24 posts · 30,094 views
Ouroboros is a community weblog for biologists of aging. The mission of the site is to provide timely, thoughtful and scholarly commentary on developments within the field, as they are reported in the literature and at relevant conferences.
We know that exercise is good for us, and increasingly we’re understanding how it works at the molecular and cellular level: Physical activity boosts levels of heat shock proteins, which help cells resist stress; it also improves mitochondrial function in a manner reminiscent of calorie restriction (CR). Our knowledge is sophisticated enough that we can [...]... Read more »
Fry, C., Glynn, E., Drummond, M., Timmerman, K., Fujita, S., Abe, T., Dhanani, S., Volpi, E., & Rasmussen, B. (2010) Blood flow restriction exercise stimulates mTORC1 signaling and muscle protein synthesis in older men. Journal of Applied Physiology. DOI: 10.1152/japplphysiol.01266.2009
Yesterday we learned that the most well-characterized mammalian sirtuin, SIRT1, is involved in the control of behavior in response to food availability. SIRT1 is just one of seven sirtuins in mammalian genomes, each of which has a characteristic expression pattern, subcellular localization, and physiological importance.
Today we’re going to talk about another member of the [...]... Read more »
Kim, H., Patel, K., Muldoon-Jacobs, K., Bisht, K., Aykin-Burns, N., Pennington, J., van der Meer, R., Nguyen, P., Savage, J., & Owens, K. (2010) SIRT3 Is a Mitochondria-Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress. Cancer Cell, 17(1), 41-52. DOI: 10.1016/j.ccr.2009.11.023
Not only does the mammalian sirtuin SIRT1 mediate the lifespan extension phenotype of caloric restriction (CR), it is also involved in controlling behavior (such as food intake) in response to CR (and possibly during ad libitum feeding as well).
Two recent papers with consistent results address the issue. Both studies employed brain-specific knockouts of SIRT1; [...]... Read more »
Çakir, I., Perello, M., Lansari, O., Messier, N., Vaslet, C., & Nillni, E. (2009) Hypothalamic Sirt1 Regulates Food Intake in a Rodent Model System. PLoS ONE, 4(12). DOI: 10.1371/journal.pone.0008322
Cohen, D., Supinski, A., Bonkowski, M., Donmez, G., & Guarente, L. (2009) Neuronal SIRT1 regulates endocrine and behavioral responses to calorie restriction. Genes , 23(24), 2812-2817. DOI: 10.1101/gad.1839209
A couple of worm genomics papers caught my eye this week.
One is about using networks of genes as biomarkers. (The first author is our own turritopsis, and we extend our heartiest congratulations on the publication of this interesting paper.) It’s a neat idea: networks make better biomarkers than single genes; furthermore, thinking about genes [...]... Read more »
Fortney, K., Kotlyar, M., & Jurisica, I. (2010) Inferring the functions of longevity genes with modular subnetwork biomarkers of Caenorhabditis elegans aging. Genome Biology, 11(2). DOI: 10.1186/gb-2010-11-2-r13
Ruzanov, P., & Riddle, D. (2010) Deep SAGE analysis of the Caenorhabditis elegans transcriptome. Nucleic Acids Research. DOI: 10.1093/nar/gkq035
The hottest thing in stem cells right now is induced pluripotency, i.e., converting somatic cells back into pluripotent cells by introducing a few stem cell-specific genes (or even the encoded proteins). Induced pluripotent stem cells (iPS) harvested from a donor’s skin would be automatically immunologically matched; furthermore, they completely circumvent some of the “ethical” and [...]... Read more »
Esteban, M., Wang, T., Qin, B., Yang, J., Qin, D., Cai, J., Li, W., Weng, Z., Chen, J., & Ni, S. (2010) Vitamin C Enhances the Generation of Mouse and Human Induced Pluripotent Stem Cells. Cell Stem Cell, 6(1), 71-79. DOI: 10.1016/j.stem.2009.12.001
To the growing list of small-molecule drugs that have a measurable effect on lifespan or healthspan (e.g., resveratrol and rapamycin) we should add metformin, an anti-diabetic drug that has shown promise as a calorie restriction mimetic. Onken & Driscoll determined some of the genetic requirements for metformin’s anti-aging properties in the worm C. elegans:
Metformin induces [...]... Read more »
Onken, B., & Driscoll, M. (2010) Metformin Induces a Dietary Restriction–Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1, and SKN-1. PLoS ONE, 5(1). DOI: 10.1371/journal.pone.0008758
Cells tend to produce unwanted protein aggregates and other molecular refuse slightly faster than they can get rid of it, resulting in a time-dependent accumulation of potentially toxic cellular garbage. This, in turn, can cause an age-dependent loss of cellular viability, which is (in certain contexts) a fair operational definition of aging.
