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CR Society Conference Schedule

Buck Institute for Research on Aging

June 2013

[Rev 5-19-13]

 

Wednesday June 5 Evening

5:00 – 7:00 Welcome Reception – Best Western Plus Novato Oaks Inn

 

Thursday June 6 Morning

9:00 Welcome messages – Meredith Averill; Brian M Delaney; Paul McGlothin

10:00 Dave Brauer, CR Society member, Evolving a more hormetic DR practice

11:00 Satchin Panda, Salk Institute (Biological Clocks, Physical Activity, and CR),

 

12:00 Lunch at the Buck

 

Thursday June 6 Afternoon

1:30 Remi-Martin Laberge, Buck Institute (CR and Cancer), Targeting the fountain of age with rapamycin

2:30 Joseph Dhahbi, UC Riverside, Integrative epigenetics analysis of CR effects on various subpopulations of circulating leukocytes

3:30 Gary Taubes, Berkeley CA, Insulin and adiposity: An alternative hypothesis of weight regulation and health.

 

Friday June 7 Morning

9:00 Deepak Lamba, Buck Institute (Stem cells, Senescence, Rejuvenation, and CR),

10:00 Heinrich Jasper, Buck Institute (Stem cells, Senescence, Rejuvenation, and CR),

11:00 Panel Discussion (Lamba, Jasper): Stem cells, Senescence, Rejuvenation, and CR

 

12:00 Lunch at the Buck

 

Friday June 7 Afternoon

1:30 Simon Melov, Buck Institute (Biological Clocks, Physical Activity, and CR)

2:30 Pankaj Kapahi, Buck Institute (Biological Clocks, Physical Activity, and CR)

3:30 Panel Discussion (Melov, Kapahi): Biological Clocks, Physical Activity, and CR

 

Saturday June 8 Morning

9:00 Don Ingram, Pennington Biomedical Research Center (CR Primate Studies), The NIA Study of Calorie Restriction and Aging

10:00 Rozalyn Anderson, U of Wisconsin (CR Primate Studies), Long-term primate CR at the University of Wisconsin

11:00 Panel Discussion (Anderson, Ingram, & George Roth): CR Primate Studies

12:00 Danica Chen, Berkeley (CR and Cancer), Cellular metabolism, aging, and disease

 

Saturday June 8 Afternoon

Laboratory Tour conducted by Pankaj Kapahi

 

 

Click here to register online.

 

View 2013 CR Conference announcement.

 

 

 

 

 

id="program">CR Society Conference Program

Buck Institute for Research on Aging

June 2013

 

Wednesday June 5 Evening

5:00 – 7:00 Welcome Reception at Best Western

 

Thursday June 6 Morning

9:00 Welcome messages

Meredith Averill Chair, CRS International Board of Directors

Brian M Delaney President CRS International

Paul McGlothin VP Research, CRS International

 

10:00 Dave Brauer CR Society member

Evolving a more hormetic DR practice, Explorations of cyclic stress and recovery

The CR Society was founded based on the hypothesis, received from Walford, and previous researchers, that calorie restriction with adequate nutrition would extend life- and health-span in human beings. Since the early days, members have come to recognize that at least three critical nutrient sensing pathways mediate the effects of CR in human beings, the IGF-1/Insulin pathway, the mTOR pathway, and AMPK. It is also recognized that there is a wide range of other interventions which extend lifespan in simpler animals by affecting systems which have human analogs. The concept of hormesis not only offers an organizing and unifying principle for making sense of the multiplicity of phenomena, but suggests possible extensions and additions to a standard CR practice, which might enhance its effects. A variety of hormetic interventions are discussed, including xenobiotics, heat and cold stress, and fasting, intensified by aerobic exercise, and then some initial results of personal exploration and measurement are presented.

