Education only. EverLife Capital publishes general, impersonal educational research, not personalized investment or medical advice. Nothing here is a recommendation to buy, sell or hold any security. Biotech investments can lose their entire value.
Why I Built A Framework
Longevity biotech is hard to evaluate. A 2011-2020 industry study estimated a 7.9% chance that a drug entering Phase 1 trials would go on to FDA approval.[1] From the outside, it is hard to tell which ones will make it.
So I use the same 25 questions every time I study a company, grouped into five areas:
The science: What biological process does it target, and how strong is the research behind it?
Human evidence: What has actually been tested in people, and what is still unproven?
The team: Have these people developed treatments and run trials before?
The money: How much cash does it have, what will the next stages cost, and does the valuation make sense?
The market: If it works, who would use it, who would pay, and what would it compete with?
I record my answers before the next milestone and keep the original assessment visible as the evidence changes, including the misses.
My hope is that a consistent, transparent process helps more people understand these companies, which means more support for the field and more awareness of what is being built. Before I review more companies, I want to lay out the map the next editions will build on.
We All Age. But What Is Actually Breaking?
Think about an old car that finally stops on the highway. It did not stop because of "age." The belts were cracked, the hoses were brittle, the battery was weak. Many small failures added up until the car quit.
Scientists have a formal version of this idea. Reliability theory models the body as a system with huge redundancy, billions of cells backing each other up, where damage slowly uses up that backup until small failures start to cascade.[2]
The 2023 framework proposed 12 hallmarks of aging:[3]
Genomic instability: DNA damage builds up.
Telomere attrition: The protective caps on chromosomes wear down.
Epigenetic alterations: The switches that turn genes on and off drift.
Loss of proteostasis: Proteins misfold and clump.
Disabled macroautophagy: The cell's recycling system slows down.
Deregulated nutrient sensing: Growth and fuel signals get miscalibrated.
Mitochondrial dysfunction: The cell's power plants run worse and leak.
Cellular senescence: "Zombie" cells stop dividing but don't die.
Stem cell exhaustion: Repair cells run low.
Altered intercellular communication: Signals between cells get noisy.
Chronic inflammation: Low-grade inflammation that never shuts off.
Dysbiosis: The gut microbiome shifts in harmful ways.
Mechanisms And Changes To Watch
I hold equity in Repair Biotechnologies and Yuva Biosciences, which work in two areas covered below: cholesterol accumulation and mitochondrial health.
A hallmark is a category. Underneath are specific pathways, cell states and tissue changes that a drug can actually be aimed at. Here are some I will keep coming back to:
The NLRP3 alarm: A sensor in immune cells that can be activated by danger signals such as DNA leaking from damaged mitochondria,[4] cholesterol crystals[5] and ATP from injured cells,[6] releasing the inflammatory signals IL-1β and IL-18. Old mice lacking NLRP3 kept better measures of function, such as bone, blood sugar control and thinking; whether they lived longer remained unknown.[7] In people with a prior heart attack and elevated inflammation, 150 mg of canakinumab, which blocks IL-1β downstream of NLRP3, reduced the relative rate of heart attack, stroke or cardiovascular death by 15%, though fatal infections were more frequent.[8]
The cGAS-STING alarm: It detects DNA in the wrong place. In aging cells, DNA copies made from LINE-1 "jumping genes" helped trigger it and drive inflammation in mice.[9]
Zombie (senescent) cells: Clearing them delayed age-related problems in mice,[10] and drugs that remove them extended remaining lifespan in old mice.[11]
The thymus: This organ trains new T cells. It shrinks with age and produces fewer of them.[12]
Crosslinks in collagen: Glucosepane, a major sugar-derived collagen crosslink, accumulates in human skin with age.[13]
Cholesterol in artery walls: It builds into plaque over decades. In mice, cholesterol crystals appeared early in plaques and activated NLRP3.[5]
Overactive growth signals (mTOR): Rapamycin, which dials down this signal, extended lifespan in mice even when started late in life.[14]
There are likely dozens more, and I will add them as the science does.
