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CELL SIGNALING AND APOPTOSIS INCELL SIGNALING AND APOPTOSIS IN
AGINGAGING
Christiaan Leeuwenburgh, Ph.D.Christiaan Leeuwenburgh, Ph.D.
University of FloridaUniversity of Florida
Biochemistry of Aging LaboratoryBiochemistry of Aging Laboratory
Web Page: http://grove.ufl.edu/~cleeuwen/
International Association of Biomedical Gerontology, 10th CongressInternational Association of Biomedical Gerontology, 10th CongressUniversity of Cambridge, England
20032003
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Simplified Signaling
Pathways of Apoptosis
Pollack M, Leeuwenburgh C:J Gerontol A Biol Sci Med Sci 2001;56:B475-482.
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Caloric Restriction (CR)
CR increases mean and maximum lifeCR increases mean and maximum life--span improvesspan improvesneuronal and muscle function as well as reducesneuronal and muscle function as well as reduces
cardiomyopathy.cardiomyopathy.
1) reduces oxidant productionreduces oxidant production
2)2) improves calcium homeostasisimproves calcium homeostasis
3)3) reduces inflammationreduces inflammation
4)4) reduces DNA damagereduces DNA damage
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Mitochondrial Dysfunction and AgingDrew, B., Phaneuf, S., Dirks, A., Selman, C., Gredilla, R., Lezza, A., Barja, G., and Leeuwenburgh, C. ( 2003).Am J Physiol
Regul Integr Comp Physiol284, R474-R480.Leeuwenburgh, C., Wagner, P., Holloszy, J.O., Sohal, R.S., and Heinecke, J.W. 1997.. Arch Biochem Biophys 346:74-80.
Oxidative stress
mt-DNA damage
mt-DNA deletions
Oxidized proteins
Lipid peroxidation
Lipid-adductformation
Decrease in repair
systems
AD CR0.0
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Caloric Restriction
Va0t
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Squier, T.C., and D.J. Bigelow. 2000. Protein oxidation
and age-dependent alterations in calcium homeostasis.Front Biosci. 5:D504-26.
Endoplasmic (Sarcoplasmic) Reticulum Stress
o
oDamage due toreactive nitrogen
and oxygen species
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The effects of age and calorie restriction on
TNF-E/ NF-OB signaling in skeletal muscle
TNF-E / NF-OB signaling
TNF receptor-associated death domain (TRADD)
TNF-R-associated factor 2 (TRAF2)
Inhibitor ofOB kinase (IKK) complex
Receptor interacting protein (RIP)
6AD 26AD 26CR
0.000
0.005
0.010
0.015
0.020
0.025
0.030
0.035 *
#
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Activation
(O
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)
W X Y
-
a
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AD 2a b
c
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*P= 0.0001e
s 6ADJP= 0.0001
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s 26AD
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JTNF-E
(g
h
/
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p)
Philli s and eeuwenbur h (un ublished)
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Myocardial Aging, Sarcopenia,
Neurodegeneration, Oxidative Stress and
Apoptosis
in total number of skeletal and heart myocytes as well asneurons with age
May lead to accelerated decline in cardiac functionalcapacity, sarcopenia, neurodegenerative diseases
Oxidative Stress and Apoptosis may be one major factor
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Neuron loss in the brain with
age and improved brain
function with CR Improved responses to enclosed alleys
Previous studies on neuronal loss with aging reported disparate
results.
Studies often measured neuron density in a given structure
instead of total neuron number.
Some studies suggest that most neocortical areas and certain
hippocampal subfields lose 25 to 50% of their neurons with age in
humans.
Specific regions of the brain appear to be effected (hippocampus,hilus of the dentate gyrus and the subiculum)
Morrison, J. H., and Hof, P. R. (1997) Science 278, 412-419; Mattson, M. P. (2000). Nat Rev Mol Cell Biol1,
120-129.
Ingram, D. K., Weindruch, R., Spangler, E. L., Freeman, J. R., and Walford, R. L. (1987) J Gerontol42, 78-
81. Ingram, D. K., Chefer, S., Matochik, J., Moscrip, T. D., Weed, J., Roth, G. S., London, E. D., and Lane,M. A. (2001)Ann N Y Acad Sci928, 316-326.
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Is there skeletal muscle fiber loss with age
in humans and animals?
5-AL 18- AL 36-AL
0
10000
20000
**
Vastus ateralis
FibersThrough
idbell
Bua EA, cKiernan SH, Wanagat J,
cKenzie D, Aiken J . itochondrial
abnormalities are more frequent in
muscles undergoing sarcopenia.
J Appl Ph siol. 2002 Jun;92(6):2617-24.
exell J, Ta lor CC, S jostrom . What is the cause of
the ageing atroph ? Total number, size andproportion of different fiber t pes studied in whole
vastus lateralis muscle from 15- to 83- ear-old men. J
Neurol Sci. 1988 Apr;84(2-3):275-94.
Humans Animals
Pesce V, Cormio A, Fracasso F, Vecchiet J, Felzani G,
ezza A , Cantatore P, Gadaleta N. Age-related
mitochondrial genot pic and phenot pic alterations
in human skeletal muscleF
ree Radic BiolMed,1;30(11):1223-33, 2001.
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0
5
10
15
25 50 75 100
Age(Years)
ApoptoticIndex
(%)
0
25
50
75
100
25 50 75 100
A e (Ye rs)
e
sitf
Striate
s
le
ells(%)
s le f r tr l f ri ati
5-weeks
56- ears
81- ears
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5- AL 30- AL 30-CR
0
250
500
750
**
Epitr l ri**p < . =
li