Freitag, 5. Dezember 2014

Parabiosis enabled mouse rejuvenation - will the data transfer to humans?

Two recent papers make you wonder, will the mouse aging data ever translate to humans? So far we have found out that mouse cancer data rarely applies to humans, but anti-aging interventions have never been tested in humans before.

Katsimpardi et al. 2014 (1a) (Wagers and Rubin labs)
GDF-11 leads to "Vascular and neurogenic rejuvenation of the aging mouse brain". Interestingly, the protein, which has been indentified in parabiosis experiments (3), is related to myostatin (!) and a "circulating transforming growth factor–β (TGF-β) family member". It also "reverses cardiac hypertrophy in aged mice" apparently mimicking many effects of actual parabiosis.

And as a side-note: "Systemic factors in old blood can have detrimental effects on hippocampal neurogenesis in young animals..."

Personal conclusion
It is time for a rejuvenation lifespan study, i.e. administration of GDF11 to aged mice and end-of-life assesment of function plus lifespan. The results are so good that pilot studies in humans should immediately commence. If they have not yet started the clinical and preclinical work necessary to move into humans*, then I do agree with the critics: something is fucking wrong with our regulatory framework. Not everything, mind you, but a treatment like this calls for immediate follow-up.

* e.g. microdose Phase I studies of different recombinant GDF-11 forms, as well as studies with human plasma (see commentary to ref. 1)

Bredenkamp, Nowell, Blackburn 2014 (2)
This group presents another single-factor rejuvenation study.

The problem as explained by the authors:
The thymus, the obligate site of T lymphocyte development (Miller, 1961), is one of the first organs to degenerate in normal healthy individuals (Chinn et al., 2012). This process, termed ‘age-related thymic involution’, results in decreased production of naive T cells with age (Weng, 2006; Lynch et al., 2009; Chinn et al., 2012). This reduced output of naive T cells severely impairs the immune response to newly encountered antigens, making thymic involution a major cause of the age-related decline in immune system function.
The solution:
"upregulating [artificially tamoxifen-inducible] FOXN1 specifically in TECs [thymic epithelial cells] in the fully involuted thymus".

The result:
What is most striking is the rejuvenation and restoration of the thymic molecular architecture, e.g. "although functional FOXN1 was upregulated in all TECs, FOXN1 targets maintained their expected TEC subset-specific expression".
Note, The effect is driven in part by increased proliferation.

"Our data thus demonstrate unequivocally that FOXN1 upregulation is sufficient to reverse the crucial hallmarks of age-related thymic involution, based on all parameters commonly used to measure thymus structure and function."

And although there was "increased numbers of naive T cells exported to peripheral lymphoid organs", we are missing long-term functional outcomes. Bring on the rejuvenation studies!

Teleologic questions
Aging is generally understood through the lens of evolution, e.g. "mutation accumulation" and "antagonistic pleiotropy".
It remains unclear why these factors, the transcription factor FOXN1 and the secreted GDF-11, are downregulated in aging. If there is no cost to keeping them high and maintaining healthy tissues, then this would yield a selective advantage even if only <<10% of animals are alive at ages when it matters. In the case of FOXN1, we can speculate that an increase in proliferation would lead to excess tumorigenesis at middle age. This would be consistent with antagonistic pleiotropy.

References
1.a. Science. 2014 May 9;344(6184):630-4. doi: 10.1126/science.1251141. Epub 2014 May 5. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Katsimpardi L1, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL.

1.b. Science. 2014 May 9;344(6184):649-52. doi: 10.1126/science.1251152. Epub 2014 May 5.Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle.Sinha M1, Jang YC, Oh J, Khong D, Wu EY, Manohar R, Miller C, Regalado SG, Loffredo FS, Pancoast JR, Hirshman MF, Lebowitz J, Shadrach JL, Cerletti M, Kim MJ, Serwold T, Goodyear LJ, Rosner B, Lee RT, Wagers AJ.

Commentary: http://www.sciencemag.org/content/344/6184/570.full

2. Development. 2014 Apr;141(8):1627-37. doi: 10.1242/dev.103614. Regeneration of the aged thymus by a single transcription factor. Bredenkamp N1, Nowell CS, Blackburn CC.

3. Cell. 2013 May 9;153(4):828-39. doi: 10.1016/j.cell.2013.04.015.
Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy.
Loffredo FS1, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P, Sinha M, Dall'Osso C, Khong D, Shadrach JL, Miller CM, Singer BS, Stewart A, Psychogios N, Gerszten RE, Hartigan AJ, Kim MJ, Serwold T, Wagers AJ, Lee RT.

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