Alan Tomusiak
@alantomusiak
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longevity + genome instability + community building | principal @age1vc
Joined February 2022
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What drives aging?
Entropy? Information loss? A software flaw? Mutations? Epigenetic drift?
Choose any - but it all comes down to maintaining the genome. And yet there are so few people working on this central pillar.
A post on why you should:
(1/7)
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My first ever paper was just published, all originally stemming from a failed experiment. The original project vision was to build out a high-throughput screening platform for longevity.
How did this lead to a deep epigenetic clock study? (1/7)
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YOU DON'T UNDERSTAND, EPIGENETIC CLOCKS BEING CHALLENGING TO INTERPRET IS NOT A FLAW BUT RATHER SUGGESTS THERE'S SOMETHING FUNDAMENTAL ABOUT AGING WE DON'T FULLY COMPREHEND
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I'm incredibly excited to share a new preprint! Briefly, we investigate how cell composition impacts existing epigenetic clocks, we build a * new clock * that predicts age evenly across cell types, and we show this new clock has interesting properties.
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An absolute gem of a paper investigating what makes longer rodent species live longer, primarily by analyzing transcriptomic data from 26 species. Some thoughts, in a thread:
(kudos to
@EdwardAnderton7
for showing me the paper!)
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"We choose to tackle aging in this decade and do the other things not because they are easy, but because they are moderately difficult"
- JFK, maybe
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One of the most important conferences of our time - the Biomarkers of Aging Symposium - is happening right now in my backyard (almost literally, as I can see the Buck from my house). Live-tweeting it in this thread...
#BoAS2023
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Immensely grateful for the longevity field & community. Ten years ago, while working as a gas station attendant in the outskirts of Atlanta, I could not have imagined working on such interesting problems with such talented and kind-hearted people.
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A lot of debate in the longevity community!
agree that biohackers are good for the field? 50%
think that the first drug to extend lifespan in humans by more than 12 years will end up being a small molecule? 20%
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Setting up an intensive genome instability -> therapeutics for longevity journal club group. Vibe is a small group of researchers/builders/founders diving deeply into a paper every week or two. Reach out if interested ~
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Loved doing a 24 hour retreat with this squad about genome instability & aging. We had debates, discussions, brainstorming, meditations, and so much more. Not pictured - afternoon sessions in a spooky cattle ranch in a rain storm. (1/4)
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Hyped to be hosting a special kind of longevity social/networking event in San Francisco on the evening of Thursday the 26th!
One of the things that struck me when I entered the longevity field was that...
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A couple of weeks ago, I successfully defended my dissertation!
Here are a few stories from my PhD that made the whole thing very worth it ~ (1/many)
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Recently piloted a ~ new type of longevity journal club ~ on the topic of chemical reprogramming with an emphasis on brainstorming next steps, next experiments, next essential findings. It was beautiful! A change of pace from many journal clubs, which...
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From arguments at academic conferences to the *Kardashians* (!?!), epigenetic clocks are everywhere. In looking at the ancient texts that started it all (Horvath's paper from 2013), I wrote a piece diving into what clocks can tell us about aging.
(1/3)
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Last night, we hosted a Longevity Trivia night at
@age1vc
. It was a pretty unique and special event, something to shake up the usual networking vibe and have something with more of a community feel.
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Lastly, I put together a useful resource of labs, interventions, and companies working on genome instability in the context of aging. It'll be continually updated, oriented so that anyone entering the field has a guidepost. (5/7)
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Turns out a strange rare cell type that super centenarians happen to have a *ton* of can survive for a mouse's entire lifespan and is very, very good at killing tumors.
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I was incredibly lucky and privileged to present my first ever presentation at a conference @
#BAAM
yesterday. What I did not have time to share, however, was that almost all of the (early!) work I shared stemmed from a series of failures. (1/many) -
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Are you working on how to measure the deep mystery of why and how we age?
