A Discussion of Calico Labs

Google founded the California Life Company, or Calico Labs, to work on aging, and has put a large amount of money into this project. It is all comparatively secretive, but so far the evidence suggests that this will, sadly, turn out much the same way as the Ellison Medical Foundation, which is to say (a) work on extending the map of all cellular biochemistry relevant to the progression of aging at the most detailed level coupled to (b) attempts to slightly slow aging via pharmaceuticals. The project is headed by someone who has little interest in translational research, the business of bringing therapies to market, and those involved - for the most part - are not people with a track record of paying attention to the SENS program of repairing damage to produce rejuvenation. The SENS research agenda is to my eyes the only viable way forward to produce meaningful extension of healthy life any time soon, and certainly the only way to help older people by turning back aging at later stages. It is also far closer to realization and far less expensive to develop than efforts to safely alter human metabolism to slow the rate at which damage is done. The field of aging research has all too little funding in comparison to its potential, but it doesn't suffer from a lack of fundamental research anywhere near as much as it suffers from a lack of taking what is already well known about the forms of cell and tissue damage that cause aging in order to build therapies here and now.

David Botstein is Calico's chief scientific officer. He is 74, with a grizzled shadow of beard reaching up from his collar. In November, I found him at a lecture hall at MIT, where he offered a rare window onto experiments under way at Calico. Botstein, a well-known Princeton geneticist whom Calico recruited out of near retirement, was in town to celebrate the birthday of a successful former student, now a sexagenarian. "The pleasure is coming to see old friends. The not-so-­pleasure is if these guys are 60, what am I?" In his lecture, Botstein described several technologies - four, in fact - that Calico has for isolating old yeast cells from the daughter cells that bud off them. These old cells are tracked and subjected to a comprehensive analysis of which genes are turned up or turned down, a technique that is Botstein's specialty. Botstein told me Calico is exactly what Google intended: a Bell Labs working on fundamental questions, with the best people, the best technology, and the most money. "Instead of ideas chasing the money, they have given us a very handsome sum of money and want us to do something about the fact that we know so little about aging. It's a hard problem; it's an unmet need; it is exactly what Larry Page thinks it is. It's something to which no one is really in a position to pay enough attention, until maybe us."

Botstein says no one is going to live forever - that would be perpetual motion which defies the laws of thermodynamics. But he says ­Cynthia Kenyon's experiments on worms are a "perfectly good" example of the life span's malleability. So is the fact that rats fed near-starvation diets can live as much as 45 percent longer. The studies Botstein described in yeast cells concerned a fundamental trade-off that cells make. In good times, with lots of food, they grow fast. Under stresses like heat, starvation, or aging, they hunker down to survive, grow slowly, and often live longer than normal. "Shields down or shields up," as ­Botstein puts it. Such trade-offs are handled through biochemical pathways that respond to nutrients; one is called TOR, and another involves insulin. These pathways have already been well explored by other scientists, but Calico is revisiting them using the newest technology. "A lot of our effort is in trying to verify or falsify some of the theories," Botstein says, adding that he thinks much of the science on aging so far is best consumed "with a dose of sodium chloride." Some molecules touted as youth elixirs that can act through such pathways - like resveratrol, a compound in red wine - never lived up to their early hype.

According to Botstein, aging research is still seeking a truly big insight. Imagine, he says, doctors fighting infections without knowing what a virus is. Or think back to cancer research in the 1960s. There were plenty of theories then. But it was the discovery of oncogenes - specific genes able to turn cells cancerous-that provided scientists with their first real understanding of what causes tumors. "What we are looking for, I think above everything else, is to be able to contribute to a transformation like that. We'd like to find ways for people to have a longer and healthier life. But by how much, and how - well, I don't know." Botstein says a "best case" scenario is that Calico will have something profound to offer the world in 10 years. That time line explains why the company declines media interviews. "There will be nothing to say for a very long time, except for some incremental scientific things. That is the problem."

