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New perspective in gerontology: epigenetic rejuvenation

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Can biological age be set back by “making the clock tick backwards”? Scientists suggest that a partial phenotypic rejuvenation can be gained.

Since the discovery of cell reprogramming, the view of aging has evolved, leading scientists to consider aging as a reversible epigenetic process [1,2,3]. The epigenome has been proposed as the driver of aging, supported by a recent discovery that the level of age-related methylation of a set of cytosine-guanine dinucleotides (CpG) located at specific positions on DNA, constitutes a highly reliable biomarker of aging defined by the multi-tissue age predictor, also known as the epigenetic clock, devised by Stephen Horvath [4].

Longevity.Technology: The epigenetic clock may be the pacemaker of aging and epigenetic rejuvenation has been proposed as a strategy to reveal to what extent biological age can be set back by making the clock tick backwards. We now have molecular tools, such as the Yamanaka factors (OSKM genes), that allow us to make the clock tick backwards, moving from aging research to epigenetic rejuvenation research.

A recent paper by the National University of La Plata team concludes that epigenetic rejuvenation seems to hold the key to arresting or even reversing organismal aging.

What is epigenetic aging?

Biological age refers to the functional and structural status of an organism at a given age. In humans, the epigenetic clock predicts biological age with high accuracy when applied to DNA taken from different tissues [4,5]. The rate of change in DNA methylation at age-dependent CpGs represents the ticking rate of the epigenetic clock. This is significantly correlated with the rate of biological aging in health and disease. Indeed, several pathologies are associated with accelerated epigenetic aging and the correlation between the rate of epigenetic and biological aging suggests that the DNAm clock may be the driver of organismal aging.

Cell Reprogramming and Stem Cell Therapy Group
Members of the Cell Reprogramming and Stem Cell Therapy Group from the National University of La Plata.

It is known that cell reprogramming rejuvenates cells. In 2011, a French group led by J M Lemaitre was able to reprogram skin fibroblasts from healthy centenarians into induced pluripotent stem (iPS) cells [6]. The incubation of iPS cells with a differentiation cocktail induced them to differentiate back into fibroblasts, which were indistinguishable from skin fibroblasts from young counterparts, thus demonstrating that the centenarians’ fibroblasts had been rejuvenated [6]. Cell rejuvenation studies like this one suggest that even at advanced ages the epigenome remains responsive to command signals, supporting the hypothesis that aging is not associated with deterioration of epigenetic mechanisms.

Morphological changes
Morphological changes induced by long-term OSKM gene action in human umbilical cord perivascular cells (HUCPVC). (A) HUCPVC incubated for 7 days with an adenovector expressing a polyscistron harboring OSKM and GFP genes. Phase contrast microscopy; (B) The same field observed under fluorescence microscopy. (C) HUCPVC incubated for 85 days with the above OSKM-GFP adenovector. Phase contrast microscopy; (D) The same field as in C observed under fluorescence microscopy. Inset (E) Control intact HUCPVC on Experimental day 7. Obj X 4 in all panels. (Goya et al., unpublished results) Source: Rodolfo G. Goya

Cyclic partial cell reprogramming has been described as a strategy to perform safe rejuvenation in vivo. This strategy is based on multiple cycles of interrupted reprogramming in which OSKM gene transcription is turned on briefly and then turned off by using regulatable promoters. In each cycle the process erases some epigenetic marks of age, sparing the epigenetic marks of cell identity [7]. So far, two studies have reported the implementation of cyclic partial cell reprogramming in vivo in mice [8,9].

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Can epigenetic age be changed?

The main limitation of cyclic partial reprogramming is that the phenotype is not completely rejuvenated. Studies using non-reprogramming strategies have also confirmed the reversal of epigenetic age associated with partial rejuvenation of the phenotype. Horvath and colleagues found out that the protein fraction from young mice plasma can markedly set back the epigenetic age of some tissues in old rats, although the old rats are not brought back to a complete young condition [10].

Making the clock tick backwards

Overall, these findings reveal that when the clock is forced to tick backwards in vivo, it is only able to drag the phenotype to a partially rejuvenated condition [8,9]. Although further investigation is needed, epigenetic rejuvenation by cyclic partial reprogramming or alternative non-reprogramming strategies seems to hold the key to both, understanding the mechanism by which the epigenome drives the aging process and arresting or even reversing organismal aging.

[1] https://doi.org/10.1016/j.cell.2012.01.003
[2] https://doi.org/10.1159/000477209
[3] https://doi.org/10.1186/s13287-018-1075-y
[4] https://doi.org/10.1186/gb-2013-14-10-r115
[5] https://doi.org/10.1016/B978-0-12-811060-7.00004-8
[6] https://doi.org/10.1101/gad.173922.111
[7] https://doi.org/10.2174/1566523219666190902154511
[8] https://doi.org/10.1016/j.cell.2016.11.052
[9] https://doi.org/10.1016/j.stemcr.2020.09.010
[10] https://www.biorxiv.org/content/10.1101/2020.05.07.082917v1.full.pdf

Images courtesy of Rodolfo G. Goya

2 COMMENTS

    • Hi David – response from Rodolfo Goya;

      ‘Sinclair vision restoration paper shows that when the OSK genes are delivered in vivo to the mouse retina via a viral vector , they have a clear regenerative effect. Furthermore, expression of OSK for weeks does not have any tumorigenic effect on the mice. In contrast, when he turned on the OSK genes in a transgenic mouse they constructed, the effects of the genes were highly toxic and the animals died in less than a week. That is a paradoxical behavior of the OKS genes.

      Elevant

      In the same line, it is well establishes that expression of the OSKM genes in vivo in transgenic mice is also toxic and kills the animals in a few days due to the generation of multiple tumors. Our experiments shown on Figure 3 shows that when an OSKM vector is delivered via a viral vector to human cells they do not show toxic effects even after 85 days of continuous expression. This shows that OSKM genes show the same paradoxical behavior than OSK. So the difference between our research and Sinclair’s is that we proved this paradoxical behavior in OSKM genes while he did that with OSK genes. Overall, our results and Sinclair’s point to the same direction.’

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Eleanor Garth
Deputy Editor Now a science and medicine journalist, Eleanor worked as a consultant for university spin-out companies and provided research support at Imperial College London and various London hospitals in a former life.
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