Sonntag, 20. Oktober 2013

Hypothesis Testing: Why I think Sonntag et al. are wrong

About one year ago Sonntag et al. published a superb review highlighting "progress and controversies" in the field of GH/IGF1 and aging (1). In this paper they are very critical of the whole hypothesis:
"These diverse results are incompatible with the concept that reductions in IGF-1 signaling increase life span in mammals as was reported in invertebrate models... 
Based on the current available studies, it appears that the definition of a conserved mechanism of aging requires clarification. If a “common” mechanism for increased life span does not relate to animals of different genders or more importantly to humans, it is difficult to conclude that it represents a conserved mechanism of aging. Importantly, the studies in humans on circulating GH and IGF-1 deficiency do not agree with the data from rodent models."
I believe instead they favor a model in which only early life exposure to low GH levels slows aging:
"In our opinion, it is plausible that the increase in life span observed in Ames and Snell dwarf animals as well as ghr knockout animals is the consequence of impairments in the developmental programming of key pathways... [NB: this would not explain why human patients with the same mutations fail to show a longevity phenotype. Emphasis mine.]"
So why do I think GH/IGF-1 matters, perhaps even throughout adulthood?
I do not want to delve into too much detail and I will try to keep this post short. Also note that my expertise lies outside of this field and I do not disagree that overall the issue is still controversial. However, I do consider the "optimistic" interpretation by e.g. Bartke et al. (2) to be more probable given my reading of the evidence.
"The role of hormones homologous to insulin-like growth factor (IGF, an important mediator of GH actions) in the control of aging and lifespan is evolutionarily conserved from worms to mammals with some homologies extending to unicellular yeast....there is yet no evidence of increased longevity in GH-resistant or GH-deficient humans, possibly due to non-age-related deaths. "
What's wrong with the Sonntag paper?
Some of my criticisms are more general in nature, e.g. their reliance on prospective epidemiology to draw conclusions about aging, or the absence of a discussion of GHRHR -/- and PAPA -/- mice.

As far as I can see they left out a few other papers, although, these did not clearly favor the "optimistic" or "pessimistic" view.

Their choice of words also seems poor at times: "...the studies in humans on circulating GH and IGF-1 deficiency do not agree with the data from rodent models"
Really? Simply put, the epidemiology and human data they cite suggests that IGF-1 lowers cardiovascular disease (CVD) but increases cancer incidence. There is tentative data in GH-deficient animals showing exactly the same, i.e. evidence of CVDisease/damage despite an extended lifespan (Csiszar 2008, Reddy 2013 [3-5]). CVD and delayed aging are not mutually exclusive. If GH-deficiency promotes CVD it might be unsafe in humans even if it slows aging and independently of this effect. This does not mean the GH/IGF-1 pathway isn't conserved. It means that humans are highly susceptible to CVD at middle age.

What do more recent studies say?
Broadly speaking, recent studies support the relevance and conservation of the GH/IGF pathway in aging (6-8). Although, the gender-dependent effect of the IGF1R +/- mutations still cannot be explained to my satisfaction (6) and seems inconsistent with a highly conserved mechanism. On the other hand, I would like to highlight the paper by Lorenzini et al. (7) using a hypomorphic IGF-1 gene, because it has a very large sample size and their mice show acceptable maximum lifespans (around 1100d), albeit not mean LS (around 7xx d). The authors found an increase in the all important maximum but not mean lifespan.

EDIT: Zhang et al. 2012 produced life span extension using FGF-21 overexpression (PMID: 23066506 ), which further supports a conserved role of GH/IGF-signalling. Again, female mice benefit the most. I have no clue why.

Is there a biologic explanation for the inconsistent data regarding IGF-1?
Viewed from another angle, there might be a mechanistic explanation for the discrepancies in rodent studies noted by Sonntag. Note that this is quite speculative:
Renna et al. (9) have shown that antagonizing the IGF-1 receptor inhibits autophagy by inhibiting mTORC2, PKCα/β, disrupting the actin cytoskeleton and endocytosis. The latter being important for autophagy.

What if experimental manipulation of IGF-1 used in aging studies (e.g. IGF1R +/-) also diminishes autophagy? We know that the most robust models of life extension (Snell, Ames and GHRKO) show both undetectable circulating IGF-1 and elevated autophagy. It is unclear why this is so. I do not know if autophagy studies in IGF1-deficient models have been carried out, but I have not looked very hard. This is an important direction for future research!

