Signal

This is a major milestone in the age of AI and toward our ultimate goal of completely reversing aging!

@InSilicoMeds developed the first AI drug, Rentosertib, now in a Phase 3 clinical trial, and it just showed something remarkable: a reversal of biological age in people!

Six different aging clocks, developed by six independent groups, all showed reversal after just 12 weeks of treatment, with participants measuring 3–4 years younger biologically!

Congratulations to my friend Alex and the entire @InSilicoMeds team on this landmark achievement!

Here's why I think this is bigger than one enzyme. The deep shift isn't the molecule — it's the paradigm. For a century all of medicine has been built on slowing damage: statins slow plaque, BP drugs slow arterial wear, even fasting and exercise only reduce the rate damage accumulates. Nobody had a tool that went back and removed what was already there.

Aging at the molecular level is largely an accumulation problem. A handful of proteins — collagen, elastin, the crystallins in your eye lens — are laid down early and never recycled. Glycation is one form of that damage, and now we know at least one type can be enzymatically erased. That's the door. Behind it: glucosepane (the crosslink welding collagen fibers together — Revel is working this), lipofuscin, amyloid and tau aggregates, oxidized lipids. Each a distinct target for a purpose-built enzyme.

And this is where your world and mine collide: AlphaFold predicts structure, RFdiffusion designs binding pockets from scratch, protein language models propose variants that never existed in biology. Damage-repair medicine may scale the way software scales — a compute problem, not a wet-lab one.

Delivery is real (a large enzyme doesn't diffuse into an arterial wall) but the elegant answer exists: don't deliver the enzyme, deliver the instructions — mRNA or gene therapy telling your own cells to make it in place. Endgame: a catalog of engineered enzymes, one per category of molecular damage, delivered as genetic instructions, run periodically across a lifetime. Not slowing accumulation — clearing it. That's not immortality. It's maintenance. [full thread on X]

I'm a cardiologist. Everyone is sharing this as a skin story — they're burying the part that matters. Scientists took the aorta of a 75-year-old donor, applied a single engineered enzyme, and stripped away >70% of the molecular damage — down to the level of a 30-year-old artery. Published in Nature Communications (Revel Pharmaceuticals, Calico, University of Colorado).

What they erased: CML, the most abundant advanced glycation end-product in aging tissue. It welds onto collagen/elastin in skin, eye lens and arterial walls, stiffening arteries and firing chronic inflammation via the RAGE receptor. Since the 1980s this damage was considered permanent — the body has no enzyme to remove it.

So they built one that doesn't exist in nature: screened 45,000 protein structures, ran directed evolution across 500M+ variants, and got CMLase — a molecular lawnmower that oxidizes CML off the protein and restores the healthy lysine underneath. Not patched. Reversed. >70% cleared from elderly arterial tissue, >55% from elderly skin, 45–78% in lens proteins.

Caveats are real: donated tissue in a dish, not a living person. No functional data yet, delivery of a large enzyme into human tissue is unsolved, trials are years away. But something considered permanent for forty years just came off human tissue. [full thread on X]

I added 2,776 medications that map to 8,382 conditions and 2,499 body parts

You can now tell it; I'm using Ibuprofen, what parts of my body does it affect and will give you the whole picture

I'm a cardiologist. After 40, stop guessing about your health. 13 numbers that tell you whether you're building a long, vibrant life — or quietly declining without knowing it. Most are cheap bloodwork, all available now:

• Fasting insulin — target <5 µIU/mL (catches insulin resistance 5–10y before A1c moves)
• HOMA-IR <1.0 · HbA1c <5.4% (not 5.7%) · Triglyceride:HDL ratio <2
• ApoB <80 mg/dL (<60 high-risk) — LDL alone misses ~54% of dangerous cases
• Lp(a) once in your lifetime — 100% genetic, triples heart-attack risk
• hs-CRP <1.0 mg/L · Vitamin D 50–80 ng/mL (with K2) · Testosterone + Free / DHEA-S
• Blood pressure → 110/70 · VO₂max (men >40, women >35 mL/kg/min) · fewest meds possible

An ApoB of 120 today becomes a heart attack in ten years. The standard annual physical finds disease that's already there — this panel finds the disease that's coming, years before it arrives. What gets measured gets improved. [full 13-point thread on X]

I'm a cardiologist. Midjourney — the AI image company — just unveiled a working prototype of a full-body ultrasonic scanner: you step into a shallow pool, ~500,000 grain-sized transducers image your whole body, no radiation, no magnets, AI-segmented 3D anatomy. The vision: a few-dollar scan you repeat monthly.

But the caveats matter enormously: Gen-1 prototype, only ~12 people scanned, real scan ~20 min (not 60s), NOT FDA-cleared, zero independent clinical validation. The physics works — the question is how fast it can be validated and scaled.

La quimio nunca ha sabido distinguir una célula cancerosa de una sana, y de ahí vienen casi todos los efectos secundarios. Que el laboratorio de Jennifer Doudna construya algo que lee el ARN y detecta el p53 mutado para atacar solo a la enferma es de lo más prometedor en oncología.