 

11:00 Satchin Panda Salk Institute for Biological Studies

(Biological Clocks, Physical Activity, and CR)

Time-restricted feeding protects against nutrition challenges

Circadian clocks and feeding-fasting cycles tune energy metabolism. The relevance of these metabolic cycles in protection against nutritional challenges that lead to obesity and diabetes has not been conclusively tested. While diet-induced obesity has been attributed to increased caloric intake from fat, animals fed high fat diet ad libitum (ad lib) exhibit a disrupted daily feeding rhythm. These animals eat frequently throughout the day and night losing the feeding cycle preserved in normal chow controls. To test whether obesity and metabolic diseases result from high fat diet or disruption of metabolic cycles, we subjected mice to either ad libitum or time restricted access to food for 8 h/day for more than 100 days. Mice with time restricted access to food consume the equivalent amount of calories from high fat diet as those with ad lib access, yet are protected against obesity, hyperinsulinemia, hyperleptinmenia, hepatic steatosis, inflammation, and have improved motor coordination. Time restricted feeding (tRF) regimen improved CREB, mTOR and AMP-activated Protein Kinase (AMPK) pathway function, oscillations of the hepatic circadian oscillators, and their target genes’ expression. These changes in catabolic and anabolic pathways led to reduced gluconeogenesis and lipogenesis, improvements in glycolysis, beta-oxidation, bile acid production, and energy expenditure. Thus, tRF regimen is a potential non-pharmacological strategy for combating obesity and its associated metabolic diseases.

 

12:00 Lunch at the Buck

 

Thursday June 6 Afternoon

1:30 Remi-Martin Laberge Buck Institute for Research on Aging

(CR and Cancer)

Targeting the tumor-promoting senescence-associated secretory phenotype with rapamycin

Cellular senescence is a potent tumor suppressive mechanism that prevents the growth of cells that experience potentially oncogenic stress. Senescent cells secrete a variety of pro-inflammatory molecules that comprise the senescence-associated secretory phenotype (SASP). The SASP can be deleterious if senescent cells accumulate, as they do during aging or after chemo- and radiotherapy. Along with pro-inflammatory cytokines and chemokines, senescent cells also secrete growth factors and matrix metalloproteinases, which can stimulate tumorigenesis and invasiveness of neighboring cells. The accumulation of senescence cells could promote aging phenotypes and age-related diseases, including late-life cancer, by causing chronic local inflammation and chronic tissue remodeling. Following chemo- and radiotherapy treatments, accumulation of senescent cells could also contribute to tumor relapse.

The mechanistic target of rapamycin (mTOR) is a major regulator of nutrient sensing and cell growth. mTOR signaling has been shown to be dysregulated in human diseases, especially certain cancers. Because inhibition of mTOR by rapamycin extends life span in mice, we hypothesized that mTOR may regulate the SASP. Indeed, we found that rapamycin decreases the SASP through the mTORC1 complex. Interestingly, rapamycin inhibited the transcription of all SASP factors interrogated with the exception of IL1α, which is an important initiator of the SASP. Polysome profile analyses revealed that the translation of IL1α mRNA, was suppressed by rapamycin. Further, exogenously added recombinant IL1α rescued the SASP after rapamycin treatment, and NF-kB activity, which is downstream of IL1α and required for the expression of other SASP genes, was suppressed by rapamycin. We also found that rapamycin suppresses the ability of senescent fibroblasts to stimulate tumorigenesis in mouse xenografts. Finally, we found that rapamycin treatment potentiates the effect of the chemotherapeutic agent Doxorubicin in syngeneic tumor mouse model. This effect was correlated with a suppression of the Doxorubicin mediated IL-6 induction by rapamycin.

These results shed light on the mechanisms by which the SASP is activated and how it might be controlled. In addition, our results might have near and long term clinical applications. Senescent cells have been shown to accumulate after genotoxic chemotherapy or radiotherapy, and could cause or contribute to the generalized inflammation and secondary cancers that often develop after these treatments. Understanding how the SASP is controlled and how it might be prevented provides a novel basis for developing rational strategies to reduce their deleterious effects after exposure to genotoxins and during normal aging.

 

2:30 Joseph Dhahbi University of California, Riverside

Integrative epigenetics analysis of CR effects on various subpopulations of circulating leukocytes

Epigenetics is the study of stable changes in gene function that are not caused by changes in DNA sequence. It has been suggested that common diseases and aging have an epigenetic component. While it has proven difficult to demonstrate that specific genes contribute more than a small proportion of disease risk, there is a considerable recent interest in the alternative possibility that epigenetic changes at certain loci contribute to disease risk. By their nature, epigenetic mechanisms are susceptible to environmental influences; they are an interface between the environment and the genome. They may be viewed as a means for the environment to impose stable changes on patterns of gene expression. Currently, there is a significant body of evidence that nutritional factors can alter epigenetic mechanisms.

