Kimi gave this talk the following title: Evolutionary Blueprints of Extreme Longevity: From Whale DNA Repair to Seaweed-Derived SIRT6 Activation for Human Healthspan Extension

Vera Gorbunova

https://www.youtube.com/watch?v=z6WzbzPa7JA

Introduction

Let's talk about science and comparative biology specifically. So I want to focus on lessons that we learned from long-lived species because we've been studying them, well inspired by Steve Olsted, we've been studying these species for probably 20 years now and there are some amazing findings that came through it.

Okay, my disclosures first.

And okay, so as it's already been said, there is dramatic difference in rates of aging and maximum lifespans across mammals. So we want to understand what makes short-lived species different from long-lived and then to find out what long-lived species do so that can we use it for human benefit. There are a few species on this slide, and I will not say much about bats because Emma will be talking about them, so I don't want to steal your thunder. But bats are amazing. And then I will talk a little bit about naked mole rat, bowhead whale, and then also comparative biology where we take many species and compare them to each other.

Translational intervention

Here is the blueprint. So we study those long-lived species, we find specific molecular mechanism, and then we put it in the mouse. Well, mice are good for something. You can use them as test tubes to test those anti-aging interventions that we take from a long-lived animal. If they can help mice, then well, hopefully they can also help humans. It's something that can be exported.

Naked mole rats

Yesterday, Andre, or even the day before yesterday, Andre gave beautiful talk about naked mole rats. So we've been studying naked mole rats for a very long time. So here is Hallmarks of Aging picture with different findings from our groups where we found all these unique adaptations in naked mole rats that address multiple hallmarks of aging. So there is this little rodent that ages extremely slowly, and they evolved various ways of doing it, and some of these ways are more easily translatable to human healthcare than others.

Hyaluronic acid

And again back to Andre presentation so we found that hyaluronic acid that is so abundant in naked molerat is something that can be translated to human. It's coming out in Nature next week it took so long a very long journey and you know eventually what we'd like to do is translate it to humans because now mice can benefit from naked mole rat hyaluronic acid and now we are starting to test how to use it in people. This is one successful example of using this pipeline from long-lived animal into human.

Whale

So now a few words about the whale.

So whale well if as Steve just mentioned naked mole rat is special because well not necessarily because it lives longer than human, but it is just very small and it is very unique in its mortality patterns. But if we talk about whale, well, it is actually the only mammal that lives longer than human.

So bowhead whale lives up to 211 years, maybe longer. So that's the only mammal that outlives human by twofold, two human life spans. And they're amazing in many ways. They're also so large.

And I could talk about how they avoid cancer, which is another big issue of big animals. How do you avoid tumors?

So this is our team in Alaska investigating whales and collecting samples. Again, for the sake of time, I'll go quickly. I must say this story is now in revision for Nature, so we still don't know what the fate will be, but I think the reviewers were kind to us, so I hope we'll manage.

So what we demonstrated was that whales don't seem to have more sophisticated tumor suppressive mechanism. They don't have multiple copies of P53 or RB. So they only need four oncogenic hits to develop malignancy, unlike humans that need five. This was a big surprise. We expected whales to have additional copies since they're so much larger. And that brought us into looking into DNA repair in whales, because we thought, okay, maybe they just don't let things progress so far. Maybe they repair damage and this is why they don't mutate-- their tumor suppressors.

Indeed we found that in the bowhead whale double strand break repair is extremely efficient, extremely fast, accurate also. So when we measured mutations in bowhead whales at the site of the damage, we found that they have much fewer mutations, so they're extremely accurate.

And here we are comparing them to humans. So human is very hard to beat. But whales are better than us at DNA repair, and they are better than other animals. So here you see mouse. Mouse is the worst, yes, no surprise. They're better than cow, better than human. So here is another strategy, just very good genome maintenance. And we drilled to the mechanism of it. So we found that in the whale, there is a protein called cold-induced RNA binding protein. It's in use by cold and this is arctic whale. It lives in icy waters, so that's probably evolutionary why they up-regulated this protein. But now, they have a ton of this protein, 100 times more than humans, and it facilitates DNA repair. So we even found that if we take this protein, the whale version of it, and express it in human cells, we can improve double-strand break repair in humans. So isn't it nice?

