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

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

GENETIC

BACKGROUND OF LONGEVITY –

MOLECULAR

MECHANISMS OF INTERVENTION

Krisztián Kvell

Molecular and Clinical Basics of Gerontology – Lecture 26

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

y = 5.58x^0.146 r² = 0.340

t max (yrs)

1000

100

10

1

1.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

• 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

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

• 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

Asthma

Renal disease Diabetes

Cardiac disease Arthritis

Cancer

Correlation of

morbidity rates and age

0 20 40 60 80 100

10 30 50

0 20 40 60

% with disease

Age (years)

Sinusitis

Cellular degradative pathways

FoxO, FoxA, HSF-1, SKN Caloric restriction

p53

Chemical substances (e.g., resveratrol)

Insulin/IGF-1 signalling TGF- β signalling

JNK signalling TOR signalling

Mitochondial respiration Protein synthesis

Temperature

Anti-ageing factors Pro-ageing factors

Ageing process

Intracellular accumulation of random cellular damage

Lifespan

Sirtuins

Molecular balance of aging and life-

span

Absent in Ames and Snell 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

ROS

PI3K

PTEN PDK

JNK FoxO

FoxO SKN-1 Rheb

FoxO target

SGK- 1 AKT/PKB TSC1/2

AMPK/

AKK-2

LKB1 elF4E 4E-BP TOR

S6K S6

Sir2/

Sirt1 SKN-1

14-3-3

E2F-1 HSF-1

SMK-1

FoxA/

PHA-4 Autophagy

AGEING ^Nucleus

Mithocondrion Cellular toxins (damaged proteins

and organelles) Protein turnover Cellular energy

AAT

AA

Cytoplasm

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

• 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

• 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

• 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

Nematode Human

catalase catalase

age-1 Pl₃-kinase

(glucose metabolism)

daf-2

Insulin-like receptor

(glucose metabolism)

daf-16 HNF3

(transcription factor)

WRN WRN

(Werner Syndrome)

*Known effect on aging

1.0 0.8 0.6 0.4 0.2 0

Animals with a mutation in the age-1 gene live longer than wild type

Proportion Surviving

Age (day)

10 20 30 40 50

wild type age-1

Longevity genes across animal

kingdom

Worm gene Yeast gene Human ortholog(s)

spg-7 AFG3 AFG3L2

F43G9.1^a IDH2 IDH3A

unc-26 INP53 SYNJ1, SYNJ2

rpl-1 9 RPL19A RPL1 9

rpl-6 RPL6B RPL6

rpl-9 RPL9A RPL9

spt-4 SPT4 SUPT4H1

inf-1^a TIF1 EIF4A2, EIF4A1 inf-1^a TIF2 EIF4A2, EIF4A1 inf-1 TIF4631 EIF4G1, EIF4G3

let-36^a TOR1 FRAP1

W09H1.5 ADH1 –

T27F7.3 ALG12 –

Worm gene Yeast gene Human ortholog(s)

B0511.6^a DBP3 –

sem-5 HSE1 –

F43G9.1 IDH1 –

unc-26 INP51 SYNJ1, SYNJ2

pdk-1 PKH2 PDPK1

eat-6 PMR1 –

C06E7.1^a SAM1 MAT1A, MAT2A rsks-1^a SCH9^b RPS6KB1, SGK2

Y46H3C.6 SIS2 –

pos-1 TIS11 –

erm-1 YGR1 30C –

rab-10 YPT6 –

Aging genes conserved in animal

kingdom

• 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

• ‘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

• 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

• 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