Scientist at @harvardmed and @WyssInstitute in @geochurch's lab | Working on solving aging
Joined October 2019
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Thanks! The frailty readouts are in the paper (~44% slower accumulation). We didn't measure grip strength this time, but we'll consider it for the next one.
No. The team handling the mice was blinded to group assignment until one group had completely died off, and the frailty index was graded by a blinded reviewer every 2 weeks throughout. We unblinded after that point and kept measuring until the last SRSF1 mouse died.
Unsure on embryonic neural-SRSF1 is ubiquitously expressed. Constitutive overexpression transforms immortalized cells, but we used moderate pulses and mice lived longer (no tumor data). I think SRSF1 promotes regeneration, predisposing cells to transformation in the right context
Our data agree with the first half. When we used constitutive CAG overexpression (>20x induction) we saw no benefit in skin/muscle healing, while the pulsed moderate one worked for skin and lifespan. The dose and frequency definitely matter. Didn't measure NMD, though.
GFP: n=9; SRSF1: n=10. Significant but a small cohort, and we acknowledge the limitation. The fact that frailty accumulation also slowed gives more confidence in the lifespan result.
Thanks!
Agreed, the identity preservation is the interesting part, and that was the motivation behind the study: find new factors that can rejuvenate without identity loss. Yes, the lifespan result (n=9/10) needs replication, and we're working on optimizing dosage and frequency.
Thanks Helen. You played a big part in this, from nominating SRSF1 as a target all the way to the in vivo validation (and of course this graphic). Excited for what you do next!
Alex Plesa retweeted
So proud to have been part of this work on cellular rejuvenation through identity-preserving reprogramming, out now in @NatureAging! Grateful to my mentors @geochurch @amplesa and all of our co-authors. nature.com/articles/s43587-0…
Our paper is out in @NatureAging. We looked for factors that make old cells' gene expression young without erasing their identity. SRSF1 came out as a promising rejuvenation target that reduced aging hallmarks in human cells and extended median lifespan of aged mice by 14%.
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ALT Watercolor-style graphic of two overlapping cells split by a curved diagonal. On the left, a muted gray cell with a dark nucleus and faint white circuit traces. On the right, the same form in luminous blue, its circuitry lit up. Short dashes standing for RNA transcripts scatter loosely in gray on the left and fan outward in blue and pale green arcs on the right. Art by Helen H. Wang.
Short answer: +11% at the 90th percentile (960 vs 865 d; quantile regression P = 0.030)
Long answer: tail-weighted log-rank gives P = 5×10⁻⁴ and restricted mean survival time is +131 d (95% CI 73–188), but Wang–Allison at the same percentile is P = 0.47 (underpowered at our n)
Thanks! Yeah, I agree outbred and longer-lived strains would be nice to see. Regarding NHPs, we first want to figure out delivery, dosing, and safety. In this study, and medicine as a whole, we're still very primitive when it comes to choosing dosing amount and frequency.
Yes, Lorna Harries' work is definitely relevant. We referenced two of her papers about splicing changes with aging. Upstream control is still an open question. We have no data on acetylation, but there is evidence for phosphorylation by CLK/SRPK kinases:
pmc.ncbi.nlm.nih.gov/article…
Thanks to @geochurch, Sascha Jung, and all our co-authors.
You can find the paper here: nature.com/articles/s43587-0…
Free to read: rdcu.be/ypTLcckieF8a
And more on the initial screen here: xitter.cf/amplesa/status/1737852…
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Can we reverse aging?
7 yrs ago, Ocampo et al. showed that partial reprogramming can ameliorate aging hallmarks. But, OSKM induction has safety limitations & no new factors have emerged since. Here, biorxiv.org/content/10.1101/… we used 🧬 screens to find new rejuvenation factors🧵1/8
Two new results since the preprint: SRSF1 reduced DNAm age of old fibroblasts, and there was no activation of pluripotency programs. Still, this is in human cells and mice; we need to figure out delivery and dosing, and ideally have another lab replicate the lifespan.
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We used a single dose of liver-directed AAV delivering SRSF1, cycling expression on and off every other week in ~20-month-old mice. Frailty accumulated ~44% more slowly, and median lifespan was extended.
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Our paper is out in @NatureAging. We looked for factors that make old cells' gene expression young without erasing their identity. SRSF1 came out as a promising rejuvenation target that reduced aging hallmarks in human cells and extended median lifespan of aged mice by 14%.
1/4
ALT Watercolor-style graphic of two overlapping cells split by a curved diagonal. On the left, a muted gray cell with a dark nucleus and faint white circuit traces. On the right, the same form in luminous blue, its circuitry lit up. Short dashes standing for RNA transcripts scatter loosely in gray on the left and fan outward in blue and pale green arcs on the right. Art by Helen H. Wang.