Attempting a Unified View of Aging and Loss of Regenerative Capacity

Today's open access paper from the AgeX Therapeutics folk discusses a conceptual framework for looking at aging and loss of regeneration in a unified way across: (a) evolutionary differences between highly regenerative lower species such as hydra and less regenerative higher species such as mammals, (b) the loss of regenerative capacity over the course of embryonic development, and (c) the loss of regenerative capacity that occurs with aging in individuals. It covers a lot of ground, and even the summaries could do with a shorter summary.

In essence this all ties back to the work being done at AgeX Therapeutics and elsewhere on the potential uses of induced pluripotency to produce regenerative therapies. The discovery that cells can be reprogrammed into what are essentially embryonic stem cells, known as induced pluripotent stem cells, was made a little over a decade ago. One of the most interesting outcomes of this process is that various markers of age found in the cells in old tissue are reversed. Epigenetic decorations characteristic of age are removed. A number of groups are working on ways to very carefully induce reprogramming-like outcomes in cells in the body in order to repair mitochondrial function and restore more youthful behavior.

This clearly cannot fix everything. It won't reverse stochastic nuclear DNA damage, for example. Further, since youthful cells cannot clear many of the forms of persistent metabolic waste that accumulate in and around long-lived cells, we should not expect this to greatly impact cross-linking or issues with dysfunctional lysosomes. We do know that mitochondrial dysfunction is very important in aging, however. It is implicated in the progression of many age-related conditions, particularly those of energy-hungry tissues such as the brain and muscles. It is worth chasing approaches that might effectively restore lost mitochondrial function. The major caveat here is cancer, of course. Methods of inducing pluripotency must be accomplished with great care.

Toward a unified theory of aging and regeneration

The advent of cell biology in the 19th century led to August Weismann's insightful hypothesis that heredity is transmitted by cells belonging to an immortal germ line, and that in most cases, the evolution of complex somatic cells and tissues is associated with a loss of immortal regeneration (somatic restriction) that results in aging. Thus, he correctly predicted the limited lifespan of cultured somatic cells due to cellular senescence. In 1957, George Williams hypothesized that aging evolved through a process of antagonistic pleiotropy, where traits benefitting fecundity early in life are selected for even though they simultaneously lead to age-related deterioration later in life. According to an emerging consensus view of the evolution of aging, primitive organisms showing negligible senescence have not traversed the Weismann barrier (loss of immortality and regeneration), while human somatic cell types cross the barrier early in development leading to downstream age-related change.

While certain evolutionarily primitive metazoans, and perhaps some vertebrates, show no evidence of aging, mammals typically show an exponential increase in the risk of mortality with age. Mammalian aging can be viewed as a global developmental program in many cells and tissues in the body wherein somatic cells are progressively restricted in their capacity for immortal regeneration. Accordingly, these steps begin with the repression of the expression of the catalytic component of telomerase TERT resulting in the antagonistic pleiotropic effect of decreased risk of cancer early in life but a finite replicative lifespan of somatic cells leading to cell and tissue aging later in life. Other genes such as TRIM71 also appear to be repressed at or around the time of the pluripotency transition, and the loss of expression may also play a role in restricting cell division. Moreover, subsequent developmental restrictions may also play a role in the cadence of developmental changes that repress tissue regeneration following the completion of organogenesis and subsequent growth. In summary, widespread gene expression changes, like TERT repression, occur early in the life cycle, in many tissues within the body, and these early changes may have an antagonistic pleiotropic effect later in life leading to tissue disrepair associated with aging.

Increasingly the theoretical framework underlying modern aging research is that progressive developmental transitions occur early in the life cycle that impact tissue regeneration and therefore aging in the body. The theory of somatic restriction highlights the dichotomy of the immortal regenerative potential of the germ-line compared to the terminal mortal phenotype of most differentiated somatic cell types. The theory posits that somatic restriction occurs progressively in stages (pluripotency to differentiating embryo, embryo to fetal, fetal to neonate, and neonate to fully grown adult) and that many of these transitions occur globally in multiple organ systems. This conceptual framework provides a context for more detailed analytical studies of developmentally-regulated molecular pathways that were selected for reproductive fitness early in the life cycle, but result in homeostatic decline and failure of organ systems in aging adults (antagonistic pleiotropy). We conclude that modern molecular approaches to regenerative medicine such as reprogramming cells to pluripotency or partially reprogramming to induce tissue regeneration effectively reverse most markers of aging and have significant potential for clinical application in aging.

