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AGEING CAN BE DEFINED AS THE PROGRESSIVE LOSS OF FUNCTION ACCOMPANIED BY DECREASING FERTILITY AND INCREASING MORTALITY.

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Presentation on theme: "AGEING CAN BE DEFINED AS THE PROGRESSIVE LOSS OF FUNCTION ACCOMPANIED BY DECREASING FERTILITY AND INCREASING MORTALITY."— Presentation transcript:

1 AGEING CAN BE DEFINED AS THE PROGRESSIVE LOSS OF FUNCTION ACCOMPANIED BY DECREASING FERTILITY AND INCREASING MORTALITY

2 IN 1955 DENHAM HARTMAN ARTICULATED A FREE RADICAL THEORY OF AGING ENDOGENOUS OXYGEN RADICALS ARE GENERATED IN CELLS AND CAUSE ACCUMULATIVE DAMAGE AGING AND AGE-RELATED DISEASES

3 REACTIVE OXYGEN SPECIES ARE SHORT-LIVED TOXIC MOLECULES THAT REACT WITH MACROMOLECULES, INCLUDING DNA, PROTEINS AND LIPIDS AND DESTROY THEIR FUNCTION

4 REACTIVE OXYGEN SPECIES INCLUDE SUPEROXIDE, PEROXIDE AND HYDROXYL RADICALS

5 MAIN SOURCE OF REACTIVE OXYGEN SPECIES IS IN MITOCHONDRIA

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9 REACTIVE OXYGEN SPECIES IN MITOCHONDRIA ARE PRODUCED DURING THE PROCESS OF ELECTRON TRANSPORT

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11 SUPEROXIDE IS PRODUCED DURING THE REDUCTION THE REDOX-ACTIVE LIPID UBIQUINONE (UQ; CO- ENZYME Q)

12 UQ IS AN INTEGRAL PART OF THE ELECTRON TRANSPORT CHAIN (ETC) AND TRANSPORTS ELECTRONS FROM COMPLEXES I AND II TO COMPLEX III

13 UBIQUINONE CAN PROMOTE THE FORMATION OF SUPEROXIDE RADICALS ONCE GENERATED THE SUPEROXIDE RADICALS CAN BE DISMUTATED BY SUPEROXIDE DISMUTASE TO FORM HYDROGEN PEROXIDE HYDROGEN PEROXIDE IS THEN PROCESSED INTO WATER AND OXYGEN BY CATALASE AND GLUTATHIONE REDUCTASE

14 THE BURDEN OF ROS PRODUCTION IS COUNTERACTED BY AN ANTIOXIDANT DEFENCE SYSTEM, INCLUDING CATALASE AND GLUTATHIONE PEROXIDASE

15 REACTIVE OXYGEN SPECIES ARE ALSO PRODUCED IN THE CYTOPLASM BY PROCESSES THAT INCLUDE REDOX REACTIONS IN OTHER MEMBRANE- BOUND ORGANELLES, SUCH A PEROXISOMES AND THE ER

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17 AGEING CELLS AND ORGANISMS ACCUMULATE INCREAED LEVELS OF OXIDANT-DAMAGED NUCLEAR DNA

18 WHEN STRESS IS SEVERE CELLS MAY RESPOND EITHER BY REPAIR, GROWTH ARREST OR APOPTOSIS

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20 REDUCED ERK SIGNALING IN AGED CELLS LEADS TO APOPTOSIS INCREASED P53 ACTIVITY MAY LEAD TO EITHER APOPTOSIS OR G1 ARREST

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24 Decreased RAS-Erk MAP kinase signaling leads to growth arrest and rapid cell death by activating the expression of the HLH proteins Id2 and Id3

25 C. ELEGANS MUTATION ISP- 1 CARRIES A MUTATION IN A COMPONENT OF COMPLEX III LEADING TO A LARGE DECREASE IN ROS AND CONSEQUENTLY IN A LARGE INCREASE IN LIFE SPAN

26 SINGLE GENE MUTATIONS CAN EXPAND LIFE SPAN IN WORMS, FLIES AND MICE

27 DAF-2 MUTANTS LIVE TWICE AS LONG AS COMPARED TO WILD-TYPE WORMS

28 IN THESE MUTANTS THE FOLLOWING PROCESSES ARE AFFECTED: 1. RESISTANCE TO INFECTION 2. RESISTANCE OF THE CUTICLE TO ENVIRONMENTAL DAMAGE 3. INCREASED RESISTANCE TO MECHANICAL STRESS 4. RESISTANCE TO MUSCLE DEGRADATION 5. CLEARANCE OF DEGRADATION PRODUCTS