We hypothesize that CR causes changes in the epigenome of the circulating leukocytes, and that these changes are reflected in patterns of CpG methylation and transcription. Circulating leukocytes contact and interact with all tissues and play crucial roles in immunity and physiological homeostasis. They are also intimately involved in inflammatory processes that are prominent in aging. To test this idea, we propose to use the next generation sequencing technology to carry out whole-genome assessment of CpG methylation patterns in leukocytes from older CR individuals and non-CR young and older controls. In parallel, we will sequence the transcriptomes as well as the cellular and circulating micronomes. We think it is essential, in any study of epigenomes or transcriptomes, to work with well defined, preferably single cell types. The commonly used analysis of total leukocytes or even mononuclear cells produces a picture that is the amalgamation of many epigenomes and transcriptomes. In such analyses, changes in a cell type may be concealed by other cell type that have not changed.

For this reason we separated the circulating leukocytes into 4 subpopulations: monocytes, lymphocytes, neutrophils, and a mix of eosinophils and basophils. We will sequence the methylomes, transcriptomes and micronomes of all four subpopulations separately. We also treated whole blood with lipopolysaccharides (LPS), which are endotoxins that elicit strong immune responses in animals. This will allow us to compare the ex vivo LPS-challenged monocytic expression of inflammation genes between CR and young and old controls, and learn whether CR enables a more youthful LPS-induced inflammatory response in peripheral monocytes. Upon completion of sequencing, the data will be analyzed with the most recent bioinformatics tools, to uncover potential CR-induced regulatory signals by identifying age- and CR-associated changes in the methylome and cellular and circulating micronomes. Integration of potential CR regulatory signals with changes in the transcriptomes would reveal mechanistic insights into the functions of CR, and could identify novel pathways that underlie the beneficial health and lifespan effects of CR.

 

3:30 Gary Taubes Berkeley CA

Insulin and adiposity: An alternative hypothesis of weight regulation and health

Since the 1950s, caloric imbalance has been perceived as a driving force in weight regulation. Virtually all research on obesity and its related chronic diseases is predicated on this notion. Prior to World War II, though, European clinicians argued that obesity was caused by a defect in the regulation of fat tissue metabolism. By the 1960s, it was clear that fat accumulation is fundamentally regulated by the hormone insulin, which in turn is secreted primarily in response to the carbohydrates in our diet. As such, a reasonable hypothesis is that adiposity is regulated by insulin and the carbohydrate content of the diet. This would implicate the quality and quantity of dietary carbohydrates as determinants of health and disease, more so than the total caloric intake. A simple revision to first principles in underlying assumption about the causes of weight gain can have profound and far-reaching implications.

 

Friday June 7 Morning

9:00 Deepak Lamba Buck Institute for Research on Aging

(Stem cells, Senescence, Rejuvenation, and CR)

Pluripotent Stem Cells for retinal degenerations

The retina, like many other regions of the nervous system, is subject to a variety of inherited

and acquired degenerative conditions. Loss of human retinal neurons including photoreceptors is not compensated by any effective regeneration from resident cells. We have been working on developing an approach towards a cell-based therapy for retinal degenerations using pluripotent stem cells. In this talk, we will review our work on directed differentiation of human pluripotent stem cells to a retinal fate as well as potential for use in cell therapy. The cells can also beused for disease modelling and we will discuss our recent work on understanding AMD modelling in retinal pigment epithelial cells as well use of bioengineering techniques for generating 3D retinas.

