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Genetic background of longevity – Molecular mechanisms of intervention

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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Genetic background of longevity – Molecular mechanisms of intervention

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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 26 Geneticbackground of longevity – Molecularmechanismsofintervention

  3. Correlation between body mass and lifespan 1000 100 tmax (yrs) 10 y = 5.58x0.146 r2 = 0.340 1 1.E+10 1.E+08 1.E+06 1.E+04 1.E+02 1.E+00 M (g)

  4. Theory of antagonisticpleiotropy • Trade-offbetweenfertility and longevitygenes • Optimalconditions: investingrowth and reproduction • Restrictiveconditions: shutoffreproduction, investinsomaticmaintenance and survival

  5. The family tree of aging theories Aging theories Evolutionary theories of living and longevity Programmed theories Damage theories Beyond molecular biology of aging • Immune system compromise • Neurological degeneration • Hormonal theory of aging • The genetic clock(programmed epigenomic theory) • Programmed death theory • Mutation accumulation theory • The antagonistic pleiotropy theory • Thermodynamics of aging • Reliability theory • Rate of living theory General formulations Individual mechanisms Stress-induced premature senescence (SIPS) • Misrepair accumulation theory • Waste accumulation theory of aging • Error catastrophe theory • Wear and tear theory • Chronic or excess infammation • Mitochondrial damage • Methylation • Glycation • Oxidative damage-Free radical • Somatic DNA damage/mutation

  6. Centenarians • Morbidityrateincreasepeaksat 60y, deceleratesafter 80y, remainslinearafter 110y • Environmentaleffectsarestrong: centenarians’ spousesgain>15years over controls • Three major categories of extremelongevity: survivors, delayers, escapers • Averagelifespan: 30% genes, 40% environment, 30% pureluck

  7. Correlation ofmorbidity ratesand age 60 Sinusitis Asthma 50 Renal disease Arthritis 40 Diabetes 30 % with disease Cancer Cardiac disease 20 10 0 0 20 40 60 80 100 Age (years)

  8. Molecular balance of aging and life-span Intracellularaccumulation of random cellulardamage Anti-ageingfactors Pro-ageingfactors Caloricrestriction Insulin/IGF-1 signalling FoxO, FoxA, HSF-1, SKN TGF- βsignalling Cellulardegradativepathways JNK signalling Ageing process TOR signalling p53 Mitochondialrespiration Chemicalsubstances (e.g., resveratrol) Protein synthesis Sirtuins Temperature Lifespan

  9. Connection of metabolism and longevity Absent in Ames and Snell dwarfs GH GHR Absent in GHR-KO Klotho Reduced levels in Ames and Snell dwarfs and GHR-KO mice Reduced levels in Ames and Snell dwarfs and GHR-KO mice Insulin IGF-I IR IGF-IR IRSs Ligand-induced phosporylation is reduced by Klotho, ressembling findings in dwarf and GHR-KO mice AKT ? Extended longevity

  10. Molecular pathways of aging and life-span Glucose, aminoacids Growth factors Resveratrol AAT INS/IGF-1 PDK PI(3,4,5)P3 TGF-β AA PI3K Plasmamembrane SGK-1 PI(4,5)P2 AMPK/ AKK-2 TSC1/2 AKT/PKB Cellularenergy PTEN Rheb FoxO JNK LKB1 elF4E 4E-BP TOR ROS SKN-1 S6 S6K Protein turnover SKN-1 FoxOtarget Sir2/ Sirt1 14-3-3 Cellulartoxins (damagedproteins and organelles) Mithocondrion Autophagy FoxO HSF-1 p53 E2F-1 SMK-1 AGEING Nucleus FoxA/ PHA-4 Cytoplasm

  11. GenesinfluencinglongevityI • DNA stability and repairgenes • Poly(ADP-ribose) polymerase (PARP) activitydirectlycorrelateswithlife-span • XPF-ERCC1 endonuclease, progeriodmutations, secondary and tertiary DNA structures • Sirtuinsdeacetylatekeyproteinsincluding p53 and show directcorrelationwithmetabolism

  12. GenesinfluencinglongevityII • Defenseagainst ROS • p66Shc (SHC1) signal transduction of oxidative stress, deletions increase ROS resistance and life-span • Paraoxonase 1 (PON1) protects LDL from oxidative damage, key in atherosclerosis • Klotho (KL) b-glucuronidase, alleles influence coronary artery disease frequency • Superoxide dismutase (SOD) and catalase (CAT) increased activity increases life-span via ROS capture • Hemochromatosis gene (HFE) alleles influence ROS damage via the Fenton reaction

  13. GenesinfluencinglongevityIII • Mitochondrialgenes • Centenarians (9/11) possess SNP at position 5178 of NADH dehydrogenase subunit 2 gene (ND2) • Haplogroupcluster frequency differences, U, J, UK, WIX were frequent in aged; whereas H, HV were rare • 150T polymorphism accumulates in aged, though significantly influenced by SNPs 489C and 10398G

  14. Longevity genes across animal kingdom Animals with a mutation in theage-1 gene live longer than wild type wild type 1.0 age-1 0.8 0.6 Proportion Surviving 0.4 0.2 0 10 30 40 20 50 Age (day) *Known effect on aging

  15. Aging genes conserved in animal kingdom

  16. Genesaffectingage-relateddiseases • Apolipoprotein E, frequency of ApoE-e4 allele is verylowamongcentenarians • Cholesterolestertransferase protein, affects HDL and LDL particlesize • Apolipoprotein C, ApoC3 promoter CC polymorphismaccumulatesincentenarians • Microsomaltransfer protein (MTP) 493 G6T variant is rareinaged • Prolylisomerase (PIN1) protein foldingchaperonegeneticvariationsaffectAlzhemier’sfrequency

  17. SENS • ‘StrategiesforEngineeredNegligibleSenescence’ (Dr. Aubrey de Grey, Cambridge, UK) • Increasetheexpectedageatdeathforhealthy 55-year old from 85 to 115 yearsby 2030 • MimicnegligiblesenescenceobservedinHydra

  18. SENS: plannedinterventions • Interventiontooccuratthreelevels: metabolism, damage, pathology • Clearance of damaged IC and EC protein aggregates • Removal of senescent cells • Telomerase-incompetent stem-cell therapy • Escape mitochondrial mutations via shift to gDNA

  19. Limitations of SENS • Longest life documented: Jeanne Calment, 122y • Haveallquestionsbeenaddressed? • Agingis notclonal (notcancer), butmosaic • Gradualloss of genomeinstability is inevitable

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