The California Life Company is Secretive, but Sadly Also Probably Irrelevant

It will not be news to this audience that the California Life Company, or Calico for short, Google's venture into aging research, is secretive. Outside of the staff, few people can do more than read the tea leaves regarding what exactly they are up to. The high level summary is that Google is channeling a large amount of funding into some sort of long-term development plan for therapeutics to treat aging as a medical condition. Over the past few years Calico has made sizable development deals with pharmaceutical and biotechnology companies, and hired some of the most noteworthy names in the aging research community. It is usual for biotechnology and drug development companies to be fairly secretive in their early stages, for reasons that largely relate to investment regulations. At some point they have to talk about what they are doing, however, given that the goal is clinical trials, customers, and revenue.

Google is super secretive about its anti-aging research. No one knows why.

In 2013, Time magazine ran a cover story titled Google vs. Death about Calico, a then-new Google-run health venture focused on understanding aging - and how to beat it. "We should shoot for the things that are really, really important, so 10 or 20 years from now we have those things done," Google CEO Larry Page told Time. But how exactly would Calico help humans live longer, healthier lives? How would it invest its vast $1.5 billion pool of money? Beyond sharing the company's ambitious mission - to better understand the biology of aging and treat aging as a disease - Page was vague. I recently started poking around in Silicon Valley and talking to researchers who study aging and mortality, and discovered that four years after its launch, we still don't know what Calico is doing.

I asked everyone I could about Calico and what it's up to - and quickly learned that it's an impenetrable fortress. Among the little more than a dozen press releases Calico has put out, there were only broad descriptions of collaborations with outside labs and pharmaceutical companies - most of them focused on that overwhelmingly vague mission of researching aging and associated diseases. The media contacts there didn't so much as respond to multiple requests for interviews. People who work at Calico, Calico's outside collaborators, and even folks who were no longer with the company, stonewalled me. There were no clinical trials or patents filed publicly under the Calico brand that I could find and only a few aging-related scientific papers.

It may be the case that Calico is simply following the standard biotechnology startup game plan over a longer time frame and with more funding than is usually the case, including the secrecy portion of that plan, but by now most of those interested in faster progress and beneficial upheaval in the research community have written off Calico as a venture unlikely to make any meaningful difference. Given who has been hired to lead it, and given the deals made, the most likely scenario is that Calico is the second coming of the Ellison Medical Foundation. By that I mean an organization that is essentially running more of the same research funded at the National Institute on Aging, with a poor or absent focus on clinical translation, and constrained in goals to the paradigm of drug development to slightly slow the progression of aging. In this area you will find things like calorie restriction mimetics, pharmaceutical enhancement of autophagy, and so forth. The past twenty years of research have made it clear that it is very hard and very expensive to produce even marginally effective and reliable drugs capable of slowing aging. Yet this is exactly what most research groups continue to try.

There is an alternative approach. Instead of altering the poorly understood intersection between metabolism and aging in an attempt to slow the damage of aging, instead periodically repair the quite well cataloged list of fundamental cell and tissue damage that causes aging. This approach is exemplified by senescent cell clearance - a way to extend healthy life and turn back symptoms of aging and age-related disease that is already showing itself more robust and useful than any of the present drug candidates aimed at altering the operation of metabolism to slow aging. Senescent cell clearance as a way to reverse aging has been pushed by the SENS rejuvenation research advocates for more than 15 years, with good evidence as support. Yet over that span of time the majority of the research community rejected damage repair in favor of focusing on efforts to slow aging, efforts that have not succeeded in producing useful therapeutics with sizable results on human health.

That rejection was clearly not sound. Once efforts started in earnest on development of methods of senescent cell clearance, it required only the past few years to robustly demonstrate its effectiveness as a rejuvenation therapy. It is gathering ever more attention now - but not from Calico, so far as we know, and not from the majority of the research community that continues to work on slowing aging through adjustment of metabolism, an approach to aging as a medical condition that is demonstrably marginal and expensive. The funding used to bring senescent cell clearance up to its present point of proven success is a tiny fraction of what has been spent on so far futile efforts to produce calorie restriction mimetic drugs that would, even if realized, be far less effective and far less useful to patients. On the whole I think Calico is most likely a larger than usual example of the primary problem in aging research: the dominance of initiatives that put their funds towards complex, lengthy, and uncertain projects that even in the best of circumstances are only capable of producing poor outcomes for patients. In short, the problem is an unwillingness to pursue the repair and rejuvenation approach that is demonstrably more effective than the adjusting metabolism to slow aging approach. Excessive secrecy is a minor quibble in comparison.