Comments

"This clearly cannot fix everything. It won't reverse stochastic nuclear DNA damage, for example. "
Can you post real studies to support your claims?
You are repeating same old-school Sens ideas that are quite outdated now (just do a reality check on beta-amyloid clearance).
deGrey is working for AgeX for a while, and he is part of this paper.
You are like the story with the Japanese soldier that was left on a remote island and he was fighting the enemies after many years.
btw AgeX is also "messing with metabolism" as they have their BAT1:
https://www.agexinc.com/agex-therapeutics-publishes-data-in-peer-reviewed-journal-to-advance-potential-cell-therapy-agex-bat1-for-type-ii-diabetes-and-obesity/
degrey doesn't seem to be bothered by this "messing with metabolism" ... quite interesting

Posted by: z at September 6th, 2019 3:41 PM

Z - I'm not sure if you're actually being serious or just having a pop at the blog writter, but you are asking him to prove a negative. Until there is repeated evidence that partial cellular reprogramming can repair all forms or damage in the human body you've got to assume the that it cannot.

Also based on the fact that certain types of damage are extra cellular e.g. glucosepane crosslinks, it seems extremely unlikely that cellular reprogramming will do anything to it.

Posted by: jimofoz at September 8th, 2019 5:33 AM

Just to shine some extra light on this question / discussion as it gets a but confused at times

There is a bit of difference between cellular reprogramming and whole organism reprogramming

The former, per the technologies of AgeX, Turn, Salk, etc., are tools for in essence "cleaning up a cell" - epigenetic modifications, organelle remodeling, telomere "re"-longation, etc.

These are all variants from the original 1952 cloning experiments by Robert Briggs and Thomas J. King, modified by Gurdon, Jaenisch, Yamanaka, and many others etc. into the current day - and they are all pretty good, from one angle or another, in making a cell "younger / rejuvenated "

The latter, organism rejuvenation via reprogramming, is a bit more complicated, but can be summed up as such:

Organisms (such as amphibians, planarians, echinoderms, hydrozoans, etc.) that have the ability to "turn back biological time", to regenerate / repair / rejuvenate most (or all) of their bodies, possess two inherent capabilities that they use in synergy: 1) The ability to re-establish the "embryogenic" potential of their cells / genomes / gene regulatory networks (per inherent cellular reprogramming dynamics - like above),

AND, of equal, if not greater, importance,

2) ...the ability to re-establish the "morphodynamic" architecture of their tissues / organs / limbs / body segments

The latter involves many other things beyond cell reprogramming - ECM remodeling, activation of the innate immune response, membrane potential changes, and a long additional list of other stuff that I won't take up space with here

But the point is, it is in the context of the regenerative micro-environments that RESULT from this reprogrammed cellular flexibility that we see the really neat stuff happening - not just in these "lower" non-human species, but also in mammalian embryos - this is why you can "dump" all sorts of "junk" into a mammalian embryos (somatic tissues, viruses, cancer cells, etc.) and it all gets organized out

Here are some links to nice reviews on the general theme of regenerative micro-environments and their ability to organize in / out stuff they don't need, and well as modify the diseased phenotype. 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) and cellular competition (seen in both development and the maintenance of tissue fitness)

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

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

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

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/

The point is that for whole organism human rejuvenation using such tools, especially for complex tissues and organs, we will need to go beyond just throwing in reprogramming factors and walking away

But there is tremendous potential with these tools if used correctly in the right bio-dyanmic context

Posted by: Ira S. Pastor at September 8th, 2019 7:26 AM

Ira: "dump all sorts of "junk" into mammalian embryos (..viruses...) and it all gets organized out."
How then come for example motherĀ“s viruses like CMV get tansfered / inherited ?

On a different note: Any information available (or anyone so far tried research or at least having thought intelligently) about any connection/possible causalities between immune mechanisms and regeneration/ rejuvenation ?

Posted by: Art F at September 9th, 2019 12:29 AM

@Art F

Embryos have fascinating mechanisms at play for silencing and extinction of many viruses, due to their lacking a traditional interferon based anti-viral response - here's a couple neat papers on the topic but you can find countless others in the literature:

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003865

https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(10)00112-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1934590910001128%3Fshowall%3Dtrue

Similarly, there are many papers on how the modulation of the innate immune response, versus the adaptive immune response, benefits complex regeneration in such organisms:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171206/

https://www.ncbi.nlm.nih.gov/pubmed/28667562

https://www.ncbi.nlm.nih.gov/pubmed/28119112

Have fun reading up on these topics

Posted by: Ira S. Pastor at September 9th, 2019 4:06 AM

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