Donnerstag, 19. November 2015

Cliffnotes: anti-aging effects GHRKO, what is the target tissue?

GHRKO - Growth hormone receptor knpck-out robustly extends lifespan, but how? Is it through lower IGF1, lowere GH, both and which tissue are the targets?

Very briefly, superficially:

Kopchick, Miller and others (1) have been running tests at two different sites to dig into an answer, but so far they haven't really uncovered any answers. So far they looked into liver, muscle and fat tissue.
An increase in survival and in maximal lifespan was detected in male MuGHRKO [muscle specific GHRKO] at UM mice, though not in a parallel experiment at OU and not in females at either test site. [OU, UM are the 2 different test sites/universities]
While removal of GH action in muscle of male mice results in features that are consistent with the hypothesis that blocking the anti-insulin activity of GH improved glucose homeostasis, the hypothesis that improved glucose homeostasis in MuGHRKO mice will improve lifespan remains questionable. However, we do know that removal of GHR in muscle did not shorten lifespan as discussed above. Since MuGHRKO mice were one of three lines simultaneously generated and studied by our laboratories, we can compare the effects of disrupting GHR in three insulin sensitive tissues (muscle, liver, and fat). Our previous work with liver- and fat-specific GHR gene disrupted mice indicates that lifespan does not always positively correlate with glucose homeostasis. For example, liver-specific disruption of the GHR (LiGHRKO) produces mice that have impaired glucose homeostasis [21, 22]. However, these mice have a normal lifespan as determined by two laboratories (OU and UM)[34]. Furthermore, fat-specific disruption of GHR (FaGHRKO) produces mice that have normal glucose homeostasis and these mice are short lived (List, Kopchick and Miller unpublished results at OU and UM). This suggests that other processes related to aging may have been altered (improved in LiGHRKO and impaired in FaGHRKO mice) to counteract the effect of glucose homeostasis on aging.
The authors state:
Collective data regarding muscle from MuGHRKO, global GHR−/−, Ames, and LiGHRKO mouse lines suggests that removing the indirect GH action, i.e. lowering IGF-1, may be more important in protection against musculoskeletal frailty.
Which to me doesn't quite add up (at a first glance). Another paper utilizing large, multi-site testing (2) found that IGF-1 itself has a small (but apprently real) effect on aging. For a few years now, I think, there has been mounting evidence that global GHRKO is somehow "better" than messing with IGF1 only. I recall quite clearly other controversial IGF1R papers (e.g. ref. 3).

I suppose lowered IGF1 could be more important in muscle, but on a whole body level there must be some beneficial effect of lowered GH.

References

1. Aging (Albany NY). 2015 Jul;7(7):500-12.
Removal of growth hormone receptor (GHR) in muscle of male mice replicates some of the health benefits seen in global GHR-/- mice.
List EO, Berryman DE, Ikeno Y, Hubbard GB, Funk K, Comisford R, Young JA, Stout MB, Tchkonia T, Masternak MM, Bartke A, Kirkland JL, Miller RA, Kopchick JJ.

2. Lorenzini A, Salmon AB, Lerner C, Torres C, Ikeno Y, Motch S, McCarter R, Sell C. Mice producing reduced levels of insulin-like growth factor type 1 display an increase in maximum, but not mean, life span. The journals of gerontology Series, A, Biological sciences and medical sciences. 2014;69:410–419.

3. Aging Cell. 2014 Feb;13(1):19-28. doi: 10.1111/acel.12145. Epub 2013 Sep 11.
Longevity effect of IGF-1R(+/-) mutation depends on genetic background-specific receptor activation.
Xu J1, Gontier G, Chaker Z, Lacube P, Dupont J, Holzenberger M.

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