Comments

Absolutely agree. It's sad that a company like google which is so ambitious in other areas of technology (self driving cars, AI) is so boringly conservative in this one.

Posted by: Link at April 27th, 2017 7:00 PM

But why the secrecy if they are doing run-of-the-mill work? I don't get them.

Posted by: Barbara T. at April 27th, 2017 7:39 PM

Two things:
1. Doesn't make sense to be secretive if all you're doing is cooking up a rapalog, there are 4-5 of those already. And why hide it from the NIA? Scientists in the NIA hold patents for half the useless rapalogs already available, just buy some of their garbage as that waste of air Barzilai says in the article. Whatever it is they're doing it is quite possibly not yet another mTOR snake oil pill - which by no means implies it will be useful.

2. Google as a larger corporation has proven grossly incapable of making good acquisitions and to top it off bad at managing the few of the good ones they have (youtube ad fiasco for instance). So it is quite possible CALICO is just another failure soon to join the growing list of train-wrecks under Google's brand.

Their acquisition of C4 Therapeutics seems like a big bust to me considering some recent papers on ubiquitin I've read. Good luck using that pathway to treat any age related condition.

I don't expect CALICO to produce anything of worth however long (or short) it exists.

Posted by: Anonymoose at April 27th, 2017 8:13 PM

1000% true. Senescent cell clearance, and repair of immune system should be #1 and #2.

Posted by: William Nelson at April 28th, 2017 1:44 AM

From the few papers they published, they seem to seek for CR mimetics. What a waste of money...

Posted by: Antonio at April 28th, 2017 2:30 AM

Larry and Sergey thought they were giving their money to
Hogwart's wizards but they turned out to be a bunch of Muggles?
This is all very sad...

Posted by: John S. at April 28th, 2017 3:21 AM

Do the Calico researchers look like they are getting any younger? My guess is no.

Posted by: NY2LA at April 28th, 2017 3:52 AM

Doing CR is easy and cheap (you even save money on food) why waste so much effort to mimic it?

Repair and rejuvenation is what we need.

I lost my faith in Calico a long time ago.

Posted by: RS at April 28th, 2017 7:39 AM

Isn't Ray Kurzweil involved with Calico and also a SENS supporter? Maybe there is at least some SENS research going on over there? It just makes no sense to me whatsoever that they didn't bring Dr. Aubrey De Grey on board, such an unnecessary wasted opportunity.

Posted by: Corbin at April 28th, 2017 11:50 AM

What I find perplexing is how a firm like Google-founded on innovation-would take an approach such as they are taking with Calico. The wrong minds are in charge at Calico; they are currently led by scientists with long, established careers as scientific *investigators* when what they actually need are scientific *innovators*.

These people, with their lengthy CVs filled with accomplishments and collaborations largely (if not wholly) irrelevant to the aim of developing transformative treatments for aging, are about as likely to do something transformative for treating aging as someone picked at random off the street. Like most life scientists, creativity and innovation has taken a backseat to investigative discipline and overall productivity during their careers. This is not meant to disparage the important work of life scientists; it is simply reflective of how most basic life science research is accomplished and how the brains of these scientists are wired.

Calico is, by all outside indications, approaching the development of transformative aging treatments as an investigatory task. This is baffling to me! Developing therapies for aging should not be approached in the same manner as basic life science research!

Google clearly understands the difference between researchers and innovators, and their appropriate respective roles in new initiatives. Heck, I can't think of two people who would be more appreciative of this distinction than Larry Page and Sergey Brin! Yet curiously, Google apparently believes that they can revolutionize life sciences with traditional researchers at the helm! History has proven time and again that this rarely works...

