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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University.

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Presentation on theme: "Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University."— Presentation transcript:

1 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

2 GENETIC BACKGROUND OF LONGEVITY – MOLECULAR MECHANISMS OF INTERVENTION Krisztián Kvell Molecular and Clinical Basics of Gerontology – Lecture 26 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

3 TÁMOP-4.1.2-08/1/A-2009-0011 y = 5.58x 0.146 r 2 = 0.340 t max (yrs) 1000 100 10 1 1.E+00 1.E+02 1.E+04 1.E+06 1.E+08 1.E+10 M (g) Correlation between body mass and lifespan

4 TÁMOP-4.1.2-08/1/A-2009-0011 Trade-off between fertility and longevity genes Optimal conditions: invest in growth and reproduction Restrictive conditions: shut off reproduction, invest in somatic maintenance and survival Theory of antagonistic pleiotropy

5 TÁMOP-4.1.2-08/1/A-2009-0011 The family tree of aging theories Stress-induced premature senescence (SIPS) Damage theories Aging theories Evolutionary theories of living and longevity Programmed death theory Mutation accumulation theory The antagonistic pleiotropy theory Programmed death theory Mutation accumulation theory The antagonistic pleiotropy theory Programmed theories Immune system compromise Neurological degeneration Hormonal theory of aging The genetic clock (programmed epigenomic theory) Immune system compromise Neurological degeneration Hormonal theory of aging The genetic clock (programmed epigenomic theory) Beyond molecular biology of aging Thermodynamics of aging Reliability theory Rate of living theory Thermodynamics of aging Reliability theory Rate of living theory General formulations Misrepair accumulation theory Waste accumulation theory of aging Error catastrophe theory Wear and tear theory Misrepair accumulation theory Waste accumulation theory of aging Error catastrophe theory Wear and tear theory Individual mechanisms Chronic or excess infammation Mitochondrial damage Methylation Glycation Oxidative damage- Free radical Somatic DNA damage/mutation Chronic or excess infammation Mitochondrial damage Methylation Glycation Oxidative damage- Free radical Somatic DNA damage/mutation

6 TÁMOP-4.1.2-08/1/A-2009-0011 Morbidity rate increase peaks at 60y, decelerates after 80y, remains linear after 110y Environmental effects are strong: centenarians’ spouses gain >15years over controls Three major categories of extreme longevity: survivors, delayers, escapers Average lifespan: 30% genes, 40% environment, 30% pure luck Centenarians

7 TÁMOP-4.1.2-08/1/A-2009-0011Asthma Renal disease Diabetes Cardiac disease Arthritis Cancer Correlation of morbidity rates and age 0 20406080100 10 30 50 0 20 40 60 % with disease Age (years) Sinusitis

8 TÁMOP-4.1.2-08/1/A-2009-0011 Cellular degradative pathways FoxO, FoxA, HSF-1, SKN Caloric restriction p53 Chemical substances (e.g., resveratrol) Chemical substances (e.g., resveratrol) Insulin/IGF-1 signalling TGF- β signalling JNK signalling TOR signalling Mitochondial respiration Protein synthesis Temperature Anti-ageing factors Pro-ageing factors AgeingprocessAgeingprocess Intracellular accumulation of random cellular damage LifespanLifespan Sirtuins Molecular balance of aging and life-span

9 TÁMOP-4.1.2-08/1/A-2009-0011 Absent in Ames and Snell dwarfs Absent in GHR-KO Reduced levels in Ames and Snell dwarfs and GHR-KO mice Ligand-induced phosporylation is reduced by Klotho, ressembling findings in dwarf and GHR-KO mice GH GHR IGF-I IGF-IR Insulin IR IRSs Extended longevity AKT Reduced levels in Ames and Snell dwarfs and GHR-KO mice ? Klotho Connection of metabolism and longevity