To some, Calico's heavy bet on basic biology is a wrong turn. The company is "my biggest disappointment right now," says Aubrey de Grey, an influential proponent of attempts to intervene in the aging process and chief science officer of the SENS Research Foundation, a charity an hour's drive from Calico that promotes rejuvenation technology. It is being driven, he complains, "by the assumption that we still do not understand aging well enough to have a chance to develop therapies." Indeed, some competitors are far more aggressive in pursuing interventions than Calico is. "They are very committed to these fundamental mechanisms, and bless them for doing that. But we are committed to putting drugs into the clinic and we might do it first," says Nathaniel David, president and cofounder of Unity Biotechnology. This year, investors put $127 million behind Unity, a startup in San Francisco that's developing drugs to zap older, "senescent" cells that have stopped dividing. These cells are suspected of releasing cocktails of unhelpful old-age signals, and by killing them, Unity's drugs could act to rejuvenate tissues. The company plans to start with a modestly ambitious test in arthritic knees. De Grey's SENS Foundation, for its part, has funded Oisin Biotechnologies, a startup aiming to rid bodies of senescent cells using gene therapy.

Link: https://www.technologyreview.com/s/603087/googles-long-strange-life-span-trip/


I feel very evil energy when looking at them, because it looks like they don't even want to cure aging (and they could with all this money) but only to cure some old age diseases.

I honestly hope I am wrong.

Posted by: RS at December 15th, 2016 9:45 AM

It's interesting that a 74 year old man feels no urgency about creating progress nearer term. Alas.

Posted by: JerseyJones at December 15th, 2016 9:59 AM

It's interesting that a 74 year old man feels no urgency about creating progress nearer term. Alas.

Indeed. I'll bet donuts to dollars he hasn't even signed up for cryonics either.

Posted by: Abelard Lindsey at December 15th, 2016 11:28 AM

'Instead, Olshansky and Austad are going with what's become a favorite play in research on aging: they plan to hit up billionaires for the money. Funding a groundbreaking advance, Olshansky promises potential investors, could be their "ticket to immortality."'

Huh?? Olshansky talking about immortality??

Posted by: Antonio at December 15th, 2016 12:33 PM

Nice to see Jason Pontin and Technology Review representing Aubrey and the SENS foundation's point of view without being condescending in tone or comment. I'm thinking that Unity Biotechnology following a strategy proposed by the SENSRF years ago and getting $127 million might be the reason it is not so easy to be dismissive any more.

Also well done to whoever wrote the TR article for be aware of Oisin Biotechnology.

Posted by: Jim at December 15th, 2016 12:41 PM

Jason Pontin's attack on SENS 10 years ago was purely ideologically driven. It was never based on technical issues at all. Jason seemed to believe that it was reasonable to to sacrifice health and vitality for something as insignificant and trivial as ideology.

Posted by: Abelard Lindsey at December 15th, 2016 1:12 PM

Pontin's last attack on SENS was in October. 2016. It's not ideology at this point, it's psychiatry.

Posted by: Spede at December 15th, 2016 1:20 PM

"v""Botstein says no one is going to live forever - that would be perpetual motion which defies the laws of thermodynamics. But he says ­Cynthia Kenyon's experiments on worms are a "perfectly good" example of the life span's malleability."

"David Botstein is Calico's chief scientific officer."

You want to know what else is perfectly good, Dave? The billion dollars you're pissing right down the toilet.

Posted by: Slicer at December 15th, 2016 1:25 PM

They are going to spend $1billion trying to figure out how our metabolism's work. Larry Ellison spent $400 million on the same research and basically got nowhere.

Posted by: Deleo at December 15th, 2016 2:45 PM

I wouldn't be so negative. I don't think Google is wasting its money ; their team could certainly pull some insightful discoveries in the coming years (decades). It's just sad that they didn't give at least a few millions to the SRF so as to edge their bets.

Posted by: Spede at December 15th, 2016 3:05 PM

No doubt Sergey and Larry are well aware of Aubrey and SENS, as well as the failure of Ellison's research efforts. Thus the big question is why are they following Ellison's lead rather than SENS?

Posted by: John at December 15th, 2016 4:37 PM

"Ellison's idea was right but his delivery was botched and backing the SRF won't make us any money". That's what might have gone through their heads. Although, like you, I do wonder why they didn't go for Google-made proprietary SENS therapies. This could have been a viable middle road.

I just hope one day, far in the future, we'll finally get an explanation from Google as to why they didn't follow the SENS lead.