Whale version of Kirb protein is not that different from human, there are only five amino acid differences. But it is optimized for maximum expression through cordon optimization, also through mRNA stability. So they just express it very well. And if we took human cells and put them in cold, we could also stimulate production of Kirb, not to the same level as in the whale, but we could stimulate it, and it improved DNA repair. So here are just human cells, and we can see improved DNA repair, which of course led us to speculate about various therapies that are based on cold exposure, brief cold exposure, which is something people been doing for years in sports medicine, that's how you reduce inflammation from injuries. Cold water swim improves mood. And perhaps it can improve your DNA repair. So this is again something we are exploring.

We be very interested to see all the benefits because this is a very simple lifestyle modification and if we can show that it does something beyond psychological effects. So that may be again very attractive. Also yesterday, there was a session on cryotherapy organ preservation. So I must say that the same protein is actually very important for preservation of organ transplants. If there is not enough of it in the tissue, the organs deteriorate much faster. So this may be another application of the whale protein to benefit human health. Okay, so now we talked about the whale.

Comparative biology

I want to say a few words about comparative biology where we're looking at multiple species. So this is the fountain of youth. Everybody's familiar with this painting. This is how we see the fountain of youth. There are whales and the closer you are to the fountain, the supposedly longer lived.

So here we undertook a study, a comparative study, where we examined about 30 different species and their transcriptomes. And that part was published in 2022. And right now we are moving it forward. So I will show you some of the new and unpublished data on the proteome analysis.

So we analyzed transcriptomes and proteomes across multiple tissues, and we were looking for genes and proteins that correlate with lifespan, either positively or negatively. So here is transcriptome, negatively correlated genes. We found a lot of metabolic genes, and genes connected to inflammation and cytosolic DNA sensing, which is, by the way, something that is really knocked down in bats, and they know how to deal with inflammation. But even if we exclude bats from analysis, we still see that these pathways are negatively associated with maximum lifespan.

So now what about proteins? So this is, again, this is all very new. Comparative proteomics is not easy. You have to find the paralogues for everything. And also transcriptomics is much more sensitive. So we only primarily looking at abundant proteins.

So what we see here is still ribosome, various metabolic enzymes, oxidative phosphorylation, mitochondria. Here is still ribosome, various metabolic enzymes, oxidative phosphorylation, mitochondria. So these pathways are negatively associated with maximum lifespan even on the protein level.

We didn't necessarily see inflammatory molecules but perhaps because they're below the limit of detection of LSMS mass spectrometry.

Now what about positive genes? That's becoming even more interesting. So from the transcriptome analysis, our favorite part was DNA repair. So we already mentioned DNA repair and how important is it to maintain genome stability, and that was clearly a winner from comparative studies. So to live for a long time, you need good DNA repair.

Now what about proteome? So here we see some new players. We find ECM, collagen, other extracellular matrix components. That from the study of Nicky Morad, we already learned that ECM is important, but now in comparative sense, we see that ECM is important.

Various stress proteins, glutathione, things related to wound healing.

Blood microparticles

And now a really new thing that I'm super excited about are blood microparticles. So we probably, you've heard about blood transfusion studies and herterochronic probiosis when young bloods were bringing beneficial effects. But this is all within species. But here we're looking across species and long-lived species have higher levels of these blood particles that can carry various types of cargo in them. We don't yet know what the cargo is. We just know that long-lived species have more of these. So that's something we are actively investigating and that's actually super exciting and again something that didn't come through transcriptome analysis. So this is the summary for that part secretory proteins including blood microparticles seem to provide us a signal.

SIRT6

So now back to DNA repair a few words about SIRT6. So here we went in a more targeted ways because we knew that SIRTUIN6 is important SIRTUINs, it extends lifespan, transgenic mice. But when we analyzed it across species we found that longer species have more active SIRTUIN6.

