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

GENETIC BACKGROUND OF LONGEVITY – MOLECULAR MECHANISMS OF INTERVENTION

Krisztián KvellMolecular and Clinical Basics of Gerontology – Lecture 26

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

TÁMOP-4.1.2-08/1/A-2009-0011

y = 5.58x0.146

r2 = 0.340

t max

(yrs

)

1000

100

10

11.E+00 1.E+02 1.E+04 1.E+06 1.E+08 1.E+10

M (g)

Correlation between body mass and lifespan

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• Trade-off between fertility and longevity genes

• Optimal conditions: invest in growth and reproduction

• Restrictive conditions: shut off reproduction, invest in somatic maintenance and survival

Theory of antagonistic pleiotropy

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The family tree of aging theories

Stress-induced premature senescence

(SIPS)

Damage theories

Aging theories

Evolutionary theories of living and longevity• Programmed death theory•Mutation accumulation theory• The antagonistic pleiotropy theory

Programmed theories• Immune system compromise• Neurological degeneration• Hormonal theory of aging• The genetic clock (programmed epigenomic theory)

Beyond molecular biology of aging

• Thermodynamics of aging• Reliability theory• Rate of living theory

General formulations•Misrepair accumulation theory•Waste accumulation theory of aging• Error catastrophe theory•Wear and tear theory

Individual mechanisms• Chronic or excess infammation•Mitochondrial damage•Methylation• Glycation• Oxidative damage-Free radical• Somatic DNA damage/mutation

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• Morbidity rate increase peaks at 60y, decelerates after 80y, remains linear after 110y

• Environmental effects are strong: centenarians’ spouses gain >15years over controls

• Three major categories of extreme longevity: survivors, delayers, escapers

• Average lifespan: 30% genes, 40% environment, 30% pure luck

Centenarians

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AsthmaRenal disease

Diabetes

Cardiac disease

Arthritis

Cancer

Correlation ofmorbidity rates and age

0 20 40 60 80 100

10

30

50

0

20

40

60

% w

ith d

iseas

e

Age (years)

Sinusitis

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Cellular degradative pathways

FoxO, FoxA, HSF-1, SKN

Caloric restriction

p53Chemical substances

(e.g., resveratrol)

Insulin/IGF-1 signalling

TGF- β signalling

JNK signalling

TOR signallingMitochondial respiration

Protein synthesis

Temperature

Anti-ageing factors Pro-ageing factors

Ageingprocess

Intracellular accumulation of random cellular

damage

LifespanSirtuins

Molecular balance of aging and life-span

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Absent in Ames andSnell dwarfs

Absent in GHR-KO

Reduced levels in Ames and Snell

dwarfs and GHR-KO mice

Ligand-induced phosporylation is reduced

by Klotho, ressembling findings in dwarf and

GHR-KO mice

GH

GHR

IGF-I

IGF-IR

Insulin

IR

IRSs

Extended longevity

AKT

Reduced levels in Ames and Snell

dwarfs and GHR-KO mice

?

Klotho

Connection of metabolism and longevity

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ROS

PI3K

PTEN

PDK

JNKFoxO

FoxO

SKN-1

Rheb

FoxO target

SGK-1

AKT/PKBTSC1/2AMPK/AKK-2

LKB1 TOR4E-BPelF4E

S6KS6

Sir2/Sirt1

SKN-1

14-3-3

E2F-1 HSF-1SMK-1

FoxA/PHA-4

Autophagy

AGEING Nucleus

Mithocondrion Cellular toxins(damaged proteins

and organelles)

Proteinturnover

Cellular energy

AAT

AA

Cytoplasm

Plasma membrane

Glucose, amino acids Growth factors

TGF-β

INS/IGF-1

PI(3,4,5)P3

PI(4,5)P2

Resveratrol

p53

Molecular pathways of aging and life-span

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• DNA stability and repair genes- Poly(ADP-ribose) polymerase (PARP) activity

directly correlates with life-span- XPF-ERCC1 endonuclease, progeriod

mutations, secondary and tertiary DNA structures

- Sirtuins deacetylate key proteins including p53 and show direct correlation with metabolism

