[ExI] Another technical paper for the CR/life extension crowd

[J. Stanton]

We're starting to understand how CR actually extends life.  Here is a 
very recent paper (November 2010):

Sirt3 Mediates Reduction of Oxidative Damage and Prevention of 
Age-Related Hearing Loss under Caloric Restriction. Shinichi Someya, Wei 
Yu, William C. Hallows, Jinze Xu, James M. Vann, Christiaan 
Leeuwenburgh, Masaru Tanokura, John M. Denu, Tomas A. Prolla. Cell - 24 
November 2010 (Vol. 143, Issue 5, pp. 802-812
http://www.cell.com/abstract/S0092-8674%2810%2901138-4

"...Here, we report that CR reduces oxidative DNA damage in multiple 
tissues and prevents AHL in wild-type mice but fails to modify these 
phenotypes in mice lacking the mitochondrial deacetylase Sirt3, a member 
of the sirtuin family. In response to CR, Sirt3 directly deacetylates 
and activates mitochondrial isocitrate dehydrogenase 2 (Idh2), leading 
to increased NADPH levels and an increased ratio of reduced-to-oxidized 
glutathione in mitochondria. In cultured cells, overexpression of Sirt3 
and/or Idh2 increases NADPH levels and protects from oxidative 
stress-induced cell death. Therefore, our findings identify Sirt3 as an 
essential player in enhancing the mitochondrial glutathione antioxidant 
defense system during CR and suggest that Sirt3-dependent mitochondrial 
adaptations may be a central mechanism of aging retardation in mammals."

This is plausible, because we already know that overexpression of SIRT3 
is associated with longevity in humans:

A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, 
is associated with survival at oldest ages
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WG1-4F14YRG-1&_user=10&_coverDate=02%2F28%2F2005&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=a429c5894fbe3f3ca905a606ae7efa90&searchtype=a

"First, we searched for variability in the human sirtuin 3 gene (SIRT3) 
and discovered a VNTR polymorphism (72-bp repeat core) in intron 5. The 
alleles differed both for the number of repeats and for presence/absence 
of potential regulatory sites. Second, by transient transfection 
experiments, we demonstrated that the VNTR region has an allele-specific 
enhancer activity. Third, by analyzing allele frequencies as a function 
of age in a sample of 945 individuals (20–106 years), we found that the 
allele completely lacking enhancer activity is virtually absent in males 
older than 90 years. Thus the underexpression of a human sirtuin gene 
seems to be detrimental for longevity as it occurs in model organisms."

JS
http://www.gnolls.org