So what does SIR2N6 do? It involved in DNA repair epigenome maintenance and also suppressing line one elements, these genomic parasites that make up a major volume of our genome, about 80% of our genome of various repetitive elements. And a couple years ago, we published, together with a group of John Sedivy, we published a series of papers where we showed that line one elements can drive inflammation, and that may be another causal mechanism of aging because they get activated with age. So like when we get older, our genome starts to look like that with different parasites waking up. So we need to find out how to suppress them because once they wake up, they activate innate immune system, and that may be contributing to sterile inflammation and to other age related diseases.

So there is this concept of inflammation introduced by Claudio Franceschi. So again, this is very new slide. I was really tempted to include it here. So we generated mice with a knockdown of line one elements of the most active families of line one elements. And these mice show lifespan extension. They also show reduced frailty and reduced inflammation. So this is a strategy to go and maybe more active SIRT6 in long-lived species. Well, part of the job would be suppressing line one elements. Also independently, I know that there is biotech around just suppressing line one elements, but here we can show lifespan extension. So that's super exciting.

Clinical translation

And finally, the last story I want to show you is about, okay, how do we translate all of this? How we benefit now from SIRT6 for rejuvenation because, well, we know DNA repair, SIRT6 is more active across species. So this is in collaboration with Steve Horvath and Ken Raj. So the first proof of principle, we took all fibroblasts from old people, like very low passage fibroblasts that can rush sent to us. Expressed SIRT for two weeks and which was arbitrary time frame And then measured mutilation age it went down You can see in majority of our test samples And it all caused various changes to gene expression related mostly to DNA confirmation chromatin assembly, and so forth. And most excitingly, transposons were silenced. So these genomic parasites were silenced. And they also gained mutilation because, well, there was a beautiful session on clocks where Vadim and Steve were talking about all the intricacies of the clocks. So there is part of the genome that gains mutilation with age, and there is part of the genome that loses mutilation with age. And if we want to reverse things, we have to perhaps treat those two types differently. So transposons lose mutilation, so we want to silence them, and that's part of the thing what SIRT6 is doing, putting them back into heterochromatin jail where they belong. So now another human factoid. When we were investigating human SIRT6, not cross-species, but in human, in collaboration with using Sue in Columbia, we found a centenarian-enriched mutation that had separation of function of SIRT6. It had reduced the acetylation activity and enhanced mono-ADP ribosylation. So we started looking then for chemical activators of mono-ADP ribosylation because that seems to be more important activity if it's enhanced in centenarians. And a very strong activator of this activity comes from seaweed. It's called phucoidin. It's a polysaccharide. You can see several structures it's not the same structure because different sea weeds have slightly different for guidance but when we tested we found that some seaweeds are very strong activators of 6 activity so you're eating seaweed is not going to harm anyone anyone so it's very safe and in collaboration with do not age we decided to do a mouse preclinical study so we tested different seaweeds, we found one that was a strong activator of SIRT6, and then we started giving it to 14-months old mice. So mice on seaweed were looking better you can see just based on the code. And most importantly this is frailty score mice receiving fucoidin were having much lower frailty and reduced inflammation because if SIRT6 reduces inflammation through silencing transposons for example reducing DNA repair that's what we would expect reduction of inflammation in these mice that's what we see and most recent result survival curve we even see a signal with lifespan there was about 70 I mean 7% lifespan extension in these mice that started receiving for coed and supplementation fairly late in life starting at 14 months. So that is all you know very exciting and you know I just I just want to leave you with these questions.

Summary

Okay, we know that there are some exceptionally long-lived species, how they manage to do that. We discovered some mechanisms, but there may be many more, and that's a really very fruitful area of investigation. We found, again, from these comparative studies, that it's important to maintain your genome and epigenome very well, and SIRT6 is important here, important here but when SIRT6 rejuvenated, we observed that rejuvenating effect of SIRT6, we don't quite understand what kind of template was used to package transposons back into heterochromatin, so we're trying to understand again what kind of template is there, so what information is being read by SIRT6. And I should also say that another approach to it is Yamanaka factors, but with Yamanaka factors you really like rewire everything completely while SIRT6 is much more conservative. It just reinforces heterochromatin. It doesn't change cell identity.

