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Reprogramming aging

Reprogramming is considered to be the potential medical miracle of the century, it should in principle help repair malfunctioning organs, or even replace them. But could it also be good for aging?

Late last year an article showed for the first time how the same strategy used for cell reprogramming, that is, to return mature cells to their totipotent state can also be used for delaying aging…at least in mice.

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Credit: Grskovic and Ramahlo-Santos. The pluripotent transcriptome (October 10, 2008), StemBook, ed. The Stem Cell Research Community, StemBook, doi/10.3824/stembook.1.24.1

Alejandro Ocampo and colleagues genetically engineered a progeria (genetic disease that leads to preterm aging) mouse model in which a cassete including the transcription factors Oct4, Sox2, Klf4 and c-Myc, also known as Yamanaka factors since it was him how showed their reprogramming effects, and which by altering the epigenetic marks on the cells’ genome, reverts them back to young healthy cells..

These factors had already been used to reprogramm cells in vivo but led to a increased cancer (totipotent cells and cancer cells have a lot in common), therefore there were doubts on the potential to serve as youth elixir. However, Ocampo’s group took a different approximation to the problem: since they didn’t want to go back to the beginning but just a few steps back they decided to activate gene expresion with a drug: doxycycline, which they then administer only twice a week. They found that these progeroid animals, when treated with doxycycline, lived up to six weeks longer than their untreated counterparts, and that without increasing cancer rates.

To test if this effect was extrapolable to healthy old mice, they followed the same protocol on middle-age mice (around 1 year of age), and found that treated mice showed an improvement in certain tissues like muscle or pancreas, but could not confirm if these effects were global or just restricted to a set or organs/tissues.

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Would one day be possible to get to this wothout surgery? Credit: Trevorristow

There remain other unanswered questions: it is still not clear what is the mechanism making possible this life extension, on one hand it is possible that these proteins help drive some senescent cells back to pluripotent cells, helping then rejuvenate the tissue they belong to, or it could be that it stops senescent cells from dying, which might be potentially dangerous since these cells accumulate genetic problems that might lead to cancer, if not taken out of the circulation.

Most likely, such an intervention will not be possible in humans (a genetically engineered mouse is far from a genetically engineered human, both ethically and biologically), at least for a while, but there should be not much of a problem with administering drugs that produce similar effects to the insertion and activation of these factors on the epigenome. Moreover, this strategy must prove to be save and not increase cancer. But of course till then, that is just science fiction.

In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Ocampo, Alejandro et al. Cell , Volume 167 , Issue 7 , 1719 – 1733.e12

For further reading:

Rethinking differentiation: stem cells, regeneration, and plasticity. Sánchez Alvarado A, Yamanaka S.Cell. 2014 Mar 27;157(1):110-9

Induction of pluripotency by defined factors. Tanabe K, Takahashi K, Yamanaka S. Proc Jpn Acad Ser B Phys Biol Sci. 2014;90(3):83-96

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