Researchers from Cambridge University exploited iPSC technology to make skin cells 30 years younger!

Aging is the progressive decline in organismal fitness that occurs over time, leading to tissue dysfunction and disease. At the cellular level, senescence is associated with functional decline, altered gene expression, and epigenomic changes. Somatic cell reprogramming, the process of converting somatic cells into induced pluripotent stem cells (iPSCs), can reverse these age-related changes. However, somatic cell identity is lost during iPSC reprogramming and may be difficult to reacquire, as re-differentiated iPSC often resemble fetal rather than mature adult cells.

Diljeet Gill et al. at the University of Cambridge released a research study titled "Multi-omic rejuvenation of human cells by maturation phase transient reprogramming". The study created the first "maturation phase transient reprogramming" (MPTR) approach, in which reprogramming factors are expressed before the regeneration point and then their induction is turned off, and demonstrated that cells temporarily lost and then regained their fibroblast identity during MPTR, perhaps due to epigenetic memory of enhancers and/or persistent expression of particular fibroblast genes, using dermal fibroblasts from mid-life donors.

Excitingly, the study's method greatly restored multiple cellular features, including the transcriptome, which was rejuvenated to around 30 years of age, according to a new transcriptome clock. In a similar way, the epigenome was revitalized, including H3K9me3 histone methylation levels and the DNA methylation aging clock. In addition, MPTR fibroblasts produced younger levels of collagen and showed partial functional recovery of their migration rate. In conclusion, this work demonstrates that more extensive reprogramming does not necessarily lead to greater rejuvenation, but rather that there is an optimal time window for rejuvenating the transcriptome and epigenome. Overall, this study demonstrates that it is possible to separate rejuvenation from full pluripotent reprogramming, which will help in the discovery of new anti-aging genes and therapies.

Molecular markers such as telomere shortening, genetic instability, epigenetic and transcriptional alterations, and the accumulation of misfolded proteins are connected with aging. Aging also causes nutrition perception problems, mitochondrial dysfunction, and an increase in cellular senescence, all of which influence overall cellular function, intercellular communication, stem cell pool depletion, and tissue dysfunction.

The progression of some aging-related changes, such as transcriptomic and epigenetic changes, can be measured with a high degree of accuracy, so they can be used to construct "aging clocks" to predict the actual age of humans and other mammals with high precision. Because transcriptomic and epigenetic changes are reversible, this raises the intriguing question of whether the molecular properties of aging can be reversed and whether cellular phenotypes can be revitalized.

iPSC reprogramming is a process by which almost any somatic cell can be transformed into an embryonic stem cell-like state, which, interestingly, reverses many age-related changes, including telomere shortening and oxidative stress. Notably, the epigenetic clock was reset to 0, suggesting that reprogramming can reverse epigenetic changes associated with aging. However, iPSC reprogramming also leads to a loss of primitive cell identity and thereby function loss.

Transient reprogramming approaches, on the other hand, in which Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc) are expressed for a short period of time (~50 days), may be able to achieve regeneration without cellular properties being lost. In vivo reprogramming is possible, and cyclic expression of Yamanaka factors in vivo has been shown to lengthen the lifespan of prematurely aged animals and improve cellular function in wild-type mice. An alternative strategy to in vivo reprogramming also exhibited reversal of aging-related changes in retinal ganglion cells and was able to restore vision in a mouse model of glaucoma.

Recently, in vitro transient reprogramming has been shown to reverse multiple aspects of human fibroblast and chondrocyte senescence. Nevertheless, the epigenetic reversal of senescence achieved by previous transient reprogramming approaches was modest (~3 years) compared to the dramatic reduction achieved by full iPSC reprogramming. This study established a novel transient reprogramming strategy (taking ~13 days) in which Yamanaka factors are expressed at the maturation stage of reprogramming and then their induction is abolished (maturation phase transient reprogramming, MPTR), which was able to achieve robust and highly significant age reversal (~30 years) while overall retaining the original cell identity.

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