NANOG Expression versus Cellular Senescence

Are there many strategies that can reverse cellular senescence? There are certainly strategies that can lower levels of cellular senescence over time, both in cell cultures and in living animals, but very few are actually reprogramming senescent cells into normal cells. It isn't clear that this reversal of the senescent state is a good idea, given that there is usually a good reason for at least some of such cells to be senescent, such as potentially cancerous mutations. The strategy described here is probably not causing senescent cells to become normal cells in any great number, but rather lowering the rate at which cells become senescent or encouraging senescent cells to self-destruct more rapidly, as well as encouraging normal cells to replicate more rapidly, thus diluting the senescent fraction of the population.

Cellular rejuvenation occurs naturally in embryonic development when sperm and egg (each having a certain chronological age) fuse to each other to form an embryo of age zero. Similarly, reprogramming of somatic cells to pluripotency, producing induced pluripotent stem cells (iPSCs), resets their biological clock as well. At this stage, a core network of transcription factors including NANOG, OCT4, and SOX2 maintains pluripotency in embryonic stem cells (ESCs) and iPSCs. In particular, the pluripotency factor NANOG is essential for maintaining the self-renewal of ESCs over many population doublings.

Although overexpression of NANOG does not confer pluripotency to somatic cells, it has been shown to restore several cellular functions that are compromised by aging including proliferation and differentiation of senescent fibroblasts and mesenchymal stem cells. In vivo endogenous expression of this transcription factor in stratified epithelia of adult mice showed that systemic overexpression of NANOG induces hyperplasia without initiating tumors.

Recently, we discovered that expression of NANOG in myoblasts restored their myogenic differentiation potential, as evidenced by expression of myogenic regulatory factors and the ability to form myotubes, which was impaired by replicative senescence. This result prompted us to investigate the anti-aging effects of NANOG on primary human myoblasts and in skeletal muscle tissue in vivo. Here, we show that overexpression of NANOG reversed the hallmarks of cellular senescence in muscle progenitors in vitro and restored the satellite cell abundance in the skeletal muscle of progeroid mice.



One obvious unstated problem here is that NANOG has been closely linked in a number of papers to tumorigenesis. For one of many studies, see Jeter et al. 2015, available in full here:

This is hardly an unknown issue. Jeter et al. have been cited in 154 later papers, including papers out this year. The authors of the new paper are surely aware of this problem. They just chose not to mention it, which is often the case in papers like this. The same problem is found in papers on the supposed anti-aging powers of NAD+ precursors.

Pleiotropy rules as always. What is sad is the way people desperate for public attention ignore it.

Posted by: Steve Farmer, PhD at September 18th, 2021 1:07 PM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.