Biomarkers of aging in Drosophila

Low environmental temperature and dietary restriction (DR) extend lifespan in diverse organisms. In the fruit fly Drosophila, switching flies between temperatures alters the rate at which mortality subsequently increases with age but does not reverse mortality rate. In contrast, DR acts acutely to lower mortality risk; flies switched between control feeding and DR show a rapid reversal of mortality rate. Dietary restriction thus does not slow accumulation of aging‐related damage. Molecular species that track the effects of temperatures on mortality but are unaltered with switches in diet are therefore potential biomarkers of aging‐related damage. However, molecular species that switch upon instigation or withdrawal of DR are thus potential biomarkers of mechanisms underlying risk of mortality, but not of aging‐related damage. Using this approach, we assessed several commonly used biomarkers of aging‐related damage. Accumulation of fluorescent advanced glycation end products (AGEs) correlated strongly with mortality rate of flies at different temperatures but was independent of diet. Hence, fluorescent AGEs are biomarkers of aging‐related damage in flies. In contrast, five oxidized and glycated protein adducts accumulated with age, but were reversible with both temperature and diet, and are therefore not markers either of acute risk of dying or of aging‐related damage. Our approach provides a powerful method for identification of biomarkers of aging.

[1]  R. S. Sohal,et al.  DNA oxidative damage and life expectancy in houseflies. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[2]  U. Brunk,et al.  Aging as a catabolic malfunction. , 2004, The international journal of biochemistry & cell biology.

[3]  R. Kodell,et al.  Survival characteristics and age-adjusted disease incidences in C57BL/6 mice fed a commonly used cereal-based diet modulated by dietary restriction. , 2002, The journals of gerontology. Series A, Biological sciences and medical sciences.

[4]  T. Kirkwood,et al.  Understanding the Odd Science of Aging , 2005, Cell.

[5]  Linda Partridge,et al.  Quantification of Food Intake in Drosophila , 2009, PloS one.

[6]  U. Brunk,et al.  Oxidized proteins: Mechanisms of removal and consequences of accumulation , 2009, IUBMB life.

[7]  L. Partridge,et al.  Dietary restriction, mortality trajectories, risk and damage , 2005, Mechanisms of Ageing and Development.

[8]  K. Yasuda,et al.  Protein carbonyl accumulation in aging dauer formation-defective (daf) mutants of Caenorhabditis elegans. , 1999, The journals of gerontology. Series A, Biological sciences and medical sciences.

[9]  M. Portero-Otín,et al.  Modification of the longevity-related degree of fatty acid unsaturation modulates oxidative damage to proteins and mitochondrial DNA in liver and brain , 2004, Experimental Gerontology.

[10]  Linda Partridge,et al.  Optimization of dietary restriction protocols in Drosophila. , 2007, The journals of gerontology. Series A, Biological sciences and medical sciences.

[11]  L. Partridge,et al.  Demography of Dietary Restriction and Death in Drosophila , 2003, Science.

[12]  R. Idilman,et al.  Evidence of oxidative injury during aging of the liver in a mouse model. , 2001, Journal of the American Aging Association.

[13]  David B. Goldstein,et al.  Genome-Wide Transcript Profiles in Aging and Calorically Restricted Drosophila melanogaster , 2002, Current Biology.

[14]  A. Jenkins,et al.  Quantification of malondialdehyde and 4-hydroxynonenal adducts to lysine residues in native and oxidized human low-density lipoprotein. , 1997, The Biochemical journal.

[15]  Beate Gerstbrein,et al.  In vivo spectrofluorimetry reveals endogenous biomarkers that report healthspan and dietary restriction in Caenorhabditis elegans , 2005, Aging cell.

[16]  K. Yasuda,et al.  Adaptive responses to oxidative damage in three mutants of Caenorhabditis elegans (age-1, mev-1 and daf-16) that affect life span , 2002, Mechanisms of Ageing and Development.

[17]  D. Neuberg,et al.  The Identification of Zebrafish Mutants Showing Alterations in Senescence-Associated Biomarkers , 2008, PLoS genetics.

[18]  L. Guarente,et al.  Calorie restriction extends yeast life span by lowering the level of NADH. , 2004, Genes & development.

