molecular / cellular effects of acute and chronic stress – metabolism and longevity part ii
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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 of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011. - PowerPoint PPT PresentationTRANSCRIPT
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Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
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MOLECULAR / CELLULAR EFFECTS OF ACUTE AND CHRONIC STRESS –METABOLISM AND LONGEVITY PART II
Krisztián KvellMolecular and Clinical Basics of Gerontology – Lecture 24
Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
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TÁMOP-4.1.2-08/1/A-2009-0011
Energy intake relative to control animals (%)
1.00
1.10
1.20
1.30
1.40
1.50
1.60
20 30 40 50 60 70 80 90 100
y = -0.0083x + 1.8321r2 = 0.9593P < 0.000
Prop
ortio
nate
incr
ease
in su
rviv
alov
er c
ontro
l ani
mal
sCR increases life-span
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TÁMOP-4.1.2-08/1/A-2009-0011
Non-CR
65% CR55% CR25% CR
Surv
ival
(%)
Age (months)0 10 20 30 40 50 60
25
75
100
0
50
Lifespan increase due to CR
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TÁMOP-4.1.2-08/1/A-2009-0011
• Reducing food-consumption by 30-50% increases mean and maximum life-span
• Opposes cancers, diabetes, renal disease, cardiovascular disease, neuronal diseases
• Major mechanism of action: decrease in ROS production (reduced mitochondrial proton leak)
CR extends life-span
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Ad libitum
NAD/NADH
AC Substrate Substrate
PNC1NA
SIR2
Glucose
Glycolysis
Calorie restriction
NAD/NADH
Respiration
AC Substrate Substrate
PNC1 NA
SIR2
Glucose
Glycolysis
Sirtuin switch inad libitum and CR mice
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• Insulin / IGF1 signaling pathway• Sirtuin signaling pathway• Redox signaling pathway• TOR signaling pathway
CR extends life-span via:
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• Subset of daf genes dramatically increase life-span
• Main target is daf 16 that is highly homologous with Foxo
• Insulin and growth-factor reduction shifts Foxo proteins to nucleus
• CR induces 50% decrease in insulin plasma levels
• CR induces 20% decrease in plasma IGF1 levels
Insulin / IGF signaling pathway
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• Snell and Ames mice (lack of GH, PRL, TSH) have increased life-span
• GHRH, GHR, IGF1R deficient mice have increased life-span
• p66shc (IGF1R substrate) deficient mice have increased life-span
• Klotho (IGF1-repressor)-transgenic mice have increased life-span
Proof of GH / IGF signaling axis in aging
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Liver
White AdiposeTissue
Pancreatic β cell
Resveratrol
Fasting
CR SIRT1
Insulin secretion
Mithocondrial biogenesis Oxidative capacityFatty acid oxidation Glucose utilization
Fat mobilization Adipogenesis
Sceletal muscle
SIRT1 N-CoR/SMRT
PPARγ
FOXO1 AC
FOXO1 AC
PGC-1α ACFOXO1 AC
?
The mechanism of action for sirtuins
UCP2
GluconeogenesisGlycolysis
Fatty acid oxidationPPARα
PPARγPGC-1α HNF-4α
PGC-1αAC
FOXO1PGC-1α
AC
FOXO1 AC
?