If so - first of all, very very cool. But also consider presenting a poster at the Biomarkers of Aging Symposium on December 4th!
Sign-up link:
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Two big papers came out recently filling out some big knowledge gaps in genome instability. The first beautifully ties together R-loops with Cockayne syndrome, TC-NER, and transcript length. Why is that a big deal?
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Buck students & I had a great time yesterday eve discussing philanthropy and investing with
@KarlPfleger
! Brings me a lot of joy to see how mission driven investors in the space are - in this case, with curation of a rich database @ and more.
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What's more fun than having deep meaningful conversations with friends about why we chose to tackle longevity?
Having those conversations over wine 🍷
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Steve Horvath opening the show with a discussion on the successes of clocks but also what still needs to be done. Some highlights on open challenges ~
1) Normalization methods could be better
2) Developing better predictors of health
3) Interpretability
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So it begins.
1 - Loyal has earned what we believe is the FDA’s first-ever formal acceptance that a drug can be developed + approved for lifespan extension
2 - We have 'technical section complete' AKA the 'does it work' data for LOY-001 - our large dog lifespan extension drug - is done
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Daniel Belsky is discussing measuring the "pace of aging" rather than aging itself. There's a nice benefit to having increased sensitivity to tracking interventions, and I imagine this will be an axis that will be important for all future biomarkers.
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I make the case that aging is exponential, like a boulder rolling down a hill. Most approaches in the longevity field are focused on the Sisyphean task of pushing it back uphill to "reverse aging" once the boulder is at full speed. But what if we slowed it down, instead? (2/7)
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Hosting a warm mixer for 30-50 founders, soon-to-be-founders, and investors in the longevity space next Wednesday evening. There's a few spots open - apply if you're interested!
Link:
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Luigi Ferrucci now stressing the importance of the loss of resilience associated with aging. This is a critical point - it is deeply under-appreciated that the effects of aging on a steady state pale in comparison to when stress is applied.
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Lab meetings are wonderful for deep dives into longevity science, coffee machine works for chit chat about the latest paper, but what’s the forum for students to discuss larger topics around longevity? Buck students have started doing a cool thing (1/n)
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And to close off...
A $101 million XPRIZE announcement for healthspan by Jamie Justice! An incredible use case for the next-generation development of biomarkers of aging, an effort that received a massive boost today.
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@mahdi_moqri
now on stage discussing the Consortium itself. I can't personally stress enough how key the work done by the Consortium is. Stepping back, it's clear the first steps to making enormous progress in the longevity field is to get everyone to agree on what aging is.
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pretty interesting how at fairly traditionalist longevity research institutions there's a strong emotional reaction against living-forever rhetoric despite an actual high desire to live forever.
ultimately debate comes down to optimism/hype and worries of public reaction to it
Here are some poll results from the Buck Institute’s Student Aging Symposium! Exciting to see how many of the top aging scientists think about the field and the future of longevity
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We hosted an
@age1vc
community event for founders/investors/soon-to-be-founders the other night. Here are some of the most interesting longevity-related conversations I overheard.
!!
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This is incredibly important! Every longevity journal club I've attended inevitably enters the "but what IS aging?" death spiral, a signal that productive conversation is about to cease. This is, imo, because we don't spend enough time creating consistent ideas of what aging is.
Pleased to share an opinion piece I wrote with
@VadimGladyshev
just published in
@PNASnews
. We discuss what I consider to be the most pressing (and interesting!) question in the field: what is aging?
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Soon to come: part 2, a more comprehensive and scientific framework for the very complex world of genome instability in aging. (6/7)
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Defining, creating, validating, and understanding biomarkers of aging is absolutely critical for the future of longevity interventions. Excited to be helping this effort!
🎉 The Consortium is excited to announce our inaugural 2023 Biomarkers of Aging Symposium, a full-day event focused on sharing the latest research on biomarkers of aging, discussing key issues we face moving forward, and defining Consortium priorities for 2024 & beyond.
