146 replies to this topic

[tunt01]

Competition is a good thing.  IDK why everyone has to hump SENS/Aubrey.  Even if Calico ends up being spectacularly wrong, I'd rather see differentiated efforts than a single (SENS-only) approach.

[Antonio2014]

Calico has access to a lot of data in this field (thanks to Google's search engine that dominates the net).

 

[Diocletian]

Will to cure aging is the most important thing and that's what Calico lacks.

 

This is the main reason why I support SENS, not because their research is superior to others but because they are truly determined to cure aging and will go to the end.

[niner]

Competition is a good thing.  IDK why everyone has to hump SENS/Aubrey.  Even if Calico ends up being spectacularly wrong, I'd rather see differentiated efforts than a single (SENS-only) approach.

 

I think it would be a lot better if even ten percent of Calico's resources were spent on something more likely to produce real cures for aging.  Calico is essentially the same old same old, so it's not like they're adding much valuable diversity to the overall research effort.

[Avatar of Horus]

Will to cure aging is the most important thing and that's what Calico lacks.

 

This is the main reason why I support SENS, not because their research is superior to others but because they are truly determined to cure aging and will go to the end.

 

Here is Calico's mission from their front webpage:
https://www.calicolabs.com/

 

We’re tackling aging,
one of life’s greatest mysteries.

Calico is a research and development company whose mission is to harness advanced technologies to increase our understanding of the biology that controls lifespan. We will use that knowledge to devise interventions that enable people to lead longer and healthier lives. Executing on this mission will require an unprecedented level of interdisciplinary effort and a long-term focus for which funding is already in place.

[PeaceAndProsperity]

Isn't it odd that a 74 year old chief scientist at one of the richest companies in the world involved in a "moonshot" and given "a handsome sum of money" is still so worried about aging yeast cells? With all that money and all that talent around him, why isn't he worried about his own aging body, and the aging bodies of his now 60 years old aging students, and the aging bodies of humans?

Methinks he is already getting anti-aging treatment. He looks seriously good and young for his age, much better than Bill Gates who is over 10 years younger than him while Bill Gates paradoxically looks 10-20 years older.

A lot of US politicians and presidents are degenerating and look horrible for their age (Bush family, fx.). I think this guy has to have some costly special treatment plan that is keeping him young looking, otherwise he shouldn't look better for his age than the other people.

[niner]

 

Isn't it odd that a 74 year old chief scientist at one of the richest companies in the world involved in a "moonshot" and given "a handsome sum of money" is still so worried about aging yeast cells? With all that money and all that talent around him, why isn't he worried about his own aging body, and the aging bodies of his now 60 years old aging students, and the aging bodies of humans?

Methinks he is already getting anti-aging treatment. He looks seriously good and young for his age, much better than Bill Gates who is over 10 years younger than him while Bill Gates paradoxically looks 10-20 years older.

A lot of US politicians and presidents are degenerating and look horrible for their age (Bush family, fx.). I think this guy has to have some costly special treatment plan that is keeping him young looking, otherwise he shouldn't look better for his age than the other people.

 

I suspect that he has a good set of hair/skin genes, and not much more than that.  He'll probably be dead before Calico has anything that will make a difference for him.

Edited by niner, 19 December 2016 - 08:28 PM.

[Darryl]

The literature emerging from Calico offers some indication of where they're at. At the moment the only publically released research that lists affiliation with Calico Life Sciences is better funded work from C. Kenyon's worm lab, and some reviews catching up with the methionine restriction fans hereabouts.

 

Research:

Bensaddek et al, 2016. Micro‐proteomics with iterative data analysis: Proteome analysis in C. elegans at the single worm level. Proteomics, 16(3), pp.381-392.

Roux et al, 2016. Reversible age-related phenotypes induced during larval quiescence in C. elegans. Cell Metabolism, 23(6), pp.1113-1126.

Narayan et al, 2016. Deep proteome analysis identifies age-related processes in C. elegans. Cell Systems, 3(2), pp.144-159.

