Transcript Replicative Senescence

International Association of Biomedical Gerontology
10th Congress
Queens College/Cambridge
September 2003
T cell Replicative senescence:
pleiotropic effects on human aging
Rita B. Effros
Dept of Pathology & Laboratory Medicine
David Geffen School of Medicine at UCLA
Viral infections and aging


increased incidence and severity (influenza,
RSV, HIV, SARS)
re-emergence of latent infections
Cytotoxic ( CD8) T cells
> 1018 different antigen receptors
Replicative senescence
Reduced apoptosis
Effect of repeated stimulation on telomerase
Effect of repeated stimulation on telomerase
*
X
Immunobiology: The Immune System in Health & Disease,
3rd edition, by Janeway & Travers
( Current Biology Limited & Garland Publishing)
CD28-negative T cells  with age
Boucher et al., Exp. Gerontol. 33:267, 1998
in CD4
in CD8
Neonates
NT
NT
Young adult (20-40)
4%
42%
Elderly (70-90)
12%
79%
Mean TRF Length (kb)
Mean TRF Length (kb)
CD28- T cells have shortened telomeres
9
8
7
6
5
+
CD28
A
AB
9
BC
8
7
6
5
-
CD28
++
CD28
CD28
*
--
CD28
unable to proliferate
resistant to apoptosis
+ SP
SN
CEN
CD28 CD28
CD28
PBMC
Do senescent CD8 T cells affect other
cell types and organ systems in vivo ?
CD8+ CD28- T cells

correlate with poor response to flu vaccine

suppress helper T cells

disease progression in ankylosing spondilitis


organ transplant patients-may suppress T cells
that would reject the graft
correlate with osteoporotic fractures
REGULATION OF BONE RESORPTION
Role
of
T
cells
REGULATION OF OC FORMATION AND FUNCTION
Model
T CELLS
MONOCYTES
Stimulatory
Factors
IL-1
TNFa
RANKL
TNFa
Inhibitory Factors
TNFa
OC PRECURSORS Differentiation
and activation
ACTIVE OC
OPG
M-CSF
IL-6
PGE2
GM-CSF
RANKL
RANKL
STROMAL CELLS
(Modified from SAGE KE/ B.L. Riggs)
TGFb
TGFb
Effect of culture “age” on
production of TNF alpha
TNFa pg/ml
80
70
60
50
40
30
20
10
0
4
16
Population Doublings
25
Production of “RANKL” by activated T cells
(Receptor Activator for NFkB Ligand)
Production of RANKL by activated T cells
Ectopic telomerase expression leads to lifespan
extension of virus-specific CD8 T cells
80
Population Doublings (PD)
70
60
50
40
30
20
hTERT
10
vector
0
0
200
400
600
Days in culture
800
1000
1200
Telomere length stablization,
prevents accumulation of p16, p21
Correction of senescenceassociated cytotoxic defect
% Specific Lysis
100
80
60
40
20
0
0 1 2 3 4 5 6 7 8
Passage
Untransduced CTL (Control)
Empty Vector-Transduced CTL (Control)
hTERT-Transduced CTL
Replicative senescence






end stage of normal T cell differentiation
increased proportions in elderly
reduced anti-viral function
once generated, senescent CD8 T cells persist
? exert broad physiological effects
hTERT corrects only some of the defects
associated with CD8 T cell senescence
(CD28, compounds that  telomerase)
Reversal of T cell replicative senescence can
improve both immune function and bone status
Collaborators and
UCLA
Xiaoming Zhu
Hector Valenzuela
Mirabelle Dagarag
Lucia Graham
Tankdik Evazyan
Support
Otto Yang
Janis Giorgi
Roger Detels
Farhad Parhami
Geron Corporation
Calvin Harley, Choy-Pik Chiu
(UC BioSTAR, NIH ,Plott Endowment,
UCLA Center on Aging)