Posted by: Spede at December 15th, 2016 5:09 PM

It's not so complicated. Page simply follows the mainstream, and the mainstream now is to try to slow aging by messing with metabolism. Don't search for a more mysterious reason.

Similarly, at Longecity, almost all people are supplement fans, not SENS fans. Simply, supplements are more mainstream (they have more publicity) and allows people to buy something now instead of waiting two or three decades. Even though it's all useless crap, it provides instant satisfaction.

Posted by: Antonio at December 15th, 2016 5:24 PM

Hi Reason, this is only tangentially related to the subject at hand but this Salk news has been blowing up on Reddit recently and I thought you might like to have a look. I should preface that by saying it almost certainly falls into the "tweak metabolism/get overhyped by mainstream press" category: http://www.salk.edu/news-release/turning-back-time-salk-scientists-reverse-signs-aging/

Though it's nothing new in terms of the gerontology/mainstream news cycle, it brings me to a question I keep mulling. How much of the damage we accumulate over time (besides DNA, obviously) could be repaired by merely restoring a youthful signalling/gene expression environment? How much do we know is the result of the body's natural repair processes dropping off, and how much is something that couldn't be circumvented no matter how well these processes are restored?

Posted by: Seth at December 15th, 2016 6:06 PM

Well, Google is home of the moonshots and unconventional thinking... so I wouldn't expect Page of all people to reject the idea of taking an uncommon path towards a grand goal.

Posted by: Spede at December 15th, 2016 6:06 PM

"Botstein says no one is going to live forever - that would be perpetual motion which defies the laws of thermodynamics."

This is either wrong or irrelevant, depending on what exactly he means. If he's talking about the ultimate fate of the universe being heat death then sure, that's plausible and likely inescapable, but who cares, that's way into the future, let's focus on the next thousand or billion years or so first. But if he means something to the effect of aging being entropy and therefore irreversible, well that's just blatantly false since entropy in a local environment can in fact be reversed if there is a steady supply of external energy, which in case of aging are the various treatments.

Posted by: Northus at December 15th, 2016 6:23 PM

@Spede - I think you will be waiting in vain for an explanation from Google as to why they didn't follow the SENS approach.

Back in the 2000s Google started up a clean energy effort titled "RE<C" standing for "Renewable Energy costing less that coal". When that didn't work out they just quietly dropped it and never mentioned it again.

It does seem like history is repeating itself with Google just giving money to the mainstream (slowing aging) while a bunch of other people (SENS) tell them publically that this won't work. With clean energy a load of experts pointed out that solar and wind are unreliable, and that they should be investing in 4th generation melt down proof nuclear or geothermal energy in order to achieve on demand clean power. So they've got a track record of not examining the received wisdom. A lot of people think these flashy initiatives are mainly PR anyway to distract the public from the fact that Google make there money from targeted online advertising (which is a bit creepy for a lot of people).

Posted by: Jim at December 15th, 2016 8:44 PM

Does anyone knows what is required to take Metformin here in the U.S.? Is a prescription required and what would the doctor prescribe it for? I would like to take it, but don't know how to get access. Given what I heard of it over this year, I think it makes sense to take what you can until the rejuv treatments become available.


Posted by: Robert at December 15th, 2016 8:51 PM

Aubrey de Grey: 'Admit you were wrong Dave, and I'll let you have this lovely new SENS rejuvenation treatment we've developed.'

David Bostein: 'Nooooooooooooooooo....'

Posted by: Mark at December 16th, 2016 4:02 AM

@Robert: I think it makes more sense to use the pills cost to fund research like SENS. Rejuvenation treatments will never arrive if they aren't funded, regardless of how much metformin you eat. And anyway metformin life extension effect will be tiny, if any, and you would need to take it all your life. So, let's assume you take a pill per day. That's around $100 per year. Let's say you take it for 40 years. That would be $4000 not spent on research. All that for what? Some months of life extension? Life extension by metformin in worms is tiny (around 30%) compared to other methods like CR and gene therapy (around 1000%), so the effects on humans will probably be mere months, if any.

If you are still interested, metformin is prescribed for diabetes.

Posted by: Antonio at December 16th, 2016 5:24 AM

It's possible Trump will appoint someone who is in favor of rejuvenation to the FDA though the matter is not settled yet.
Hopefully Thiel will help him make up his mind.