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The warmest thanks to the people who inspired and helped shape the piece into what it is. It's come as the culmination of conversations with dozens of professors, students, Twitterati, VCs, founders, and geese at the park.
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A neat piece on market size for potential longevity interventions. I'm curious about how true these estimates will end up being. There's a deep section on drug pricing, but I suspect a true healthspan/lifespan-extending drug will have quite a lot of pricing flexibility. (1/2)
We found that a drug approved and indicated for aging would conservatively have a peak global market size ~$150-$200 billion annually.
A company that owned only this drug would be more valuable than the top 2 big pharma companies (J&J and Pfizer) in terms of revenue…combined.
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Absolutely incredible time at BSAS this year. Honored to have
@NirBarzilaiMD
not only give a talk but go head-to-head with other panelists in a longevity interventions debate!
This year’s BSAS (Buck Student Aging Symposium) kicked off with an amazing talk by keynote speaker, Nir Barzilai, who discussed genetics in centenarians. Excited for student and early-stage trainee talks today and interventions debate and sci comm and education panel in afternoon
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Aging is not (yet!) an FDA-approved indication in humans, so the follow-up question for genome stability interventions is *in what disease?* We are still in the pioneering days of this field, but I found five that are promising starts. (4/7)
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There's interesting chatter on Twitter about a paper suggesting lifespan interventions in worms and flies are not predictive of success in mice or humans, but sometimes even humans are a lousy model for humans. Here's what I mean -
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I make the case (standing on the shoulders of giants here!) that the key to slowing down the aging process - the equivalent of adding friction to the rolling boulder - is in tackling genome stability. There's basically four ways of doing this, each progressively harder. (3/7)
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There’s chatter on Twitter on the choice between industry and academia, but there are so many other possibilities. Yesterday,
@BuckInstitute
students had the joy of chatting with Mariëlle van Kooten, operating in the exciting new world of Focused Research Organizations (FROs)!
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We come up with an interesting theme, do some warm up activity, then meet up at a wine bar for two hours. This week, we listened to some
@BioAgePodcast
(Translating Aging) podcasts and discussed how to effectively & ethically communicate the work that we do.
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Albert Higgins-Chen just did a fantastic showcase of how to find an aspect of epigenetic clocks that is challenging to understand, deconstructing it, and then pulling a compelling and informative result out of it. In the surprising context of depression!
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I've been as enthusiastic about AI recently as everyone else, but I had a difficult time seeing the applicability to longevity & science as a whole. This is partially due to science being inherently creative (and thus not as much of a good fit for pre-trained models) but MOSTLY..
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Working on longevity seems like an effective way to contribute good to the world, but is it the MOST efficiently moral thing to do? (1/n)
(pictured: Singer's drowning child thought experiment, 2022, colorized)
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As the New Year is rapidly approaching, I've been reflecting on all I've learned & read in 2022. Here are some of my favorite papers that I have stumbled across ~
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!!
Why has menopause become a normal part of every woman's life, when it causes unnecessary suffering?
Why is reproductive aging research still significantly underfunded when half of the population experiences menopause?
I believe this *needs* to change, so I wrote a piece about
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to what extent does increased incidence of aging-associated disease at 70 inform our knowledge of how we age between years 20 to 40?
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Many people working on pathway engineering to decouple rejuvenation and de-differentiation in the context of reprogramming, but is anyone trying protein engineering? (1/4)
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Thank you
@MartinBJensen
for the honor of presenting! So many interesting questions, comments, and ideas. Wishing you and
@GordianBio
all the best in your mission.
Big thanks to
@alantomusiak
for presenting at
@GordianBio
happy hour yesterday. Loads of questions about how to design epigenetic
#aging
clocks to avoid conflating cell type distribution changes with per cell methylation changes.
