CR VII Program Schedule
Wednesday October 26 ▪ Evening 6:00 Saturday October 29
Thursday October 27 ▪ Morning 9:00Meredith Averill
Welcome message and CRS updatePeter Voss
CRON, artificial general intelligence, and radical life extensionBen Best
Cryonics and calorie restrictionMichael Rae
Late-onset calorie restriction: findings and prospects from mouse to manCR Group Lunch 12:45
Afternoon 2:00Nick Colby
Longevity farming and a rapidly changing environmentPaul McGlothin & Michael Rae
Macronutrient Panel Discussion
Friday October 28 ▪ Morning 9:00Joseph Dhahbi
mRNA-Seq reveals complex patterns of gene regulation and expression in the mouse skeletal muscle transcriptome associated with calorie restrictionPankay Kapahi
TOR pathway, dietary restriction and the importance of invertebrate models in dietary restriction studiesStephen Spindler
Statins increases mean lifespan and improve cardiac health independently of their effects on serum cholesterol levelsMidday break 12:45
Afternoon 2:00Andrzej Bartke
Effects of calorie restriction on long-lived miceLuigi Fontana
Metabolic and molecular effects of long-term calorie restrictionCR Group dinner 7:00
Saturday October 29 ▪ Morning 9:00Irina Conboy
TGFβ receptor signaling contributes to decline in muscle regeneration in mice with perturbed glucose metabolismScientific Panel Discussion and Q & A
CR Group Lunch 12:15
Thursday October 27
Peter Voss ▪ Founder, Smart Action Company
CRON, Artificial general Intelligence, and radical life-extension
For many of us Calorie Restriction with Optimal Nutrition is a bridge to a bridge of indefinite lifespans. In this talk I will discuss radical life extension and lifestyles and technologies; detailing my own 13-year "Easy CRON" experience and exploring various futurist technologies that will help us survive and flourish. In addition to touching on nanotechnology, cryonics, and anti-aging research I will explain what AGI (Artificial General Intelligence) is and how and why it may just be the key to achieving our ambitious goals within
Ben Best ▪ President, Cryonics Institute
Cryonics and calorie restriction
Calorie Restriction and cryonics are complementary life extension strategies because CR can facilitate improved cryopreservation, but CR can do no more than slow aging, whereas cryonics has the potential to vastly extend human lifespan. Although the evidence that CR will work is more substantial than the evidence for cryonics working, there are nonetheless good reasons to believe that cryonics may work.
Michael Rae ▪ SENS Foundation
Late-onset calorie restriction: findings and prospects from mouse to man
Calorie restriction without malnutrition (CR) remains the best-established and most well characterized environmental intervention for the retardation of biological aging. The unresolved issues of the range of efficacy, mechanisms, and human translatability of the "anti-aging" effects of CR are central issues in to individual practice and the development of "Calorie restriction mimetics" to harness the mechanisms CR pharmacologically for aging humans without requiring strict dietary adherence. These issues are particularly salient in the case of persons who are already entering the initial stages of age-related physical decline, where the medical and societal imperative is greatest and the evidence is sparsest. This presentation will address these questions based on animal and human CR studies, as well as the relevance and interpretation of the epidemiological findings surrounding anthropometry and mortality risk.
Nick Colby ▪ Owner-Operator, Swallow Valley Farms; Professor Emeritus, University of California, Irvine
Longevity farming and a rapidly changing environment
A new farm designed for organic farming and a longevity diet plus experimentation now requires changes due to global warming and the prospect of a long depression. The choice of various crops and livestock must not only consider maximum nutritional value and profitability but also the improvement of soil, the sequestration of carbon, the availability of water, local bartering and last, but not least, connections to the local community.
Macronutrient Panel Discussion led by P McGlothin & M Rae
Paul McGlothin ▪ Vice President, Research, CRS International
Great progress has been made in identifying cell-signaling patterns that are fundamental to calorie restriction benefits. Aside from limiting calories, macronutrient choices have a major effect on CR cell-signaling patterns. Further, some foods within each macronutrient category have special characteristics that affect cell signaling. Emphasizing practical application, my comments will include the CR Way approach to testing macronutrient effects and understanding how the effects can help or hinder achieving optimal health through a CR lifestyle.
Michael Rae ▪ SENS Foundation
The place of protein in a CR diet is a vexedly uncertain issue. On the one hand, rodent studies find that animals on CR fare at least as well, and often better, on a high-protein diet and that actual restriction of protein intake below the level required to maximize growth and fertility in AL animals is deleterious. Combined with this, human epidemiology consistently supports the benefits of a high-protein diet, for cardiovascular disease, bone health, total mortality, and other outcomes. But the finding that protein at levels much above the RDA can block the lowering of IGF-1 by CR in humans, combined with the strong body of evidence supporting the reduction of IGF-1 signaling in retarding aging via CR or mutations, offers a compelling rationale for minimizing protein intake. The unfortunate fact is that we are in a place of uncertainty on this question, and that a great deal may hang in the balance. Individual CR practitioners must weigh these data points in conjunction with their age, quality of life, and even immediate health status (injury and infection), and make the choice that seems both evidence-based and right for them in their own unique situation.