Finally, okay, how do we silence line ones and restore heterochromatin? Is this sufficient, or do we need to combine different interventions? And this is my final summary of different lessons we learned from long-leaf species about genome stability, inflammation, SIRT6 activators, ECM. And of course we would like to at some point to combine all of them, so I love Aubrey's approach in combining interventions. And here we may be able to take all these different adaptations that evolved naturally and then make a super model combining interventions. combining interventions. And here we may be able to take all these different adaptations that evolved naturally and then make a super mouse, or super human at some point by combining those evolutionary adaptations. Señor President

End raw transcript. AI slop now commences!

1. Concise Technical Summary

The talk surveyed comparative gerontology in mammals, focusing on molecular adaptations that enable extreme longevity in species such as the naked mole‑rat, bowhead whale, and bats, and how these adaptations can be transferred to mouse models and ultimately humans. Key findings include (i) abundant high‑molecular‑weight hyaluronic acid in naked mole‑rat tissue that improves tissue homeostasis and can be administered to mice; (ii) exceptionally rapid and accurate double‑strand break repair in bowhead whales driven by a highly expressed cold‑inducible RNA‑binding protein (CIRBP), whose whale ortholog enhances DNA repair when expressed in human cells and can be induced by brief cold exposure; (iii) a comparative transcriptomic‑proteomic survey of ~30 mammals that identified negative correlations between lifespan and metabolic/translation pathways, and positive correlations with DNA‑repair genes, extracellular‑matrix (ECM) components, stress‑response proteins, and circulating microparticles; (iv) evolutionary up‑regulation of SIRT6 activity in long‑lived taxa, which suppresses LINE‑1 retrotransposons, stabilises heterochromatin, and reduces chronic inflammation; (v) a centenarian‑derived SIRT6 variant with enhanced mono‑ADP‑ribosyltransferase activity that can be pharmacologically mimicked by fucoidan (a sea‑weed polysaccharide), extending healthspan and modestly increasing lifespan in aged mice. The presenter concluded with open mechanistic questions—how SIRT6 re‑establishes heterochromatin, the cargo of longevity‑associated blood microparticles, and the optimal combination of interventions—to guide future “super‑model” strategies integrating multiple evolutionary adaptations.

2. Re‑formatted Transcript

2.1 Introduction

Scope: Comparative biology of exceptionally long‑lived mammals.
Goal: Identify mechanisms that differentiate short‑ and long‑lived species and assess translatability to human health.
Species Covered: Bats (briefly, Emma’s talk), naked mole‑rat, bowhead whale, and a broad comparative panel (~30 mammals).

2.2 Experimental Blueprint

Discovery Phase – Study long‑lived species → pinpoint molecular mechanisms.
Validation Phase – Engineer mouse models to test these mechanisms.
Translation Phase – Move promising interventions toward human application.

2.3 Naked Mole‑Rat

Hallmarks of Aging: Multiple unique adaptations identified (see Hallmarks of Aging diagram).
Key Molecule: High‑molecular‑weight hyaluronic acid (HA).
- Translational Step: HA from naked mole‑rat improves mouse health; now being evaluated in humans.

2.4 Bowhead Whale

Longevity: Documented lifespan ≈ 211 years (≈ 2× human).
Cancer Suppression: No extra copies of classic tumor suppressors (p53, RB). Only four oncogenic hits needed for malignancy (vs. five in humans).
DNA Repair:
- Phenotype: Extremely fast, accurate double‑strand break (DSB) repair.
- Comparative Ranking: Whale > human > cow > mouse (mouse worst).
- Molecular Driver: Cold‑inducible RNA‑binding protein (CIRBP).
  - Expression: ~100‑fold higher in whale tissues.
  - Function: Enhances DSB repair; the whale ortholog differs by only five amino acids from human CIRBP.
  - Proof‑of‑Concept: Human cells expressing whale CIRBP show improved repair; cold exposure also up‑regulates CIRBP modestly.
Potential Applications:
- Cold Exposure: Brief, controlled cold may boost DNA repair in humans (parallels sports‑medicine cryotherapy).
- Organ Preservation: CIRBP levels correlate with transplant tissue viability.

