Rick Klausnerās part of that presentation was great and caused me to look into cell reprogramming. I found a really good article to help me understand the process.
The long and winding road of reprogramming-induced rejuvenation
Organismal aging is inherently connected to the aging of its constituent cells and systems. Reducing the biological age of the organism may be assisted by reducing the age of its cells - an approach exemplified by partial cell reprogramming through the expression of Yamanaka factors or exposure to chemical cocktails. It is crucial to protect cell type identity during partial reprogramming, as cells need to retain or rapidly regain their functions following the treatment. Another critical issue is the ability to quantify biological age as reprogrammed older cells acquire younger states. We discuss recent advances in reprogramming-induced rejuvenation and offer a critical review of this procedure and its relationship to the fundamental nature of aging. We further comparatively analyze partial reprogramming, full reprogramming and transdifferentiation approaches, assess safety concerns and emphasize the importance of distinguishing rejuvenation from dedifferentiation. Finally, we highlight translational opportunities that the reprogramming-induced rejuvenation approach offers.
Preventive treatments targeting aging present a considerable potential as an alternative approach to combating aging-related diseases. However, to control the aging processāby either slowing it down or reversing itāone must understand the fundamental mechanisms of aging. For example, it is now well appreciated that epigenetic information is progressively lost over the lifetime of an organism, disrupting cellular homeostasis. Epigenetic biomarkers of aging (aging clocks) can predict biological age through a variety of training approaches, even when based only on the variance of DNA methylation during aging. Interestingly, reacquisition of the lost epigenetic information may be observed during the natural rejuvenation process that occurs during early embryogenesis as well as during cell reprogramming. These strategies are in line with the notion of reprogramming-induced rejuvenation (RIR), a recent discovery wherein old cells can revert to a younger state upon transcription factor or chemical treatments. RIR is commonly accomplished through partial cell reprogramming, a method in which cells transiently undergo an induced pluripotent stem cell (iPSC) reprogramming. In this perspective, we discuss recent advances in this area, offer insights how they are related to the nature of aging and rejuvenation, and highlight potential advantages and drawbacks of this RIR and its translational potential.
Partial reprogramming holds significant therapeutic potential due to its capacity for cellular rejuvenation. There are two primary approaches that may help realize the therapeutic applications of this procedure. Organismal rejuvenation is the most challenging but also the most direct approach, due to its potential to reverse aging in a manner that is independent of the identity of the cells to which it is applied. Methods for reversing aging carry the potential to generate therapies that are more efficient and effective than those aiming merely to slow down the aging processes.
While the reversal of biological age as measured by epigenetic clocks suggests rejuvenation, these two terms should not be used interchangeably39. Rejuvenation can be defined as the reversal of cellular or organismal state to a state that would be found in a younger version of the organism, even though the trajectories of aging and rejuvenation may not necessarily be the same. Epigenetic, transcriptomic, and chromatin accessibility clocks may be capable of capturing certain aspects of these overall states. However, the most striking difference between epigenetic clock reversal and rejuvenation lies in their relation to causality. The first developed clocks show high correlation with age6,40, but their causal relationship with rejuvenation is yet to be determined, which is crucial for ascertaining their value as aging biomarkers for this type of treatment.
In recent years, clocks claiming to measure biological age based on phenotypic aging and future mortality, as opposed to chronological age, have emerged41,42. Yet, their full applicability to rejuvenation has not been firmly established. One reason is that many clocks capture all age-related changes, whereas only some of them represent the accumulation of deleterious changes characterizing the aging process.
In this regard, the identification of CpG sites causal to aging through a Mendelian randomization approach coupled with age-related changes in DNA methylation, and the subsequent use of these sites for the development of epigenetic clocks is a new promising approach43. This strategy permits the construction of epigenetic clocks that may better predict longevity or a shortened lifespan. Interestingly, it was shown that commonly used epigenetic clocks are not enriched for CpG sites causally related to aging. Importantly, CpG sites that have a causal relationship with aging could be used to examine potential therapies. For example, DamAge, a clock specifically trained to capture age-related damaging changes in the DNA methylome, showed reversal of biological age, whereas AdaptAge, a clock trained to capture age-related adaptive changes, does not show this effect upon full iPSC reprogramming43. Further studies in this area may result in the next generation causality-informed clocks that are tuned for testing longevity interventions.
Additionally, persistence of rejuvenation mediated by partial cell reprogramming is an aspect that necessitates further investigation. A transcriptional analysis of adipogenic cells, reprogrammed for three days and then followed for an additional ten days, suggests that broad gene programs continue to exhibit rejuvenation62. However, it is crucial to note that cellular identity states of these cells post-partial reprogramming are not identical to those of their parental cells. It is essential to investigate in detail whether these cells maintain their rejuvenated states after the reprogramming period, lose all rejuvenation signs upon reverting to their initial cellular state, or experience an accelerated loss of their youthful states compared to regular cells. Therefore, the longevity of rejuvenation effects mediated by partial reprogramming continues to be a relevant and unresolved question.
https://www.nature.com/articles/s41467-024-46020-5