Here's his preprint:
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Lots of recent literature on the role of G4 quadruplexes in driving aging, possibly via modulating autophagy. Spermidine extends lifespan in mice; also possibly via autophagy. Spermidine has been found to strongly bind G4 quadruplexes.
Curious if there's a direct connection?
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It’s the laser focus on aging itself that I love here. So excited to see the field march forward!
Why don’t we target the inevitable cause of our decline, aging, before it happens?
Excited to announce a moonshot fund to catalyze the longevity field to new heights. We won’t stop until we all have agency over how long we can live in good health.
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This conference has been amazing, and I feel lucky to have witnessed it, participated in it, and helped organize it.
We're at an inflection point in the longevity field, and it is events like this that make it feel tangible.
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Reading a lot of transcriptomic clock papers recently, wishing there was less focus on R^2s and more focus on everything else interesting about using transcriptomics to predict age
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(4) We have a genome stability longevity hallmark enthusiasts group, and in the winter we opted to do a retreat at some distant farmhouse. We succeeded at Learning but failed at getting food, as we accidentally got lost during a rainstorm and ended up at a Coast Guard base.
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So far, the discussions have been incredibly fun! There’s a real appetite to debate the larger implications of longevity research. There is so much more to science than benchwork & experiments, and greater contextualization makes the work feel much more meaningful.
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@mahdi_moqri
Next up: Deep thinking around the relationship of aging biomarkers with causality, and how they tie into the hallmarks of aging.
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This is happening *this Thursday!* It's going to be a lot of fun. Great people, amazing conversations, an Activity, and...
...
~ Polish desserts ~
RSVP soon!
Hyped to be hosting a special kind of longevity social/networking event in San Francisco on the evening of Thursday the 26th!
One of the things that struck me when I entered the longevity field was that...
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Just finished reading a paper that opens like this.
I love immunology.
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(2) I remember standing on stage nervously at my first ever presentation @ the Bay Area Aging Meeting. I opened my talk with a joke I prepared to ease the tension.
It *completely* bombed. Afterwards, people came up to me to sympathetically tell me they definitely got the joke.
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Lots of focus on clocks for tracking longevity interventions in people, but (perhaps more excitingly!) they can be used to understand the aging process itself. Great new paper from
@OcampoLab
on this point - why do some mouse mutants age faster epigenetically? More below...
Latest paper from the lab where we analyze epigenetic age in multiple mouse models of premature aging. Importantly, our data reinforces the link between DNA damage and epigenetic dysregulation. Congratulations to all the authors!!
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More than these findings, however, I'm a huge fan of the approach. One key question I always ask myself is which of the aging hallmarks are more important than others, and studies like this go a long way in disentangling that Gordian knot.
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Here’s a fairly recent great paper that has lived in my head rent-free, and not necessarily for reasons that are the objective of the study -
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Turns out if you ask an LLM trained on proteins to simply provide you with a suggested mutation, you will heavily enrich for gain-of-function mutations. The idea is beautifully simple - if a model saw a mutation occur several times across evolution, it was likely beneficial.
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... less so, like a music festival where I did most of my qualifying exam reading (which prompted a fellow festival-goer to ask if I was autistic).
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(1) A few students (led by
@EdwardAnderton7
!) organized a deep dive on long-lived species and what influences their longevity. Everyone had to present on a particular species *and* dress accordingly. The result:
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(3) A couple of years later, I got to help run the Buck's very own student conference. We wanted to have a debate panel, but were worried about the common panel failure mode where one panelist keeps rambling. My solution?
Blowing a vuvuzela when anyone went on too long.
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Overall, very excited to see this project out in the world & the potential for applications. Very grateful for the full team that made this project a reality, including
@strongsciren
and our mentor
@EricVerdin
. (7/7)
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We re-arranged the Airbnb and plastered the walls with way more post-it notes than I care to admit. The main priorities for ideas:
(1) molecular mechanisms underlying DNA repair disorders for better understanding and
(2) ideas for clinical indications to target (2/4)
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@wedonthavetodie
@MateMaus
There's also the beautiful Lanna et al. paper from late 2022 showing that APCs hand off telomeres to T cells, which is a *very* direct mechanism for environmental maintenance of youthfulness in T cells.