2.5 Comparative Multi‑Species Analysis

2.5.1 Transcriptomics (30 species)

Negatively Correlated Pathways:
- Central metabolism, oxidative phosphorylation, ribosomal biogenesis.
- Inflammation and cytosolic DNA‑sensing pathways (also suppressed in bats).
Positively Correlated Pathways:
- DNA‑repair genes (most robust signal).

2.5.2 Proteomics

Challenges: Orthology mapping, limited sensitivity of LC‑MS (detects mainly abundant proteins).
Negative Correlates (protein level): Same metabolic and ribosomal signatures as transcriptomics.
Positive Correlates (protein level):
- Extracellular matrix (ECM) components (collagen, other matrix proteins).
- Stress‑response proteins (glutathione, wound‑healing factors).
- Novel Finding: Elevated circulating microparticles in long‑lived species; cargo unknown.

2.6 SIRT6 (Sirtuin 6)

Cross‑Species Trend: Higher SIRT6 activity in long‑lived mammals.
Functions:
- Promotes DNA repair and epigenomic stability.
- Suppresses LINE‑1 retrotransposons (≈ 80 % of the genome).
- Reduces sterile inflammation driven by transposon activation.
Experimental Evidence:
- Knock‑down of active LINE‑1 families in mice → extended lifespan, reduced frailty and inflammation.
- Centenarian‑derived SIRT6 variant (reduced acetylation, enhanced mono‑ADP‑ribosylation).
Pharmacological Activation:
- Fucoidan (sea‑weed polysaccharide) identified as a potent activator of SIRT6 mono‑ADP‑ribosylation.
- Mouse Study: 14‑month‑old mice fed fucoidan showed lower frailty scores, reduced inflammation, and ≈ 7 % lifespan extension.

2.7 Translational Demonstrations

SIRT6 Over‑Expression in Human Fibroblasts:
- Two‑week expression reduced epigenetic “methylation age”.
- Global transcriptional shift toward DNA‑conformation and chromatin‑assembly pathways.
- LINE‑1 elements re‑silenced, supporting heterochromatin re‑jailing.
Cold‑Induced CIRBP Up‑regulation:
- Brief cold exposure in vitro modestly increased CIRBP, enhancing DNA repair.
Fucoidan Supplementation:
- Demonstrated healthspan benefits in aged mice; ongoing pre‑clinical evaluation for humans.

2.8 Open Questions & Future Directions

Mechanistic Gap: What template or co‑factor does SIRT6 use to re‑establish heterochromatin at LINE‑1 loci?
Microparticle Cargo: Which proteins/RNAs in blood‑derived microparticles mediate longevity signals?
Intervention Synergy: How do multiple longevity mechanisms (DNA repair, ECM remodeling, SIRT6 activation, cold exposure) combine—additively or synergistically?
Alternative Re‑programming: Comparison of SIRT6‑based rejuvenation vs. Yamanaka factor‑mediated epigenetic reprogramming (the latter alters cell identity, while SIRT6 is more conservative).

2.9 Concluding Vision

Evolution‑Inspired “Super‑Model”: Integrate naturally evolved longevity adaptations (e.g., whale CIRBP, naked‑mole‑rat HA, SIRT6 hyper‑activity, ECM robustness) into a composite mouse (or eventually human) platform.
Reference to Aubrey de Grey’s “combination therapy” philosophy as a guiding framework for multi‑modal anti‑aging strategies.

