Leeuwenburgh (1)

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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

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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)

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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?

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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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Leeuwenburgh (1)