Would it be plausible to present SENS as an alternative to Americas horribly broken medical system? "Thinking outside the box".

Posted by: Arren Brandt at December 16th, 2016 9:19 AM


Hi Robert,

I can't speak for the US, but my guess is yes seeing the regulatory process is heavier in the states and healthcare costly for most people; you can't find metformin on drugstore shelfs (in Canada here) it needs a prescription. The doctor would prescribe it for diabetes mostly (Type 2). If you have diabetes, you will get it, if you don't my guess is it will be hard obtaining it because there 'won't be anything to prescribe' (you're not ill); basically they will refuse prescribing you anything - even if you demand it. You have to be ill from it to receive it (even if you're offering to 'pay' to get it) after a doctor verifies your diabetes condition (measures your blood glucose, insulin and glycated hemoglobin levels (which you can already do with a glucometer like Bayer/Ascencia One Touch; they too have been removed, you must ask them at the drugstore). No diabetes, no metformin access (here in Canada, perhaps in USA it's different since the healthcare is unaccessible there (but that could be a good thing) although FDA is probably even worse than Health Canada regulation on such 'Drugs'; health care and pharmacy is more strict in USA than other countries). It is not seen as a CR like-supplement that you can 'just take by yourself' to 'add' on top of your supplements - to live longer when you don't have diabetes. It is seen as a prescription drug for a disease, not a off/on-the-shelf supplement.

As Antonia said, Metformin will do little if nothing on lifespan in - humans. And that has be shown recently with 40% CR in Rhesus Macaques - there was absolutely nothing that happened in them in terms longevity - but a reduced early mortality (slowing of disease onset). Metformin acts akin to CR on glucose levels, reducing AGEs formation and hyperglucose. Plus one study showed that Metformin increases amyloid formation in rodent brain (it's rather ironic since it reduces glucose levels (which are tied to amyloid and AGEs formation); my guess is its mess-up certain brain pathways and can, actually, increase Amyloid formation rather than decrease it. As for mice who lived longer on Metformin - untranslatable in humans; it will only improve the diabetic condition to 'normal (normoglycemia). My father takes Metformin, for many years..it does nothing whatsoever on aging - only on improving your glucose homeostasis (and with your glucose in check, you become insulin responsive, reduction of diabetes, reduction of AGEs, reduction of glycated/glycoxydated hemoglobin (HbA1c), thus a longer 'normal healthy-enough' lifespan...basically, it's as if you don't have diabetes - on it as it 'controls' your glucose levels.). My father is well on this drug and for a while he was off of it (the moment he went off his glucose level creeped up yet again), but now back on and glucose level back to Ok. Most likely, he will have to take it for the remainder of his life (as the levels keep on rising over the years - despite on Metformin, it's just a natural part of aging (the aging beta-cells in the pancreas have difficulty with age to make glucose disposition by secreting not enough 'insulin bursts' thus you become insulin resistant as there is post-prandial and fasting glucose levels that stay too long in the blood (increase glycoxidation/AGEs, ROS production by excess latent glucose).

Avoid Metformin if you can, if you don't have diabetes. If you have diabetes you can get it, ask doctor.

Posted by: CANanonymity at December 16th, 2016 9:39 AM

PS: Early-day 'mornin-still-waking-up' typo, sorry : ''As Antonio* said, Merformin...''

Posted by: CANanonymity at December 16th, 2016 10:00 AM

@Robert - I think you can buy metformin OTC here in Australia (the government got sick of people needing to see a GP X times per year just to get another script, as the government pays for GP visits in this country).

It is about USD 200 for 100 pills. You could probably find cheaper on the internet. But I agree with Antonia that it is largely a waste of time and you'd be better off donating to SENS research.