 

Reviews:

McIsaac, 2016. From yeast to human: exploring the comparative biology of methionine restriction in extending eukaryotic life span. Annals of the New York Academy of Sciences, 1363(1), pp.155-170.

Brown-Borg and Buffenstein, 2016. Cutting back on the essentials: Can manipulating intake of specific amino acids modulate health and lifespan?. Ageing Research Reviews.

 

Edited by Darryl, 22 December 2016 - 02:38 PM.

[sthira]

Evidently, Calico also co-funded this (human) trial for blood transfusions, and we see the Conboys are involved:

A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Justin Rebo, Melod Mehdipour, Ranveer Gathwala, Keith Causey, Yan Liu, Michael J. Conboy & Irina M. Conboy
Nature Communications 7, Article number: 13363 (2016)
doi:10.1038/ncomms13363

Edited by sthira, 22 December 2016 - 07:59 PM.

[alc]

 

Calico has access to a lot of data in this field (thanks to Google's search engine that dominates the net).

 

 

 

... like all the sens trolls you are in the same bracket: ignorance is bliss ... rather than do a search to find out about how Calico Labs work (or at least for Daphne Koller their CCO ...) you spend time on posting clips ... no wonder you do not understand much of what is going on in the research field ... let's revisit this post after Calico Labs moves on, and we will see how many of you pooh-pooh-ers/sens trolls will still laugh ...

[Antonio2014]

Evidently, Calico also co-funded this (human) trial for blood transfusions, and we see the Conboys are involved:

A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Justin Rebo, Melod Mehdipour, Ranveer Gathwala, Keith Causey, Yan Liu, Michael J. Conboy & Irina M. Conboy
Nature Communications 7, Article number: 13363 (2016)
doi:10.1038/ncomms13363

 

One of the authors is part of the staff of SENS RF. Anyway, the experiments in that paper were done in mice, not humans. Maybe you are citing the wrong paper?
 

Edited by Antonio2014, 26 December 2016 - 04:53 PM.

[reason]

For those who like reading the Calico tea leaves, here are a few details on one of their recent partnerships. Calico, the California Life Company, is the aging research venture funded by Google. It launched a few years back, but so far those involved appear to be doing nothing particularly radical, insofar as we know anything about what is going on there. Calico is certainly not supporting the SENS view of damage repair as the best way to treat aging, and may well be turn out to be simply a larger and more secretive version of the Ellison Medical Foundation in the end: an expansion of the largely investigative work already taking place at the NIA, undertaking no projects with the potential to make a large difference to the course of aging in humans. More research is always better than less research, of course, but nonetheless this has grown to have the look of another missed opportunity to add to the recent history of aging research.

Here, Calico is partnering to obtain access to a technology that could be turned to ways to adjust the level of any one or any few of the proteins present in a cell. The approach works by harnessing one of the cell's established recycling mechanisms. This might be intended as an alternative to methods such as RNA interference for use in adjusting cellular operation. The goal is to tinker with the switches and dials of metabolism, all of which are influenced or determined by levels of specific proteins, in order to test approaches that might slightly slow aging by reducing the pace at which damage accumulates. More positively, it might be turned to degrading forms of metabolic waste that cause aging, though beyond amyloid and Alzheimer's disease, there is little sign that Calico researchers are interested in the list of waste compounds outlined in the SENS rejuvenation research proposals, such as cross-links, lipofusin, and so forth.

C4 Therapeutics (C4T) and Calico today announced a five-year collaboration to discover, develop, and commercialize therapies for treating diseases of aging, including cancer. Under the terms of the agreement, the parties will leverage C4T's expertise and capabilities in targeted protein degradation to jointly discover and advance small molecule protein degraders as therapeutic agents to remove certain disease-causing proteins. The partnership will pursue preclinical research and Calico will be responsible for subsequent clinical development and commercialization of resulting products that may emerge from the collaboration.