How The Pieces Relate
These do not work alone. Damaged mitochondria and cholesterol crystals can trip NLRP3, which feeds chronic inflammation, and zombie cells add inflammatory signals of their own. One problem can make others worse.
So no one knows yet which pieces matter most, or which fixes will work best together. It is likely not one thing. And a company that fixes one piece could help several hallmarks at once.
The Goal: The Best-In-Class Company For Each Piece
For each hallmark or mechanism, I look for the companies, anywhere in the world, that are leading on it, and I review them with the same 25 questions every time. If enough strong companies each chip away at one or more pieces, together they could start to slow the decline we call aging.
Past editions already covered several pieces: the NLRP3 alarm, zombie cells, mitochondria, the thymus, mTOR, epigenetic reprogramming, blood stem cells and artery plaque. This is the map those pieces fit into. From here on, each review will show where it sits on the map and why I am looking at it.
What I Look For In Every Company
A real business: A path to approval for a disease that exists today. Aging itself is not an approved indication, which is why researchers proposed the TAME trial, designed to test whether metformin delays a group of age-related outcomes.[15]
A target on the map: One or more hallmarks or mechanisms.
The framework fits a specific window. Seed-stage science usually lands on my Watch List until there is data. Large, proven companies are often priced for much of their success. My focus is public micro caps, lower-valuation companies and private companies around Series A and B, where there is progress to evaluate.
Each review ends with one call, plus dated milestones:
Tracker: the strongest cases
Scout: worth following closely
Watch List: interesting, too early to judge
What's Next
My next edition goes deep on one hallmark of aging. The goal is to put the pieces of the puzzle together, apply the same principles each time, and spot the better companies so they can potentially get more support, move faster, and build more public awareness of what is possible.
One tap decides which piece comes first:
Which piece of the aging map should we go deep on first?
Thank You For Reading This Far
If you have read this far, thank you. Here are a few newsletters I think are worth your time. Subscribing helps keep these editions free, with no membership required. Information is power, and I hope you find something useful.
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Alternative Investing Report: a daily private-markets update from Vincent covering alternative assets such as private credit, real estate and litigation finance.
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Eric
EverLife Capital publishes general educational research, not personalized investment or medical advice. Nothing here is a recommendation to buy or sell any security. The Hypothetical Research Tracker is a research project, not a fund. Animal results may not apply to people. EverLife Capital earns referral fees when readers subscribe to the recommended newsletters above. No company covered paid for coverage, directly or indirectly. EverLife Capital is published by Consult US, LLC. Some research and summaries are prepared with AI assistance and reviewed before publication.
References: 1. Informa Pharma Intelligence, BIO, QLS Advisors. Clinical Development Success Rates 2011-2020. 2021. 2. Gavrilov LA, Gavrilova NS. J Theor Biol. 2001;213(4):527-545. 3. López-Otín C et al. Cell. 2023;186(2):243-278. 4. Zhou R et al. Nature. 2011;469:221-225; Shimada K et al. Immunity. 2012;36(3):401-414. 5. Duewell P et al. Nature. 2010;464:1357-1361. 6. Mariathasan S et al. Nature. 2006;440:228-232. 7. Youm YH et al. Cell Metab. 2013;18(4):519-532. 8. Ridker PM et al. N Engl J Med. 2017;377:1119-1131. 9. De Cecco M et al. Nature. 2019;566:73-78. 10. Baker DJ et al. Nature. 2011;479:232-236. 11. Xu M et al. Nat Med. 2018;24:1246-1256. 12. Palmer DB. Front Immunol. 2013;4:316. 13. Sell DR et al. J Biol Chem. 2005;280(13):12310-12315. 14. Harrison DE et al. Nature. 2009;460:392-395. 15. Barzilai N et al. Cell Metab. 2016;23(6):1060-1065.