Finally, the authors, Renna et al., almost suggest the experiment I'm going to suggest. Almost:

“…it is tempting to speculate that one may be able to achieve synergistic benefits by inhibiting the key effectors of the IGF-1R pathway, alongside pharmacological stimulation of the autophagic pathway.”
I hope I am one of the first to actually spell it out: it is possible that inhibiting mTOR[C1] and IGF-signalling will have synergistic effects on lifespan, e.g. using rapamycin + picropodophyllotoxin (PPP, an IGF1R inhibitor).

Conclusions and Hypotheses
(Hypothesis 0: GH/IGF-1 signalling is involved and conserved in mammalian aging up to humans.)
Hypothesis 1: Inhibition of autophagy through IGF-1 antagonism may explain inconsistent lifespan data seen in mouse studies of the GH/IGF-1 pathway.
Hypothesis 2: Autophagy stimulation + IGF1R antagonism will increase lifespan to a larger extent than either of them alone.

1. J Gerontol A Biol Sci Med Sci. 2012 Jun;67(6):587-98. doi: 10.1093/gerona/gls115. Epub 2012 Apr 20.
Diverse roles of growth hormone and insulin-like growth factor-1 in mammalian aging: progress and controversies.
Sonntag WE, Csiszar A, deCabo R, Ferrucci L, Ungvari Z.

2. Somatotropic signaling: trade-offs between growth, reproductive development, and longevity.
Bartke A, Sun LY, Longo V.
Physiol Rev. 2013 Apr;93(2):571-98. doi: 10.1152/physrev.00006.2012. Review.

3. J Gerontol A Biol Sci Med Sci. 2013 May 16. [Epub ahead of print]
Young Little Mice Express a Premature Cardiovascular Aging Phenotype.
Reddy AK, Hartley CJ, Pham TT, Darlington G, Entman ML, Taffet GE.

4. Am J Physiol Heart Circ Physiol. 2008 Nov;295(5):H1882-94. doi: 10.1152/ajpheart.412.2008. Epub 2008 Aug 29.
Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice.
Csiszar A, Labinskyy N, Perez V, Recchia FA, Podlutsky A, Mukhopadhyay P, Losonczy G, Pacher P, Austad SN, Bartke A, Ungvari Z.

5. J Gerontol A Biol Sci Med Sci. 2012 Jun;67(6):553-64. doi: 10.1093/gerona/glr197. Epub 2011 Nov 10.
Growth hormone and IGF-1 deficiency exacerbate high-fat diet-induced endothelial impairment in obese Lewis dwarf rats: implications for vascular aging.
Bailey-Downs LC, Sosnowska D, Toth P, Mitschelen M, Gautam T, Henthorn JC, Ballabh P, Koller A, Farley JA, Sonntag WE, Csiszar A, Ungvari Z.

6. Aging Cell. 2013 Jul 30. doi: 10.1111/acel.12145. [Epub ahead of print]
Longevity effect of IGF-1R+/- mutation depends on genetic background-specific receptor activation.
Xu J, Gontier G, Chaker Z, Lacube P, Dupont J, Holzenberger M.


7. J Gerontol A Biol Sci Med Sci. 2013 Jul 20. [Epub ahead of print]
Mice Producing Reduced Levels of Insulin-Like Growth Factor Type 1 Display an Increase in Maximum, but not Mean, Life Span.
Lorenzini A, Salmon AB, Lerner C, Torres C, Ikeno Y, Motch S, McCarter R, Sell C.

8. Sasaki, T., et al. "Lifespan extension in the spontaneous dwarf rat and enhanced resistance to hyperoxia-induced mortality." Experimental gerontology (2013).

9. Hum Mol Genet. 2013 Jul 10. [Epub ahead of print]
IGF-1 receptor antagonism inhibits autophagy.
Renna M, Bento CF, Fleming A, Menzies FM, Siddiqi FH, Ravikumar B, Puri C, Garcia-Arencibia M, Sadiq O, Corrochano S, Carter S, Brown SD, Acevedo-Arozena A, Rubinsztein DC.