1/ Can we find more precise and even safer ways to rejuvenate vision? As a step towards this goal, I am excited to share this preprint of my 1st postdoc work from @JswLab with amazing collaborators, esp. @Bruce_Ksander! Using functional genomics, we discovered GSTA4 as a key OSK

Congratulations, Ania! A wonderful contribution to solving the puzzle of aging metabolites in organelles. It’s been inspiring to witness your perseverance and a privilege to be a small part of this journey.

Legend David Baltimore died yesterday. He understood the way things should work: "the real contribution of @MIT is that it doesn't take itself too seriously. It takes ideas seriously, but the people are relatively informal. They are not self-aggrandizing the way academics can be.

NEW DISCOVERY: Congrats to co-author & former PhD student @Y_Ryan_Lu for finding a new rejuvenation factor that reverses transcriptomic age & vision loss due to macular degeneration, a leading cause of blindness 👏

Exciting work from the lab, on the mechanism of OSK rejuvenation, led by @Y_Ryan_Lu with lab co-authors James Cameron, @MohamedBrolosy, @AniaPuszynska, @Xiaojie_Qiu.

Stock Market Week in Review: After a sharp fall to close the last trading week, we ended this one on a positive note. - The S&P is up +0.51%, - Nasdaq ended the week 0.45% higher - DJI gained the most, +1.08% for the week To start the week, U.S. and Chinese representatives

19/ This discovery journey had no shortage of challenges, yet the outcome exceeded expectations—thanks to 29 incredible students, collaborators & mentors here! @DavidaSinclair has always been supportive. And Jonathan @JswLab + Bruce have been truly exceptional postdoc mentors,

18/ We believe many similar stem-cell-intrinsic anti-aging pathways remain to be found. By dissecting & deploying them, we can harness these early-life rejuvenation programs to combat late-life degeneration.

17/ Together, our work provides novel mechanistic insights into OSK-mediated rejuvenation, positions GSTA4 as a therapeutic target, and outlines a framework to deconstruct rejuvenation pathways with functional genomics.

16/ Our findings in RPE resonate with this, and further suggest that oxidative stress and the accumulation of 4-HNE play a causal role in driving this in the RPE, as GSTA4 counteracts EMT. It would be interesting to explore how broadly GSTA4 can reverse mesenchymal drift across

15/ Excitingly, a recent work reported broad mesenchymal drift across aging & diseases, reversible by partial reprogramming. https://t.co/aFrrRgOiQU

14/ Supplementing cells with precursors of glutathione (Glycine+NAC), the cofactor of GSTA4, can effectively mimic its oxidative protection in vitro. This opens another translational path in addition to AAV-GSTA4.

13/ GSTA4 is consistently upregulated across diverse lifespan-extending interventions suggesting a broader pro-longevity role and likely safety profile.

12/ Mechanistically, GSTA4 detoxifies 4-HNE, a lipid peroxidation byproduct that progressively accumulates in aging RPE. Unlike generic antioxidants that just mop up ROS, GSTA4 repairs the damage.

11/ Step 4: In vivo, AAV-GSTA4 rejuvenates aged RPE transcriptomes by 8.5 months (~50%) and improves vision (check bioRxiv sup. video)—without the long-term concern with OSK. Shoutout to Aleks from @gladyshev_lab for the tAge analysis.

10/ Step 3: Using ATAC-seq & a novel seq2PRINT method developed by @YanHu41082612 and @JD_Buenrostro lab, we showed OSK directly & dynamically regulates GSTA4 in non-persistent manner, consistent with what we saw for OSK’s protection. This pattern mirrors GSTA4 regulation in

9/ Step 2: We performed transcriptomic profiling across the above 3 systems to identify shared OSK-induced gene changes. Correlating each gene’s expression with functional protection across lines nominated 6 top candidates, which were subjected to targeted gain-of-function

8/ Step 1: Aging RPE shows increased oxidative stress; we found that AAV-OSK boosts resistance & restores vision but prolonged use impairs ERG; In vitro, OSK confers broad oxidative protection (esp. vs NaIO₃ in RPE and fibroblasts). Interestingly, the protection is via a

7/ We focused on retinal pigment epithelium (RPE)—cells under oxidative stress whose decline drives AMD (Age related Macular Degeneration), affecting >200M people. Unlike retinal neurons, RPE can be cultured and offer oxidative stress resistance as a screenable phenotype.

6/ Due to the large number of genes impacted by OSK(M) treatment, we used functional genomics to search for OSK(M) effectors that are sufficient to mediate rejuvenation effects.

William Lane Craig Reacts! Jordan Peterson & Church Hurt

5/ However ideally, for each application one would identify and utilize the specific downstream gene effectors of OSK that mediate each desired beneficial biological process. So far, only a few (e.g. Tet2 in retina, Top2a in liver) have been identified and these only work in

4/ One strategy to mitigate these risks comes from my PhD work with @DavidaSinclair, where we and subsequent studies showed: using OSK (without oncogene c-Myc), rejuvenates retinal ganglion cells, restores vision in glaucoma & aging, is safe long-term, effective in MS models &