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Genetics of longevity 1.Heritability 0.23-0.26 2.Exceptional longevity (90+) a. appears to be a real category b. what is the basis? -reduced incidence.

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Presentation on theme: "Genetics of longevity 1.Heritability 0.23-0.26 2.Exceptional longevity (90+) a. appears to be a real category b. what is the basis? -reduced incidence."— Presentation transcript:

1 Genetics of longevity 1.Heritability Exceptional longevity (90+) a. appears to be a real category b. what is the basis? -reduced incidence of cancer and heart disease -slowed process of aging in general GENETICS AND LIFESPAN

2 Centenarians: People 100 years old and older Is there something special about them? GENETICS AND LIFESPAN

3 Change in number centenarians in the Netherlands GENETICS AND LIFESPAN

4 Age distribution of centenarians in the Netherlands GENETICS AND LIFESPAN

5 Marital status of male and female Dutch centenarians GENETICS AND LIFESPAN

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7 Longevity seems to be only moderately heritable. The nature of genetic influences on longevity is probably non-additive (ie. Single genes), suggested by both statistical partitioning of heritability as well as the class of “exceptional longevity”. As if Exceptional longevity were like a discrete trait. Is there evidence for particular genes? GENETICS AND LIFESPAN

8 Cholesterol ester transfer protein (CETP) Two functional variants produced by the V and v alleles VV higher % of larger lipoproteins (favorable) vv lower % of larger lipoproteins (unfavorable) GENETICS AND LIFESPAN

9 VV 25% in patients 100 years or greater vv 8 % in patients years old VV genotype significantly enriched in those exhibiting the exceptional longevity phenotype. GENETICS AND LIFESPAN

10 Genetics and tissue transplantation Why is it so hard to find a match?

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12 Rejection of transplanted tisssue: Graft versus Host reaction Fever Skin rashes Inflammation surrounding transplanted tissue

13 Genetics of successful tissue transplantation Histocompatibility = tissue compatibility Main factors in successful tissue transplanation? ABO blood type for transfusions MHC: Major Histocompatibility Complex HLA: Human Leukocyte Antigen

14 HLA genes are tightly linked on chromosome 6

15 The frequency of each of these alleles in a population is low

16 Which HLA loci are most important in determining transplant success? HLA - A HLA - B HLA - DR Why, even among family members, a match is difficult to obtain…..

17 What is the chance of a match between a parent and a child? What is the chance of a match between two siblings ?

18 Need to match for ABO also when doing tissue transplantation

19 DISEASEHLA alleleRelative risk Ankylosing spondylitisB Rheumatoid arthritisDR 44.2 Systemic lupus erythematosus DR 35.8 Graves diseaseDR 33.7 Celiac diseaseDR Myasthenia gravisB 83.4 Multiple sclerosisDR 24.1 Insulin dependent diabetes HemochromatosisA38.2 HLA genotype and disease associations

20 Ankylosing spondylitis Autoimmune disease 1. Arthritis in spine 2. Other joints 3.90% men 4.Onset between 16-40

21 Nervousness Irritability Anxiety Muscle weakness fatigue Increased appetite, Weight loss despite normal eating Sweating, Shaking, heart pounding Hair loss or thinning Bulging eyes Vision disturbances Skin rash Graves Disease: Immune System sends signals to the thyroid to make more hormone

22 Dementia: Loss of cognitive function Alzheimer's disease: neurodegenerative Symptoms: Loss of short term memory Recognition problems Language disorders Motor skill decline Progressive

23 Types of Alzheimer’s Disease (AD)

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26 All involves the accumulation of abnormally folded amyloid beta protein Age 65: 2-3% show symptoms Age 85: 25%+ show symptoms Heritability: % Early onset: Symptoms appear in 30’s and 40’s Highly familial, dominant? Late onset: APOE Apolipoprotein A 3 alleles ApoE 2, ApoE3 (dysfunctional), ApoE4 ApoE4 associated with late onset AD

27 Other senile dementias involve different steps in the Pathway synthesizing the plaques: “presenilins” Proposed environmental factors: Early head injury Aluminum in the diet Smoking

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