More on RasGrf1 and Aging

As you might recall, manipulation of RasGrf1 extends life in mice: "The most intriguing finding was that the complete elimination of normal RasGrf1 increased both average and maximal longevity independent of a role in cancer. We found this to be surprising ... The effect of RasGrf1 deletion on aging, which is also accompanied by lower frailty and retention of motor control, appears to be mediated by greater protection against oxidative damage as observed by lower brain lipid peroxidation, liver protein oxidation and maintenance of the brain and liver glutathione redox potential. We must note that the use of malondialdehyde levels as a measure of overall lipid peroxidation in whole tissues is rather suspect and subject to numerous artifacts; nevertheless, the approximate 25% lower MDA levels in RasGrf-/- mice (in comparison with wild-type mice) were significant. ... it is impressive that the old RasGrf1 deletion mutants exhibited almost 30% lower levels of oxidized liver proteins than did the young wild-type mice. ... RASGRF1 is expressed in pancreatic β-cells where it regulates β-cell mass. So the effects on glucose metabolism is unsurprising. RasGrf1 is also expressed in the hippocampus and hypothalamus is involved in learning and memory. So, one wonders how a human without RasGrf1 would be able to do those functions and whether living longer and stronger might be accompanied by not remembering why one cared. ... Another interesting point raised by the authors is that RasGrf1,which is an exclusively paternal allele imprinted gene, suggests that only the male parent determines the effect of this gene's expression on longevity. In several ways, the RasGrf1-/- mice metabolically resemble mice fed a calorie-restricted diet. One exciting outcome of these studies is that RasGrf1 may be a potential target for design of agents that prolong lifespan and healthspan without the obvious difficulty of restricting caloric intake."

Link: http://www.impactaging.com/papers/v3/n5/full/100331.html

Comments

It would be interesting to know whether these long-lived RasGrf-/- mice would see further benefit from a CR-diet. A lack of a CR effect would appear to confirm the hypothesis of GH/IGF-1/insulin involvement.

This may also have a tie-in to depletion of stem cell pools, since RasGrf1 activation appears to favor differentiation over retention of "stemness" (if I interpret the following paper correctly) --

"A novel insight into aging: are there pluripotent very small embryonic-like stem cells (VSELs) in adult tissues overtime depleted in an Igf-1-dependent manner?"
http://www.ncbi.nlm.nih.gov/pubmed/21084728

Posted by: Lou Pagnucco at June 1st, 2011 12:05 PM

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