Posted by: Jim at December 16th, 2016 10:20 AM

PPS: Metformin natural therapeutic/herbal alternatives (they do almost the same thing, if better than Metformin/less side-effects and act on the same pathways as CR, Metformin, Rapamycin or exercise (all of them acting mostly on insulin/mTOR pathways)) :

- Red Wine/Resveratrol/Trans-Resveratrol/Quercetin/Myrecetin/Hesperidin(and the whole '-in' cousins group of polyphenols of the red grapes used for wine red mine making)

- Antocyanin/nidin/protocyanin/cyanins (Blue berries and other berries/grapes contain blue cyanide)

- Mulberry Leaves/or the berry (its polyphenols do well on diabetes)

- Green Tea (gallates, gallic acid, catechins, ECG/EPCG, epicatechin gallate, very strong, always get the green not black or earl gray tea (black tea) these are oxidized tea polyphenols; they have some good effects but mostly it's bad because they are already oxidized and contribute to increasing oxidizing susceptibility - while green polyphenols (which are chrolophyl giving the green pigment) are non-oxidized and do help diabetes or atherosclerosis (albeit, green tea is strong, it should be in modereation as it burns fat very quickly - that's dangerous, you don'T want to be anorexic either (I know i suffered atheroscleorsis and when you are too thin your body 'extracts' whatever ounce of fat left you have with much difficulty (and green tea exacerbates that strongly)/you become weak and anemic/frail worse off).
You need a slight enveloppe of weight to maintain strenght (this slight enveloppe contains adiponectin,
you need it to improve insulin sensitization; burning too much fat is very dangerous if you are diseased, frail, thin and weak alraedy. If you are Overweight/Fat/Obese than you can fear less about, but you need to do it in a progressive manner (my father lost is big fatty belly, now he has almost a thin abdmomen with muscles more showing - no fat around waist, waist fat = increased chances of diabetes).

- Berberine (apparently, this one is very effective my father took some, indeed it does help diabetes strongly (better than Metformin; still he went back on Metformin anyways - so not the best afterall. It could mean that the body gets used to these herbal supplement and the effect weakens : shake it up, mix-it up and try variety; not always the same supplement and vary in intervals so you don't 'prime'your body
to them (randomness)).

- Cinnamon (also highly effective, in fact it's oldest spice remedy dating back to Roman times for diabetes
(back then it was a general 'aid' for health, now we know it is a insulin sensitizer and is the best
spice to act akin to insulin (some studies say it works, exactly, like insulin) The active pungent element is cynnamaldehydes.

- Gingko Biloba (very effective, especially as memory improver, it reduces amyloid formation by its bilobalides and terpenes lactones)

- Ginseng (another one that packs a huge punch, Red Chinese/Korean Ginseng or American Ginseng are the two
varietes with their respective effect (the Red one packs more punch as it contains more Gingenosides).

- Ginger (we're staying the 'Gin-'Herbs...also Very strong spice that has many protective polyphenols...almost Chinese Spice is 100% good for diabetes)

- Bitter Melon (contains a bitterness element that reduces 'the sweetness'...it's acid forming elements just citrus acidic flavones).

- Anything bitter will most likely reduce your glucose (including Bitter Dark Chocolate at 99% Cocoa...but only the bitter Cocoa polyphenols - not the fat from the cocoa butter or cocoa liquor parts of darl chocolatE (these two will Increase diabetes from excess fat-intake (we have to remember that plasma free fatty acid content equals insulin sensitivity/also, visceral fat around your belly; while adiponectin helps (it increase WBGD (whole body glucose disposal) which improves insulin sensitivity). Cocoa polyphenols should only be gotten from the Cocoa/Cacao Theobroma leaves. Even then, some react badly at the 'Theobromines' in cacao (feeding chocolate/cacao to dogs is dangerous because of the theobromines content).

- Lemon/Lime/Peels (contain citric acid and methoxylated flavones that reduced glucose strongly. Oranges too, avoid drinking sugar/pasterized orange juice at all costs. My father said that juices are Killer for diabetes (their fructose, glucose content is enormous and creates insulin spikes since there is nothing to reduce that (there is no soluble or insoluble fiber to mitigate the spike - you're getting straight as water directly in your bloodstream - it greatly accelerates diabetes complication)).

- Vinegar (melts away fat like nothing...because of its Acetic Acid content - a powerful fat burner;
it reduces a meal Glycemic load by 35% when taken before eating it (about 5 ml of vinegar that contains acetic acid and, better, with the 'Mother' (like Apple Cider Vinegar) the fermentation by bacteria inside that produce enzymes that also reduce glucose)). My father took all of these supplements...and still back on
Metformin, so that tells you, it's hard to control your glucose levels as a long-term diabetic when you reach 70 years old.

