In this week’s newsletter

✅ Introduction to episode 26 with Daniel Ives. ✅ A lone gene that rejuvenates without inducing pluripotency. ✅ Detailed show notes.  ✅ Virtual cells. ✅ A new horizon for partial reprogramming.

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A finding that could change aging research

Just about the hottest thing in longevity science right now is partial reprogramming - using Yamanaka factors to rewind the biological clock in our cells. Billion-dollar giants like Altos, Retro, and New Limit are betting on it. But in this episode a far smaller player, Shift Bioscience, argues the field may be looking in the wrong place.

In an exclusive interview CEO Daniel Ives* explains how his team used AI-driven virtual cells to uncover one gene that seems to match OSK-level rejuvenation. Without the tumor risk that haunts classical reprogramming.

And their just-released data could change aging research.

* This is actually our second interview with Daniel in under a year. If you read my feature on Shift back in October 2024, this latest development probably didn’t come as much of a surprise.

🔍 In this episode:

✅ Daniel’s journey from mitochondrial PhD to founding Shift Bioscience.

✅ Why Yamanaka-factor partial reprogramming excites the field and why it’s risky.

✅ Epigenetic clocks 101 - Horvath, single-cell versions, what they really measure.

✅ Building AI “virtual cells” (transformers / GNNs) to run millions of in-silico experiments.

✅ Discovery of new rejuvenation factor sets - incl. SB000, a lone gene that rejuvenates without inducing pluripotency.

✅ Early wet-lab validation in fibroblasts & keratinocytes; mouse studies already under way.

✅ How inhibition targets (not just over-expression) could cut timelines from 15 yrs to ~5 yrs.

✅ Mapping a “risk landscape” of age-linked diseases and why fibrosis may be the fastest clinical entry point

✅ Funding Shift: from redundancy payout to a $16 M seed - and the next raise.

✅ Timelines, escape-velocity hopes, and where cryonics still fits.

✅ What Daniel would ask Jeff Bezos, and why pharma needs to “plug in” now.

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Introduction

• Co-host Peter Ottsjö sets the stage:

“Today’s guest is Dr. Daniel Ives, founder and CEO of Shift Bioscience. … Shift’s focus has moved from mitochondria to mouse epigenetic clocks to what may now represent a paradigm shift in longevity science: the development of AI-powered cell simulations to discover novel rejuvenation interventions.”

• Peter notes Shift’s recent $16 million raise and promises discussion of a new, as-yet-unpublished study that will be public by release time.

Daniel’s origin story - From biochemistry student to longevity start-up

• Daniel recalls watching Aubrey’s 2005 TED talk declaring “now’s the time to do something about aging” and says it “captured a whole generation of scientists.”

• Early PhD focus on mitochondria.

• He targeted “the hardest problem” — moving the damaged mitochondrial genome into the nucleus (a core SENS strategy).

• Mentions working with Mark Hamalainen (now head of LBF) on a side-project after the main effort stalled. [Note: Don’t miss our episode with Mark Hamalainen, embedded below.]

Persistence & redundancy payout

• When his lab lost grant funding, Daniel chose redundancy over half-pay, used the lump sum (“tax-free money”) to fund his own mouse experiment, and drew in friends, family, and small donations.

• Famous anecdote: he asked his girlfriend for her life savings; she told him, “No, go to an investor.”

Finding capital & first pivot

• Jonathan Milner (Abcam co-founder) supplied a small conditional donation, later the first equity check when data arrived.

• Daniel: “The first thing that happened with that investment was we disproved the hypothesis behind the company.”

• Milner introduced him to the concept of epigenetic clocks.

• Their mitochondrial-damage fix did not move the epigenetic clock.

Meeting Steve Horvath & the single-cell clock idea

• 2018 XPRIZE longevity workshop (Los Angeles):

• Attendees included Aubrey de Grey & Laura Deming.

• When someone asked for an aging biomarker, Daniel proposed the Horvath clock - unaware Steve Horvath was actually in the room.

