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
Cellular senescence
? whether senescent cells are causally implicated in age related
Dysfunction
? whether their removal is beneficial
P161: Cyclin-dependent kinase inhibitor 2A
multiple tumor suppressor 1 (MTS-1)
1 http://en.wikipedia.org/wiki/P16_(gene)
mouse embryonic fibroblast
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).
Pronuclear injection of the INKATTAC 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)
1. Transgenic INK-ATTAC and endogenous p16Ink4a are
under the same transcriptional control mechanism
Rosiglitazone
2. INK-ATTAC is expressed in senescent cells in
BubR1 hypomorphic tissue.
Expression of senescence markers in tissues
SA-b-Gal stained IAT
INK-ATTAC is selectively expressed in p16Ink4a-positive
senescent cells
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 p16Ink4apositive senescent cells in vitro.
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
Continuous removal of p16Ink4a-expressing cells from
BubR1H/H;INK-ATTAC mice selectively delays age-related
phenotypes
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.
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
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.
• 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.