Turning Back The Clock

Overview

Aging is a complex process characterised by the progressive decline of cellular and physiological function over time. As our global population rapidly ages, the development of interventions to slow or reverse aging and age-related disease has become a key priority ^{1, 2.} In recent years, partial cellular reprogramming has emerged as a promising rejuvenation technology. This approach involves the transient expression of reprogramming factors like Oct4, Sox2, Klf4 and c-Myc (OSKM) ^{1, 3}. In contrast to full reprogramming which generates pluripotent stem cells, partial reprogramming aims to reset the age-related epigenetic alterations in cells while preserving cell identity ^{1, 6}.

A growing body of research has demonstrated the remarkable effects of partial reprogramming in vitro and in vivo. In aged mice, cyclic induction of OSKM extended lifespan, improved tissue regeneration, and reversed multiple hallmarks of aging like DNA damage and senescence ¹. Excitingly, these effects were achieved without the formation of teratomas, a key safety concern with full reprogramming ^{1, 4}. In vivo reprogramming has also been shown to ameliorate aging features in specific cell populations, such as dentate gyrus cells in the brain, leading to improved memory function in mice ⁵.  

Therapeutic Potential

The therapeutic potential of partial reprogramming is vast. By reversing aging at the cellular and epigenetic level, it could serve as a treatment for a wide spectrum of age-related diseases, including neurodegenerative disorders, cardiovascular disease, type 2 diabetes, and certain cancers ^{2, 6}. Partial reprogramming could also enhance regenerative capacity in aged tissues, promoting faster healing and recovery from injury ^{1, 2}. Additionally, by improving overall health and resilience in the elderly population, this technology could greatly reduce the burden on healthcare systems and improve quality of life for millions of people worldwide ⁶.

However, significant challenges remain in translating partial reprogramming into clinical therapies. Safety is a paramount concern, as the reprogramming process must be carefully controlled to avoid adverse effects like tumorigenesis or loss of cell identity ^{4, 6}. Efficient delivery methods must also be developed to target the reprogramming factors to specific tissues or organs in the body ⁶. While these obstacles are formidable, the rapid advancements in the field provide reason for optimism. As our understanding of the mechanisms underlying partial reprogramming grows, more refined and targeted approaches can be developed to maximize therapeutic benefits while minimizing risks ^{2, 6}.

Newer approaches are pushing the boundaries even further. Gill et al. developed a "maturation phase transient reprogramming" method in human fibroblasts that rejuvenated the epigenome by ~30 years based on epigenetic clocks ³. Another study used adeno-associated viruses (AAV) to deliver reprogramming factors to 124-week-old mice, extending remaining lifespan by 109% and improving health parameters ⁶. Most recently, a "transient naive reprogramming" technique was shown to correct aberrant epigenetic alterations in induced pluripotent stem cells, increasing their similarity to embryonic stem cells ⁶.

While the field is still young, partial reprogramming is opening up exciting new possibilities to reverse aging and treat age-related disease. With further research to optimise protocols and ensure safety, this technology may one day transform the way we age. The societal and economic implications would be immense - a world where biological age can be set back with a single treatment. As the science advances, a future where aging is a treatable condition may be closer than we think.

References:

1. Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., Li, M., Lam, D., Kurita, M., Beyret, E., Araoka, T., Vazquez-Ferrer, E., Donoso, D., Roman, J. L., Xu, J., Rodriguez Esteban, C., Nuñez, G., Nuñez Delicado, E., Campistol, J. M., … Izpisua Belmonte, J. C. (2016). In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell, 167(7), 1719-1733.e12. https://doi.org/10.1016/j.cell.2016.11.052
2. Ocampo, A., Reddy, P., & Izpisua Belmonte, J. C. (2016). Anti-aging strategies based on cellular reprogramming. Trends in Molecular Medicine, 22(8), 725–738. https://doi.org/10.1016/j.molmed.2016.06.005
3. Gill, D., Parry, A., Santos, F., Hernando-Herraez, I., Stubbs, T. M., Milagre, I., & Reik, W. (2022). Multi-omic rejuvenation of human cells by maturation phase transient reprogramming. eLife, 11, e71624. https://doi.org/10.7554/eLife.71624
4. Zhao, T., Zhang, Z.-N., Westenskow, P. D., Todorova, D., Hu, Z., Lin, T., Rong, Z., Kim, J., He, J., Wang, M., Clegg, D. O., Yang, Y.-G., Zhang, K., Friedlander, M., & Xu, Y. (2015). Humanized Mice Reveal Differential Immunogenicity of Cells Derived from Autologous Induced Pluripotent Stem Cells. Cell Stem Cell, 17(3), 353–359. https://doi.org/10.1016/j.stem.2015.07.021
5. Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. Stem Cell Reports, 15(5), 1056–1066. https://doi.org/10.1016/j.stemcr.2020.09.010
6. Yücel, A.D., Gladyshev, V.N. The long and winding road of reprogramming-induced rejuvenation. Nat Communications (2024). https://doi.org/10.1038/s41467-024-46020-5