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Clearance of p16 Ink4a -positive senescent cells delays ageing-associated disorders

1 0 N O V E M B E R 2 0 1 1 | VO L 4 7 9 | N AT U R E | 2 3 3. Clearance of p16 Ink4a -positive senescent cells delays ageing-associated disorders Darren J. Baker1,2,3, TobiasWijshake1,4, Tamar Tchkonia3, Nathan K. LeBrasseur3,5, Bennett G. Childs1, Bart van de Sluis4,

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Clearance of p16 Ink4a -positive senescent cells delays ageing-associated disorders

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  1. 1 0 N O V E M B E R 2 0 1 1 | VO L 4 7 9 | N AT U R E | 2 3 3 Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders Darren J. Baker1,2,3, TobiasWijshake1,4, Tamar Tchkonia3, Nathan K. LeBrasseur3,5, Bennett G. Childs1, Bart van de Sluis4, James L. Kirkland3 & Jan M. van Deursen1,2,3 Presented by: Chang chu Jan.13, 2013

  2. P161: Cyclin-dependent kinase inhibitor 2A multiple tumor suppressor 1 (MTS-1) 1 http://en.wikipedia.org/wiki/P16_(gene) mouse embryonic fibroblast  Cellular senescence ? whether senescent cells are causally implicated in age related Dysfunction ? whether their removal is beneficial

  3. An earlier mouse model： FAT-ATTAC2 (fat apoptosis through targeted activation of caspase） Transgenic strategy: Fabp4 promotor 2 Pajvani, U. B. et al. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nature Med. 11, 797–803(2005).

  4. Pronuclearinjection of the INK-ATTAC construct into FVB oocytes Nine transgenic INK-ATTAC founder lines BubR1H/H mice • BubR1 encodes a key member • of the mitotic checkpoint • shortened lifespan • age-related phenotypes • adipose tissue, skeletal muscle • and eye inguinal adipose tissue (IAT)

  5. 1. Transgenic INK-ATTAC and endogenous p16Ink4a are under the same transcriptional control mechanism Rosiglitazone

  6. Expression of senescence markers in tissues SA-b-Gal stained IAT 2. INK-ATTAC is expressed in senescent cellsin BubR1 hypomorphic tissue.

  7. INK-ATTAC is selectively expressed in p16Ink4a-positive senescent cells

  8. 3. INK-ATTAC can eliminate senescent cells • Bone marrow cells of WT;INK-ATTAC transgenic lines 3 and 5 • Cultured with rosiglitazone for 5 days • Treated with AP20187 for 48h FKBP–Casp8 activation efficiently eliminates p16Ink4a-positive senescent cells in vitro.

  9. 4. Clearance of p16Ink4a-expressing cells from BubR1H/H mice prevents or delays the onset of age-related phenotypes BubR1H/H;INK-ATTAC-3 and -5 mice at 3 weeks of age : AP20187 every third day Untreated Sarcopenia, cataracts and loss of adipose tissue 9-month-old mice

  10. Continuous removal of p16Ink4a-expressing cells from BubR1H/H;INK-ATTAC mice selectively delays age-related phenotypes

  11. 5. The delayed onset of age-related pathologies coincided with a reduction in the number of senescent cells in these tissues. Senescent cells were cleared from tissues and that this delays acquisition of age-related dysfunction in BubR1 hypomorphic mice.

  12. 6.Investigating the effect of senescent cell clearance later in life BubR1H/H at 5 months: age-related phenotypes are apparent AP20187 treatment Measured p16Ink4a-dependent age-related phenotypes at 10 months

  13. Senescence markers were substantially reduced Late-life clearance of p16Ink4a positive senescent cells attenuates progression of age-related decline rather than a reversal of ageing in BubR1 hypomorphic mice.

  14. A novel transgenic mouse model • Both life-long and late-life clearance of the p16Ink4a expressing senescent cells selectively delayed age-related pathologies in tissues that accumulate these cells. • Therapeutic interventions to clear senescent cells or block their effects may represent an avenue for treating or delaying age-related diseases and improving healthy human lifespan.

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