Cellular Rejuvenation Strategies
Cellular rejuvenation strategies aim to restore youthful cellular function, combat age-related decline, and potentially extend healthy lifespans. These strategies focus on reversing the hallmarks of ageing at the cellular level, including epigenetic changes, mitochondrial dysfunction, cellular senescence, and stem cell exhaustion.
Partial Reprogramming
A promising approach involves partial reprogramming, which temporarily exposes cells to factors that induce a pluripotent state (similar to embryonic stem cells) without complete dedifferentiation. This process resets ageing clocks, improves tissue repair, and extends lifespan in animal models.
Key aspects:
- Yamanaka Factors: OSKM (Oct4, Sox2, Klf4, c-Myc) are transcription factors used for reprogramming. Cyclic or transient expression of these factors is crucial to avoid tumor formation and maintain cell identity.
- Epigenetic Changes: Partial reprogramming reverses DNA methylation and transcriptomic changes associated with ageing, leading to a more youthful cellular state.
- Applications: This strategy shows promise in treating age-related diseases, improving wound healing, and potentially extending healthspan.
Thymic Rejuvenation
The thymus, essential for T-cell development, atrophies with age, contributing to immunosenescence. Strategies to rejuvenate the thymus aim to restore its structure and function.
Key approaches:
- FOXN1-TEC Axis: FOXN1 is critical for thymic epithelial cell (TEC) function. Strategies include cell therapy (transplanting FOXN1-producing cells) and gene therapy (enhancing FOXN1 expression).
- Cytokine Therapy: Keratinocyte growth factor (KGF), IL-22, and IL-7 are being investigated for their role in promoting thymic regrowth and improving thymopoiesis.
- Periphery-Thymus Axis Modulation: Growth hormones, sex hormones, and blood-borne factors influence thymic function and are potential targets for rejuvenation.
- Lifestyle Interventions: Physical exercise and maintaining a healthy weight can positively impact thymic function.
Other Strategies
- Maturation Phase Transient Reprogramming (MPTR): This method selectively expresses reprogramming factors until rejuvenation is achieved, then withdraws them. MPTR has shown significant rejuvenation of cellular attributes, including the transcriptome and epigenome.
- Targeted Partial Reprogramming: Using adeno-associated viruses (AAVs) to deliver reprogramming factors specifically to aged cells, this approach has shown promise in improving health markers and extending lifespan in mouse models.
Challenges and Future Directions
While cellular rejuvenation strategies hold immense potential, challenges remain. These include optimizing delivery methods, minimizing off-target effects, and ensuring long-term safety. Further research is needed to translate these findings into safe and effective therapies for human ageing and age-related diseases.