C. Leeuwenburgh

There is strong evidence that mitochondrial dysfunction in vivo plays a significant part in the pathogenesis of neurological disorders and sarcopenia (atrophy and loss of skeletal muscle myofibers) (1-4). Life-long caloric restriction (CR) has been shown to have neuroprotective effects and prevents the age-associated loss in muscle fibers as well as function, but the mechanisms in vivo are poorly understood. We investigated apoptosis and apoptotic transduction signalling pathways in skeletal muscle and the brain frontal cortex of 12-month old, 26-month old ad libitum fed and 26-month old CR male Fischer-344 rats (CR = 40% of ad lib levels). We found that specific DNA fragmentation, indicative of apoptosis, was increased with age in these two post-mitotic tissues and that CR attenuated this age-associated increase significantly (5, 6). We determined levels of inhibitors, such as ARC (apoptosis repressor with a caspase recruitment domain), which inhibits caspase-2 activity and attenuates cytochrome c release from the mitochondria in addition to levels of XIAP (X-linked inhibitor-of-apoptosis), which inhibits caspase-3 activity. We found a significant age-associated decline in ARC levels. CR attenuated the age-associated decline of this anti-apoptotic protein. In accordance with the changes in ARC expression in the brain, CR attenuated the increases in cytosolic cytochrome c and caspase-2 activity observed during aging (5). Moreover, we found that CR suppressed the age-associated rise in cleaved caspase-3 in skeletal muscle and in the cerebral cortices. XIAP protein content increased with age and was reduced by CR in both tissues. Our studies demonstrate that post-mitotic tissues show significant alterations in apoptotic signalling with aging and that caloric restriction is able to modulate these changes towards cellular survival.

Support of the presented work is provided by the NIH-NIA)

1. J. Wanagat, Z. Cao, P. Pathare, J. M. Aiken, Faseb J 15, 322-32. (2001).

2. M. Pollack, S. Phaneuf, A. Dirks, C. Leeuwenburgh, Ann N Y Acad Sci 959, 93-107 (Apr, 2002).

3. M. Pollack, C. Leeuwenburgh, J Gerontol A Biol Sci Med Sci 56, B475-82. (2001).

4. B. Drew et al., Am J Physiol Regul Integr Comp Physiol 284, R474-R480 (Feb, 2003).

5. R. R. J. Shelke, C. Leeuwenburgh, FASEB J., 02-0803fje (January 2, 2003, 2003).

6. A. Dirks, C. Leeuwenburgh, Am J Physiol Regul Integr Comp Physiol 282, R519-27. (2002).

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