Urolithin A may be one of the most interesting supplements for mitochondrial aging

It activates mitophagy, the cellular cleanup process that removes damaged mitochondria before they drag down energy production, muscle function, and immune resilience

In older adults, 1,000 mg/day improved markers of immune aging, increasing CD8+ T cells and natural killer cells while lowering markers of cellular senescence

In untrained athletes, the same dose boosted VO2 max by 10% beyond exercise alone, and improved hamstring strength in older adults by 10–12% versus exercise alone

Woah. I'm slightly embarrassed that I missed this for a few weeks. Finally there is approval, in a Large Nation, for a stem cell-based REPLACEMENT therapy for an age-related condition. The condition is, no surprise, Parkinson's, which I always highlight in talks as the archetypical one amenable to RepleniSENS. The approval is "conditional" (Japan's very sensible system essentially merges Phase 3 with Phase 4), but that's still huuuuge. https://www.sumitomo-pharma.com/news/20260306.html

These numbers are shocking. It's like we got a new frontier AI model but for the body.

Lilly's phase 3 results for retatrutide:

> highest dose lost 28.3% of body weight in 80 wks
> 70 lbs ave
> 45% lost 30% or more of their body weight
> 65% on the top dose no longer clinically obese

Retatrutide is more dynamic than semaglutide and tirzepatide because it targets three receptors (GIP, GLP-1, and glucagon), versus one and two, respectively.

Side effects, on the highest dose (12mg), were higher for retatrutide than tirzepatide (nausea and GI), with an 11.3% drop out rate. The lowest 4mg dose still delivered 19% loss with fewer dropouts than placebo.

Creatine is amazing

UCLA researchers found that creatine helps dendritic cells, the immune "scouts" that detect tumor material and activate killer T cells.

In mouse melanoma models, creatine treatment increased dendritic cell activation, improved immune signalling, and slowed tumor growth.

Human cell tests also showed stronger activation and better T-cell stimulation.

Acarbose is an alpha-glucosidase inhibitor prescription medicine that slows carbohydrate digestion. It increases median lifespan in mice around ~20% in males and smaller (~4–5%) in females

New paper suggests its effects may not be by controlling sugar but by raising NAD!

True. Testing ER-100 in humans now

Pleased to share a new paper on medicines, supplements & other factors associated with decreased epigenetic age with Dr Adiv Johnson @JoinLifespan:
1. Exercise
2. Plant-rich diets
3. Semaglutide
4. CR
5. Ketamine
6. Omega-3s
7. Plasma
8. Pitavastatin
https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2026.1836446/full

New paper @Nature analyzing 11,000 profiles of cellular gene expression provides further evidence that aging is not just wear & tear but a reversible loss of epigenetic information linked directly to mortality risk

Reprogramming, embryogenesis & young blood partially reversed aging signals. Why is this important?

The work implies that the youthful state of tissues is not lost permanently during aging.

It can be restored

The work is also the strongest systems-level support yet for the idea that aging is not just random wear and tear, but a coordinated and reversible loss of biological information.

In many ways, it strengthens the Information Theory of Aging (ITOA), which we first formulated back in 2008-2009.

The striking thing is not simply that damage accumulates. It is that cells enter a coordinated transcriptional state associated with mortality risk, which strongly argues aging is an organized systems phenomenon. This is exactly what you would expect if cells progressively lose youthful epigenetic control information.

The work by the Gladyshev lab @harvardmed (no link to us) suggests aging is not a collection of unrelated damage. It behaves more like an attractor state.Cells under many forms of stress drift toward a common aged configuration.

That is deeply compatible with the idea that epigenetic information loss causes cells to progressively collapse due to informational noise. We call this process epigenetic drift, leading to ex-differentiation.

One of the most important aspects is that it links aging directly to mortality risk rather than simply chronological time. Prof Gladyshev and team developed transcriptomic clocks that don’t just estimate age, they measure the progressive loss of cellular function and predict biological decline and mortality risk across mammals.

That is a major advance because it brings us closer to measuring the underlying process of aging itself, not just the passage of time, in a way first shown by Prof. Steven Horvath in 2013.

The team also launched TACO (Transcriptomic Age Calculator Online) allowing researchers to estimate the biological age and mortality risk of tissues using RNA data they may already have. A potentially powerful new tool for aging research

What I find especially important is that the strongest mortality-associated changes involve chromatin organization, epigenetic regulation, inflammation, and mitochondrial dysfunction.

These are all deeply connected to the maintenance of cellular identity and the preservation of biological information over time.

The study strongly supports the idea that aging is not merely the accumulation of damage, but a progressive loss of the systems that maintain youthful cellular organization.

In many ways, this aligns with the Information Theory of Aging, which proposes that cells lose epigenetic information over time but retain a backup copy that can potentially be restored.

Importantly, the paper also confirms that these molecular signatures are reversible, which we and others have previously shown.

They accelerate after DNA damage, and during disease and stress, but slow or reverse during interventions such as reprogramming, heterochronic parabiosis, and early embryogenesis.

That gives real hope that aging is biologically malleable & perhaps, one day, medically treatable

Thanks for reading all the way down. I gave this whole analysis to a reporter and my quote was 2 words: "Major advance"

So we can all stay abreast of this fast paced field, @JoinLifespan has a new show & a magazine written by real scientists. As a community we are sponsoring young scientists, too. Maybe check us out

Two FDA-approved drugs just produced one of the largest lifespan extensions in mice
• Trametinib: +7.2% (f), +10.2% (m)
 • Rapa: +17.4% (f), +16.6% (m)
 • Both: +29% (f), +27% (m)
The drugs target different aspects of/insulin/TOR to mimic fasting 
https://www.nature.com/articles/s43587-025-00876-4

A virus has stopped pancreatic cancer in its tracks in three people in a clinical trial in the US.

All currently known diseases will be curable by the 2030s.

We are accelerating toward cures for even the worst of them.

AI will soon speed up this process 1000s of times.