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4) The circadian rhythm is heavily involved, but primarily by regulating genes *negatively* associated with longevity. Authors suspect this is due to longevity requiring tight control of metabolism.
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Gotta do the next one in a freezing room to get CIRBP activated, bowhead whale style ()
Fully immersing myself in my research by doing genome instability journal club in a 87℉ windowless room where the lights turn off every 10 min. My genome is definitely destabilizing rn
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For a little bit of context ~
We had an awesome event yesterday at the Loyal HQ. ~40-50 folks attended from a diverse array of backgrounds, suspect 50% or so academics, 20% tech background, 10% business/VC and 20% other. Most (~70%) active in the aging field.
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These thoughts stemming from conversations held with Buck students - thank you
@BuckInstitute
for sponsoring! Helps put the "Ph" in "PhD." (:
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I think about this particular paper a lot when I consider how distant many of the models we use are from humans - if even incredibly subtle differences in very good models lead to non-translatable results, what does that mean for far-removed models?
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The goal was to stimulate conversations around Important Topics in Longevity rather than getting robust statistical data on field consensus, but nevertheless it's interesting that almost none of the questions had more than 70% agreement. And these are critical themes!
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... except caloric restriction, where you get a mixed bag! Perhaps there's some clues there as to why caloric restriction works in some contexts and not others.
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We started off with a deep four-hour dive comparing Werner's/Bloom syndrome. Thinking if you can find a genome instability mutation that leads to faster aging(ish) and compare it to one that doesn't, you can start drawing enough Venn diagrams until you figure out what aging is.
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1) Inflammation-related genes turn out to be even more important than I anticipated, and I work in an immune aging lab. A few usual suspects involved (JUNB, IRF4, STATs), but also some surprises (RAG2?).
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(5) I thought I'd get to know like-minded people, but I didn't expect to meet some of the best friends of my life. Some of these experiences were deeply wholesome, like a cute Friendsgiving where we all shared what we were grateful for. Others were...
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(6) There was a lot of work - many midnights at the flow sorter, so many energy-drink-fueled days trying to understand why R does the things that R does. But overall, would I do it again?
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Two intriguing important longevity papers came out recently, and I’m very curious as to the depth of the link between them. A 🧵 of thoughts:
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... seem to focus more on critically finding flaws. Important, but collaborative construction rather than destruction feels somehow more meaningful.
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The lack of consensus around focusing more on the root causes of aging in particular struck me as interesting. My personal bias is that we'll need more clarity on this in order to have consensus on any of the other questions. But perhaps I'm wrong.
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Overall, a phenomenal night. Incredibly grateful to everyone who came out. :)
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On the flip side, I wonder if COGS estimates will be quite different if the first intervention ends up being a gene or cell therapy. (2/2)
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This is the first article in a weekly series discussing key papers in the field of aging, designed to be interesting both for folks just entering the longevity space and for those who have been around for awhile. (3/3)
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5) Authors also did a clever thing by predicting in silico whether or not longevity interventions (rapamycin and friends) would regulate the positively- or negatively- associated genes with longevity. Found that most interventions move the needle as expected...
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Nevertheless, I feel inspired by this. Long nights in lab feel less painful when those long nights might be literally the best possible thing you could do with your time.
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This Venn diagram drawing could be extended across many diseases to start drawing parallels & frameworks to start thinking about genome instability and aging in a more interconnected way. We did a first stab at this at the retreat - but there's a lot more to be done (4/4)
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@MateMaus
I love this paper, but it's not clear to me that this indicates T cells do not age. They can be maintained for at least 10 years, which is very long for a mouse but would be rather short for humans!
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