"We know from decades of translational research that it can be incredibly challenging to find effective pharmacologic inhibitors of many of the biologically well-validated targets, particularly in cancer. Through the alternative strategy of specifically targeting such proteins for degradation, we believe we have the opportunity to identify promising new therapeutics in cancer and in other diseases as well. We're looking forward to collaborating with C4T's scientists and applying their protein degradation technology to the discovery and development of effective new treatments."

C4 Therapeutics is a private biotechnology company developing a new class of drugs based on Targeted Protein Degradation (TPD) to address a broad range of life-threatening and life-impairing diseases. C4T's platform uses small molecule drugs to direct the machinery of the ubiquitin-proteasome system to selectively degrade disease-relevant proteins for therapeutic benefit. This distinctive mechanism provides new opportunities to target traditionally difficult-to-treat diseases and diseases plagued by drug resistance.

Link: http://www.calicolab...ews/2017/03/23/

View the full article at FightAging

[alc]

"SENS view of damage repair as the best way to treat aging" ... says who? fa guy/girl ... let's be serious here ... sens has many issues understanding lots of things ... one simple example:

 

"CohBar, Inc. Continues Exploration of Mitochondrial Genome and Expansion of Its IP Portfolio with Filing of 29 New Provisional Patents"

 http://www.pharmiweb...V#ixzz4cZ4NChaO

 

[btw: this is coming from a team that has David Sinclair in, the one that fa guy/girl is trying to pooh-pooh for years ... bummer:

 

http://cohbar.com/ty...-and-advisors/]

 

 

 

... now from claiming that what they do is the best way to treat aging, to reality ... there is a long way ...

[Junk Master]

Vox had an intriguing article about the culture of secrecy at Calico, Google's 1.5 billion dollar, anti-aging project:

 

http://www.vox.com/s...tality-research

 

I'm curious if anyone here knows what paths they are exploring.   I'd say, given Google's data crunching prowess, genomic medicine seems a perfect fit; but, they are throwing as much money as the NIH into this, so that's incredibly exciting.

 

I just hope they rethink what seems to be their "culture of secrecy."

[reason]

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.

View the full article at FightAging

[YOLF]

There are many solutions. Calico is positioning itself to have control over which ones get tested and what it will mean for the future of the advertising agency. They obviously don't want to delete any genes that lead to clicking behavior which they make money off of. Any disease associated with that will cut off other revenue streams and must be inhibited... at least that's my guess as to what they're doing.

[alc]

 The elephant keeps walking (Calico) as the dogs (Sens, FightAging, etc.) keep barking.

[Nate-2004]

I'm inclined to agree with the SENS approach since it appears that Calico is trying to tackle aging and does not seem even remotely aware of the SENS approach or that the mechanisms of aging are well known by now. It's like they're reinventing the wheel, which is fine, but not helpful as far as progress goes. Sure, competition is great, I love competition, but they appear to be going after drugs that treat existing age related diseases rather than going upstream. It's more profitable that way. The healthcare industry thrives on age and this is why tackling aging directly means the demand on healthcare, supply and demand being one of the biggest reasons why it's expensive, is one of the first problems to be resolved.

Edited by Nate-2004, 31 July 2017 - 03:08 PM.

[Mind]

Ray Kurzweil (Google) was at RAADfest claiming that we now have enough computational capability to solve almost any problem human society has "within a few days".

 

Calico continues to spend hundreds of millions of dollars per year screening DNA and other cellular machinery for patterns involved in aging. After 4 years, I am still unaware of any concrete translational efforts. I know they have partnered with big-pharma, but they are very secretive about it. The best thing they have produced thus far is this (IMO): https://elifescience.../articles/47362

 

In contrast, the SENS platform is expanding, fostering numerous companies/start-ups, producing more human and animal trials every year, etc...

 

Maybe Calico with discover some holy grail of aging very soon. So far, they haven't contributed that much, especially considering the truly MASSIVE funding they have.

 

 

[Kentavr]

Ray Kurzweil (Google) was at RAADfest claiming that we now have enough computational capability to solve almost any problem human society has "within a few days".

