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• AIDS ?? ? Caposi sarcoma
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• AIDS ?? ? Caposi sarcoma (??)
• Papilloma virus ????? (?????)
• HTLV ? T cell leukemia (??)

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B,C,D,
A,B,C,D,..
B,C,D,
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Thomas J. Lynch et. al. (2004) N Engl J Med
3502129-2139
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Feb. 24 2005
Wild type
T790M mutation
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??????????????????
??(Apoptosis)
?? (Senescence)
??
?? (Differentiation)
?? (Quiescent)
????? (Growth Division)
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? ??????????????????????

• Yes!
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• ???????,?????????????????
• But???

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????????????!
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????????????????????????!
Protected
Survival
Wild
Age
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???????????????????(Why we age?)

• ???????????????(How we age?)

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?????????????????Why we age?
????????????2-3?,??????????
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Accumulation of germ-line mutations with
late-acting deleterious effects ?????30??????????6
0??????????
the forces of natural selection weakens with
increasing age . If a genetical disaster
happens late enough in individual life, its
consequences may be completely unimportant. Even
in such a crude and unqualified form, this
dispensation may have a real bearing on the
origin of innate deterioration with increasing
age. Medawar, 1952
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??????????????????????? 40??????????! ??10???????
,?????? ???????
George Sumner Huntington
Frank Gaillard
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?????,??????????????????????????!
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Survival
Good
Bad
Age
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A
Young animal
Elderly animal
mutant gene action
mutant gene action
Increased fitness
Reduced fitness
B
Young animal
Elderly animal
Latent damage unmasked
mutant gene action
???????
Increased fitness
Reduced fitness
Latent damage
?????
???
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????????????????????????!
Survival
Effective maintenance and repair
Age
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??????,??????????
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??????????????,????????????????????

• ???????

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Wild-type (left specimen)and long-lived dwarf
(right specimen) yeast, flies and mice with
mutations that decrease glucose or insulin/IGF-I
signaling.
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???????????????,???????????

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???????????????How we age?

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Cellular senescence
Human diploid fibroblast has limited replicative
life span, termed replicative senescence or
cellular senescence. Human diploid fibroblasts
can divide 60-80 times.
???
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Young vs. senescent fibroblasts

• Senescent cells are generally larger, less
  motile, decreased saturation density.
• Senescent cell is different from the quiescent
  cell in G0. Senescence is irreversible process
  whereas G0 cells can reenter cell cycle upon
  induction.
• Senescent cells resist apoptosis, this may
  explain why senescent cells are not cleared and
  thus accumulate with age.

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Aging is an autonomous property of normal cells
Hayflick and Moorhead
40th population doubling
10th population doubling
Male control
Female control
Male, female Mixture



230
230
230
Female control
Male control
Female cell remain
???
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Telomere in Greek, Telos means end meros, part
Telomere
Telomere
Centromere
AGGGTTAGGGTTAGGG-3
TCCC-5
???
????????????????????????????????????????????????!
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???,????????
Cell divisions
Cell divisions
Cell cycle arrest (M1)
???????????(??),??????!
Catastrophe (M2)
???
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Human telomere shortening during replication
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Is cellular senescence the same as biological
aging?

• Cells cultured from old donors tend to senesce
  after fewer population-doublings than cells from
  young cell.
• Interspecies comparison suggests that cell
  replicative life span and biological life span is
  genetically related.

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Correlation between telomere length and human
aging
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Cells from long-lived species are capable of
replicating more times
Sci Am. 1968 Mar218(3)32-7
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What is the cause of Dollys death?

• Dolly was cloned in 1997.
• Analysis of telomere lengths in Dolly indicates
  that Dollys telomere length is similar to normal
  six-year-old sheep (1999).
• Dolly die on 14 Feb, 2003

Toni Barros
Dolly, 1997-2003
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Werner Syndrome

• Autosomal recessive Life Span in Years 60
• Loss of WRN, a RecQ family helicase.
• Reduced replicative life span of cultured cells.
  Increased mutation rate, particularly DNA
  deletions. Rapid telomere shortening during
  cellular replicative life span.

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????????????????
Cell divisions
???????
Cell divisions
Cell cycle arrest (M1)
?????????
Catastrophe (M2)
???
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Telomerase is expressed in immortal and cancer
cells
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???????????????How we age?

• ??????????
• ??????????

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?????
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?? ???? ??/??
Susumu Kobayashi et al, EGFR Mutation and Resistance of NonSmall-Cell Lung Cancer to Gefitinib, N Engl J Med, 352786-792 2005
Thomas J. Lynch et. al. (2004) Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of NonSmall-Cell Lung Cancer to Gefitinib. N Engl J Med 3502129-2139
Susumu Kobayashi et al, EGFR Mutation and Resistance of NonSmall-Cell Lung Cancer to Gefitinib, N Engl J Med, 352786-792 2005
Zhi-Xiang Shen et al, All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia, Proc Natl Acad Sci U S A , 101(15)5328-35 2004
Douglas Hanahan and Robert A. Weinber, The Hallmarks of Cancer, Cell 100, 57-70 2000

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KelloggsComstock http//commons.wikimedia.org/wiki/File11-stages-womanhood-1840s.jpg 2010/09/29 visited
Rory Curtis et al, Ageing and metabolism drug discovery opportunities , Nature Reviews Drug Discovery 4, 569-580 July 2005
Xtreambar http//commons.wikimedia.org/wiki/FilePeter_Brian_Medawar.jpg 2010/09/29 visted
Frank Gaillard http//commons.wikimedia.org/wiki/FileHuntington.jpg 2010/09/30 visited
http//commons.wikimedia.org/wiki/FileGeorge_Sumner_Huntington.jpg 2010/09/30 visited
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Valter D. LONGO, Caleb E. Finch, Evolutionary Medicine From Dwarf Model Systems to Healthy Centenarians?, Science Vol.299, pp 1342 1346 2003
Hayflick and P. S. Moorhead , The serial cultivation of human diploid cell strains, Experimental Cell Vol.25 585-621Dec 1961
L. Hayflick and P. S. Moorhead , The serial cultivation of human diploid cell strains, Experimental Cell Vol.25 585-621Dec 1961
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G. A. McFarland and R. Holliday (1994) Experimental Cell Research 212, p167-175
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Calvin B. Harley, A. Bruce Futcher  Carol W. Greider, Telomeres shorten during ageing of human fibroblasts, Nature 345, 458 460 May 1990
Calvin B. Harley, A. Bruce Futcher  Carol W. Greider, Telomeres shorten during ageing of human fibroblasts, Nature 345, 458 460 May 1990
Nicholas D. Hastie et al,Telomere reduction in human colorectal carcinoma and with ageing , Nature 346, 866 868 Aug 1990
Nicholas D. Hastie et al,Telomere reduction in human colorectal carcinoma and with ageing , Nature 346, 866 868 Aug 1990
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L Hayflick (1968) Human cells and aging. Sci Am. 21832-7.
Toni barros http//commons.wikimedia.org/wiki/FileDolly_face_closeup.jpg 2010/09/30 visted
Genes and Genetics, National Library of Medicine??? http//www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?bookgndpartwernersyndrome
Fiona S. Wyllie et al, Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts, Nature Genetics  24, 16 17 2000
Kim NW et al, Specific association of human telomerase activity with immortal cells and cancer, Science 23, 266 Dec 1994
Kim NW et al, Specific association of human telomerase activity with immortal cells and cancer, Science 23, 266 Dec 1994
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Kim NW et al, Specific association of human telomerase activity with immortal cells and cancer, Science 23, 266 Dec 1994