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Molecular / cellular effects of acute and chronic stress – Metabolism and longevity Part II

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.

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Molecular / cellular effects of acute and chronic stress – Metabolism and longevity Part II

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat 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 / cellulareffects of acute and chronicstress –MetabolismandlongevityPart II

  3. CR increaseslife-span 1.60 y = -0.0083x + 1.8321 r2 = 0.9593 P < 0.000 1.50 1.40 Proportionate increase in survivalover control animals 1.30 1.20 1.10 1.00 20 30 40 50 60 70 80 90 100 Energy intake relative to control animals (%)

  4. Lifespan increase due to CR Non-CR 100 25% CR 55% CR 75 65% CR Survival(%) 50 25 0 0 10 20 30 40 50 60 Age(months)

  5. CR extends life-span • Reducingfood-consumptionby 30-50% increasesmean and maximum life-span • Opposescancers, diabetes, renaldisease, cardiovasculardisease, neuronaldiseases • Major mechanism of action: decreasein ROS production (reducedmitochondrial proton leak)

  6. Sirtuin switch inad libitum and CR mice Ad libitum Calorierestriction Glucose Glucose PNC1  NA  PNC1 NA Respiration  NAD/NADH NAD/NADH  SIR2 SIR2 Substrate Substrate Substrate Substrate AC AC Glycolysis Glycolysis

  7. CR extends life-span via: • Insulin / IGF1 signalingpathway • Sirtuinsignalingpathway • Redoxsignalingpathway • TOR signalingpathway

  8. Insulin / IGF signaling pathway • Subset of dafgenesdramaticallyincreaselife-span • Main target is daf 16 that is highlyhomologouswithFoxo • Insulin and growth-factorreductionshiftsFoxoproteinstonucleus • CR induces 50% decreaseininsulinplasmalevels • CR induces 20% decreaseinplasma IGF1 levels

  9. Proof of GH / IGF signaling axis in aging • Snell and Amesmice (lack of GH, PRL, TSH) haveincreasedlife-span • GHRH, GHR, IGF1R deficientmicehaveincreasedlife-span • p66shc (IGF1R substrate) deficientmicehaveincreasedlife-span • Klotho (IGF1-repressor)-transgenicmicehaveincreasedlife-span

  10. The mechanism of action for sirtuins Mithocondrial biogenesis  Oxidative capacity Fatty acid oxidation  Glucose utilization PGC-1α AC FOXO1 AC Sceletal muscle PPARα Fatty acid oxidation Resveratrol ? PGC-1α HNF-4α AC Gluconeogenesis Glycolysis PGC-1α PGC-1α PPARγ Liver FOXO1 AC SIRT1 CR FOXO1 AC N-CoR /SMRT  Fat mobilization Adipogenesis SIRT1 PPARγ ? Fasting White Adipose Tissue FOXO1 AC FOXO1  Insulin secretion UCP2  AC Pancreatic β cell

  11. Features of Sir2 family • Sir2 familyproteins, called ‘sirtuins’ • Regulation of transciptionalsilencing • Silencestelomeres, rDNArepeats • Component of RENT silencerattelomeres • Formsheterochromatin • ADP-ribosyltransferaseactivity • H4-specific deacetylase (NAD-dependent) • Energysensor, linksmetabolism and aging

  12. Sirtuins as regulators for aging • Highlyconservedenzymaticcoredomain • Mediateslife-extendingeffects of CR • Mammalshave 7 sirtuins, Sirt 1-7 • Sirt1 showshighesthomologywithyeast Sir2

  13. Sirt1 as regulator for aging I • Pancreas: improvesglucosetolerance and insulinsensitivity, represses Ucp2, deacetylates Foxo1 • Liver: promotesgluconeogenesys and inhibitsglycolysis, deacetylates PGC-1a • Fat(WAT): interacts and repressesPPARg, increasesadiponectinsecretion

  14. Sirt1 as regulator for aging II • Muscle: regulatesglucoseuptake and insulinsensitivity, effectalsoachievedviaresveratrol • Brain: beneficialindegenerativediseaseslikeAlzheimer’s, Parkinson’s, Huntington

  15. Sirt1 and stress resistance • Deacetylates p53, inhibitsapoptosis, promotescellsurvival • DeacetylatesFoxofamilymembersaffectingDNA-damagerepair, cellcyclearrest, apoptosis • DeacetylatesNF-kB, a prosurvivaltanscriptionfactor (contextdependent)

  16. Sirt1 and CR • Severalbeneficialeffects of CR effectuatedthroughsirtuins • CR induceseNOS and NO, upregulating Sirt1 and mitochondrialbiogenesis • Affectsbrainactivity and indirectlyphysicialactivity

  17. Propertiesof other mammalian sirtuins • Sirt2: cytoplasmic, tumor supressorgene • Sirt3: mitochondrial, thermogenesisin BAT • Sirt4: mitochondrial, responsetoaminoacids • Sirt5: mitochondrial, highinthymus, lymphoblasts • Sirt6: nuclear, DNA repair, genomestability • Sirt7: nucleolar, lacksenzymaticactivity

  18. Redox signaling pathway • Changesinredoxsignalingmay be more importantthanoxidativedamage? • RedoxsensitivetrsncriptionfactorsincludeNF-kB, Nrf2, HIF1 • Thioredoxin and glutathionesystemsmodulateredox status • Agingdecreases GSH and thioredoxinlevels • CR increases GSH and thioredoxinlevels

  19. TOR signaling pathway • TOR (target of rapamycin), evolutionarilyhighlyconserved, regulatescellgrowth • Targeteddeletionsincreaselife-span • Daf-16 dependent, requiresFoxo • Reduction(Amesdwarfmouse) leadstodecreased ROS production

  20. Resveratrol increases life-span Resveratrol Treated Group 100 Percent Survivors Untreated Group 10 0 1 2 3 4 5 6 Dose

  21. Resveratrol • Currently few pharmacological Sirt1 mimetics are known: resveratrol, qercetin, piceatannol • Natural source: red grapes / wine; cardio-protective, neuro-protective, cancer suppressing • Can efficiently mimick certain CR-induced positive effects despite high-fat diet

  22. Resveratrol / paclitaxel combination in cancer Resveratrol GeneExpression Resveratrol Bax Bid tBid Paclitaxel Combined Bcl-xL Mitochondria Paclitaxel Mcl-1 Smac/ Diablo  Cytc Apaf-1 Apoptosome Caspase-9 Survivin Caspase-7 C-IAP-1 PARP CHEMOSENSITIVE APOPTOSIS Caspase-3 XIAP

  23. Mechanism of action forGH / IGF pathway Altered output of adipose tissue products reduces insulin resistance Reduced abdominal fat? Insulin resistance of skeletal muscles Increased brain IGF-1 Reduced hepatic output of IGF-1 Small size, late puberty, reduced reproduction, low insulin, reduced body temperature and increased resistance to oxidative stress Delayed aging and long life Primary effects of IGF-1 GH deficiency or GH resistance Secondary effects Primary effects of GH Enhanced liver sensitivity to insulin Reduced oxidative damage Reduced size of islets and secretion of insulin Reduced metabolism and growth Reduced ROS production

  24. Environmental effects in expected life-span

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