• Horvath stood up: “I am Steve Horvath.”

• Afterward Horvath sent Daniel to collaborator Dr Ken Raj who was reverse-engineering clocks.

• Outcome: Shift built a single-cell aging clock using gene-expression (transcriptome) rather than DNA methylation.

• Daniel calls it the company’s new direction: “[You can] systematically go through every single gene … and assign a relationship to the aging process.”

Crash-course on epigenetic aging clocks

• Daniel explains:

• DNA methylation = methyl tags on DNA bases that modulate gene expression.

• Original Horvath multi-tissue clock (2013) vs. Skin & Blood clock (Horvath + Ken Raj) vs. blood-based risk clocks GrimAge & DunedinPACE.

• Clocks are excellent for group-level data; individual testing remains “mostly entertainment at this stage.”

Partial reprogramming & Yamanaka factors (OSKM)

• Daniel’s primer:

• Shinya Yamanaka (Nobel, 2012) showed four TFs convert adult fibroblasts to induced-pluripotent stem cells (iPSCs).

• 2016: Tamir Chandra applied Horvath’s clock to Yamanaka’s time-course data → aging clock went to zero.

• Risk: OSKM can form teratomas (“a body without a body plan”).

• Daniel’s critique: OSKM were “optimized to make stem cells, not to rejuvenate” and remain a “blunt instrument”.

• [Note: I’ve written a deep dive on partial reprogramming. It’s available here. Be aware though that the archive is unlocked for PREMIUM members only.]

Building AI “virtual cells”

• Need to test 562 million combinations of 3-factor sets → impossible in wet lab.

• Shift trained transformers / GNNs on paired single-cell transcriptome + methylome data from hundreds of donor fibroblasts:

• “For the first time, you can take these machine-learning models and actually create a cell simulation that behaves similarly to real cells.”

• Daniel calls it “like putting your hand through a wormhole into the future … and bringing back the best results.”

Breakthrough discoveries

• Six new rejuvenation interventions surfaced in silico.

• Recurrent single-gene motif → tested experimentally:

• Comparable rejuvenation to OSK without pluripotency markers.

• Worked in fibroblasts and keratinocytes (different germ layers).

• Gene code-name SB000; Daniel notes it is naturally expressed mainly in germ cells.

• Ongoing mouse AAV study: first ask if SB000 expresses in multiple organs and shifts tissue clocks.

Scaling the discovery engine

• Computational screen expanded: 150 single genes with rejuvenation potential, 40 pro-aging genes (possible inhibition targets).

• Daniel: inhibiting broadly expressed pro-aging genes with small molecules could cut translation timelines “from 15 years to ~5 years.”

• Links fibrosis biology to aging; cites IL-11 ‘super-granny’ mice (25 % lifespan boost).

Funding & company strategy

• Shift: 24 people (20 Cambridge UK, 4 Toronto ML group with Prof. Bo Wang, author of scGPT).

• Raised $16 M seed; seeking an additional $15 M “to get all of our options together” before a larger drug-development raise.

• Daniel on fundraising burden vs. focus; sees large-pharma collaboration as key.

Timelines, escape velocity & cryonics

• Estimate: Over-expression gene therapy ⇒ whole-body delivery challenge → ~15 years.

• Estimate: Small-molecule inhibition route ⇒ ~5 years to first human trials sensing clock reversal.

• On cryonics: useful for people near end-of-life; diversity of approaches important.

• AGI: may help but still needs the biological datasets Shift is generating.

Culture, language & public perception

• Daniel supports a “Longevity Pride Day” for scientists hiding pro-rejuvenation views.

• On rhetoric: tries to avoid “live forever” clickbait; emphasizes “wake up feeling better every day.”

• Company name “Shift” originally referenced “mitochondrial DNA heteroplasmic shift,” now serendipitously fits each pivot.

Recommended reading

• Walter Isaacson, Elon Musk – Daniel admires Musk’s “all-in” risk tolerance as a template for hard-tech ventures.