Friday October 28
Joseph Dhahbi ▪ University of California, Riverside
mRNA-Seq reveals complex patterns of gene regulation and expression in the mouse skeletal muscle transcriptome associated with calorie restriction
Sarcopenia is an age-associated loss of skeletal muscle mass and strength that increases the risk of disability. Calorie restriction (CR), the consumption of fewer calories while maintaining adequate nutrition, mitigates sarcopenia and many other age-related diseases. To identify potential mechanisms by which CR preserves skeletal muscle integrity during aging, we used mRNA-Seq for deep characterization of gene regulation and mRNA abundance in skeletal muscle of old mice compared with old mice subjected to CR. mRNA-Seq revealed complex CR-associated changes in expression of mRNA isoforms, many of which occur without a change in total message abundance and thus would not be detected by methods other than mRNA-Seq. Functional annotation of differentially expressed genes reveals CR-associated upregulation of pathways involved in energy metabolism and lipid biosynthesis, and downregulation of pathways mediating protein breakdown and oxidative stress, consistent with earlier microarray-based studies. CR-associated changes not noted in previous studies involved downregulation of genes controlling actin cytoskeletal structures and muscle development. These CR-associated changes reflect generally healthier muscle, consistent with CR's mitigation of sarcopenia. mRNA-Seq generates a rich picture of the changes in gene expression associated with CR, and may facilitate identification of genes that are primary mediators of CR's effects.
Pankay Kapahi ▪ Buck Institute
TOR pathway, dietary restriction and the importance of invertebrate models in dietary restriction studies
Dietary restriction (DR) provides the most robust method of lifespan extension in species as diverse as yeast, worms, fruit flies and rodents. Reduction of nutrients in the diet by DR not only extends lifespan but also protects against a number of age related diseases including neurodegeneration, cancer, diabetes and cardiovascular diseases. It is therefore likely that investigation of the molecular mechanisms underlying DR will promote a greater understanding of the pathogenesis of various human age related diseases and help advance the development of therapeutics for these disorders. Due to their short lifespan and ease of genetic manipulation; invertebrate models continue to be useful for understanding aging and disease. In particular, the conservation of biological processes and signaling pathways between mammals and invertebrates provides a unique opportunity to use model organisms such as Drosophila melanogaster to understand the biological mechanisms of lifespan extension by DR and identify new targets for therapeutic intervention. Our laboratory has previously identified the nutrient sensing TOR (target of rapamycin) pathway as a critical regulator of nutrient modulated lifespan changes in flies. This genetic pathway now appears to play a conserved role in lifespan extension in yeast, worms, flies and mice. We have previously demonstrated that 4E-BP (eukaryotic initiation factor 4E binding protein) plays a key role in mediating lifespan extension by DR. We have also described the genome-wide translational changes that result from DR using a method that combines polysomal profiling with microarrays. Using this method we have identified a subset of mRNAs that are preferentially translated upon DR, despite a decrease in global translation which included genes involved in mitochondrial functions, protein folding, fat metabolism and calcium signaling. We have shown that upon DR there is an increase in mitochondrial function which is required for DR mediated longevity. We hypothesize that the increase in mitochondrial function is part of a metabolic switch towards enhanced fatty acid metabolism which extends lifespan in the fly. We observe that enhanced fat metabolism increases muscle activity which plays a critical role in lifespan extension upon DR. We believe that understanding the basic process of DR by conserved signaling pathways in D. melanogaster will help unravel some of the mysteries of aging and age-related diseases in humans.
Stephen Spindler ▪ University of California, Riverside
Statins increases mean lifespan and improve cardiac health independently of their effects on serum cholesterol levels
Statins, such as simvastatin, are standard therapy for the prevention and treatment of cardiovascular diseases in mammals. We have shown that simvastatin significantly increases the mean and maximum lifespan of Drosophila melanogaster (Drosophila) and enhances cardiac function in aging flies by significantly reducing heart arrhythmias and increasing the contraction proportion of the contraction/relaxation cycle. These results are independent of internal changes in ubiquinone or juvenile hormone levels. Rather, they appeared to involve decreased protein isoprenylation. Simvastatin decreased the membrane association isoprenylation of specific small Ras GTPases in mice. Both farnesyl (L744832) and type 1 geranylgeranyl transferase (GGTI-298) inhibitors increased Drosophila lifespan. These data are the most direct evidence to date that decreased protein prenylation can increase cardiac health and lifespan in any metazoan species, and may explain the pleiotropic (non-cholesterol related) health effects of statins. We also found that simvastatin in combination with ramipril, an ACE inhibitor, extended the mean lifespan of mice.
