More funding is devoted to the exploration of partial reprogramming than any other approach to the treatment of aging as a medical condition, arguably more funding than all of the other approaches combined. Partial reprogramming recaptures processes that take place in early embryonic development, and is a matter of exposing aged cells to the Yamanaka factors for long enough to produce restoration of youthful epigenetic patterns, but not for so long as to produce a transformation of state into induced pluripotent stem cells. The present consensus is that this balance will be challenging to achieve safely in the context of a drug delivered to much of the body, where the right exposure time differs from cell type to cell type, but that isn't stopping researchers and companies from making the attempt.
Recent studies have shown that limited use of Yamanaka factors or chemicals that mimic their effects can partially reverse cellular or organismal aging. This has been observed in both in vitro human and mouse models, as well as in vivo mouse studies, without fully de-differentiating cells into a pluripotent state. These studies encompass various models, including healthy aged and diseased mice, such as progeroid mice, and involve pulsed, short-term, and medium-term reprogramming regimes; these we call "partial reprogramming" as long as no induction of pluripotency is observed.
Comparing in vitro and in vivo mouse studies, and in vitro studies in humans, supported by visualizations of the interconnections among the data, we show consistent patterns in how such reprogramming modulates key biological processes. Generally, it leads to enhanced chromatin accessibility, upregulation of chromatin modifiers, and improved mitochondrial activity. These changes are accompanied by shifts in stress response programs, such as inflammation, autophagy, and cellular senescence, as well as dysregulation of extracellular matrix pathways.
Ultimately, until we achieve a more robust understanding of aging at the molecular level - and identify much more reliable biomarkers of biological age - the extent to which reprogramming can reverse aging will remain unclear. The effects and potential side effects of reprogramming are context-dependent, varying with the specifics of the reprogramming protocol (such as duration) and the characteristics of the target, including species and tissue or cell types involved. Nonetheless, reprogramming holds significant promise in reversing various biomarkers of aging.
Link: https://doi.org/10.2...s202410.0122.v1
View the full article at FightAging
