A Few of the Important Differences in Regeneration Between Young and Old Hearts

Young enough hearts, soon after birth, are much more regenerative than adult hearts. Some species, such as zebrafish, never lose the youthful ability to regenerate damaged or lost sections of heart tissue. Mammals, however, all too quickly grow into an inferior regenerative capacity, most evident after injury to the nervous system or the heart. Is it possible to find the systems of molecular regulation that shut down very early in life, and at least temporarily and partially restore the ability to regenerate the heart without scarring, or to turn back heart failure? Finding the important parts of the complex network of genes and proteins that controls regeneration is a work in progress, and this open access paper covers some of what has been discovered to date. Answering the question of whether or not these discoveries can be used to safely enable regeneration, without risk of cancer or other issues, is similarly in progress. There have been interesting demonstrations in mice in the past few years, for example.

While a regenerative response is limited in the mammalian adult heart, it has been recently shown that the neonatal mammalian heart possesses a marked but transient capacity for regeneration after cardiac injury, including myocardial infarction. These findings evidence that the mammalian heart still retains a regenerative capacity and highlights the concept that the expression of distinct molecular switches (that activate or inhibit cellular mechanisms regulating tissue development and regeneration) vary during different stages of life, indicating that cardiac regeneration is an age-dependent process. Thus, understanding the mechanisms underpinning regeneration in the neonatal-infarcted heart is crucial to develop new treatments aimed at improving cardiovascular regeneration in the adult.

The present review summarizes the current knowledge on the pathways and factors that are known to determine cardiac regeneration in the neonatal-infarcted heart. In particular, we will focus on the effects of microRNA manipulation in regulating cardiomyocyte proliferation and regeneration, as well as on the role of the Hippo signaling pathway and Meis1 in the regenerative response of the neonatal-infarcted heart. We will also briefly comment on the role of macrophages in scar formation of the adult-infarcted heart or their contribution for scar-free regeneration of the neonatal mouse heart after myocardial infarction. Although additional research is needed in order to identify other factors that regulate cardiovascular regeneration, these pathways represent potential therapeutic targets for rejuvenation of aging hearts and for improving regeneration of the adult-infarcted heart.

Link: https://doi.org/10.3389/fcvm.2018.00007

Comments

This new science of regeneration is very much catching my interest. AgeX, George Church and a few others are working on this. Animal studies have been done and I wonder what the results are like.

From my understanding, its pretty powerful stuff, but it won't undo the damage that the body can't deal with naturally. So I would assume that this combined with SENS therapies would be a really good way to go.

Does anyone have any info on what we can expect from this kind of technology?

Posted by: Mark Borbely at February 26th, 2018 9:54 AM

@Mark Borbely

In my opinion, we can expect quite a bit from it.

The elegance of the regenerators in nature is not just their remarkable ability to "turn back time" at a cellular level, but the "re-organization" dynamics within the higher level tissue architectures

FYI - I've posted some of these before, but here are some links to nice reviews on the general theme of regenerative micro-environments and their ability to organize in / out, and well as modify the diseased phenotype:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706275/

downloads.hindawi.com/journals/tswj/2010/742904.pdf

The seminal work on embryos and teratocarcinoma was done by Mintz et al in Philadelphia in the 1970s:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC433040/

Similar dynamics also occur in the plant kingdom:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC335936/

As a subset of this re-organization theme, here are also papers on the topics of revertant mosaicism (primarily seen in tissues with an active regenerative niche), cellular competition (seen in both development and the maintenance of tissue fitness), and the correction of aneuploidy in early human embryos - all interesting human dynamics for re-organizing tissue and eliminating the "junk"

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1735296/pdf/v040p00721.pdf

http://jcb.rupress.org/content/200/6/689.full

http://precedings.nature.com/documents/6045/version/1/files/npre20116045-1.pdf

Nature has much to teach us still

Posted by: Ira S. Pastor at February 26th, 2018 11:01 AM

@Mark Borbely

Also of interest are a couple related topics:

- The paradoxical positive connections now emerging between the innate immune response and regeneration that are showing up in the literature which highlight how aspects of the response benefits regenerative ability

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102125

http://www.sciencedirect.com/science/article/pii/S1044532314000621

http://www.nature.com/nri/journal/v13/n6/full/nri3460.html

- The unique mechanisms for viral silencing and extinction, found during embryogenesis, due the need to protect the early embryo and their lack of interferon based anti-viral mechanisms:

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1003865

http://www.sciencedirect.com/science/article/pii/S1934590910001128

http://www.nature.com/mt/journal/v21/n8/full/mt2013131a.html

http://www.retrovirology.com/content/11/1/31

http://humrep.oxfordjournals.org/content/17/3/760.long

http://www.nature.com/mt/journal/v3/n4/pdf/mt200176a.pdf

Have fun reading

Posted by: Ira S. Pastor at February 26th, 2018 11:15 AM

Thanks Ira!
I've been looking for some reading material this week.

You are right at Ground Zero for this kind of tech. I'm really interested in the trials you are going to carry out in South Africa this year! Keep us posted.

Posted by: Mark Borbely at February 26th, 2018 3:33 PM

@Mark Borbely, this is really a part of SENS, namely RepleniSENS. In strict sense you can think of RepleniSENS as of only ex vivo cell therapies, but more widely this includes any technology that fixes cell loss, including new organs. Of course, that fixes damage because cell loss is a damage! When you grow new organ, one is young, damage free. I like WICT approach, which combined with WILT looks like all-in-one solution for ageing.

Posted by: Ariel at February 26th, 2018 4:33 PM

@Ariel

There are other components to a WILT/WICT strategy that would need to be ironed out first before it was anything like "all-in-one" solution (putting aside of course its own translational hurdles of it as a therapeutic intervention)

Part of this has to do with the "cross-age" transplantation research literature from the 1940s-1970s regenerative biology era, where you find a wealth of papers documenting the dynamics how putting "young into old" does much worse than "old into young" due to the older body's negative "micro-environmental mellieu"

The other part has to do with all the altered hierarchies above the genes / cells that factor into what is going on below (tissue membrane potentials, biomechanics / tensegrity of the extracellular space, viscoelascocity of bio-fluids, etc.)

What makes Turritopisis trans-differentiation, or newt limb regeneration, or other proxies, so perfect throughout a lifetime is not just a cell level replacement of some old with some new, but a whole systems process of change - all of which must be taken into account for "all-in-one" rejuvenation

Posted by: Ira S. Pastor at February 27th, 2018 9:04 AM

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