10 TÁMOP-4.1.2-08/1/A-2009-0011 ROS PI3K PTEN PDK JNK FoxO SKN-1 Rheb FoxO targe t SGK- 1 AKT/PKB TSC1/2 AMPK/ AKK-2 AMPK/ AKK-2 LKB1 TOR 4E-BP elF4 E S6K S6 14- 3-3 E2F- 1 HSF- 1 SMK-1 FoxA/ PHA-4 FoxA/ PHA-4 Autophagy AGEINGAGEING Nucleus Mithocondrion Cellular toxins (damaged proteins and organelles) Cellular toxins (damaged proteins and organelles) Protein turnover Protein turnover Cellular energy AAT AA Cytoplasm Plasma membrane Glucose, amino acidsGrowth factors TGF-β INS/IGF-1 PI(3,4,5)P 3 PI(4,5)P 2 Resveratrol p53 Molecular pathways of aging and life-span

11 TÁMOP-4.1.2-08/1/A-2009-0011 DNA stability and repair genes -Poly(ADP-ribose) polymerase (PARP) activity directly correlates with life-span -XPF-ERCC1 endonuclease, progeriod mutations, secondary and tertiary DNA structures -Sirtuins deacetylate key proteins including p53 and show direct correlation with metabolism I Genes influencing longevity I

12 TÁMOP-4.1.2-08/1/A-2009-0011 Defense against 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 II Genes influencing longevity II

13 TÁMOP-4.1.2-08/1/A-2009-0011 Mitochondrial genes -Centenarians (9/11) possess SNP at position 5178 of NADH dehydrogenase subunit 2 gene (ND2) -Haplogroup cluster 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 III Genes influencing longevity III

14 TÁMOP-4.1.2-08/1/A-2009-0011NematodeHuman catalase age-1 Pl 3 -kinase (glucose metabolism) daf-2 Insulin-like receptor (glucose metabolism) daf-16 HNF3 (transcription factor) WRN WRN (Werner Syndrome) *Known effect on aging 1.0 0.8 0.6 0.4 0.2 0 Animals with a mutation in the age-1 gene live longer than wild type Proportion Surviving Age (day) 10 20 30 40 50 wild type age-1 Longevity genes across animal kingdom

15 TÁMOP-4.1.2-08/1/A-2009-0011 Worm gene Yeast gene Human ortholog(s) spg-7AFG3AFG3L2 F43G9.1 a IDH2IDH3A unc-26INP53SYNJ1, SYNJ2 rpl-1 9RPL19ARPL1 9 rpl-6RPL6BRPL6 rpl-9RPL9ARPL9 spt-4SPT4SUPT4H1 inf-1 a TIF1 EIF4A2, EIF4A1 inf-1 a TIF2 EIF4A2, EIF4A1 inf-1TIF4631 EIF4G1, EIF4G3 let-36 a TOR1FRAP1 W09H1.5ADH1– T27F7.3ALG12– Worm gene Yeast gene Human ortholog(s) B0511.6 a DBP3– sem-5HSE1– F43G9.1IDH1– unc-26INP51SYNJ1, SYNJ2 pdk-1PKH2PDPK1 eat-6PMR1– C06E7.1 a SAM1MAT1A, MAT2A rsks-1 a SCH9 b RPS6KB1, SGK2 Y46H3C.6SIS2– pos-1TIS11– erm-1YGR1 30C– rab-10YPT6– Aging genes conserved in animal kingdom

16 TÁMOP-4.1.2-08/1/A-2009-0011 Apolipoprotein E, frequency of ApoE-e4 allele is very low among centenarians Cholesterol ester transferase protein, affects HDL and LDL particle size Apolipoprotein C, ApoC3 promoter CC polymorphism accumulates in centenarians Microsomal transfer protein (MTP) 493 G6T variant is rare in aged Prolyl isomerase (PIN1) protein folding chaperone genetic variations affect Alzhemier’s frequency Genes affecting age-related diseases

17 TÁMOP-4.1.2-08/1/A-2009-0011 SEN S‘Strategies for Engineered Negligible Senescence’ (Dr. Aubrey de Grey, Cambridge, UK) Increase the expected age at death for healthy 55-year old from 85 to 115 years by 2030 Mimic negligible senescence observed in Hydra SENS

18 TÁMOP-4.1.2-08/1/A-2009-0011 Intervention to occur at three levels: 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 SENS: planned interventions

19 TÁMOP-4.1.2-08/1/A-2009-0011 Longest life documented: Jeanne Calment, 122y Have all questions been addressed? Aging is not clonal (not cancer), but mosaic Gradual loss of genome instability is inevitable Limitations of SENS


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