Towards Reprogramming with Small Molecules

A great deal of modern medicine starts out as genetic studies in cells and animal models, but then the programs abandon genetics to use small molecules to produce a small fraction of the effect of the genetic alteration of interest. The reasons for this have a lot to do with the high cost of regulation and conservatism of funding sources, to the point at which the development of a poor therapy using well-proven approaches is very much favored over the development of a much better therapy using new approaches. In the broader sense, in the longer term, the true promise of gene therapies, the various approaches that dial up and dial down the expression of specific genes, is that the research and development industry can stop producing treatments that are objectively bad in comparison to the alterations of gene expression that inspired them.

Given the state of the industry today, however, one should absolutely expect that any promising form of therapy derived from genetic studies will be the subject of intense effort to translate it into a small molecule treatment that produces only a fraction of the benefits. So it goes with cellular reprogramming as an approach to rejuvenation, resetting epigenetic patterns in old cells by overexpressing the Yamanaka factors, typically for only a short period of time. Researchers are trying to find combinations of small molecules that tinker with transcription factor expression or downstream mechanisms to use in place of the mRNA therapies currently employed for partial reprogramming of cells in animal studies. It will be interesting to see the degree to which they succeed as this initiative moves forward in the years ahead.

Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan

The dedifferentiation of somatic cells into a pluripotent state by cellular reprogramming coincides with a reversal of age-associated molecular hallmarks. Although transcription factor induced cellular reprogramming has been shown to ameliorate these aging phenotypes in human cells and extend health and lifespan in mice, translational applications of this approach are still limited. More recently, chemical reprogramming via small molecule cocktails have demonstrated a similar ability to induce pluripotency in vitro, however, its potential impact on aging is unknown.

Here, we demonstrated that partial chemical reprogramming is able to improve key drivers of aging including genomic instability and epigenetic alterations in aged human cells. Moreover, we identified an optimized combination of two reprogramming molecules sufficient to induce the amelioration of additional aging phenotypes including cellular senescence and oxidative stress. Importantly, in vivo application of this two-chemical combination significantly extended C. elegans lifespan by 42%. Together, these data demonstrate that improvement of key drivers of aging and lifespan extension is possible via chemical induced partial reprogramming, opening a path towards future translational applications.

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