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TÁMOP-4.1.2-08/1/A-2009-0011
• Sir2 family proteins, called ‘sirtuins’• Regulation of transciptional silencing• Silences telomeres, rDNA repeats• Component of RENT silencer at telomeres• Forms heterochromatin• ADP-ribosyl transferase activity• H4-specific deacetylase (NAD-dependent)• Energy sensor, links metabolism and aging
Features of Sir2 family
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TÁMOP-4.1.2-08/1/A-2009-0011
• Highly conserved enzymatic core domain • Mediates life-extending effects of CR• Mammals have 7 sirtuins, Sirt 1-7• Sirt1 shows highest homology with yeast
Sir2
Sirtuins as regulators for aging
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• Pancreas: improves glucose tolerance and insulin sensitivity, represses Ucp2, deacetylates Foxo1
• Liver: promotes gluconeogenesys and inhibits glycolysis, deacetylates PGC-1a
• Fat (WAT): interacts and represses PPARg, increases adiponectin secretion
Sirt1 as regulator for aging I
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• Muscle: regulates glucose uptake and insulin sensitivity, effect also achieved via resveratrol
• Brain: beneficial in degenerative diseases like Alzheimer’s, Parkinson’s, Huntington
Sirt1 as regulator for aging II
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• Deacetylates p53, inhibits apoptosis, promotes cell survival
• Deacetylates Foxo family members affecting DNA-damage repair, cell cycle arrest, apoptosis
• Deacetylates NF-kB, a prosurvival tanscription factor (context dependent)
Sirt1 and stress resistance
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• Several beneficial effects of CR effectuated through sirtuins
• CR induces eNOS and NO, upregulating Sirt1 and mitochondrial biogenesis
• Affects brain activity and indirectly physicial activity
Sirt1 and CR
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TÁMOP-4.1.2-08/1/A-2009-0011
• Sirt2: cytoplasmic, tumor supressor gene• Sirt3: mitochondrial, thermogenesis in BAT• Sirt4: mitochondrial, response to amino acids• Sirt5: mitochondrial, high in thymus,
lymphoblasts• Sirt6: nuclear, DNA repair, genome stability• Sirt7: nucleolar, lacks enzymatic activity
Properties of other mammalian sirtuins
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TÁMOP-4.1.2-08/1/A-2009-0011
• Changes in redox signaling may be more important than oxidative damage?
• Redox sensitive trsncription factors include NF-kB, Nrf2, HIF1
• Thioredoxin and glutathione systems modulate redox status
• Aging decreases GSH and thioredoxin levels
• CR increases GSH and thioredoxin levels
Redox signaling pathway
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TÁMOP-4.1.2-08/1/A-2009-0011
• TOR (target of rapamycin), evolutionarily highly conserved, regulates cell growth
• Targeted deletions increase life-span• Daf-16 dependent, requires Foxo• Reduction (Ames dwarf mouse) leads to
decreased ROS production
TOR signaling pathway
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Resveratrol Treated Group
Untreated Group
Dose
Perc
ent S
urvi
vors
0 1 2 3 4 5 6
10
100
Resveratrol increases life-span
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• Currently few pharmacological Sirt1 mimetics are known: resveratrol, qercetin, piceatannol
• Natural source: red grapes / wine; cardio-protective, neuro-protective, cancer suppressing
• Can efficiently mimick certain CR-induced positive effects despite high-fat diet
Resveratrol
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CHEMOSENSITIVEAPOPTOSIS
Caspase-9
Caspase-3
Resveratrol
Paclitaxel
Caspase-7
Apoptosome
Resveratrol
Paclitaxel
Combined
Gene Expression
Cytc
Bid tBid
Smac/ Diablo
PARP
Bax
Bcl-xL
Mcl-1
Apaf-1
Survivin
C-IAP-1
XIAP
Mitochondria
Resveratrol / paclitaxel combination in cancer
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TÁMOP-4.1.2-08/1/A-2009-0011
GH deficiencyor
GH resistance
Reducedhepatic
output ofIGF-1
Reduced sizeof islets and
secretionof insulin
Reduced metabolism and growthReduced ROS production
Enhanced liversensitivity to
insulin
Altered output of adiposetissue products reduces
insulin resistanceReduced abdominal fat?
IncreasedbrainIGF-1
Small size, late puberty,reduced reproduction, low insulin,
reduced body temperature and increased resistance to oxidative stress
Reduced oxidative damage
Delayedagingand
long life
Insulinresistance of
skeletal muscles
Primary effects of IGF-1Secondary effects
Primary effects of GH
Mechanism of action forGH / IGF pathway
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Environmental effects in expected life-span