29 DAF2 ENCODES AN INSULIN-LIKE RECEPTOR TRANSMEMBRANE TYROSINE KINASE DAF2 MUTANTS ARE RESISTANT TO A VARIETY OF STRESSES OXIDATIVE, HEAT, ULTRAVIOLET AND HEAVY METAL STRESSES

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32 DAF-2 MEDIATED SIGNALING AFFECTS DAF-16 ACTIVITY DAF-16 IS A FOXO-FAMILY TRANSCRIPTION FACTOR THE ACTIVITY OF DAF-16 IS INHIBITED BY THE PI3K/AKT PATHWAY

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34 TWO CLASSES OF GENES ARE REGULATED BY DAF-16 CLASS I GENES ARE ACTIVATED BY DAF16 AND ARE ASSOCIATED WITH INCREASED LIFE SPAN CLASS II GENES ARE REPRESSED BY DAF16 AND ARE ASSOCIATED WITH DECREASED LIFE SPAN

35 189 CLASS I GENES ARE REGULATED BY DAF CLASS II GENES ARE CONTROLLED BY DAF16 ACTIVITY

36 GENES THAT REPAIR OXIDATIVE DAMAGE ARE INDUCED BY DAF16 CATALASE GLUTATHIONE-S- TRANSFERASE

37 USING RNAI THESE GENES WERE INACTIVATED AND DEMONSTRATED TO CAUSE A SHORTENED LIFE SPAN IN PART BY PREVENTING OXIDATIVE DAMAGE TO MACROMOLECULES

38 ANTIBACTERIAL LYSOZYME GENES WERE ALSO INDUCED IN DAF-2 MUTANTS RNAI TREATMENT OF THESE GENES SHORTENED LIFE SPAN

39 A SUBSET OF TARGET GENES CONTAIN DAF-16 BINDING SITES IN THE PROMOTER REGION INDICATING DIRECT REGULATION

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41 IN YEAST LIFE SPAN IS DETERMINED BY HOW MANY TIMES MOTHER CELLS DIVIDE TO GIVE RISE TO DAUGHTER CELLS

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43 MOTHER CELLS REACH SENESCENCE AFTER CELL DIVISIONS

44 IN YEAST LIFE SPAN IS INCREASED IN ORGANISMS THAT CARRY MUTATIONS IN THE SIR2 GENE

45 SIR2 ENCODES FOR A DEACETYLASE IN YEAST SIR 2 IS TARGETED TO THE RIBOSOMAL DNA REPEATS WHERE IT SILENCES GENE TRANSCRIPTION THIS SILENCING PROMOTES LONGEVITY BY REDUCING THE PRODUCTION OF EXTRACHROMOSOMAL rDNA CIRCLES

46 SIR2 IS A SENSOR FOR ENVIRONMENTAL CONDITIONS IT REQUIRES NAD+ AS A COFACTOR LINKING THE ACTIVITY OF SIR2 TO THE METABOLIC STATE OF THE CELL

47 DIETS LOW IN CALORIES, A REGIMEN CALLED CALORY RESTRICTION, PROMOTE A LONGER LIFE-SPAN SIR2 MAY SENSE CALORIE RESTRICTION THROUGH ALTERED LEVELS OF NAD+ SILENCING TRANSCRIPTION OF rDNA MAY LEAD TO EXTENDED LIFE SPAN

48 IT REMAINS TO BE DETERMINED WHETHER MAMMALIAN SIR2 HOMOLOGUES ALSO SENSE CALORIE RESTRICTION TO CONTROL GENETIC STABILITY AND AGING

49 IN WORMS SIR2 EXTENDS LIFE SPAN BY INHIBITING A INSULIN-LIKE HORMONE INDUCED SIGNALING PATHWAY

50 THE MAMMALIAN HOMOLOGUE OF DAF-2, THE IGF-1 RECEPTOR, ALSO REGULATES LIFE SPAN AND RESISTANCE TO OXIDATIVE STRESS

51 IN HUMANS AFTER PUBERTY THE THYMUS BEGINS TO DECREASE IN SIZE IN MICE THYMOCYTE CELL NUMBERS DECLINE ONE MONTH AFTER BIRTH

52 HOW IS THE DECREASE IN THYMUS SIZE REGULATED?

53 THE HLH PROTEINS ID2 AND ID3 ARE REGULATED BY INSULIN-LIKE GROWTH FACTOR

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55 ID2 LEVELS ARE MODULATED IN AGING THYMOCYTES DOES INSULIN-LIKE GROWTH FACTOR REGULATE THYMIC INVOLUTION?

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