 

10:00 Heinrich Jasper Buck Institute for Research on Aging

(Stem cells, Senescence, Rejuvenation, and CR)

Age-related Stem Cell Dysfunction: Causes and Consequences

Proliferation of stem and progenitor cells has to be carefully balanced to maintain long-term regenerative capacity of high-turnover tissues while preventing cancer. As a genetically accessible model in which to explore the control of proliferative plasticity of somatic stem cells, we study the Drosophila intestine. Our work focuses on the regulation of intestinal stem cell (ISC) proliferation by stress and growth factor signaling, and we have explored age-related changes in stem cell activity. ISCs over-proliferate in aging flies due to excessive stress signaling, and conditions that improve proliferative homeostasis in this cell lineage extend lifespan of the organism. These conditions include reduced Insulin/IGF or Jun-N-terminal Kinase (JNK) signaling activities, as well as over-expression of cytoprotective genes in the ISC lineage. Interestingly, proliferative activity in aging intestinal epithelia predicts longevity over a range of genotypes, with maximal lifespan when intestinal proliferation is reduced but not completely inhibited. These results highlight the importance of strategies to maintain the balance between processes that promote regenerative capacity and ones that prevent hyper-proliferative disorders, and demonstrate that promoting proliferative homeostasis in aging metazoans is a viable strategy to extend lifespan.

In recent work, we have explored some of the underlying causes of the hyperproliferative phenotype, and have established an interaction between Foxo and the Rel/NFkB innate immune signaling pathway as a driver of age-related immunosenescence in the intestinal epithelium. Immunosenescence results in dramatic expansion of the commensal bacterial population in the gut, resulting in increased inflammatory signaling. We are currently testing whether preventing immunosenescence is sufficient to prevent dysplasia and extend lifespan of the organism.

Our findings deepen our understanding of the regulation of proliferative homeostasis in the aging intestinal epithelium and suggest potentially conserved mechanisms by which proliferative homeostasis can be preserved in the long term.

 

11:00 Panel Discussion Lamba, Jasper

Stem cells, Senescence, Rejuvenation, and CR

 

12:00 Lunch at the Buck

 

Friday June 7 Afternoon

1:30 Simon Melov Buck Institute for Research on Aging

(Biological Clocks, Physical Activity, and CR)

Does exercise slow aging?

The last 20 years or so has seen a dizzying array of discoveries in the basic biology of aging. However, we still lack fundamental insights into how to translate these discoveries in laboratory animals to human beings; the so called "translational gap". There is one exception to this generalization though, it has become increasingly obvious as to the clear cut benefits of regular exercise to maximize both longevity and healthspan. The reasons for this association are still under active investigation. It is unlikely that we will ever discover a single pharmacological solution with all the associated benefits of exercise. I will discuss recent discoveries on the value of regular exercise on human health in aging, as well as potential techniques for gauging physiological age, or biomarkers of aging.

 

2:30 Pankaj Kapahi Buck Institute for Research on Aging

(Biological Clocks, Physical Activity, and CR)

Behavioral changes that modulate responses to dietary restriction

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 as models 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 also shown that DR enhances mitochondrial function which is required for extended longevity. We have recently demonstrated 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. Our current model suggests that lifespan extension by DR requires both a metabolic switch and a behavioral change that increases physical activity. Thus monitoring of physical activity may serve as an excellent biomarker in order to optimize diets for maximal healthspan benefits.

 

3:30 Panel Discussion Melov, Kapahi

Biological Clocks, Physical Activity, and CR

 

Saturday June 8 Morning

9:00 Don Ingram Pennington Biomedical Research Center

(CR Primate Studies)

The NIA Study of Calorie Restriction and Aging

Dietary caloric restriction (CR) is the only intervention repeatedly demonstrated to retard the onset and incidence of age-related diseases, maintain function, and extend both lifespan and healthspan in mammals. In 70 years of study, such beneficial effects have been demonstrated in rodents and lower animals, but prior to 1987, had never been examined in primates. To determine whether CR might eventually be applied to humans, the NIA initiated a study of CR and aging in nonhuman primates. After 25 years, approximately 150 rhesus monkeys (Macaca mulatta) have been involved in the study, mostly rhesus monkeys aged across their respective lifespans at the time of initiation. Control monkeys received two meals per day of a standardized, natural ingredient diet sufficient to attain apparent satiety, while the CR group received 30% less, adjusted for age and body weight. The diet is supplemented with extra micronutrients such that the only substantive variable is the amount of calories consumed. Results to date indicate that CR animals are healthier than fully-fed counterparts based on reduced incidence of various chronic diseases, exhibit significantly better indices of predisposition to disease (such as lower insulin levels and greater insulin sensitivity, reduced blood lipids and pressure, and elevated HDL), and appear to age at a slower rate, based on a number of hormonal and functional indices, including behavioral performance. In addition, CR rhesus monkeys that were juveniles at the onset of the study showed delayed skeletal and sexual maturation, and CR groups have lower body temperatures than controls. Regarding the health of older monkeys, our results indicate several significant beneficial effects and few negative effects. However, a recent analysis of current mortality data indicated no evidence of improved survival when CR was initiated at younger or older ages, which contrasted with results reported from the University of Wisconsin study of CR in rhesus monkeys. How differences in dietary regime might account for the differences in results will be discussed.