Calico continues to spend hundreds of millions of dollars per year screening DNA and other cellular machinery for patterns involved in aging. After 4 years, I am still unaware of any concrete translational efforts. I know they have partnered with big-pharma, but they are very secretive about it. The best thing they have produced thus far is this (IMO): https://elifescience.../articles/47362

In contrast, the SENS platform is expanding, fostering numerous companies/start-ups, producing more human and animal trials every year, etc...

Maybe Calico with discover some holy grail of aging very soon. So far, they haven't contributed that much, especially considering the truly MASSIVE funding they have.

Calico Plan - Patent. If they find something universal and simple, they may not make it public, since it will be unprofitable for them.

P.S .: Google’s motto “Don't be evil” was removed in 2018 from its code of conduct.

[orion22]

so there is no way you can invest just in calico?

[YOLF]

You can invest in something CaLiCo might buy some day...

[Kalliste]

Ray Kurzweil (Google) was at RAADfest claiming that we now have enough computational capability to solve almost any problem human society has "within a few days".

 

Calico continues to spend hundreds of millions of dollars per year screening DNA and other cellular machinery for patterns involved in aging. After 4 years, I am still unaware of any concrete translational efforts. I know they have partnered with big-pharma, but they are very secretive about it. The best thing they have produced thus far is this (IMO): https://elifescience.../articles/47362

 

In contrast, the SENS platform is expanding, fostering numerous companies/start-ups, producing more human and animal trials every year, etc...

 

Maybe Calico with discover some holy grail of aging very soon. So far, they haven't contributed that much, especially considering the truly MASSIVE funding they have.

 

Reason right about Calico being a disappointment. I also suspect the vested Google interest in Calico partially motivated Google to ruin their search engine for alt medicine. 

[Engadin]

.

 

 

 

 

 

S O U R C E :   Izod News

 

 

 

 

 

 

 

 

 

 

• Bill Maris, who founded Google Ventures and left to build his own investment fund called Section 32, just brought aboard several former Googlers to his new company.
• Among those is Claire Stapleton, a previous YouTube executive who led an employee walkout at Google in 2018 to protest the company’s handling of sexual-misconduct allegations.
• Maris also founded Calico, the secretive life-sciences company that still sits under Alphabet.
• He said he’s “disappointed” with the lack of progress Calico has shown since his departure.

 

Bill Maris, the founder of Google Ventures and creator of the Alphabet life-sciences division Calico, parted ways with Google in 2016 to form his own investment fund, Section 32.

 

According to Maris, Section 32 is investing in about 40 companies and just added a handful of new members to its ranks — most of whom also hail from Google. They include Claire Stapleton, a previous YouTube executive who led an employee walkout in 2018 over Google’s handling of sexual-misconduct allegations against its former exec Andy Rubin.

 

They also include Alice Cheung, who worked as a Google recruiter for 10 years and joins Section 32 as its head of talent. Kenzo Fong Hing, the former head of marketing for Android, came aboard as an adviser.

 

“We still use the word Googly internally as it means something to us in its best sense, or what it used to mean at least,” Maris told IzodNews about the Google theme among its new hires. “I think all of those values carry over, which is why it’s not surprising to me to see quite a number of people I used to work with at Google join here.”

 

Maris said Section 32’s investments were at the crossroads of technology, healthcare, and life sciences. Names in the portfolio include Alector, which focuses on eliminating neurodegeneration, and the robotic-endoscopy company Auris.

 

“We’re not making 100 investments a year like I was at Google. We’re making maybe one a month, so we’re being extremely selective about that, and we invest a lot of time and energy into the things we do,” Maris said.

 

And even though he said it was “mission accomplished” when he left Google Ventures in 2016, he said he didn’t feel quite as accomplished when it came to Calico.

 

Maris founded the Calico life-sciences division under Alphabet in 2013 with a mission to research and combat aging-associated diseases.

