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Age is the greatest carcinogen

Age is the greatest carcinogen. Age & Cancer. Source: SEER Program, NCI. Loss of Heterozygosity. M. m. Recombination. Chromosome loss. m. m. m. Michael McMurray. 24. 12. 25. 25. 37. 37. 38. 38. 50. 50. 51. 51. 63. 63. Pedigree plate. Mother “A”. 1. 2. 3. 4. 5.

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Age is the greatest carcinogen

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  1. Age is the greatest carcinogen

  2. Age & Cancer Source: SEER Program, NCI

  3. Loss of Heterozygosity M m Recombination Chromosome loss m m m

  4. Michael McMurray

  5. 24 12 25 25 37 37 38 38 50 50 51 51 63 63 Pedigree plate Mother “A” 1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5 6 7 8 9 10 11 Mother “B” 12 24

  6. 24 12 25 25 37 37 38 38 50 50 51 51 63 63 25 Mother “A” 1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5 6 7 8 9 10 11 Mother “B” 12 24

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  8. Abnormal chromosomes increase dramatically with the mother cell’s age Incidence of abnormal chromosomes

  9. The first LOH event has a late onset with age Relative Frequency Number of Cell Divisions

  10. LOH in aging yeast cells • Age-dependent increase in LOH • “Switch” to higher rate in late-middle life • All recombination mediated - linked to DNA damage Science301:1908 (2003); CSHSQB69:339 (2004)

  11. Derek Lindstrom

  12. The problem: Old mothers live in a “sea of youth” fa= 1:2a f1= 1:2 f2= 1:4 f3= 1:8 0 1 0 2 0 1 0 3 0 1 0 1 0 1 0 f25= 1:33,554,432

  13. 0 1 0 2 0 1 0 3 0 1 0 1 0 1 0 Enriching for old cells by eliminating daughter cell propagation fa= 1:a+1 f25= 1:26 (~106-fold enrichment)

  14. The Mother Enrichment Program

  15. The Mother Enrichment Program: Plenty of highly purified old cells

  16. What causes the switch to higher LOH rate in aging cells?

  17. Two modes of increased age-dependent LOH • Genome-wide LOH due to mitochondrial dysfunction: a role for Fe-S cluster proteins • Chromosome-specific LOH in cells with functional mitochondria: repeat instability

  18. Two modes of increased age-dependent LOH • Genome-wide LOH due to mitochondrial dysfunction: a role for Fe-S cluster proteins • Chromosome-specific LOH in cells with functional mitochondria: repeat instability

  19. A cascade of events leads to age-associated LOH Cellular aging/growth ? Mitochondrial dysfunction “Crisis” Nuclear genome instability

  20. Dysfunctional Mitochondria with Cellular Age Young Middle age Senior

  21. Two modes of increased age-dependent LOH • Genome-wide LOH due to mitochondrial dysfunction: a role for Fe-S cluster proteins • Chromosome-specific LOH in cells with functional mitochondria: repeat instability

  22. Replicative age increases LOH on chromosome XII - but not IV Chr XII Chr IV * * * % Half sectors * Hours

  23. Potential of the Mother Enrichment Program: Getting at Causality • Genetics • Cell biology • Biochemistry

  24. Fred Hutchinson Cancer Research Center

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