Transcript sitcg wine
Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Krisztián Kvell Molecular and Clinical Basics of Gerontology – Lecture 24 MOLECULAR / CELLULAR EFFECTS OF ACUTE AND CHRONIC STRESS – METABOLISM AND TÁMOP-4.1.2-08/1/A-2009-0011 CR increases life-span 1.60 Proportionate increase in survival over control animals y = -0.0083x + 1.8321 r2 = 0.9593 P < 0.000 1.50 1.40 1.30 1.20 1.10 1.00 20 30 40 50 60 70 80 Energy intake relative to control animals (%) 90 100 TÁMOP-4.1.2-08/1/A-2009-0011 Lifespan increase due to CR Non-CR 100 25% CR 55% CR Survival (%) 75 65% CR 50 25 0 0 10 20 30 Age (months) 40 50 60 TÁMOP-4.1.2-08/1/A-2009-0011 CR extends life-span • Reducing food-consumption by 30-50% increases mean and maximum life-span • Opposes cancers, diabetes, renal disease, cardiovascular disease, neuronal diseases • Major mechanism of action: decrease in ROS production (reduced mitochondrial proton leak) TÁMOP-4.1.2-08/1/A-2009-0011 Sirtuin switch in ad libitum and CR mice Ad libitum Glucose Calorie restriction Glucose NAD/NADH Respiration NAD/NADH SIR2 AC Glycolysis Substrate PNC1 PNC1 NA NA SIR2 Substrate AC Glycolysis Substrate Substrate TÁMOP-4.1.2-08/1/A-2009-0011 CR extends life-span via: • Insulin / IGF1 signaling pathway • Sirtuin signaling pathway • Redox signaling pathway • TOR signaling pathway TÁMOP-4.1.2-08/1/A-2009-0011 Insulin / IGF signaling pathway • Subset of daf genes dramatically increase life-span • Main target is daf 16 that is highly homologous with Foxo • Insulin and growth-factor reduction shifts Foxo proteins to nucleus • CR induces 50% decrease in insulin plasma levels • CR induces 20% decrease in plasma IGF1 levels TÁMOP-4.1.2-08/1/A-2009-0011 Proof of GH / IGF signaling axis in aging • Snell and Ames mice (lack of GH, PRL, TSH) have increased life-span • GHRH, GHR, IGF1R deficient mice have increased life-span • p66shc (IGF1R substrate) deficient mice have increased life-span • Klotho (IGF1-repressor)-transgenic mice have increased life-span TÁMOP-4.1.2-08/1/A-2009-0011 The mechanism of action for sirtuins Mithocondrial bioge PGC-1α AC Oxidative capacity FOXO1 AC Fatty acid oxidation Sceletal muscle Glucose utilization PPARα Resveratr ol ? PGC-1α Liver PPARγ Fatty acid oxidation PGC-1α HNF-4α AC Glycolysis PGC-1α FOXO1 CR SIRT1 FOXO1 SIRT1 Gluconeogenesis AC AC N-CoR /SMRT Fat mobilization Adipogenesis PPARγ Fasting White Adipose Tissue ? FOXO1 AC FOXO1 AC Pancreatic β cell UCP2 Insulin secretion TÁMOP-4.1.2-08/1/A-2009-0011 Features of Sir2 family • Sir2 family proteins, called ‘sirtuins’ • Regulation of transciptional silencing • Silences telomeres, rDNA repeats • Component of RENT silencer at telomeres • Forms heterochromatin • ADP-ribosyl transferase activity • H4-specific deacetylase (NAD- TÁMOP-4.1.2-08/1/A-2009-0011 Sirtuins as regulators for aging • Highly conserved enzymatic core domain • Mediates life-extending effects of CR • Mammals have 7 sirtuins, Sirt 1-7 • Sirt1 shows highest homology with yeast Sir2 TÁMOP-4.1.2-08/1/A-2009-0011 Sirt1 as regulator for aging I • Pancreas: improves glucose tolerance and insulin sensitivity, represses Ucp2, deacetylates Foxo1 • Liver: promotes gluconeogenesys and inhibits glycolysis, deacetylates PGC-1a • Fat (WAT): interacts and represses PPARg, increases adiponectin secretion TÁMOP-4.1.2-08/1/A-2009-0011 Sirt1 as regulator for aging II • Muscle: regulates glucose uptake and insulin sensitivity, effect also achieved via resveratrol • Brain: beneficial in degenerative diseases like Alzheimer’s, Parkinson’s, Huntington TÁMOP-4.1.2-08/1/A-2009-0011 Sirt1 and stress resistance • Deacetylates p53, inhibits apoptosis, promotes cell survival • Deacetylates Foxo family members affecting DNA-damage repair, cell cycle arrest, apoptosis • Deacetylates NF-kB, a prosurvival tanscription factor (context dependent) TÁMOP-4.1.2-08/1/A-2009-0011 Sirt1 and CR • Several beneficial effects of CR effectuated through sirtuins • CR induces eNOS and NO, upregulating Sirt1 and mitochondrial biogenesis • Affects brain activity and indirectly physicial activity Properties of other mammalian sirtuins TÁMOP-4.1.2-08/1/A-2009-0011 • Sirt2: cytoplasmic, tumor supressor gene • Sirt3: mitochondrial, thermogenesis in BAT • Sirt4: mitochondrial, response to amino acids • Sirt5: mitochondrial, high in thymus, lymphoblasts • Sirt6: nuclear, DNA repair, genome stability TÁMOP-4.1.2-08/1/A-2009-0011 Redox signaling pathway • Changes in redox signaling may be more important than oxidative damage? • Redox sensitive trsncription factors include NF-kB, Nrf2, HIF1 • Thioredoxin and glutathione systems modulate redox status • Aging decreases GSH and thioredoxin levels • CR increases GSH and thioredoxin TÁMOP-4.1.2-08/1/A-2009-0011 TOR signaling pathway • TOR (target of rapamycin), evolutionarily highly conserved, regulates cell growth • Targeted deletions increase lifespan • Daf-16 dependent, requires Foxo • Reduction (Ames dwarf mouse) leads to decreased ROS production TÁMOP-4.1.2-08/1/A-2009-0011 Resveratrol increases lifespan Resveratrol Treated Group Percent Survivors 100 Untreated Group 10 0 1 2 3 4 Dose 5 6 TÁMOP-4.1.2-08/1/A-2009-0011 Resveratrol • Currently few pharmacological Sirt1 mimetics are known: resveratrol, qercetin, piceatannol • Natural source: red grapes / wine; cardio-protective, neuroprotective, cancer suppressing • Can efficiently mimick certain CRinduced positive effects despite high-fat diet TÁMOP-4.1.2-08/1/A-2009-0011 Resveratrol / paclitaxel combination in cancer Resveratro l Bax Bid Gene Expression Resveratrol tBid Paclitaxel Combined Bcl-xL Mitochondria Mcl-1 Cytc Apaf1 Survivin Paclitax el Smac/ Diablo Apoptosom e Caspase9 C-IAP-1 Caspase7 XIAP Caspase3 CHEMOSENSITIVE APOPTOSIS PARP TÁMOP-4.1.2-08/1/A-2009-0011 Mechanism of action for GH / IGF pathway Altered output of adipose tissue products reduces insulin resistance Reduced abdominal fat? Insulin resistance of skeletal muscles GH deficiency or GH resistance Reduced hepatic output of IGF-1 Primary effects of GH Primary effects of IG Secondary effects Increased brain IGF-1 Small size, late puberty, reduced reproduction, low insulin, reduced body temperature and increased resistance to oxidative stress Enhanced liver sensitivity to insulin Reduced size of islets and secretion of insulin Reduced metabolism and growth Reduced ROS production Delayed aging and long life Reduced oxidative damage TÁMOP-4.1.2-08/1/A-2009-0011 Environmental effects in expected life-span