Posted by: BigB at April 28th, 2017 12:20 PM

The only thing good I've ever heard of coming from Calico is the protein business Reason pointed out last month.

Google doesn't make good acquisitions. It recently paid $120,000,000 for a company that makes a wi-fi enabled, DRM enabled, JUICE PACKET SQUEEZING MACHINE. (I'm not making that up. It's called the Juicero.)

Posted by: Slicer at April 28th, 2017 12:28 PM

@Corbin: Kurzweil and de Grey are long-time friends and, while Kurzweil doesn't seem to think that SENS is crazy, he doesn't seem to be a supporter either. His preferred path to immortality seems to be supplements as a first stage and then using nanotechnology/AI/singularity. Anyway, he doesn't seem to be a supporter of Calico's approach either (CR mimetics and/or comparative genetics with long-lived species).

Posted by: Antonio at April 28th, 2017 2:02 PM

Hi all!

Interesting points, just a 2 cent.

Why the extreme (-ly shady corp 'The Firm' or 'The Cube') secrecy,
I think it's a bit like others said, (image) reputation protection/damage control. Google is a ''brand'', an image, they know they
are not Specialists (even if they hired reknown biogerontologists and biomedical researchers) at Biogerontology or making a claim
to reverse aging (which is their hopefull goal if throwing 1000 Billion dollars at it of their monies - 'something' 'should' come
out if it one day/something 'should' 'stick' no matter if it's CR mimetics and the most flawed approach. I'm thinking, 4 years later,
they are realizing it's much harder than was predicted back then and/or their goal was never to 'end aging' but rather, as said, simply
delay it by using the old research mentality that CR will save the day - so make CR mimetics... as such,
Silence is the best solution when you fail and don't want others to see you as such).

They are about : Internet search engine and other gadgets... they 'try' things (such as Calico inception), they try to innovate;
they gave us Maps/3D Google Earth - the best thing since sliced bread (traveling the world while sitting still on your home chair, very 'still'
never stepping a single foot out side your home or your chair and/or get blown to pieces/shot when you 'virtually' travel some place or crash to death in
your mid-ocean plane escale flight. You can even watch 'Thunder Lightning' and never get fried)).

They are not about : Curing Death, no matter if they call themselves Calico (in fact, that was a smart move to avoid direct obvious 'association'
to 'Google' pristine brand - should it fail/their brand is saved/intact - like 'birthing a demon' and
'having to destroy your Own child, when you, sadly, realize it's a demon 'unwanted spawn' after all ('fail').

Thus, they remain tight-lipped to the point years pass and they behave like spy/secret gov. services agencies 'acting' in the complete dark and total secrecy.

They do not want to tarnish their reputation/image/brand in people's eyes - it's sacro-saintly-sacred - it would mean damage control to not be seen
as a snake oil company - it would hurt their internet monopoly dominance as an internet search engine (money making) powerhouse.
Loss of money, loss of image/brand power.

Plus, they may see other research as futile (the irony when theirs is too) such as SENS. They may think producing better' CR drugs is the solution to everything.
Better Metformin... sadly, only, better fooling themselves and throwing their cash dollars down into the' burning furnace that asks for more.
Paper dollars ignite well. (Good combustive).

But, then, it's also ironic (or not so much depending on how you see it) because Calorie Restriction - is still - one of the most powerful (yes)
ways of slowing damage (not reversing anything but drastically slows it via AMPK survival pathway, something many therapies can't even do;
still it will not stop aging nor cure death either; we all know that but it does improve health - if controlled depending on the body's reaction
of overt/more/less CR which can lead to starvation. We have to remember how dramatic it is to just cut the amount of Carbs you take each day;
it affects the Whole IGF/mTOR pathway which is Central to our lifespan as it dictates cell senescence geroconversion) :

