable economy and solvent social security in our health care system. To achieve this goal, much work is being done to identify regulators and signaling pathways that, when modified, may slow down the process of aging. One such regulator has recently attracted major attention in the field of aging science, that is, Sir2 (silent information regulator 2). Sir2 orthologs are an evolutionarily conserved family of NAD-dependent protein deacetylases (Imai et al., Nature 403, 795-800, 2000). In yeast, worms, and flies, Sir2 proteins regulate aging and longevity in response to nutritional and hormonal cues. Sir2 proteins are also required for the lifespan extension mediated by caloric restriction, the most consistent regimen to retard aging and extend longevity in many different species, in certain genetic backgrounds and conditions in those organisms.
In mammals, the Sir2 ortholog, Sirt1, plays an important role in the regulation of metabolism in response to nutrient availability in multiple tissues. In pancreatic ? cells, we previously demonstrated that Sirt1 promotes glucose-stimulated insulin secretion and improves glucose tolerance in mice, providing insight into the development of new interventions for type 2 diabetes (Moynihan et al., Cell Metab 2: 105-107, 2005). Sirt1 activity is regulated by the NAD biosynthetic pathway mediated by nicotinamide phosphoribosyltransferase (Nampt, a.k.a. PBEF/visfatin) (Revollo et al., JBC 279:50754-50763, 2004). We have recently found that Nampt functions both intra- and extracellularly as a robust NAD biosynthetic enzyme and regulates NAD biosynthesis at a systemic level. Strikingly, nicotinamide mononucleotide (NMN), a product of Nampt reaction, circulates systemically in blood and plays a critical role in the regulation of NAD biosynthesis and glucose-stimulated insulin secretion in pancreatic cells. Interestingly, we have also found that plasma NMN levels are significantly reduced with advanced age and therefore that NMN administration can restore the beneficial effects mediated by Sirt1 in aged pancreatic ? cell-specific Sirt1-overexpressing (BESTO) mice. Therefore, Nampt-mediated systemic NAD biosynthesis as a driver and Sirt1 as a mediator are critical components in the NAD world that may be excellent targets to develop preventive/therapeutic interventions for aging-associated metabolic complications, such as type 2 diabetes.




10:40
Neural Mechanisms That Influence Physiology and Longevity
Joy Alcedo
Junior Group Leader
Friedrich Miescher Institute


The aging of an animal is influenced by a complex interaction between its environment and the signaling pathways that control its physiology. This interaction appears to be mediated by the sensory system, since animal lifespan is influenced by mutations and treatments that inhibit the function of its sensory neurons. However, it remains unclear how an animal translates the sensory information it receives into physiological changes that ultimately influence its longevity. Although not all sensory cues elicit changes that affect lifespan, we have found that a specific subset of gustatory and olfactory neurons influence C. elegans longevity, suggesting that this sensory influence is mediated by changes in feeding behavior. Interestingly, we also found that gustatory neurons elicit physiological changes that are distinct from those elicited by olfactory neurons to influence lifespan. Since both gustatory and olfactory neurons are known to express different neuropeptides, sensory cues may regulate the release of these peptides that would have different effects on behavior and physiology, and consequently lifespan.
One of the longevity-influencing neuropeptide receptors we have identified has a mammalian homolog that has been shown to regulate appetitive behavior and metabolism. Thus, it is possible that this protein affects worm lifespan by altering feeding behavior and/or metabolism. We are now determining whether this receptor acts downstream of the sensory system and/or with other signaling pathways previously known to influence worm lifespan. Since obesity and the resulting age-related health complications affect a significant fraction of our population, understanding how this neuropeptide receptor pathway influences longevity is important as it can lead to therapies that would alleviate such diseases.



Related Articles:
a Regulation of C. elegans Longevity by Specific Gustatory and Olfactory Neurons
a The Alcedo Lab



11:05
Panel Discussion
Moderator, John Sterling
Editor in Chief
Genetic Engineering and Biotechnology News (GEN)




11:30
Refreshment Break and Networking



Mitochondria and Aging



11:55
Revisiting Ponce De Leon: Mitochondria and the Metabolic Diseases of Aging
ADVISOR; Charles Alexander,
Senior Director, Global Outcomes Research & HTA
Merck


* Metabolic syndrome was not a problem as mankind evolved due to short lifespan and inadequate food supply and the syndrome was well known in ancient times (Obesity, Type 2 Diabetes, and Gout) prior to the development of modern lab tests.
* Two similar definitions (Revised NCEP ATP III and IDF) for metabolic syndrome are currently widely accepted and used.
* Prevalence of metabolic syndrome increases with age and worsening glucose status is associated with an increasing number of metabolic syndrome components
* Metabolic syndrome increases risk for type 2 diabetes and cardiovascular disease, however metabolic syndrome is not an independent predictor of CV risk.
* Obesity and insulin resistance have been proposed etiologies for metabolic syndrome; acquired loss of mitochondrial function and reduced capacity for oxidative phosphorylation has been more recently proposed as the etiology.
* Benefit observed from physical activity and reduced caloric intake may be via improved mitochondrial function which may also explain mechanism of action of thiazolidinediones (TZDs, PPARs).