3. Core Intuitions, Mechanistic Insights, and Translational Tricks

Concept	Intuition / Insight	Mechanistic Basis	Translational Trick
Genome Maintenance is Central	Longevity correlates with superior DNA repair.	Faster, more accurate DSB repair; up‑regulated CIRBP; high SIRT6 activity.	Express whale CIRBP in human cells; brief cold exposure to up‑regulate endogenous CIRBP.
Extracellular Matrix (ECM) Reinforcement	Robust ECM may protect tissues from mechanical stress and inflammation.	Elevated collagen/ECM protein abundance in long‑lived species (proteomics).	Potential ECM‑targeted therapeutics or lifestyle interventions (e.g., nutrition, exercise).
SIRT6 as a Longevity Hub	SIRT6 integrates DNA repair, epigenetic stability, and transposon suppression.	Mono‑ADP‑ribosylation activity crucial; centenarian variant shows enhanced function.	Fucoidan from seaweed as a natural SIRT6 activator; gene therapy or small‑molecule SIRT6 enhancers.
LINE‑1 Retrotransposon Suppression	Reactivation drives inflammation and genomic instability.	SIRT6‑mediated heterochromatin reinforcement; knock‑down of active LINE‑1 families extends lifespan.	Develop LINE‑1–targeted antisense or CRISPR‑based silencers; leverage SIRT6 activation.
Blood‑Derived Microparticles	Possible systemic “longevity hormone” across species.	Higher concentrations in long‑lived mammals; cargo likely includes proteins/RNAs influencing DNA repair, ECM, or inflammation.	Isolate and characterize microparticle cargo; develop exosome‑based therapeutics.
Cold‑Induced Proteins	Evolutionary adaptation to icy habitats yields DNA‑repair boosters.	CIRBP up‑regulated in bowhead whales; enhances DSB repair.	Controlled cryotherapy or cold‑water immersion to transiently boost CIRBP.
Hyaluronic Acid (HA) from Naked Mole‑Rat	High‑MW HA confers tissue resilience and anti‑inflammatory effects.	HA supplementation improves mouse healthspan; under clinical investigation for humans.	Purified high‑MW HA formulations or HA‑mimetic drugs.
Comparative “Omics” Strategy	Cross‑species correlation uncovers conserved longevity pathways.	Integrated transcriptome‑proteome analyses across 30 mammals.	Use omics pipelines to prioritize candidate genes/proteins for functional testing.

4. Transcription‑Quality Issues & Interpretative Notes

Segment (as heard)	Likely Intended Term	Reasoning / Uncertainty
“CERT‑6” / “CERT6”	SIRT6 (Sirtuin 6)	Contextual clues (DNA repair, LINE‑1 suppression) match known SIRT6 functions; “CERT” likely a speech‑to‑text error.
“Kirb protein”	CIRBP protein (Cold‑Inducible RNA‑Binding Protein)	Discussed as a cold‑induced factor in whales; “Kirb” not a known protein.
“Mutilation age”	Methylation age (epigenetic clock)	Mentioned alongside clocks and age reversal; “mutilation” is a phonetic mis‑recognition.
“phucoidin”	Fucoidan (sea‑weed polysaccharide)	Later description matches fucoidan’s known bioactivity; spelling error.
“Nicky Morad”	Nikki Moradi (researcher on ECM) – or possibly Nikki Moradi (if that is the correct name).	Context of ECM studies; the name appears garbled.
“cold‑induced RNA binding protein … arctic whale … cordon optimization”	CIRBP; “codon optimization”	The phrase “cordon optimization” is a mis‑recognition of “codon optimization”.
“centenarian‑enriched mutation … separation of function of CERT‑6”	Centenarian‑enriched SIRT6 mutation with altered acetylation vs. mono‑ADP‑ribosylation activities.
“Aubrey’s approach”	Aubrey de Grey’s combinatorial rejuvenation strategy.
“Señor President協sh”	[Unintelligible] – likely a closing remark to the session chair; transcription garbled.
“bowhead whale double stern break repair”	double‑strand break repair.
“cryotherapy organ preservation”	cryopreservation of organs – correct concept, but phrasing off.

Overall transcription quality was good for scientific terminology, but several protein/gene names and technical phrases were distorted. The above table lists the most salient corrections made to preserve technical accuracy.