CR does this :
- it curbs senescence
- it improves (at the very least 'stabilizes' or curbs a bit) diseases advancement/postpones these things.
- it reduces DNA lesions/deletions/damages.
- it reconstitutes a viable redox.
- it improves immunity and senescent and/or cancer-killing power.
- it heals tissues (although not quick since you lack protein/DNA syntehsis).
- it Dramatically redudes Inflammation (TNF, IL-6, p53/p16 culprits...)
- it makes your skin look like your 20-30 years old again, some of your wrinkles smooth out (again slowly since most of this depends on protein/amino acid intake/synthesis).
- it detoxifies the body like no other thing does, it makes your body 'eject' the crap that accumulated for so long in you - you are Brand New.
- it can stop a heart attack - almost - (I know, I had to do CR to survive - in the next 24 hours - or I was dead). 'Water Fasts' hate them but they can save your life.
- it alters a gazillion of (epi)genes - all at the same time.
- it improves insulin/glucose - sometimes so much it's freaky - my father has type II diabetes, metformin is already a CR mimetic - but it will
never equal exactly the same effect of a true CR/or intermitant 'control' fasting. I suggested him CR, his doctors told him he can't do
CR it's too dangerous on his blood glucose spikes/insulin changes. Yet, it improves them and reduces HbA1c. I think, in some people,
CR can be serioulsy detrimental and accelerate frailty/problems/complications (be worse than good altogether) and that's because mTOR is behind this. mTOR is a regular of protein/fatty acid/
glucose/nutrient/insulin activating it, it conversion to muscle synthesis = it is a 'switch' to 'reproductive mode' 'it's the Fitness pathway/It increases your fitness and reproduction power - at the cost of reduced cell replicative rounds (accelerated replicative senescence)'
where the body is 'strengtened' (don't ask yourself why males
have higher mTOR levels/bigger muscle mass than women and can make sperm for their whole life while women are smaller and live longer but
have limited reproductive capability (only so many eggs and developp menopause (that's because it's a 'futile' program called a 'Quasi program' that
is activated at puberty (for sexual reproductive capacity) and then it 'never shuts down' in old age - until it makes the whole thing falter; see all of 'Mihkail Blagosklonny's incredible research papers
that explain this perfectly. This means that growth stops at puberty and the organims dies over the years because growth slows down/but metabolism is slowed down to slow
that downhill slope to death (yielding senescence in the end by cell replication arrest)) - women have less mTOR and IGF activity in them. I.e. less Growth/GH. Less insulin signaling = form of CR.
They are also smaller and more frail (BMD is more hollow). It's also why mutant C.elegans who are frail (thanks to KO of mTOR/IGF) live Longer than 'fit/strong' mTOR-loaded C.elegans. Yet, in those mutants, many die of Frailty/'sarcopenia' if you will by slugging pumping..
It's a proof that mTOR/IGF is a survival 'fitness/hardness' mechanism to - assure reproduction (also why hormones increase with mTOR availability). In return, mTOR accelerates senescence because evolution made us 'that we die' once our 'purpose' is done : make kids at teenage puberty
/reproduce ourselves and make the specie continue. mTOR, by creating geroconversion to senescence - after cell cycle arrest - thus truly dictactes our lifespan (as MV Blagosklonny says).

With all this said though, CR or CR mimetics will not stop ever anyone from dying at 122 or so. We will all die by 122. SENS could offer
the potential to at least reach that, while CR gives a 'slight' chance of that happening since it doesn'T stop any disease from coming later on.
It just curbs things - but for that - it is still the most powerful one at that.

That's why I don'T really defend CR but I understand why it has such long staying power...so much so, that a company like Calico would be
trying to replicate it and 'redo a metformin-like CR mimetic' in the confines of their labs shrouded in secret.

Just a 2 cent.

Posted by: CANanonymity at April 29th, 2017 5:10 AM

Google/Alphabet has been putting a lot more resources into Verily. You can see that they have some nice projects going below. They are not necessarily targeting age related diseases though.

I think Calico is an example of what can happen when you start down the wrong path. They picked researchers to lead it that were totally committed to what aging science was before SENS. It's an outdated approach that has probably led them down a research black hole.

https://verily.com/projects/

Posted by: Deleo at April 29th, 2017 11:21 AM

Deleo: It seems that most of those projects will be obsolete soon due to progress in SENS-related work, like A2E and glucosepane removal, and research in Parkinson's and immune system reboot. The only one that seems to have a future is robotic surgery.

Posted by: Antonio at April 29th, 2017 11:49 AM

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