Alex Plesa

Scientist at @harvardmed and @WyssInstitute in @geochurch's lab | Working on solving aging

[Alex Plesa @amplesa]

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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[Alex Plesa @amplesa]

@ShorterLab Thanks for sharing. Free to read here: https://t.co/PpK2vOavcD

[Alex Plesa @amplesa]

@MichaelFloreaX Thanks Michael! Looking forward to seeing what you've been up to at Olden.

[Alex Plesa @amplesa]

@gonzaloruizutri 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.

[Alex Plesa @amplesa]

@khangruni @NatureAging 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.

[Alex Plesa @amplesa]

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

[Alex Plesa @amplesa]

@NeuralGrndState @NatureAging 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

[Alex Plesa @amplesa]

@johnhemming4mp @geochurch @NatureAging 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.

[Alex Plesa @amplesa]

@khangruni @NatureAging 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.

[Alex Plesa @amplesa]

@wanghelenh @NatureAging @geochurch 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!

[Helen Wang @wanghelenh]

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. https://t.co/Apu4MK6gr7

[Alex Plesa @amplesa]

@heroic @NatureAging 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)

[Alex Plesa @amplesa]

@AdamRochussen @NatureAging 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.

[Alex Plesa @amplesa]

@elander777 @NatureAging You can access here: https://t.co/PpK2vO9Xn5
It's total lifespan.

[Alex Plesa @amplesa]

@geochurch @NatureAging Combinations are the obvious next step! Curious to see which ones are additive/synergistic.

[Alex Plesa @amplesa]

@johnhemming4mp @jpsenescence @geochurch 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:
https://t.co/njUCLsrMvD

[Alex Plesa @amplesa]

Thanks to @geochurch, Sascha Jung, and all our co-authors.

You can find the paper here: https://t.co/2YpmdWysLB

Free to read: https://t.co/PpK2vOavcD

And more on the initial screen here: https://t.co/A3PNbo6UWc
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[Alex Plesa @amplesa]

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, https://t.co/7ZXhqHYDAD we used 🧬 screens to find new rejuvenation factors🧵1/8

[Alex Plesa @amplesa]

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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[Alex Plesa @amplesa]

@HumanOmegaHQ @jpsenescence @geochurch Therapy started in late life (~20 months old), and based on bodyweight and survival, it was safe for the remainder of the lifespan. More tests are needed to fully establish in vivo safety (we're working on it). That said, yes, diet, sleep, and exercise are still the most robust.