I listened to a number of talks at the Mechanisms of Aging conference at Cold Spring Harbor Laboratory (CSHL) this week [1].
There were four back-to-back talks today that were especially promising for epigenetic reprogramming:
1. PRC2 clock—A universal epigenetic biomarker of aging and rejuvenation by Vittorio Sebastiano (Stanford University). Vittorio shared data supporting a new epigenetic biomarker of age, which is the DNA methylation of PRC2 in lowly methylated regions [2]. They found that this single measure could account for 90% of the DNA methylation age from other clocks pulling on many regions. The benefit of this clock is that is interpretable (measured directly) and without model bias (no training). It also suggests alignment with an underlying epigenetic mechanism, as PRC2 catalyzes histone methylation. Interestingly, Vittorio found in mice that rapomycin did not lower the PRC2 clock "age", while caloric restriction did.
2. Reprogramming to recover youthful epigenetic information and restore vision in age-related macular degeneration (sic) by Yuancheng Lu (Sinclair Lab, Ksander Lab, Margerete Karg; Harvard University). Yuancheng was the first author on the incredible Nature 2020 paper that showed youthful DNA methylation patterns, axon regeneration and vision restoration in mice with optic nerve crush and mice with a model of glaucoma [3]. This talk reiterated that data and then shared new data on similar results in a mouse model of macular degeneration. OSK were again the reprogramming factors used. No evidence of terratoma/cancer were found after a period of observation, though this bears more study. Most encouraging is that epigenetic reprogramming 1) works in a new use case (macular degeneration) and 2) did not lead to cancer. A paper is forthcoming.
3. Epigenetic reprogramming reverses neuronal aging and improves cognitive performance by Xiao Tian (Sinclair Lab, Harvard University). Xiao built on Yuancheng's work with a focus on the brain. There have been concerns that the blood-brain-barrier would make it difficult to deliver epigenetic reprogramming to the brain. Xiao & team created a new AAV to address this. They showed powerful benefits in the brain for memory and vs. old mice and mice with a model of Alzheimer's. Once again, this provides a powerful new use case. A paper is forthcoming.
4. Transcriptomic reprogramming screen using functional RNA clock for cellular rejuvenation by Alex Plesa (Church Lab, Harvard University). Alex pointed out that reprogramming been focused on the OKSM Yamanaka factors for over a decade now. They wondered if there might be other factors that work as well, that might be safer or have other complementary effects. Using a functional RNA clock (vs. a DNA methylation clock), they identified several candidates. SRSF1, a protein splicer and regulator of transcription, was the most promising in their data. When will we see SRSF1 tested in experimental models of aging? A paper is forthcoming.
Together, these build support for the promise of epigenetic reprogramming in treating aging. One of the most important things for long-term aging science is to identify the right paradigm for the core drivers of aging. Epigenetic reprogramming seems to address aging by rewiring gene expression to a more youthful state. This seems to align with a paradigm where epigenetic unwinding leads to loss of protein homeostasis, which then leads to cellular and tissue dysfunction. The talks above shared new data points in new situations (macular degeneration, Alzheimer's, etc), which shows that reprogramming might be fundamental across cells and tissues. It also points out that there may be other or complementary reprogramming factors, like SRSF1, that could overcome obstacles with OSK (or OSKM).
What comes next? We need to see if epigenetic reprogramming can work in vivo across tissues and lead to better health and longer life. This will require continued work, like Xiao's, to find ways to get the factors safely to their target. It would be especially convincing to see this across multiple organisms (worms, flies, mice, rats, primates?), to prove it is a conserved feature. How long will it be before we have a mouse living for 5+ years with epigenetic reprogramming?
References:
[1] Full list of abstracts for the 2022 Mechanisms of Aging conference at CSHL: https://meetings.cshl.edu/abstracts.aspx?meet=AGING&year=22
[2] Moqri et al. PRC2 clock: a universal epigenetic biomarker of aging and rejuvenation. bioRxiv (2022). doi: https://doi.org/10.1101/2022.06.03.494609
[3] Lu, Y., Brommer, B., Tian, X. et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129 (2020). https://doi.org/10.1038/s41586-020-2975-4