Epidermis in Retrograde: Researchers De-Age Human Skin Cells by 30 Years
Is there any point in reversing aging if you can’t stop the process? After all, while captivating and curious, would you want to experience a life akin to Benjamin Button, backtracking to being a newborn? You’d more likely want a controlled jump back into time to a more youthful state.
A study from the Babraham Institute in the UK has now provided initial evidence of turning back the aging clock on human cells in a controlled manner. By deploying cellular reprogramming – a Nobel Prize-winning technology for turning back mature cells into stem cells – in a quick, controlled way, researchers were able to de-age skin cells from several people and pump the brakes on the process after rewinding decades of biological age.
Dr. Diljeet Gill, who conducted the work as a Ph.D. student, said, “Our results represent a big step forward in our understanding of cell reprogramming. We have proved that cells can be rejuvenated without losing their function and that rejuvenation looks to restore some function to old cells. The fact that we also saw a reverse of aging indicators in genes associated with diseases is particularly promising for the future of this work.”
Reprogramming Cell Age
Aging is the gradual decline in cell and tissue function over time that occurs in almost all organisms and is associated with a variety of molecular hallmarks that can be used to calculate biological age. Unlike chronological age, some of the molecular hallmarks for aging are reversible – at least in principle, raising the intriguing question of whether molecular attributes of aging can be reversed and cells rejuvenated.
In 2006, Shinya Yamanaka shocked the scientific world by unveiling induced pluripotent stem cell (iPSC) reprogramming, the process by which almost any mature cell can be converted into an embryonic stem cell-like state. Intriguingly, using molecules now known as “Yamanaka factors” to drive iPSC reprogramming, researchers have been able to reverse many age-associated changes, even resetting some hallmarks all the way back to year 0. However, iPSC reprogramming also results in losing the original cell identity and therefore function. If you reprogrammed a whole human, they’d basically turn into a useless ball of stem cells.
New Technique Rewinds the Age of Skin Cells by 30 Years
By contrast, transient reprogramming approaches where the Yamanaka factors are activated for short periods of time may be able to achieve rejuvenation without loss of cell identity. The extent of rejuvenation achieved by previous transient reprogramming methods has been modest (~3 years) compared to the drastic reduction achieved by complete iPSC reprogramming. This study from the Babraham Institute established a novel transient reprogramming strategy where Yamanaka factors are activated in a controlled manner to achieve robust and very substantial rejuvenation whilst retaining original cell identity overall.
Gill and colleagues took skin cells from middle-aged donors and applied their method – which they’ve called “maturation phase transient reprogramming” (MPTR) – to rewind the clock on the cells without losing their identity. Excitingly, their method substantially rejuvenated multiple cellular attributes, including the patterns of DNA modifications and gene activity, which was rejuvenated by around 30 years as measured by a novel transcriptome clock.
In addition, the de-aged skin cells not only looked younger, but they acted young; the transiently reprogrammed skin cells produced youthful levels of collagen proteins and showed partial functional rejuvenation in their movements.
Overall, the British research team demonstrates that it is possible to separate rejuvenation from complete pluripotency reprogramming, which should facilitate the discovery of novel anti-aging genes and therapies. Professor Wolf Reik, who led the research, said: “This work has very exciting implications. Eventually, we may be able to identify genes that rejuvenate without reprogramming and specifically target those to reduce the effects of aging. This approach holds promise for valuable discoveries that could open up an amazing therapeutic horizon.”
How Low Can You Safely Go?
The effect of starting age is a factor that remains to be explored. In this study, Gill and colleagues examined the effects of MPTR on skin cells from middle-aged donors and observed an approximately 30-year rejuvenation. It will be interesting to perform this method on fibroblasts from younger and older donors to see if the rejuvenating effect of MPTR is constant. In that case, cells would always become 30 years younger than their controls. Alternatively, the effect of MPTR may scale with starting age, with more rejuvenation being observed in cells from older donors compared to cells from younger donors.
The Babraham Institute researchers note that multiple cycles of transient reprogramming can be performed with some approaches. It will be interesting to examine if MPTR can be performed repeatedly on cells and if this may improve the extent of rejuvenation.
Gill D, Parry A, Santos F, et al. Multi-omic rejuvenation of human cells by maturation phase transient reprogramming. Elife. 2022;11:e71624. Published 2022 Apr 8. doi:10.7554/eLife.71624