We might think of medicine as largely a matter of exerting control over cells, beginning with changing their behavior in defined ways, and moving on to creating cells and complex structures made of cells as needed. For all that this is an age of biotechnology, the research community has yet not advanced all that far along this road. Present capabilities are far removed from what we know to be possible in principle. Greater control over cells and ability to build with cells will enable many forms of rejuvenation, regeneration, and replacement relevant to treating age-related diseases and extending healthy life.
In regenerative medicine, there are three major therapeutic categories known collectively as the "R3" paradigm: (1) Rejuvenation - restoring the functional capacity of existing cells or reversing cellular aging processes; (2) Regeneration - stimulating repair or regrowth of tissues using stem cells or host repair mechanisms; and (3) Replacement - directly substituting lost or damaged cells with functional ones. The objective of this review is twofold: (1) to critically analyze the processes of cellular senescence that contribute to neurodegenerative disorders, and (2) to discuss cell-based strategies in the R3 context.
In recent years, remarkable advancements have been made in the field of regenerative medicine. By integrating R3 concepts, we distinguish how certain approaches focus on rejuvenation, some on regeneration, and others on outright replacement. These strategies aim to counteract the effects of aging and mitigate neurodegeneration by specifically targeting the underlying mechanisms of aging, such as cellular senescence. This review comprehensively examines the mechanisms of cellular senescence and explores potential R3 strategies. Specifically, it summarizes the role of cellular senescence in neurodegenerative diseases, highlighting its contributions to disease onset, progression acceleration, and the hindrance of traditional treatment effectiveness.
Additionally, various cell-based strategies, such as stem cell therapy, direct lineage reprogramming, and partial reprogramming, are explored. Their potential benefits and challenges in treating neurodegenerative diseases are evaluated, with a focus on how these strategies may target senescent cells to restore functionality (rejuvenation), enhance endogenous repair (regeneration), or replace lost neurons (replacement). By delving into these underlying mechanisms and investigating innovative therapeutic approaches, we aim to pave the way for more effective treatments that can enhance patients' quality of life and potentially delay or even reverse the aging process.
Link: https://doi.org/10.1186/s13287-025-04285-7
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