The mystery of C. elegans aging: An emerging role for fat

New C. elegans studies imply that lipases and lipid desaturases can mediate signaling effects on aging. But why might fat homeostasis be critical to aging? Could problems with fat handling compromise health in nematodes as they do in mammals? The study of signaling pathways that control longevity could provide the key to one of the great unsolved mysteries of biology: the mechanism of aging. But as our view of the regulatory pathways that control aging grows ever clearer, the nature of aging itself has, if anything, grown more obscure. In particular, focused investigations of the oxidative damage theory have raised questions about an old assumption: that a fundamental cause of aging is accumulation of molecular damage. Could fat dyshomeostasis instead be critical?

[1]  G. Shulman,et al.  On Diabetes: Insulin Resistance Cellular Mechanisms of Insulin Resistance , 2022 .

[2]  K. Leske,et al.  Two distinct yolk lipoprotein complexes from Caenorhabditis elegans. , 1990, The Journal of biological chemistry.

[3]  J. Kimble,et al.  Tissue-specific synthesis of yolk proteins in Caenorhabditis elegans. , 1983, Developmental biology.

[4]  A. Fraser,et al.  Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. , 2002, Genetics.

[5]  Cori Bargmann,et al.  Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans , 2003, Nature.

[6]  S. Hekimi,et al.  Reactive Oxygen Species and Aging in Caenorhabditis elegans: Causal or Casual Relationship? , 2010, Antioxidants & redox signaling.

[7]  D. Hall,et al.  Autophagy Genes Are Essential for Dauer Development and Life-Span Extension in C. elegans , 2003, Science.

[8]  T. Utsumi,et al.  Roles of long chain fatty acids and carnitine in mitochondrial membrane permeability transition. , 2001, Biochemical pharmacology.

[9]  C. Kenyon The genetics of ageing , 2010, Nature.

[10]  C. Wolkow,et al.  Regulation of Caenorhabditis elegans vitellogenesis by DAF-2/IIS through separable transcriptional and posttranscriptional mechanisms , 2011, BMC Physiology.

[11]  Arlan Richardson,et al.  Genetic mouse models of extended lifespan , 2003, Experimental Gerontology.

[12]  D. Gems,et al.  Increased life span from overexpression of superoxide dismutase in Caenorhabditis elegans is not caused by decreased oxidative damage , 2011, Free radical biology & medicine.

[13]  M. Hansen,et al.  A Role for Autophagy in the Extension of Lifespan by Dietary Restriction in -1 , 2011 .

[14]  P. Scherer,et al.  Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity , 2010, Trends in Endocrinology & Metabolism.

[15]  L. Scorrano,et al.  Arachidonic Acid Causes Cell Death through the Mitochondrial Permeability Transition , 2000, The Journal of Biological Chemistry.

[16]  Cynthia Kenyon,et al.  Signals from the reproductive system regulate the lifespan of C. elegans , 1999, Nature.

[17]  R. Branicky,et al.  Redox Regulation of Germline and Vulval Development in Caenorhabditis elegans , 2003, Science.

[18]  V. Matyash,et al.  Distribution and transport of cholesterol in Caenorhabditis elegans. , 2001, Molecular biology of the cell.

[19]  C. Wrede,et al.  Protein Kinase B/Akt Prevents Fatty Acid-induced Apoptosis in Pancreatic β-Cells (INS-1)* , 2002, The Journal of Biological Chemistry.

[20]  Xianlin Han,et al.  The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. , 2002, The Journal of clinical investigation.

[21]  G. Shulman,et al.  Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. , 1999, Diabetes.

[22]  D. Hall,et al.  Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans , 2002, Nature.

[23]  A. Bokov,et al.  Is the oxidative stress theory of aging dead? , 2009, Biochimica et biophysica acta.

[24]  T. Vellai,et al.  Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans , 2008, Autophagy.

[25]  J. Schaffer,et al.  Lipotoxicity: when tissues overeat , 2003, Current opinion in lipidology.

[26]  M. Prentki,et al.  Oleate activates phosphatidylinositol 3-kinase and promotes proliferation and reduces apoptosis of MDA-MB-231 breast cancer cells, whereas palmitate has opposite effects. , 2000, Cancer Research.