- Perhaps the best of the best is Magnesium mineral. This beats everything. Because there is a causal-link between glucose homeostasis, insulin sensitivity and serum magnesium levels (magnesium activates 300 enzymes including a ton responsible for glucose disposal; in fact, beta-cells die when magnesium is removed. Upon reintroduction, beta-cells begin to function anew. Plus, it has been shown that fibroblasts die of premature replicative senescence when magnesium ions are removed. That is because, magnesium ions are a calcium antagonist (it block calcium overload and calcification, which both of these mechanisms are responsible for mitochondrial failure (Bax/Bad/Caspase-3/-9 activating Mitochondrial Permeability Transition Pore Opening and Cytochrome C loss through its pores at the InnerMembrane when the mitochondria is about to enter senescence or activate apoptosis) due to the fact that magnesium ions act on cysteine residues (thus they affect the Redox thiols of the cell). In fact, hospitals oftain put patients on continuous intravenous magnesium to bring back patients under control (not just diabetics one, many other types).

Posted by: CANanonymity at December 16th, 2016 11:01 AM

"Botstein says no one is going to live forever - that would be perpetual motion which defies the laws of thermodynamics"

That doesn't even make sense...

Posted by: Nicola at December 16th, 2016 12:21 PM


Hi Nicola,

I second that. Hydras are already immortal and Ancient Trees live 5000 years, why would it be so different for humans. Entropy and thermodynamic laws are malleable; randomness is part of it but it can be con(s)t(r)ained if you will. Simply put, it's just that we must crack that code and it has nothing to do with 'perpetual motion', since as said certain organisms of animal kingdom defeat this perpetual motion. People make theories, such as this last one, but theories are theories; they can be debunked. Why does a hydra have a capacity to be infinite lifespan but humans don't; because it's down to biology and biology is a code - that can be coded/decoded/recoded aka Rigged yes just like Hackers do on the internet when the 'hack' the code (with their Cracks) to get illegit places - they still cracked it. How is taht so different from rigging biology and evolution to our liking.
Damage theory is only big problem in our way, we just have to alter both damages and epigenetics mechanisms; we'll be on our way to reaching centuries lifespan - if not immortality (albeit chances are ultra-slim). We may Have to die, but - When - we die is what we will work on and my idea of lifespan was always something that beats the human maximum (100 years is - not - long, for some is utter boredom long thing..ok. I believe in 1 digit extra - a 1000 years. Trees lives 5000 years, again why not us ?). We have to rig the evolutionnary 'energy/sexual/damage/growth trade-offs' that all mammals face (high sexuality/short lifespan, low offspring/long lifespan).

For people who say, if we live infinitely 'there is no more place on Earth' = overcrowding. Solution, find more place (other planets, Mars? The Moon?...there is a solution - for everyone - if we live a 1000 years). We have to spot the fatalists 'earth will crumble, people will be bored 'to death' (pun intended), resources, wars, 'Bad Innmate People' who are immortal and immortaly in prison costing Taxes (who wants that?), this all of this becomes fluff compared to the urgency of curing death once and for all in the history of humanity....

Posted by: CANanonymity at December 16th, 2016 1:43 PM

@can As soon as age becomes reversible, most of those people will stand in line for therapy. Be sure of it. If that wasnt the case and only few people would take advantage of rejuvenation, then we wouldn't even need to discuss overpopulation. 200 years ago they would have probably warned us that doubling our lifespan will be our doomsday. Some people are just slow.

Posted by: K. at December 16th, 2016 4:57 PM

I very much agree with others that Calico will invest further vast amounts of money on top of that already spent to see an extremely poor return on investment. What I can't understand is why they cannot appreciate the obvious in that SENS could potentially come to fruition for vastly less money than is being expended currently by Calico and in many areas already shows proof of concept. My feeling is 20 or 30 million dollars would be money well invested if it were allocated to the SENS foundation but a drop in the ocean to Calico and this is something people like Cynthia Kenyon must be very aware of already. So the question is why are the people in charge unable to see the wood for the trees?

Posted by: John Andersen at December 19th, 2016 9:35 AM
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