Cellular reprogramming involves expressing the Yamanaka factors discovered twenty years ago. Given robust expression over days, a somatic cell dedifferentiates into an induced pluripotent stem cell, replicating what happens to germline cells in early embryonic development. But with just a little expression of the Yamanaka factors, partial reprogramming occurs: the cell retains its state but resets its epigenetic control of nuclear DNA structure and gene expression to be more youthful. This is a desirable goal for the medical community, and in recent years a very large amount of funding has poured into early stage development programs aimed at producing rejuvenation therapies based on partial reprogramming. It remains to be seen as to how well this will go.
A hoped-for ideal is body-wide reprogramming, to hit every cell in an aged body and brain to restore youthful function to the degree that this is possible given damage to nuclear DNA, signaling environment, extracellular matrix, and so forth. One of the more interesting lines of research to emerge from the cellular reprogramming field is the use of small molecules to induce the expression of Yamanaka factors. Gene therapies are always going to be more effective at producing the altered gene expression one wants, and are more easily tailored to produce specific outcomes inside a cell, but gene therapies have at present several large disadvantages, all of which revolve around the delivery systems necessary to carry nucleic acids into cells. There is no good way to deliver a gene therapy fairly uniformly to the whole body; even the best approaches largely end up in the liver and lungs when injected intravenously. The delivery systems have dose limiting toxicities that mean that the largest whole body dose one could deliver, so as not to overload the liver and lungs, do not deliver meaningful amounts of the payload to other organs.
Small molecules, on the other hand, largely have this desirable characteristic of body-wide delivery. So there is a growing literature of studies making use of the few small molecules known to induce expression of one or more of the Yamanaka factors. A few companies appear to be quietly conducting screening programs to find more such small molecules, but these are early days yet. Today's open access paper is illustrative of some of the work taking place to assess the capabilities of existing reprogramming small molecules; it is in vitro rather than in vivo, and focused on one specific capability of tissue that declines with age. Researchers would typically move on from here to animal studies or screening for further similar small molecules with better specificity or side-effect profiles.
Vascular function is highly impaired during aging, and vascular dysfunction is the underlying cause of cardiovascular diseases, the leading cause of death worldwide. Clinically these alterations are among others observable by an increased systolic blood pressure and increased size and stiffness of the large arteries. Recent studies indicate that these alterations mainly result from a dysfunctional endothelium developing with advancing age. The existence of senescent endothelial cells can draw a causal correlation between aging, endothelial dysfunction, and cardiovascular diseases. Senescent cells accumulate over the life span in the vasculature, in older healthy humans and in diseased tissue in the pathogenesis of heart failure or ischemic heart disease. Senescent cells negatively impact several downstream pathways such as inflammation, DNA damage, molecular regulators as well as cell cycle regulation. Together, these processes lead to an impaired function of the aged endothelium by mainly minimizing the angiogenic and regenerative potential.
This makes reversing and rejuvenating senescent endothelial cells a highly interesting target to improve vascular regeneration in old individuals. Currently, different approaches to counteract cellular senescence are under intensive investigation, such as the use of senolytics to induce cell death or the process of cellular reprogramming mainly relying on viral transduction. The concept of cellular reprogramming was originally used to illustrate the transformation of somatic cells into induced pluripotent stem cells using retroviral overexpression of OCT3/4, SOX2, KLF4, and c-MYC (OSMK). This reprogramming has exhibited therapeutic promise and has also indicated the potential to reverse aging-related traits, particularly evident in initial experiments conducted on senescent and centenarian cells. However, prolonged induction of OSKM using viral methods in living organisms has led to teratoma formation and changes in DNA methylation patterns. In the context of aging and cellular senescence, the term cellular reprogramming has been more commonly associated with the rejuvenation process of senescent cells rather than the generation of pluripotent stem cells.
Here, we aimed to develop a pharmacological strategy to improve senescent endothelial cell function, especially in the context of angiogenesis. Recently, a cocktail of small pharmacological compounds was presented, that contributed to liver regeneration and hepatic function in vivo by promoting cellular reprogramming. This cocktail is composed of three compounds, namely tranilast, valproic acid, and lithium carbonate. All three substances are not only described for their supporting regenerative effect but also for beneficial effects on aging. Indeed, here we are the first to demonstrate that the cocktail favors a reversion of the EC senescent phenotype in vitro. Importantly, all three substances are FDA-approved drugs already in use in clinical settings or at least clinical trials simplifying a potential transition from bench to bedside.
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