AGEING CAN BE DEFINED AS THE PROGRESSIVE LOSS OF FUNCTION ACCOMPANIED BY DECREASING FERTILITY AND...
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Transcript of AGEING CAN BE DEFINED AS THE PROGRESSIVE LOSS OF FUNCTION ACCOMPANIED BY DECREASING FERTILITY AND...
AGEING CAN BE DEFINED AS THE PROGRESSIVE LOSS
OF FUNCTION ACCOMPANIED BY
DECREASING FERTILITY AND INCREASING
MORTALITY
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
REACTIVE OXYGEN SPECIES ARE SHORT-LIVED TOXIC MOLECULES THAT
REACT WITH MACROMOLECULES,
INCLUDING DNA, PROTEINS AND LIPIDS AND
DESTROY THEIR FUNCTION
UQ IS AN INTEGRAL PART OF THE ELECTRON
TRANSPORT CHAIN (ETC) AND TRANSPORTS ELECTRONS FROM
COMPLEXES I AND II TO COMPLEX III
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
THE BURDEN OF ROS PRODUCTION IS
COUNTERACTED BY AN ANTIOXIDANT DEFENCE
SYSTEM, INCLUDING CATALASE AND GLUTATHIONE PEROXIDASE
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
REDUCED ERK SIGNALING IN AGED CELLS LEADS TO
APOPTOSIS
INCREASED P53 ACTIVITY MAY LEAD TO EITHER
APOPTOSIS OR G1 ARREST
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
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
IN THESE MUTANTS THE FOLLOWING PROCESSES ARE
AFFECTED:1. RESISTANCE TO INFECTION
2. RESISTANCE OF THE CUTICLE TO ENVIRONMENTAL DAMAGE3. INCREASED RESISTANCE TO
MECHANICAL STRESS4. RESISTANCE TO MUSCLE
DEGRADATION5. CLEARANCE OF DEGRADATION
PRODUCTS
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
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
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
USING RNAI THESE GENES WERE INACTIVATED AND
DEMONSTRATED TO CAUSE A SHORTENED LIFE SPAN
IN PART BY PREVENTING OXIDATIVE DAMAGE TO
MACROMOLECULES
ANTIBACTERIAL LYSOZYME GENES WERE ALSO INDUCED IN DAF-2
MUTANTS
RNAI TREATMENT OF THESE GENES SHORTENED
LIFE SPAN
A SUBSET OF TARGET GENES CONTAIN DAF-16 BINDING SITES IN THE
PROMOTER REGION INDICATING DIRECT
REGULATION
IN YEAST LIFE SPAN IS DETERMINED BY HOW MANY TIMES MOTHER
CELLS DIVIDE TO GIVE RISE TO DAUGHTER CELLS
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
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
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
IT REMAINS TO BE DETERMINED WHETHER
MAMMALIAN SIR2 HOMOLOGUES ALSO SENSE CALORIE RESTRICTION TO
CONTROL GENETIC STABILITY AND AGING
THE MAMMALIAN HOMOLOGUE OF DAF-2, THE
IGF-1 RECEPTOR, ALSO REGULATES LIFE SPAN AND RESISTANCE TO OXIDATIVE
STRESS
IN HUMANS AFTER PUBERTY THE THYMUS
BEGINS TO DECREASE IN SIZE
IN MICE THYMOCYTE CELL NUMBERS DECLINE ONE
MONTH AFTER BIRTH
ID2 LEVELS ARE MODULATED IN AGING THYMOCYTES
DOES INSULIN-LIKE GROWTH FACTOR REGULATE THYMIC INVOLUTION?