A Popular Science View of the Road to Partial Reprogramming Therapies
Reprogramming via expression of the Yamanaka factors slowly transforms somatic cells from tissues of any age into induced pluripotent stem cells that are essentially identical to embryonic stem cells. Along the way, aged epigenetic patterns are reset to a youthful configuration, and age-related decline of mitochondrial function is reversed. This approach recapitulates the cellular rejuvenation that takes place in early embryonic development.
Interestingly, temporarily exposing old animals to Yamanaka factors produces improved health and far less cancer than one might expect. It appears that it may be possible to build therapies for aging based on partial reprogramming, meaning exposing cells to expression of the reprogramming factors for long enough to obtain epigenetic rejuvenation, but not so long as to create pluripotent cells that can go on to generate cancer. The animal data is promising, but it may still turn out to be challenging to establish that point of balance sufficiently well to convince regulators to approve treatments.
An aging research initiative called Altos Labs recently launched with $3 billion in initial financing from backers. This is the latest in a recent surge of investment in ventures seeking to build anti-aging interventions on the back of basic research into epigenetic reprogramming. In December, NewLimit was founded, an aging-focused biotech backed by an initial $105 million investment.
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 - transformed stem cell research by providing a new source of embryonic stem cell (ESC)-like cells, induced pluripotent stem cells (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 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.
Even though Life Biosciences and several other startups are investigating Yamanaka factors with a view to reversing human aging, the biology of rejuvenation by reprogramming remains enigmatic and opaque, at best. "These first papers make some astonishing observations. But much more research is needed to dig into the molecular and mechanistic processes that are occurring." Given that fully reprogrammed iPSCs readily form tumors known as teratomas, scientists must determine whether the cellular clock can be wound back safely in humans - which means the race to the clinic will likely be a marathon rather than a sprint.