 

“I still remain interested in accelerating that part of what I set out to do there,” Maris said. “I have a lot of ideas in that space, and it remains to be seen how they take shape.”

 

Maris said he has been “disappointed” with the lack of visible progress Calico has made in the field and that he still has an active interest in antiaging and genetics. Fulcrum Therapeutics, a biomedical company focused on patients with genetically defined rare diseases, is also a Section 32 investment.

 

Maris said Calico had a two-part goal. “One was to legitimize the area of research into aging, which at the time was seen as fringe and unfundable by government grants and so forth, and I think we achieved that goal by making it legitimate to understand aging as a genetic disease essentially,” he said.

 

“The second goal was to actually make progress towards the goal, which was to really understand aging as a genetic condition that could be treatable and curable in the sense of the diseases and the debilitations that come with age, both cognitively and physically. And I’m pretty disappointed personally to see a lack of progress or a lack of any statement of progress from Calico in that regard,” he added.

 

Calico has been relatively quiet compared with other Alphabet companies. The last big news came in 2018, when Calico and the drug giant AbbVie came together for a $1 billion pledge toward developing therapies associated with age-related diseases.

 

In 2019, Amgen’s head of translational medicine, Aarif Khakoo, joined Calico to lead drug development, but otherwise there’s been very little movement, especially compared with Alphabet’s other life-science division Verily.

 

“I think things don’t progress because of a lack of leadership, right? I don’t know,” Maris said. “I have no idea why they don’t publish articles. I have no idea why we haven’t seen anything come out. I don’t know why no one seems to know what they’re working on doing. It all seems very contrary to the spirit of openness and transparency that advances science, but no, I don’t get it; it’s not how I envisioned it at all.”

 

 

 

 

.../...

 

 

 

 

 

T O   A C C E S S   T H E   R E S T   O F   T H E   A R T I C L E ,   P L E A S E   V I S I T   T H E   S O U R C E .

 

 

 

 

 

.

 

Edited by Engadin, 02 June 2020 - 10:19 PM.

[albedo]

What might be more in Calico's innovation pipeline that I do not know? Just my ignorance I guess! I do not know you, but feel while this a nice research a lot more exciting is going on elsewhere:

https://www.longevit...ith-calicos-pi/

[reason]

Calico is Google's venture into aging research. It has, in general, been a disappointment to the community - though I suspect that this is a matter of unrealistic expectations as to the path that any new, large deployment of capital is likely to follow. Rather than taking on any of the approaches to rejuvenation that might plausibly produce sizable gains in life span, such as those of the SENS portfolio, Calico has focused on very staid, long-standing metabolic manipulations derived from the study of calorie restriction and growth hormone loss of function mutants. These lines of research are highly unlikely to produce sizable gains in health and longevity in humans, as the calorie restriction response and disruption of growth hormone metabolism are known to produce only modest gains in our species. Calico, like the Ellison Medical Foundation that preceded it, has in essence become a small arm of the National Institute on Aging, characterized by conducting fundamental rather than translational research, and in areas of the field that won't do much for human health and life span at the end of the day.

What area of aging and age-related diseases has Calico's biggest focus at the moment?

Our top-level goal is to develop interventions that delay aging, but to test such interventions, we have to be able to measure aging. This is easier said than done - the gold standard, lifespan, takes a long time and is relatively information-poor. There are molecular and cellular changes that occur with age, but it's not always clear which are the most relevant readouts. We'd like to measure aspects of physiological decline, but current healthspan assays take a lot of time and effort, and even then tend to be pretty noisy. To address those limitations, we've spent a lot of time developing innovative tools and novel analyses for quantifying physiological decline in mouse models. We emphasize automated, longitudinal monitoring and multi-dimensional time-series analysis.

On the intervention side, one area of focus for my lab is IGF signaling. This was a pretty straightforward choice - reduced IGF signaling is the most validated anti-aging intervention known (slows aging from worms to mammals, with the largest effect sizes ever reported). There are challenges with targeting this pathway, of course - dose-limiting toxicity, endocrine feedback, lack of biomarkers, just to name a few - but we think we've identified a viable therapeutic strategy.

