How to ‘Time Jump’ Skin Cells

Research from the Babraham Institute has developed a method to “time jump” human skin cells by 30 years, turning back the aging clock for cells without losing their specialized function. Work by researchers in the Institute’s Epigenetics research program has been able to partly restore the function of older cells, as well as rejuvenating the molecular measures of biological age. The research is published today in the journal eLife, and while this topic is still at an early stage of exploration, it could revolutionize regenerative medicine.

As we age, our cells‘ ability to function declines and the  accumulates marks of aging. Regenerative biology aims to repair or replace cells including old ones. One of the most important tools in regenerative biology is our ability to createinducedstem cells. The process is a result of several steps, each erasing some of the marks that make cells specialized. In theory, these stem cells have the potential to become any cell type, but scientists aren’t yet able to reliably recreate the conditions to re-differentiate stem cells into all cell types.

The new method, based on the Nobel Prize-winning technique scientists use to make stem cells, overcomes the problem of entirely erasing cell identity by halting reprogramming part of the way through the process. This allowed researchers to find the precise balance between reprogramming cells, making them biologically younger, while still being able to regain their specialized cell function.

In 2007, Shinya Yamanaka was the first scientist to turn normal cells, which have a specific function, into  which have the special ability to develop into any cell type. The full process of stem cell reprogramming takes around 50 days using four key molecules called the Yamanaka factors. The new method, called “maturation phase transient reprogramming,” exposes cells to Yamanaka factors for just 13 days. At this point, age-related changes are removed and the cells have temporarily lost their identity. The partly reprogrammed cells were given time to grow under normal conditions, to observe whether their specific skin cell function returned. Genome analysis showed that cells had regained markers characteristic of  (fibroblasts), and this was confirmed by observing collagen production in the reprogrammed cells.

Young fibroblasts in the first image, the two are after 10 days, on the right with treatment, the last two are after 13 days, right with treatment. Red shows collagen production which has been restored

To show that the cells had been rejuvenated, the researchers looked for changes in the hallmarks of aging. As explained by Dr. Diljeet Gill, a postdoc in Wolf Reik’s lab at the Institute who conducted the work as a Ph.D. student, “Our understanding of aging on a molecular level has progressed over the last decade, giving rise to techniques that allow researchers to measure age-related biological changes in human cells. We were able to apply this to our experiment to determine the extent of reprogramming our new method achieved.”


Rejuvenation by Controlled Reprogramming

On 19 January 2022, co-founders Rick Klausner and Hans Bishop publicly launched an aging research initiative called Altos Labs, with $3 billion in initial investment from backers including tech investor Yuri Milner and Amazon founder Jeff Bezos. This is the latest in a recent surge of investment in ventures seeking to build anti-aging interventions on the back of basic research programs looking at epigenetic reprogramming. In December, cryptocurrency company Coinbase’s cofounder Brian Armstrong and venture capitalist Blake Byers founded NewLimit, an aging-focused biotech backed by an initial $105 million investment, with the University of California, San Francisco’s Alex Marson and Stanford’s Mark Davis as advisors.

The discovery of the Yamanaka factors’ — four transcription factors (Oct3/4, Sox2, c-Myc and Klf4) that can reprogram a differentiated somatic cell into a pluripotent embryonic-like state — earned Kyoto University researcher Shinya Yamanaka a share of the Nobel prize in 2012. The finding, described in 2006, transformed stem cell research by providing a new source of embryonic stem cell (ESC)-like cells, induced pluripotent stem cell (iPSCs), that do not require human embryos for their derivation. But in recent years, Yamanaka factors have also become the focus for another burgeoning area: aging research.

So-called partial reprogramming consists in applying Yamanaka factors to cells for long enough to roll back cellular aging and repair tissues but without returning to pluripotency. Several groups, including those headed by Stanford University’s Vittorio Sebastiano, the Salk Institute’s Juan Carlos Izpisúa Belmonte and Harvard Medical School’s David Sinclair, have shown that partial reprogramming can dramatically reverse age-related phenotypes in the eye, muscle and other tissues in cultured mammalian cells and even rodent models by countering epigenetic changes associated with aging. These results have spurred interest in translating insights from animal models into anti-aging interventions. “This is a pursuit that has now become a race,” says Daniel Ives, CEO and founder of Cambridge, UK-based Shift Bioscience.

The Yamanaka factors that can reprogram cells into their embryonic-like state are at the heart of longevity research

We’re investing in this area [because] it is one of the few interventions we know of that can restore youthful function in a diverse set of cell types,” explains Jacob Kimmel, a principal investigator at Alphabet subsidiary Calico Life Sciences in South San Francisco, California. The zeal is shared by Joan Mannick, head of R&D at Life Biosciences, who says partial reprogramming could be potentially “transformative” when it comes to treating or even preventing age-related diseases. Life Biosciences, a startup co-founded by David Sinclair, is exploring the regenerative capacity of three Yamanaka factors (Oct4, Sox2 and Klf4).