Bay Area Aging Club – Session III: Calorie restriction; protein aggregation

(previous session)

Craig Skinner (Lin Lab, UC Davis): Identification of potential calorie restriction mimics in yeast using a nitric oxide-based screen. Yeast are an important model system in biogerontology, useful not only for genetic studies of longevity control but also for discovery of bioactive compounds. Calorie restriction (CR) in yeast causes increased levels of nitric oxide (NO) — somewhat surprising in that yeast cells lack a homolog of nitric oxide synthase — and elevated NO is sufficient to extend yeast lifespan. These observations led Skinner to screen a yeast deletion library for elevated NO levels, yielding several genes that extend lifespan.

Mark Lucanic (Lithgow Lab, Buck): Endocannabinoid signaling mediates the effect of diet on lifespan in C. elegans. Mutants in the dauer pathway in C. elegans often influence longevity; the daf-2 mutation, which causes constitutive dauer formation at elevated temperatures, extends lifespan by several fold. Lucanic discovered that endocannabinoids are involved in the regulation of the dauer pathway — and therefore, of longevity — either independently of or far downstream of daf-2 and daf-16. Endocannabinoids are upregulated under well-fed conditions, and shorten lifespan.

Delia David (Kenyon Lab, UCSF): Widespread protein aggregation is an inherent part of aging in C. elegans. Protein aggregates are a hallmark of many age-related neurodegenerative diseases, leading to the hypotheses that the cellular mileu changes with age in a manner that causes native, aggregation-prone proteins to form aggregates. David used mass spectrometry to identify a subset of normal worm proteins aggregate as a function of age. As with the proteins associated with neurodegeneration, specific proteins aggregate in specific cell types. Mutations that extend lifespan (such as daf-2) decrease aggregation, and tend to downregulate the expression of genes encoding aggregation-prone proteins. Curiously, regulators of protein homeostasis tend to aggregate themselves, leading to a destructive positive feedback loop in which the very factors that protect the cell from proteotoxicity disappear into aggregates, leading to further aggregation.

Cherry Tang (Zhong Lab, Berkeley): The Clearance of Ubiquitinated Protein Aggregates Via Autophagy. Autophagic protein degradation has been implicated in control of lifespan: autophagy slows cell and tissue aging. Tang has identified a protein that participates in degradation of ubiquitinated proteins and co-localizes with autophagosomes; when the protein is knocked down, protein aggregates become more toxic.

(next session)


One comment

  1. i posted this elsewhere on the site but this might be the right place

    hi there
    i like the website as i am interested in the science and use to be a research agronomist.
    i found the following interesting an on topic
    Mannoheptulose: glycolytic inhibitor and novel caloric restriction mimetic George Roth1, Mike Hayek2, Stefan Massimino2, Gary Davenport2, Robert Arking3, Andrzej Bartke4, Michael Bonkowski4 and Don Ingram5
    Caloric restriction (CR) is the most robust and reproducible strategy for retarding aging. Benefits of CR have been demonstrated in multiple species, but application to human or companion animal aging represents a challenge. In 1998 the concept of CR “mimetic” (CRM) was introduced as a method to obtain “anti-aging” and health-promoting benefits of CR without reducing food intake. We hypothesized that an effective CRM would best mimic the effects of CR if it impeded initial stages of energy metabolism. We focused initially on glycolytic inhibition using 2-deoxyglucose (2DG). Upon entry into cells, this glucose analog is phosphorylated and becomes a strong competitive inhibitor of phosphohexose isomerase. 2DG effectively induces a CR-like state in rats based on metabolic effects such as reduced plasma glucose, insulin, body temperature, pulse, heart rate and inhibiting tumor growth. Results show 2DG has a narrow window between efficacy and toxicity so recently we shifted our focus to mannoheptulose (MH), a seven-carbon sugar that reduces glycolysis via hexokinase inhibition. MH appears non-toxic with negligible effects on food intake and BW, and increased insulin tolerance by 25% in mice. MH extends median and maximal lifespan (~15%) in D. melanogaster and median lifespan (~30%) in C3H/HeJ mice. These findings, coupled with simple extraction from avocados, suggest that MH may be a practical, highly effective CRM.
    for abstract

    the amount of avocado which needs to be taken as far as i can calculate is about one large avocado a day

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