[27]  D. Gems,et al.  Antioxidant defense and aging in C. elegans: Is the oxidative damage theory of aging wrong? , 2009, Cell cycle.

[28]  S. Homma,et al.  Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. , 2003, The Journal of clinical investigation.

[29]  R. Unger,et al.  Lipotoxic diseases. , 2002, Annual review of medicine.

[30]  M. Czaja,et al.  Autophagy regulates lipid metabolism , 2009, Nature.

[31]  J. Speakman,et al.  The free‐radical damage theory: Accumulating evidence against a simple link of oxidative stress to ageing and lifespan , 2011, BioEssays : news and reviews in molecular, cellular and developmental biology.

[32]  Di Chen,et al.  With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. , 2010, Cell metabolism.

[33]  Kailiang Jia,et al.  Autophagy is Required for Dietary Restriction-Mediated Life Span Extension in C. elegans , 2007, Autophagy.

[34]  M. Hansen,et al.  Autophagy and Lipid Metabolism Coordinately Modulate Life Span in Germline-less C. elegans , 2011, Current Biology.

[35]  G. Ruvkun,et al.  C. elegans major fats are stored in vesicles distinct from lysosome-related organelles. , 2009, Cell metabolism.

[36]  C. Schmitz‐Peiffer,et al.  Ceramide Generation Is Sufficient to Account for the Inhibition of the Insulin-stimulated PKB Pathway in C2C12 Skeletal Muscle Cells Pretreated with Palmitate* , 1999, The Journal of Biological Chemistry.

[37]  P. Herrero,et al.  A novel mouse model of lipotoxic cardiomyopathy. , 2001, The Journal of clinical investigation.

[38]  Michele Purrello,et al.  Chronic exposure to free fatty acids or high glucose induces apoptosis in rat pancreatic islets: possible role of oxidative stress. , 2002, Metabolism: clinical and experimental.

[39]  Siegfried Hekimi,et al.  A Mitochondrial Superoxide Signal Triggers Increased Longevity in Caenorhabditis elegans , 2010, PLoS biology.

[40]  B. Zwaan,et al.  Shuttling between species for pathways of lifespan regulation: a central role for the vitellogenin gene family? , 2005, BioEssays : news and reviews in molecular, cellular and developmental biology.

[41]  J. Apfeld,et al.  Regulation of Life-Span by Germ-Line Stem Cells in Caenorhabditis elegans , 2002, Science.

[42]  Anja Voigt,et al.  Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. , 2007, Cell metabolism.

[43]  Yang Shi,et al.  The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span , 2009, Proceedings of the National Academy of Sciences.

[44]  Nir Barzilai,et al.  Role of visceral adipose tissue in aging. , 2009, Biochimica et biophysica acta.

[45]  M. Blagosklonny,et al.  Aging: ROS or TOR , 2008, Cell cycle.

[46]  Kyle Duke,et al.  Transcriptional Profile of Aging in C. elegans , 2002, Current Biology.

[47]  E. Siegel,et al.  Modulation of lipid biosynthesis contributes to stress resistance and longevity of C. elegans mutants , 2011, Aging.

[48]  Janet M. Thornton,et al.  Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span , 2009, Science.

[49]  H. Aguilaniu,et al.  Fatty Acid Desaturation Links Germ Cell Loss to Longevity Through NHR-80/HNF4 in C. elegans , 2011, PLoS biology.

[50]  Simon Melov,et al.  Loss of intestinal nuclei and intestinal integrity in aging C. elegans , 2011, Aging cell.

[51]  G. Ruvkun,et al.  Fat Metabolism Links Germline Stem Cells and Longevity in C. elegans , 2008, Science.

[52]  Chengcheng Hu,et al.  Autophagy Regulates Ageing in C. elegans , 2007, Autophagy.

[53]  M. Driscoll,et al.  A Role for Autophagy in the Extension of Lifespan by Dietary Restriction in C. elegans , 2008, PLoS genetics.

[54]  D. Harman Aging: a theory based on free radical and radiation chemistry. , 1956, Journal of gerontology.