12:20
Incorporating Cellular Bioenergetic Measurements in Aging Research
George W. Rogers, Ph.D.
Field Applications Scientist
Seahorse Bioscience


Current theories of aging implicate mitochondrial dysfunction such as decreased OXPHOS capacity, mtDNA mutations, and increased ROS production as key underlying factors of the aging process. These abnormalities are increasingly linked to apoptosis and therefore to a variety of age-related diseases including cancer, neurodegenerative and metabolic disorders. The ability to measure mitochondrial bioenergetics under many different conditions is enabling investigators to link various forms of mitochondrial dysfunction with those degenerative processes involved in aging. Here we present a novel method to study mitochondrial function and cellular bioenergetics using the Seahorse XF24 Analyzer which non-invasively measures cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), indicators of aerobic respiration and glycolysis, respectively. Discussed are examples of using established cell lines and primary tissue cultures to measure OXPHOS capacity, proton leak, apoptosis and the effects of various compounds on the mitochondrial complexes and electron transport chain function. In conclusion, we suggest how this XF technology may be applied to investigate mitochondrial function and cellular bioenergetics in the context of current in vitro models of aging and age-related disease.




12:45
Mitochondrial Dysfunction and Rejuvenation With Age:
Kevin Conley,
Professor of Radiology and of Physiology & Biophysics
Adjunct Professor of Bioengineering
University of Washington


Mitochondrial changes underlie a wide range of age-related diseases, such as late onset diabetes, neurodegeneration and muscle wasting (i.e. sarcopenia). New insights into the onset of mitochondrial changes from in vivo functional measurements and the regulation of mitochondrial turnover from gene transcription studies challenge both the chronology and irreversibility of degeneration of this organelle in aging tissues. This new functional, cell signals and gene transcription findings are synthesized in this talk to provide insight into the mechanisms underlying mitochondrial dysfunction and the potential for rejuvenation in aged muscle.



Related Articles:
a Mild mitochondrial uncoupling impacts cellular aging in human muscles in vivo
a Mitochondrial Dysfunction: Impact on Exercise Performance and Cellular Aging.
a Mitochondrial function, fibre types and ageing: new insights from human muscle in vivo.



1:10
Regulation of Mitochondrial Function by SIRT3, a Mitochondrial Protein Deacetylase.
Eric M. Verdin, M.D.
Senior Investigator
Gladstone Institute of Virology and Immunology
Professor of Medicine
University of California, San Francisco

xxxxxxxx Silent information regulator 2 (Sir2) proteins, or sirtuins, are protein deacetylases/mono-ADP-ribosyltransferases found in organisms ranging from bacteria to humans. Their dependence on nicotinamide adenine dinucleotide (NAD+) links their activity to the metabolic status of the cell. The bacterial sirtuin CobB regulates the metabolic enzyme acetyl-coenzyme A synthetase. This observation suggests that the earliest function of sirtuins was to regulate cellular metabolism in response to nutrient availability. Recent findings support the idea that sirtuins also play a pivotal role in metabolic control in higher organisms, including mammals. I will be discussing the emerging role of SIRT3, a mitochondrial sirtuin, on mitochondrial function and metabolism.



Related Articles:
a Sirtuins: Sir2-related NAD-dependent protein deacetylases
a Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2


1:35 Panel Discussion
Moderator, John Sterling
Editor in Chief
Genetic Engineering and Biotechnology News (GEN)




1:55 Networking Lunch and Featured Presentation

2:30
Getting anti-aging drugs approved—what’s it going to take
G. Alexander Fleming M.D.
President and CEO
Kinexum LLC.

FDA routinely approves treatment indications on the basis of survival data from trials of treatments for life-threatening disease, but FDA has never approved an indication for life-extension of a healthy population. Nothing prevents FDA from approving an indication for life-extension but no data have emerged to date, which could support such an indication. However, agents are on the horizon, which could actually extend life span along with improved function and quality of life. A former regulator addresses these and other questions: What kind of trial designs and development strategies could be used to win such indications? Is there any point in pursuing such indications if disease indications are less challenging? What are practical intermediate steps that could be used to get to life extension claims? Will regulatory claims necessarily lead to reimbursement by government and managed care organizations.



