Epigenetic Rejuvenation (3)
Dreams of Perpetual Youth (5)
Research aimed at reversing the aging process has increasingly moved to the private sector. Private corporate research has a much different ethos than public research, given the divergent incentives. In public research the aim is to enhance your reputation, in privatized research the aim is to become wealthy. Some researchers have a foot in both realms, attempting to have it both ways. David Sinclair is a success story in this respect*. He has more social media followers than many celebrities from the world of entertainment (including sports). Call it celebrity science. As a celebrity scientist it matters less to him, and apparently Harvard University, that the research on which he made himself rich and famous is viewed with disdain by many disinterested scientists (and Glaxo Smith Kline, though they have invested too much money in his sirtuin con to admit that.) On the academic side, he seduced many scientists into investing their reputations on sirtuins,. Hence, the sirtuin as anti-aging elixir story continues, only partly abated within the scientific community. The uninitiated would be forgiven for thinking that it is still full speed ahead on the anti-aging effects of sirtuins. It took an outsider, in both the public and private spheres, to initially call bullshit, as I discussed in the previous post in this series.
Sirtuins are indirect epigenetic actors. When bound to NAD (nicotinamide adenine dinucleotide) they can influence how tightly histones bind to DNA, thereby altering gene activity. Without NAD sirtuins are inert. Not so NAD sans sirtuins. NAD has many fundamental cellular functions related to aging independent of sirtuins. And NAD—but not sirtuin-- levels are known to decline with age.
Sinclair himself has now moved on from sirtuins. His recent research is directed toward aging as it relates to something he calls “epigenetic information”, which is the foundation of his new “Information Theory of Aging” (10.1038/s43587-023-00527-6). The premise is that aging is caused by the loss of epigenetic information. Whether the epigenetic changes associated with aging should be considered a loss of epigenetic information or just progressive alteration of epigenetic states is certainly debatable. Sinclair uses the information idiom metaphorically, not at all in the technical information theoretic sense, in which information gain or loss can actually be measured in bits and bytes. As such, the term information functions mainly as a zeitgeisty gloss, without theoretical weight. Ergo, his Information Theory of Aging is not a theory at all, more like a narrative framework.
Be that as it may, Sinclair views rejuvenation as the restoration of epigenetic information, or, even more idiosyncratically, as accessing a backup epigenetic program that all cells putatively have in reserve. On this view, embryonic stem cells have more epigenetic information than fully differentiated cells, such as neurons and fibroblasts. The Yamanaka factors create and or unmask this epigenetic information. When used to create the analogs of embryonic stem cells that we call induced pluripotent stem cells (iPSCs), the lost epigenetic information is restored by the Yamanaka factors. When used to partially reprogram cells, as in rejuvenation research, the restoration of epigenetic information is partial. Are we to believe, then, that embryonic stem cells, which essentially lack DNA methylation, nonetheless contain more epigenetic information than differentiated cells? Or is it when cells first fully differentiate that their epigenetic information is maximal and then progressively lost? This makes no sense whatsoever. The information speak just muddies the waters.
In his recent rejuvenation papers, Sinclair reiterates his epigenetic information—I refuse to call it a theory—story. But notwithstanding this silly framework, his most recent research is noteworthy as a step beyond the Yamanaka factors. In this regard, though, the work of the Sinclair lab is in no way pioneering.
The Yamanaka factors are key transcription factors that regulate the activity of many genes. Until quite recently, the strategy for creating induced pluripotent stem cells was to insert the genes that code for the Yamanaka factors into the genomes of cultured cells, often with viral vectors. This is essentially the same technique employed in gene therapies for various medical maladies. It is good old fashioned genetic engineering. In its medical applications, including rejuvenation research, the technology is expensive and inefficient.
A group of Stanford researchers made an important advance by bypassing the genetic engineering. Instead, they introduced (called transfection) the messenger RNA for the Yamanaka factors into the cell cultures. With the addition of two other transcription factors they were able to efficiently produce pluripotent stem cells, as efficiently as when the Yamanaka factors were incorporated into the genome (PMC7093390). This was a huge advance in rejuvenation research.
The next step was to bypass the mRNA step, and directly introduce biochemicals that enhance epigenetic rejuvenation, often but not necessarily via the Yamanaka factors. (10.1038/s41586-022-04593-5. In other words, a much more varied set of biochemical actors that don’t need to be genetically engineered, or even transfected.
Sinclair’s group built on this research. They tested six cocktails of five or six biochemicals chosen for their known epigenetic influences. (None of these cocktails, it should be noted, included sirtuins, resveratrol or rapamycin.) The efficacy of the cocktails varied somewhat but all showed promise with respect to the measure of rejuvenation employed in the study.
That rejuvenation measure requires some scrutiny. According to Sinclair, one of the widely recognized hallmarks of aging is a leaky cell nucleus. That is, the membrane separating the contents of the nucleus from those of the rest of the cell, become permeable in senescent cells. However, a leaky nucleus is not recognized as one of the twelve hallmarks of aging, much less “a widely recognized” one (10.1016/j.cell.2022.11.001; here is one reference cited by Sinclair: PMC2805151). Senescent cells are certainly one of the twelve hallmarks of aging, but a leaky nucleus is not one of the widely recognized hallmarks of senescent cells.
Nonetheless, the criterion for rejuvenation in this study was to reduce this leakage in senescent fibroblast cells maintained in vitro. The goal was not to convert these senescent fibroblast cells into fully functional fibroblast cells. Rejuvenation-wise that’s a low bar. We’re not talking about causing an old blind mouse to regain vision, or anything approaching that. Nonetheless, these results, if replicable, may be a step forward in chemical rejuvenation, which is a step forward with respect to rejuvenation based on the genetically engineered Yamanaka factors.
*All scientific research reports require author disclaimers with respect to potential conflicts of interest. This began when scientists, especially molecular biologists, mixed public funds with those from corporations with which they had financial stakes. Sinclair’s conflict of interest statement is almost comical in its extent. He lists half a dozen or so corporations but that list is not exhaustive. For the rest he refers the reader to his Harvard website.