Genes influencing longevity I

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• Defense against ROS- p66Shc (SHC1) signal transduction of oxidative

stress, deletions increase ROS resistance and life-span

- Paraoxonase 1 (PON1) protects LDL from oxidative damage, key in atherosclerosis

- Klotho (KL) b-glucuronidase, alleles influence coronary artery disease frequency

- Superoxide dismutase (SOD) and catalase (CAT) increased activity increases life-span via ROS capture

- Hemochromatosis gene (HFE) alleles influence ROS damage via the Fenton reaction

Genes influencing longevity II

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• Mitochondrial genes- Centenarians (9/11) possess SNP at position

5178 of NADH dehydrogenase subunit 2 gene (ND2)

- Haplogroup cluster frequency differences, U, J, UK, WIX were frequent in aged; whereas H, HV were rare

- 150T polymorphism accumulates in aged, though significantly influenced by SNPs 489C and 10398G

Genes influencing longevity III

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Nematode Humancatalase catalase

age-1Pl3-kinase(glucose

metabolism)

daf-2Insulin-like receptor(glucose

metabolism)

daf-16HNF3

(transcription factor)

WRNWRN

(Werner Syndrome)*Known effect on aging

1.00.80.60.40.2

0

Animals with a mutation in theage-1 gene live longer than wild

type

Prop

ortio

n Su

rviv

ing

Age (day)10 20 30 40 50

wild typeage-1

Longevity genes across animal kingdom

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Worm gene Yeast gene Human ortholog(s)

spg-7 AFG3 AFG3L2F43G9.1a IDH2 IDH3Aunc-26 INP53 SYNJ1, SYNJ2rpl-1 9 RPL19A RPL1 9rpl-6 RPL6B RPL6rpl-9 RPL9A RPL9spt-4 SPT4 SUPT4H1inf-1a TIF1 EIF4A2, EIF4A1inf-1a TIF2 EIF4A2, EIF4A1inf-1 TIF4631 EIF4G1, EIF4G3

let-36a TOR1 FRAP1W09H1.5 ADH1 –T27F7.3 ALG12 –

Worm gene Yeast gene Human ortholog(s)

B0511.6a DBP3 –sem-5 HSE1 –

F43G9.1 IDH1 –unc-26 INP51 SYNJ1, SYNJ2pdk-1 PKH2 PDPK1eat-6 PMR1 –

C06E7.1a SAM1 MAT1A, MAT2Arsks-1a SCH9b RPS6KB1, SGK2

Y46H3C.6 SIS2 –pos-1 TIS11 –erm-1 YGR1 30C –rab-10 YPT6 –

Aging genes conserved in animal kingdom

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• Apolipoprotein E, frequency of ApoE-e4 allele is very low among centenarians

• Cholesterol ester transferase protein, affects HDL and LDL particle size

• Apolipoprotein C, ApoC3 promoter CC polymorphism accumulates in centenarians

• Microsomal transfer protein (MTP) 493 G6T variant is rare in aged

• Prolyl isomerase (PIN1) protein folding chaperone genetic variations affect Alzhemier’s frequency

Genes affecting age-related diseases

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• ‘Strategies for Engineered Negligible Senescence’ (Dr. Aubrey de Grey, Cambridge, UK)

• Increase the expected age at death for healthy 55-year old from 85 to 115 years by 2030

• Mimic negligible senescence observed in Hydra

SENS

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• Intervention to occur at three levels: metabolism, damage, pathology- Clearance of damaged IC and EC protein

aggregates- Removal of senescent cells- Telomerase-incompetent stem-cell therapy- Escape mitochondrial mutations via shift to

gDNA

SENS: planned interventions

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• Longest life documented: Jeanne Calment, 122y

• Have all questions been addressed?• Aging is not clonal (not cancer), but mosaic• Gradual loss of genome instability is

inevitable

Limitations of SENS