Diseases of Aging


3:00
Mitochondria in Neurodegeneration: Focus on Parkinson`s Disease
Ian J. Reynolds, Ph.D.
Senior Director,
Ophthalmics Research and Parkinson`s Disease
Merck Research Laboratories


Mitochondrial dysfunction is frequently proposed as a fundamental pathophysiology underlying neurodegenerative diseases, including Parkinson`s disease, Alzheimer`s disease and Huntington`s disease. This dysfunction is manifested in the form of bioenergetic deficits and oxidative stress. However, the mechanisms that give rise to mitochondrial impairment are rarely understood. In this presentation I will review recent developments in the understanding of pathological mechanisms mediated by mitochondria that impact neuronal viability, including bioenergetic impairment and alterations in mitochondrial morphology and trafficking. Specifically in the context of Parkinson`s disease, I will also review the potential opportunities to both model and treat neurodegenerative disease using approaches focused on mitochondrial biology.




3:25
Neuroprotection Strategies for Age-Related Macular Degeneration Therapeutics
Aicha Laabich,
Senior Scientist,
Acucela Inc.


The degeneration of retinal photoreceptors and retinal pigment epithelial (RPE) cells is the final step leading to loss of central vision in age-related macular degeneration (AMD). The retina is particularly susceptible to oxidative stress due to its high levels of photo-sensitizers and pigments, its high consumption of oxygen and its exposure to visible light. Multiple factors have been linked to the pathogenesis of AMD. In particular, N-retinylidene-N-retinylethanolamine (A2E) and its photoisomers, the major blue light absorbing fluorophore of lipofuscin in the RPE is believed to be associated with AMD pathogenesis. As photoreceptors are particularly susceptible to excessive light exposure and A2E excitotoxicity, the discovery of compounds that protect photoreceptor cells from light- and A2E-induced cell death would provide an important approach in the identification of “dry” AMD treatment.

A primary retinal cell culture system in 96-well plate format (OcuScreen™) has been developed for screening compounds to identify photoreceptor neuroprotectants against light and A2E-induced stress using high-throughput and high-content screening. Using the caspase-3 inhibitor Z-DEVD-fmk, we have shown that light and A2E-induced cell death are mediated through different pathways. The feasibility of using OcuScreen™ for the discovery of retinal protective agents was demonstrated by identifying neuroprotective molecules from compound libraries. The structure-activity relationships and the protective activity of hits were confirmed in vivo against light stress. Our results indicate that this assay is suitable for the discovery of retinal anti-apoptotic compounds and the development of dry AMD therapeutics.



Related articles:
a Protective Effect of Crocin against Blue Light– and White Light–Mediated Photoreceptor Cell Death in Bovine and Primate Retinal Primary Cell Culture
a Protective effects of myricetin and related flavonols against A2E and light mediated-cell death in bovine retinal primary cell culture
a Acucela Inc.



3:50
Regulating Neuroinflammation to Treat Age-Related Cognitive Impairment: Is IL-1β a Good Target.
Carmelina Gemma,
Research Biologist, James A. Haley VAMC,
Assistant Professor Center of Excellence for Aging and Brain Repair
University of South Florida


Scientific research on the unprecedented and growing number of older adults in the United States and other industrialized countries has focused much attention on the health consequences of aging. During the last few decades inflammation in the brain and its implication in the progression of aging and aging-related cognitive dysfunction has been of increasing attention to neuroscientists and is now considered as one of the most interesting and promising topics for aging research. One of the critical aspects of inflammatory processes is that the activation of one upstream inflammatory molecule initiates a cascade of self-sustaining inflammatory events which lead to the activation of a number of different downstream functions. Adult hippocampal neurogenesis dramatically decreases with increasing age, and this decline might contribute to age-related memory deficits. Decreased neurogenesis, age-related cognitive decline, and neuroinflammation might share common molecular mechanisms. An understanding of these mechanisms will lead to the development of preventive or protective therapies for cognitive decline associated with aging and age-related neurodegenerative disease.

• What are the inflammatory signals that modulate memory function?

• Is IL-1? a good target for drugs aimed at memory impairment?

• Does healthy diet bolster neuroprotective mechanisms reducing the risk of age-related disorders?



4:15 Refreshment Break and Exhibiting



4:40 Oral Presentations from Submitted Abstracts



5:40 Closing remarks: Conference Chair, Michael Rose



6:00 Conference Concludes