 

10:00 Rozalyn Anderson University of Wisconsin, Madison

(CR Primate Studies)

Impact of CR on aging in rhesus monkeys – a focus on metabolism

Caloric restriction (CR) without malnutrition delays aging and extends lifespan in diverse species; however, mechanisms have remained elusive. Furthermore, the translatability of CR to primate species, and thus the applicability of insights from CR to human health, remains an open question. Here I will discuss the longitudinal adult-onset CR study in rhesus monkeys initiated at UW Madison in the late 1980s. In this population of rhesus macaques moderate CR lowered the incidence of aging-related deaths. In addition, CR delayed the onset of age-associated pathologies. Analysis of metabolic rate and energy expenditure indicate that the CR animals differ from controls in metabolic rate and in efficiency of metabolic output. These findings are supported by serum metabonomic data that show the CR animals to be metabolically distinct from their control-fed counterparts. Subsequent studies in skeletal muscle have revealed a metabolic component to the aging process, where a shift in metabolism anticipates the onset of sarcopenia - the age related loss of muscle mass. In CR animals the onset and progression of sarcopenia is delayed and multiple indicators of cellular metabolism suggest a “younger” profile than would be expected based on chronological age. The findings from the UW-Madison study suggest that CR does slow aging in rhesus monkeys and that changes in energy metabolism are central to its mechanisms of action.

 

11:00 Panel Discussion Anderson, Ingram, George Roth

(CR Primate Studies)

Outcomes from parallel CR monkey studies

Caloric restriction without malnutrition extends lifespan and delays the onset of age-associated disorders in diverse species, from unicellular organisms to laboratory mice and rats. Until recently, evidence of the translatability of CR’s effects to human health has been a critical gap in CR research. In the late 1980s two parallel rhesus monkey caloric restriction (CR) studies were initiated to determine the effect of CR on resistance to illness and mortality in nonhuman primates. With more than 20 years of longitudinal data accrued, both studies have demonstrated improvements in health in CR animals compared to controls, significant in the University of Wisconsin (UW) study, and approaching significance in the National Institute on Aging (NIA) study. The impact of CR on survival in nonhuman primates; however, is a point of departure in the two studies. In 2009 the UW-Madison-based research team reported improved survival for animals on CR. In contrast, the NIA-based research team reported in 2012 that there was no difference in survival between CR and Control monkeys. Here we present a comparison of key differences in study design that could explain differences in survival outcome, including the genetic origin of the study cohort, age of onset for the dietary intervention, dietary composition, feeding regimens, and protocols for animal husbandry. The relative contributions of these differences to study outcomes will be discussed, and NIA and UW perspectives on the impact of these findings on CR research and its potential to reveal insights into human health will be presented.

 

12:00 Danica Chen University of California, Berkeley

(CR and Cancer)

Cellular metabolism, aging, and disease

Calorie restriction improves metabolic homeostasis, slows aging, and prevents a wide spectrum of diseases. Evidence is accumulating to support the notion that sirtuins are key mediators of various aspects of the calorie restriction response. Sirtuins are nutrient sensors that are amenable to the regulation of nutritional inputs. Through their unique enzymatic activities, sirtuins modulate key players in diverse pathways implicated in the calorie restriction response. The implications in understanding cellular metabolism, aging, and diseases will be discussed.

 

Saturday June 8 Afternoon

Laboratory Tour conducted by Pankaj Kapahi

 

 

Click here to register online.

 

View 2013 CR Conference announcement.

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