[19]  F. Botta,et al.  Anti malondialdehyde-adduct immunological response as a possible marker of successful aging , 2003, Experimental Gerontology.

[20]  Elisa T. Lee,et al.  Statistical Methods for Survival Data Analysis , 1994, IEEE Transactions on Reliability.

[21]  Sterling C. Johnson,et al.  Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys , 2009, Science.

[22]  D. Yin,et al.  Biochemical basis of lipofuscin, ceroid, and age pigment-like fluorophores. , 1996, Free radical biology & medicine.

[23]  Linda Partridge,et al.  Mechanisms of aging: public or private? , 2002, Nature Reviews Genetics.

[24]  H. Parving,et al.  Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death. , 2002, Diabetes.

[25]  J. Vanfleteren,et al.  Life extension via dietary restriction is independent of the Ins/IGF-1 signalling pathway in Caenorhabditis elegans , 2003, Experimental Gerontology.

[26]  R. Weindruch,et al.  The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. , 1986, The Journal of nutrition.

[27]  Paul J Thornalley Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs. , 1998, Cellular and molecular biology.

[28]  E. Masoro Caloric restriction-induced life extension of rats and mice: a critique of proposed mechanisms. , 2009, Biochimica et biophysica acta.

[29]  R. S. Sohal,et al.  Overexpression of glutathione reductase extends survival in transgenic Drosophila melanogaster under hyperoxia but not normoxia , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  L. Partridge,et al.  Female fitness in Drosophila melanogaster: an interaction between the effect of nutrition and of encounter rate with males , 1996, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[31]  T. Lyons,et al.  The Advanced Glycation End Product, N-(Carboxymethyl)lysine, Is a Product of both Lipid Peroxidation and Glycoxidation Reactions (*) , 1996, The Journal of Biological Chemistry.

[32]  Pletcher Model fitting and hypothesis testing for age‐specific mortality data , 1999 .

[33]  Paul J Thornalley,et al.  Advanced glycation endproducts: what is their relevance to diabetic complications? , 2007, Diabetes, obesity & metabolism.

[34]  E. Stadtman,et al.  Oxidative modification of proteins during aging , 2001, Experimental Gerontology.

[35]  A. Oudes,et al.  Age-dependent accumulation of advanced glycation end-products in adult Drosophila melanogaster , 1998, Mechanisms of Ageing and Development.

[36]  M. Portero-Otín,et al.  Proteins in Human Brain Cortex Are Modified by Oxidation, Glycoxidation, and Lipoxidation , 2005, Journal of Biological Chemistry.

[37]  Elisa T. Lee,et al.  Statistical Methods for Survival Data Analysis , 1994, IEEE Transactions on Reliability.

[38]  Ana Navarro,et al.  Rat brain and liver mitochondria develop oxidative stress and lose enzymatic activities on aging. , 2004, American journal of physiology. Regulatory, integrative and comparative physiology.

[39]  J. Curtsinger,et al.  Why do life spans differ? Partitioning mean longevity differences in terms of age-specific mortality parameters. , 2000, The journals of gerontology. Series A, Biological sciences and medical sciences.

[40]  S. Wright,et al.  The Rate Of Living , 2011 .

[41]  H. Atlan,et al.  Effects of temperature on the life span, vitality and fine structure of Drosophila melanogaster , 1976, Mechanisms of Ageing and Development.

[42]  Judith Berman,et al.  Haplotype Mapping of a Diploid Non-Meiotic Organism Using Existing and Induced Aneuploidies , 2007, PLoS genetics.

[43]  C. Wilbert,et al.  Aging induces cardiac diastolic dysfunction, oxidative stress, accumulation of advanced glycation endproducts and protein modification , 2005, Aging cell.

[44]  O. Pansarasa,et al.  Age and sex differences in human skeletal muscle: Role of reactive oxygen species , 2000, Free radical research.

[45]  C M McCay,et al.  The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. , 1935, Nutrition.

[46]  R. S. Sohal,et al.  Mitochondrial oxidative damage, hydrogen peroxide release, and aging. , 1994, Free radical biology & medicine.

[47]  M. Herman,et al.  Fluorescent products and lysosomal components in aging Drosophila melanogaster. , 1974, Journal of gerontology.

