Partial reprogramming exposes cells to the Yamanaka factors for long enough to reset their epigenetic patterns to those of a youthful cell, but not so long as to force a change of state into induced pluripotent stem cells. This is an active area of research, not yet an exact science in practice, and the long-term risk of cancer via current techniques remains unknown, but animal studies have produced promising results in the short term when it comes to improved function following the application of a partial reprogramming therapy.
What will partial reprogramming do to senescent cells? In today's open access paper, researchers discuss the prospects of using partial reprogramming therapies targeted to senescent cells to minimize their harmful metabolic activity. As is usually the case, this sort of approach compares unfavorably with the proven senolytic strategy of destroying lingering senescent cells. At least some senescent cells are senescent for a good reason, meaning damage, potential for cancer, and so forth, and giving these cells a new lease on life seems a bad idea.
In this review, we seek a novel strategy for establishing a rejuvenating microenvironment through senescent cells specific reprogramming. We suggest that partial reprogramming can produce a secretory phenotype that facilitates cellular rejuvenation. This strategy is desired for specific partial reprogramming under control to avoid tumour risk and organ failure due to loss of cellular identity. It also alleviates the chronic inflammatory state associated with ageing and secondary senescence in adjacent cells by improving the senescence-associated secretory phenotype (SASP).
Senescence-specific phenotypes are manifested by increased expression of senescence-associated genes and altered metabolic state, while cell cycle (cell cycle withdrawal) and protein synthesis also appear to be characteristically altered. Of these, the SASP is an essential component of the senescence microenvironment. The multiple cytokines, enzymes, and extracellular vesicles (EVs) that make up the SASP can interact with young cells through the senescence microenvironment, a balance that generally promotes senescence. Still, the rejuvenating microenvironment of immature cells can also improve the metabolic state of senescent cells at the tissue level and thus break the senescence signature within senescent cells through the remodelling of protein synthesis and gene expression. It is possible that the vicious cycle of senescence within senescent cells can be broken through the remodelling of protein synthesis and gene expression patterns.
This may be an opportunity left by evolution to combat senescence with controlled reprogramming of local tissues (based on the Yamanaka factors, which essentially create a persistent young environment in a controlled manner), in turn, radically improving the overall senescence homeostasis of senescent cells through metabolic reprogramming and epigenetic remodelling, and this deadlock-breaking anti-ageing strategy is autonomously regulated by the ageing microenvironment, depending on the degree of senescence (the more the microenvironment is inclined to senescence, the easier the local reprogramming, metabolic reprogramming, and epigenetic remodelling). In summary, the phenomena we expect to see in future research and clinical translation are as follows: As rejuvenation becomes more pronounced, local reprogramming loses the promotion from SASP and combines with a controlled induction system to avoid tumours and loss of cellular function.