Lecture 15

If some people have active phenotypes, is it genetically controlled? The genetics of progeria: some genetic alterations show accelerated ageing phenotypes and are associated with reduced lifespan. The genetics of ageing: generally concerned with life extension associated with genetic alterations Hutchinson – Guilford progeria syndrome Resembling aspects of ageing manifest at a very early age It is extremely rare and is rarely inherited as people with HGPS do not usually live to reproduce The syndrome consist of:

Slow growth, dwarfism
Loss of body hair early
Disproportionatly large head
Coronary heart disease, usually die in teens
Like accelerated ageing basically The HGPS phenotype can be mapped to chromosome 1q – the long arm of chromosome 1 This region in 20 cases of HGPS was sequenced and compared with the human genome project consensus sequence Mutations were found in the LMNA gene that encodes the nuclear lamin A protein 18 cases had the same de novo single base substitution, a C to T transition resulting in a silent gly to gly change at codon 608 with exon 11
Didn’t make much sense How does silent mutation have such a large effect? Its not about protein its about altering splicing Passage: transfer of cells from one flask to another for growth. From passage 6 to passage 26 there are progressive changes in nuclear shape in HGPS fibroblasts. In late passage normal cells, lamin A and lamin B mostly co localise at the nuclear lamina. In late passage HPGS cells, progerin (mutant lamin A) is mis localised The A tpe lamin maintain levels of protein required to repair DNA double stranded breaks.
Occurs in end of nucleus If you take mice cells and mutant them so that they are deficxient in lamin A, you alter their growth rate. In HPGS, this inability to adeuetly repair DNA damages may cause aspects of premature ageing. HGPS is not a perfect model for ageing:
Diabetes is rare
Blood pressure is rare
No increased risk of cancer or catheter Werner syndrome Normally starts happening during pouberty Affected teenagers usually lack a growth spurt, resulting in short stature Accelerated ageing typically begins in their twenties; greying and loss of hair; hardened skin Symptoms are ageing symptoms, such as loss of fertility, cataract Most mutations in werner syndrome is null mutations, loss of all function Faulty DNA replication – at the telomeres Telomeres that are normally replicated by lagging strand synthesis are not replicated efficiently in Werner cells Wener syndrome not a good model for ageing as:
No alzhemers
No stroke
No high blood pressure Downs syndrome Three types: Trisomy 21, 95% of cases, extra chromosome 21 Translocation Downs, 4% of cases. There is an extra chromosome 21 and is attached to another chromosome Mosaic downs, 1% of cases. Some cells are trisomic, others are not

From looking at all three diseases, there is a very clear target: The nuclear lamina: seems to control DNA double break repair and also to control telomeres takes us into the area of genetic instability. Human Ageing genomic resources GenAge: a database of genes related to human ageing and a database of ageing- and longevity-associated genes in model organisms. GenDR: a database of genes associated with dietary restriction based on genetic manipulation experiments and gene expression profiling. CellAge: is a database of senescence-associated genes taken from studies using various human cell types. There are 2150 known genes that influence lifespan in model organisms

Age 1 is a mutation in PI3 kinase If you can no longer express PI3a kinase you can express lifespan by 10 folds in some organsms If you cant make PI3 kinase, you cant change membrane lipids as second messenger so you lose all pathway downstream which means GLUT 4 transporters remain intracellular and you cant take up glucose. Taking up glucose to cells reduces blood concentration and therefore rescues us from toxicity of glucose. Raises the question maybe glucose makes us age? If you reduce acitivyt of biochemical pathway that takes glucose from blood to cels, you can live longer as long as you don’t have glucose present. There are twice as many 90 year olds than males We are getting a worldwide ageing population Compared with younger adults, centenarians have a: lower body mass index (BMI). lower body fat. lower plasma triglycerides. lower oxidative stress levels. higher insulin sensitivity (less susceptible to type II diabetes.) higher plasma levels of active IGF-1 (insulin-like growth factor 1).

a slower age-related decline and marked delay in onset of chronic diseases of ageing, such as Alzheimer's Disease, cardiovascular disease and cancer. A genome-wide association study (GWAS) is an examination of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait. The most frequent type of variation in our genome is the single nucleotide polymorphism (SNP), a variation at a single site in DNA. SNPs are inherited in a Mendelian manner, and so people can be ‘genotyped’ for an SNP… and also for about a million other SNPs. The APOE-4 allele is a risk factor for Alzheimer’s: homozygotes have a 15-fold increased risk. ApoE regulates lipid homeostasis by mediating lipid transport from one tissue or cell type to another. More in Y2: Blood and Circulation In peripheral tissues, ApoE is primarily produced by the liver and macrophages, and mediates cholesterol metabolism in an isoform-dependent manner. In the CNS, ApoE is mainly produced by astrocytes, and transports cholesterol to neurons via ApoE receptors (members of the low-density lipoprotein receptor (LDLR) family). The ApoE4 isoform is associated with hyperlipidaemia and hypercholesterolemia, which lead to atherosclerosis, coronary heart disease and stroke (all diseases associated with ageing). A hallmark of Alzheimer’s: accumulation of amyloid-β (Aβ) plaques in the brain. The plaques are aggregates of a peptide generated in vivo by proteolytic cleavage of the amyloid precursor protein Study of French centenarians. 338 centenarians, controls aged 20-70. ApoE4 allele is significantly less frequent in centenarians than in controls Inheritance of the ApoE4 allele is the most common known genetic risk factor for Alzheimer’s disease after the age of 60. ApoE4 promotes the polymerization of amyloid-β into plaque-forming fibrils. Frequency of the ApoE2 allele is significantly increased in centenarians ApoE2 protects against cardiovascular disease and Alzheimer’s disease. If this is the case, the allele frequency of E2 in older populations should be greater than in younger (old age selects for E2 individuals), and the allele frequency of E4 should be lower in older populations than in younger (people with E4 don’t make old age as easily)… Hydra (a freshwater polyp) has only one FOXO gene. If it is mutated, the hydra start to age and senesce.The single wild-type Hydra FOXO gene confers immortality. What about people? We have four FOXO genes (FOXO1, FOXO3, FOXO4 and FOXO6), that encode transcription factors that control expression of genes that regulate energy metabolism, oxidative stress, proteostasis, apoptosis, cell cycle regulation, metabolic processes, immunity, inflammation and stem cell maintenance.