How can cells deal [...]... Read more »
Liu, B., Larsson, L., Caballero, A., Hao, X., Öling, D., Grantham, J., & Nyström, T. (2010) The Polarisome Is Required for Segregation and Retrograde Transport of Protein Aggregates. Cell, 140(2), 257-267. DOI: 10.1016/j.cell.2009.12.031
A study of Ashkenazi Jewish centenarians by Atzmon et al. has revealed that telomere length is correlated with longer lifespan and slower biological aging (reflected in measurements of several biomarkers of aging). Both lifespan and telomere length are, in turn, correlated with polymorphisms at the hTERT and hTERC loci, two genes that respectively encode the [...]... Read more »
Atzmon, G., Cho, M., Cawthon, R., Budagov, T., Katz, M., Yang, X., Siegel, G., Bergman, A., Huffman, D., Schechter, C.... (2009) Evolution in Health and Medicine Sackler Colloquium: Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proceedings of the National Academy of Sciences, 107(suppl_1), 1710-1717. DOI: 10.1073/pnas.0906191106
A prominent scholar of the CLK-1 story has called the coroner on the mitochondrial free radical theory of aging (MFRTA). From Lapointe & Hekimi:
When a theory of aging ages badly
According to the widely acknowledged mitochondrial free radical theory of aging (MFRTA), the macromolecular damage that results from the production of toxic reactive oxygen species [...]... Read more »
We are all descendents of an unbroken line of cell divisions, dating back to the last common ancestor of all life on Earth. At some point, long after our lineage had acquired features like nuclei and mitochondria, a less distant ancestor stumbled on a major innovation: it grew a body, bringing with it the advantages [...]... Read more »
Curran, S., Wu, X., Riedel, C., & Ruvkun, G. (2009) A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants. Nature. DOI: 10.1038/nature08106
The TOR (”target of rapamycin”) protein is a master regulator of cell growth, governing connect nutrient sensing, protein synthesis, and proliferation. It has become increasingly clear that the TOR pathway plays an essential role in longevity determination — specifically, higher TOR activity is associated with more rapid aging and shorter lifespan.
In mammals, TOR interferes [...]... Read more »
Chen, D., Thomas, E., & Kapahi, P. (2009) HIF-1 Modulates Dietary Restriction-Mediated Lifespan Extension via IRE-1 in Caenorhabditis elegans. PLoS Genetics, 5(5). DOI: 10.1371/journal.pgen.1000486
How did aging evolve? Some evolutionary theories invoke tradeoffs between maintenance/repair and reproduction. Others postulate that genes that cause age-related decline can be positively selected, so long as these same genes confer a fitness advantage early in life.
A common feature of these theories is that they operate at the level of the individual organism, [...]... Read more »
Mitteldorf, J., & Pepper, J. (2009) Senescence as an adaptation to limit the spread of disease. Journal of Theoretical Biology. DOI: 10.1016/j.jtbi.2009.05.013
In collaboration with the estimable Vivan Siegel, I’m writing a series of op/ed articles on the future of scientific publishing. The first of these was about the challenges of filtering the scientific literature. The second piece, explores the prospect of using “Web 2.0″ approaches to accelerate scientific progress. The article starts from the assumption that [...]... Read more »
Patil, C., & Siegel, V. (2009) This revolution will be digitized: online tools for radical collaboration. Disease Models and Mechanisms, 2(5-6), 201-205. DOI: 10.1242/dmm.003285
The idea that translation fidelity might play a role in aging dates back at least as far as 1963, when Leslie Orgel proposed the “error catastrophe” theory of aging: in this model, mistranslation of the translational machinery creates a feedback loop that leads to further translation errors, ultimately causing loss of cell viability. From the [...]... Read more »
Silva, R., Duarte, I., Paredes, J., Lima-Costa, T., Perrot, M., Boucherie, H., Goodfellow, B., Gomes, A., Mateus, D., Moura, G.... (2009) The Yeast PNC1 Longevity Gene Is Up-Regulated by mRNA Mistranslation. PLoS ONE, 4(4). DOI: 10.1371/journal.pone.0005212
One of the central precepts of biogerontology is that meaningful lifespan extension will be concomitant with extension of the “healthspan”, i.e., the vigorous part of life — life that is, for lack of a better phrase, worth living.
