Today, we want to highlight another study that takes us a step closer to getting partial cellular reprogramming to the clinic.
Can we both have our cake and eat it?
As previous studies [1] have taught us, partial cellular reprogramming is a balancing act of epigenetically rejuvenating cells without completely resetting them.
Building upon these studies, today’s new study shows how exposing cells to reprogramming factors in a living animal for just long enough can reverse age-related epigenetic alterations. The mice in this study had their cells engineered to react to doxycycline, a common antibiotic used in veterinary practice, in order to produce the OSKM reprogramming factors. The researchers found that giving the mice just enough exposure to OSKM improved their cognitive function without an increase in mortality during a four-month period.
In a behavioral test, wild-type and OSKM-expressing mice of the same age appeared to have a similar capacity to remember an object previously seen following a two-hour familiarization period. However, when the mice were shown the object again five days later, the wild-type mice had forgotten about it. On the other hand, the OSKM mice appeared to remember the object, suggesting superior memory retention. Moreover, there was also a correlation between the degree of induced OSKM expression in treated mice and their memory indices.
The researchers suggest that these results might be explained by the increase of OSKM-dependent proteins, which decline during aging, particularly the GluN2B subunit protein, which facilitates calcium permeability and increased synaptic potentiation – a critical function that declines with advancing age. The researchers found that the number of GluN2B-positive neurons in the OSKM mice had increased compared to the wild-type mice, which suggests changes to the neuronal plasticity of mature neurons.
There were no significant changes to ambulatory time in movement tests, nor were there any differences in anxiety in an open field test, which ascertains general movement and activity levels, anxiety, and the willingness to explore in scientific research. By nature, rodents are cautious, and when faced with open areas and bright lights, they have a tendency to hug walls or become stationary, both of which are anxiety responses. Any reduction of anxiety would be obvious, as the mice would be more inclined to move around and explore.
Post-translational epigenetic modifications take place in mouse neurons of the dentate gyrus (DG) with age. Here, we report that age-dependent reduction in H3K9 trimethylation (H3K9me3) is prevented by cyclic induction of the Yamanaka factors used for cell reprogramming. Interestingly, Yamanaka factors elevated the levels of migrating cells containing the neurogenic markers doublecortin and calretinin, and the levels of the NMDA receptor subunit GluN2B. These changes could result in an increase in the survival of newborn DG neurons during their maturation and higher synaptic plasticity in mature neurons. Importantly, these cellular changes were accompanied by an improvement in mouse performance in the object recognition test over long time. We conclude that transient cyclic reprogramming in vivo in the central nervous system could be an effective strategy to ameliorate aging of the central nervous system and neurodegenerative diseases.
Conclusion
Based on the results of previous studies, it is likely that the target cells are being rejuvenated and making positive changes to the signaling environment, cell behavior, reversing mitochondrial dysfunction, and epigenetic changes.
This is yet another step forward for partial cellular reprogramming in the context of age reversal in living animals and ultimately humans. While it is probably at least a decade if not more away from reaching human trials, these animal studies are paving the way for this to ultimately happen.
The road to rejuvenation is not going to be a short one; science, especially aging biology, is complex, and there are many challenges ahead to get partial cellular reprogramming to the clinic. Reversing cellular aging to prevent or reverse age-related diseases is going to be a long haul, not something that will happen overnight, but rather the work of decades.
However, it can be done and it is being done right now. The necessary studies to maximize safety when the approach finally does reach humans are being done right now, and, if successful, the results in people could be game-changing.
Literature
[1] Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., … & Araoka, T. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.