[48]  G. Bartosz,et al.  Accumulation of oxidative damage during replicative aging of the yeast Saccharomyces cerevisiae , 2006, Experimental Gerontology.

[49]  M. Klass,et al.  Aging in the nematode Caenorhabditis elegans: Major biological and environmental factors influencing life span , 1977, Mechanisms of Ageing and Development.

[50]  P. Hollman,et al.  Aging increases Nepsilon-(carboxymethyl)lysine and caloric restriction decreases Nepsilon-(carboxyethyl)lysine and Nepsilon-(malondialdehyde)lysine in rat heart mitochondrial proteins. , 2002 .

[51]  N. Ishii,et al.  Effects of tocotrienols on life span and protein carbonylation in Caenorhabditis elegans. , 2000, The journals of gerontology. Series A, Biological sciences and medical sciences.

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

[53]  R. Pamplona,et al.  Life and death: metabolic rate, membrane composition, and life span of animals. , 2007, Physiological reviews.

[54]  M. Portero-Otín,et al.  Aging Increases N epsilon -(Carboxymethyl)lysine and Caloric Restriction Decreases N epsilon -(Carboxyethyl)lysine and N epsilon -(Malondialdehyde)lysine in Rat Heart Mitochondrial Proteins , 2002, Free radical research.

[55]  Jeen-Woo Park,et al.  Role of Thioredoxin Peroxidase in Aging of Stationary Cultures of Saccharomyces cerevisiae , 2004, Free radical research.

[56]  R. Weindruch,et al.  Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. , 1982, Science.

[57]  J. Baynes,et al.  The role of AGEs in aging: causation or correlation , 2001, Experimental Gerontology.

[58]  G. Bartosz,et al.  Oxidative stress during aging of stationary cultures of the yeast Saccharomyces cerevisiae. , 2000, Free radical biology & medicine.

[59]  H. Warner Current status of efforts to measure and modulate the biological rate of aging. , 2004, The journals of gerontology. Series A, Biological sciences and medical sciences.

[60]  M. Portero-Otín,et al.  Protein nonenzymatic modifications and proteasome activity in skeletal muscle from the short-lived rat and long-lived pigeon , 2004, Experimental Gerontology.

[61]  Gemma Reverter-Branchat,et al.  Oxidative Damage to Specific Proteins in Replicative and Chronological-aged Saccharomyces cerevisiae , 2004, Journal of Biological Chemistry.

[62]  R. S. Sohal,et al.  Mitochondrial superoxide and hydrogen peroxide generation, protein oxidative damage, and longevity in different species of flies. , 1995, Free radical biology & medicine.

[63]  S. Spindler Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction , 2005, Mechanisms of Ageing and Development.

[64]  J. He,et al.  Advanced glycation endproduct (AGE) receptor 1 is a negative regulator of the inflammatory response to AGE in mesangial cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[65]  Linda Partridge,et al.  Mechanisms of ageing: public or private? , 2002, Nature reviews. Genetics.

[66]  R. S. Sohal,et al.  Aging and proteolysis of oxidized proteins. , 1994, Archives of biochemistry and biophysics.

[67]  R. Pamplona,et al.  Highly resistant macromolecular components and low rate of generation of endogenous damage: Two key traits of longevity , 2007, Ageing Research Reviews.

[68]  S. Jazwinski,et al.  An intervention resembling caloric restriction prolongs life span and retards aging in yeast , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[69]  Jan Vijg,et al.  Puzzles, promises and a cure for ageing , 2008, Nature.

[70]  E. Bergamini,et al.  The age-related accumulation of protein carbonyl in rat liver correlates with the age-related decline in liver proteolytic activities. , 1999, The journals of gerontology. Series A, Biological sciences and medical sciences.

[71]  L. Partridge,et al.  Pitfalls of measuring feeding rate in the fruit fly Drosophila melanogaster , 2008, Nature Methods.

[72]  D. Berrigan,et al.  Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. , 2003, Annual review of medicine.

[73]  J. Loeb,et al.  ON THE INFLUENCE OF FOOD AND TEMPERATURE UPON THE DURATION OF LIFE , 1917 .