This relationship is borne out both in nature (where longer-lived organisms also have longer healthspans) and in [...]... Read more »
Avanesian, A., Khodayari, B., Felgner, J., & Jafari, M. (2009) Lamotrigine extends lifespan but compromises health span in Drosophila melanogaster. Biogerontology. DOI: 10.1007/s10522-009-9227-1
The free radical theory of aging (FRTA) was first advanced by Denham Harman more than 50 years ago. The theory proceeds logically from a small number of straightforward assumptions, based on observations from radiation biology. From the Science of Aging Timeline:
Harman’s logic proceeds from three observations: (1) irradiation causes premature aging; (2) irradiation creates oxygen [...]... Read more »
Harman, D. (2009) Origin and evolution of the free radical theory of aging: a brief personal history, 1954–2009. Biogerontology. DOI: 10.1007/s10522-009-9234-2
Recently, some human survival data – together with matching gene expression data from lymphoblastoid cell lines – have become available from a long-range study that began in the early 1980s. In the first aging study to take advantage of this resource, Kerber et al. mine the data to identify gene changes associated with longevity:... Read more »
Kerber, R., O’Brien, E., & Cawthon, R. (2009) Gene expression profiles associated with aging and mortality in humans. Aging Cell, 8(3), 239-250. DOI: 10.1111/j.1474-9726.2009.00467.x
Over at Fight Aging!, Reason has penned a very nice piece of analysis on a recent article demonstrating that stimulation of one autophagic pathway can reduce plasma lipoproteins and triglycerides. From the blog post:
A Tangible Benefit of Artificially Boosting Autophagy
The researchers used a compound to block lipolysis in order to provoke greater levels of autophagy [...]... Read more »
Straniero, S., Cavallini, G., Donati, A., Pallottini, V., Martini, C., Trentalance, A., & Bergamini, E. (2009) Stimulation of Autophagy by Antilipolytic Drugs May Rescue Rodents from Age-Associated Hypercholesterolemia. Rejuvenation Research, 12(2), 77-84. DOI: 10.1089/rej.2008.0806
Protein degradation is an essential longevity assurance pathway. Maintaining high levels of autophagy can delay age-related decline in liver function. Obstacles to protein degradation tend to shorten the lifespan: blocking autophagy causes hypersensitivity to stress, and inhibiting the ubiquitin/proteasome pathway damages the mitochondria; both of these treatments kill neurons.
Conversely, longevity enhancement tends to enhance [...]... Read more »
Mehta, R., Steinkraus, K., Sutphin, G., Ramos, F., Shamieh, L., Huh, A., Davis, C., Chandler-Brown, D., & Kaeberlein, M. (2009) Proteasomal Regulation of the Hypoxic Response Modulates Aging in C. elegans. Science. DOI: 10.1126/science.1173507
The insulin-like growth factor (IGF) pathway is one of the longest-known and well-studied regulators of longevity. Extracellular signals (insulin-like peptides) activate insulin-receptor homologs (in worm, DAF-2) which in turn recruit and activate phosphoinositol 3-kinases (AGE-1). PI3Ks convert PIP2 into PIP3, which tethers and recruits other kinases such as AKT-1. Eventually, activation of these upstream kinases [...]... Read more »
Tazearslan, C., Ayyadevara, S., Bharill, P., & Shmookler Reis, R. (2009) Positive Feedback between Transcriptional and Kinase Suppression in Nematodes with Extraordinary Longevity and Stress Resistance. PLoS Genetics, 5(4). DOI: 10.1371/journal.pgen.1000452
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