Transcript Lecture notes for the aging lecture

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
REACTIVE OXYGEN SPECIES
INCLUDE SUPEROXIDE,
PEROXIDE AND HYDROXYL
RADICALS
MAIN SOURCE OF
REACTIVE OXYGEN SPECIES
IS IN MITOCHONDRIA
REACTIVE OXYGEN
SPECIES IN
MITOCHONDRIA ARE
PRODUCED DURING THE
PROCESS OF ELECTRON
TRANSPORT
SUPEROXIDE IS PRODUCED
DURING THE REDUCTION
THE REDOX-ACTIVE LIPID
UBIQUINONE (UQ; COENZYME Q)
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 MEMBRANEBOUND ORGANELLES,
SUCH A PEROXISOMES AND
THE ER
AGEING CELLS AND
ORGANISMS ACCUMULATE
INCREAED LEVELS OF
OXIDANT-DAMAGED
NUCLEAR DNA
WHEN STRESS IS SEVERE
CELLS MAY RESPOND
EITHER BY REPAIR,
GROWTH ARREST OR
APOPTOSIS
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 ISP1 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
SINGLE GENE MUTATIONS
CAN EXPAND LIFE SPAN IN
WORMS, FLIES AND MICE
DAF-2 MUTANTS LIVE
TWICE AS LONG AS
COMPARED TO WILD-TYPE
WORMS
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
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
189 CLASS I GENES ARE
REGULATED BY DAF16
122 CLASS II GENES ARE
CONTROLLED BY DAF16
ACTIVITY
GENES THAT REPAIR
OXIDATIVE DAMAGE ARE
INDUCED BY DAF16
CATALASE
GLUTATHIONE-STRANSFERASE
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
MOTHER CELLS REACH
SENESCENCE AFTER 20-30
CELL DIVISIONS
IN YEAST LIFE SPAN IS
INCREASED IN ORGANISMS
THAT CARRY MUTATIONS IN
THE SIR2 GENE
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
IN WORMS SIR2 EXTENDS
LIFE SPAN BY INHIBITING A
INSULIN-LIKE HORMONE
INDUCED SIGNALING
PATHWAY
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
HOW IS THE DECREASE IN
THYMUS SIZE REGULATED?
THE HLH PROTEINS ID2 AND
ID3 ARE REGULATED BY
INSULIN-LIKE GROWTH
FACTOR
ID2 LEVELS ARE MODULATED IN
AGING THYMOCYTES
DOES INSULIN-LIKE GROWTH FACTOR
REGULATE THYMIC INVOLUTION?