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; CO-ENZYME 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 MEMBRANE-

BOUND 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 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

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 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

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-S-TRANSFERASE

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?