1 / 15

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,

teryl
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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.

More Related