Andrzej Bartke ▪ Southern Illinois University
Effects of Calorie Restriction on Long-Lived Mice
In mice, mutations which interfere with biosynthesis or actions of growth hormone (GH) produce remarkable extension of longevity. Many phenotypic characteristics of these long-lived mutants resemble the phenotype of genetically normal animals subjected to calorie restriction (CR). It was therefore of interest to examine the interactive effects of CR and life-extending mutations. In Ames dwarf mice which lack GH (along with prolactin and thyrotropin), 30% CR started at approximately two months of age improved insulin sensitivity and produced a further extension of longevity. GH-resistant GH receptor knockout (GHRKO aka “Laron dwarf”) mice are extremely insulin sensitive and exposing them to CR did not produce further improvements in either insulin signaling or longevity. More recently developed GH releasing hormone (GHRH) knockout mice have isolated GH deficiency and are also long-lived. In these mutants, CR improved insulin sensitivity and extended longevity only in females. We conclude that improved insulin signaling is importantly involved in linking GH deficiency or resistance with delayed aging and increased lifespan. Interestingly, in the human, improved insulin sensitivity was detected in the offspring of families with exceptional longevity (Wijsman CA, et al. Aging Cell 2011;10:114-121), and individuals affected with Laron dwarfism are completely protected from diabetes (Guevara-Aguirre J, et al. Sci Transl Med 2011;3:70ra13).
Luigi Fontana ▪ Washington University & Istituto Superiore di Sanità
Metabolic and molecular effects of long-term calorie restriction
Cardiovascular disease, cancer, stroke and diabetes account for nearly 70% of the deaths in the United States and Europe. The financial burden caused by these age-associated chronic diseases is already overwhelming and, if present trends continue, is likely to become unbearable in the next few decades. One of these trends involves the overconsumption of diets rich in empty calories and poor in nutrients and a sedentary lifestyle leading to a marked increase in age-associated chronic diseases. Another is the rapid increase in the proportion of older individuals, with the most dramatic increases in the number of adults over 65 years of age. In contrast to these harmful effects of overeating unhealthy foods, restriction of calorie intake with adequate intake of nutrients has a wide range of benefits. Moderate calorie restriction (CR) with optimal nutrition can prevent and reverse the harmful effects of obesity, type 2 diabetes, hypertension and other age-associated metabolic alterations and diseases. Studies on laboratory animals and preliminary studies on humans have shown that more severe CR without malnutrition has additional benefits on the aging process itself. Although there are currently no interventions or gene manipulations that can prevent, stop or reverse the aging process, there are a number of interventions that can slow aging and prolong maximal lifespan up to 60% in experimental animals. Long-term calorie restriction without malnutrition and reduced function mutations in the insulin/IGF-1 signaling pathway are the most robust interventions known to increase maximal lifespan and healthspan in rodents. Although it is currently not known if long-term CR with adequate nutrition extends maximal lifespan in humans, we do know that long-term CR without malnutrition results in some of the same metabolic and molecular adaptations related to longevity in CR rodents. CR alters neuroendocrine function, decreases growth factors and inflammation, improves diastolic function, and down-regulates the insulin/IGF-1 pathway. These are among the adaptations that have been hypothesized to mediate the slowing of aging and protection against cancer by CR in rodents.
Saturday October 29
Irina Conboy ▪ University of California, Berkeley
TGFβ receptor signaling contributes to decline in muscle regeneration in mice with perturbed glucose metabolism.
Insulin insufficiency following the depletion of insulin producing pancreatic β-cells or peripheral insulin resistance cause diabetes mellitus, a severe metabolic disorder that affects many organ systems and results in poor wound healing. We studied the direct influence of acute insulin insufficiency and deregulated glucose metabolism on the regenerative potential of skeletal muscle stem cells (satellite cells). Our results establish that in an animal model of type 1 diabetes, muscle stem cells fail to activate within 72 hours of high glucose blood levels, and repair of young muscle instantly deteriorates, resembling that of old tissue. Furthermore, our data demonstrate that this deleterious effect of perturbed glucose metabolism on organ stem cells is direct and leads to a diminished mitochondrial membrane potential, and that both mitochondrial function in satellite cells and their ability to regenerate muscle can be rescued by exogenous insulin. Importantly, this work establishes that the increase of myostatin expression and of TGFβ receptor signaling accompany the insulin insufficiency and that poor muscle regenerative capacity can be restored to healthy levels in vivo by the administration of follistatin or an Alk5 inhibitor or TGFβ receptor I. Notably, transient Alk5 inhibitor treatment does not normalize glucose metabolism in insulin depleted mice, but rather restores satellite cell responses by antagonizing the TGFβ signaled cell-cycle halt by CDK inhibitors. In summary, the regenerative responses of muscle stem cells rapidly fail when glucose metabolism is perturbed due to the diminished mitochondrial membrane potential and because of the increased TGFβ receptor signaling; even a brief lack of insulin and perturbed glucose metabolism have immediate negative consequences for tissue maintenance and repair, and follistatin or TGFβ receptor I inhibition is predicted to rescue tissue regeneration in the presence of diabetes.
CR VII Organized by David Stern & Robert Krikorian
Dr. Luigi Fontana Presents to the Group
Q & A with CR Researcher
Enjoy Meals with the CR Community
Meet Other CRS Members
Journalists Interview CRS Member Michael Rae
2011 Las Vegas Conference Attendees