Scientist at @harvardmed and @WyssInstitute in @geochurch's lab | Working on solving aging
Joined October 2019
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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%.
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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.
The most widely used way to study a living cell is to kill it and read out 20,000 genes. Once.
Then we train AI on that data and wonder why it can't predict what cells do...
amplesa.substack.com/p/ai-fo…
I recently looked up life expectancy over time for an essay. Wonder how the curve's going to look in a few hundred years...
ALT Period life expectancy at birth - Our World in Data
They don't contribute equally. I think there might be a mix of general ones (WNT, methylation, ER, translation, lipid transport) and cell type-specific ones (actin, junction organization). Would have to check other cell type and pan-tissue predictors to see which ones generalize
But does this work in living organisms? - It does, at least in the skin!
We showed that SRSF1 gene therapy rejuvenates old skin and reverses its wound healing ability to youthful levels in 🐁 @justsaysinmice. Oh, and it’s also linked to longevity in worms 🪱 6/8
Ok, so from a gene expression standpoint, SRSF1 induction makes these cells younger. Does that mean they also function better? - Yes, in certain aspects.
We observed a reduction in cellular senescence, proteasome load, and an increase in collagen production. 5/8
In search for new rejuvenation factors, we tested our top 90 genes by overexpressing them in human aged skin fibroblasts. Using the resulting gene expression profiles, we mapped out a landscape of fibroblast aging and rejuvenation, and identified SRSF1 as a promising target. 4/8
Next, to measure aging, we looked at gene expression changes in skin fibroblasts from donors aged 1-96yrs old. Assuming cells from young donors are healthier, we built transcriptomic functional indicators for 8 cellular processes and used them to measure overall cellular age. 3/8
With 1000s of genes changing throughout aging, how do we know which ones to target? - Networks!
To increase our odds of finding the right targets and comprehensively rejuvenating cells, we decided to focus on the central nodes in the aged gene regulatory networks. 2/8
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