What emerging discoveries and techniques is Calico utilising?

I'm excited about using outbred mice for intervention testing. We're clearly not the first people to think of this, but we've embraced the concept. Outbred mice are somewhat more resource-intensive than inbred mice because they have more variability, but we think they're worth it. As we're all painfully aware, many published results fail to replicate. I think that a big fraction of what's being called irreproducibility is actually a lack of generalizability. In other words, the results might repeat under the exact same conditions, but alter those conditions just a little and it's a different answer. For mouse studies, strain background is an important condition, and we worry about results from a single, homozygous-at-all-loci genotypes not being generalizable. Outbred mice help us avoid this

What do you think is the best way to quantify longitudinal decline - are there key biomarkers that you're addressing?

Aging manifests at all levels of biological organization (i.e. molecules, cells, tissues, organs, organ-systems, and whole organisms), and measuring aging at each level has pros and cons. Molecular and cellular data provide mechanistic insight and can point to new therapeutic targets, but it can be hard to know if effects are truly relevant to the organism (e.g. does delaying mutation accumulation delay decline in organ function)? Organ-level and physiological data provide health relevance, but it can be hard to tease out mechanism - good for testing putative targets, less good for target discovery. My lab focuses on developing tools for measuring organism-level decline because we think the state of the art is lacking and robustly testing putative targets is rate-limiting in the field.

Link: https://www.longevit...ith-calicos-pi/

View the full article at FightAging

[Steve H]

In a preprint paper, scientists from Calico, Google’s longevity research behemoth, suggest that contrary to our previous understanding, transient reprogramming of cells using Yamanaka factors involves suppressing cellular identity, which may open the door to carcinogenic mutations. They also propose a milder reprogramming method inspired by limb regeneration in amphibians [1].

Rejuvenation that can give you cancer

In 2006, a group of scientists led by Shinya Yamanaka developed a technique for reprogramming somatic cells back into pluripotent stem cells by transfusing them with a cocktail of transcription factors [2]. These four pluripotency-associated genes, Oct4, Sox2, Klf4, and c-Myc (OSKM), became known as the Yamanaka factors. This breakthrough because made it possible to produce patient-specific stem cells from their own somatic cells.

On the other hand, induced pluripotent stem cells (iPSCs), which are the product of cellular reprogramming, are known to acquire carcinogenic mutations. This hurdle has been limiting their use, with scientists all over the world trying to overcome it in order to fully utilize iPSCs’ immense potential [3].

When somatic cells revert to the pluripotent state, they also shed many features of cellular aging, effectively becoming young again. iPSCs from young and aged donors are almost indistinguishable, and this similarity remains even after the cells differentiate again into various cell types.

This led scientists to attempt cellular rejuvenation with Yamanaka factors but without reprogramming the cells back to a pluripotent state. Such “transient reprogramming”, in which the factors are introduced for a short period of time, stops before the cells reach the Point of No Return (PNR) on the road back to pluripotency – or so it was thought. Transient reprogramming has been shown to improve multiple physiological functions in aged animals and extend lifespan in progeroid mice [4].

To pluripotency and back

This new paper was published by scientists from Calico, a secretive and well-funded Alphabet (Google) subsidiary in the field of longevity research. Since its inception several years ago, expectations from Calico have been high, but we have only seen a slow trickle of papers. This study is one of the most important to ever come out of the company.

Utilizing their almost unlimited resources, Calico researchers were able to study the effects of transient reprogramming by performing single-cell RNA sequencing for tens of thousands of individual cells. They found that transient reprogramming restored youthful gene expression in adipogenic cells and mesenchymal stem cells, but, at the same time, temporarily suppressed their cell identity programs. These results stand in contrast with the previous notion that transient reprogramming rejuvenates cells without making them revert to a pluripotent state. By analyzing transcription levels of several pluripotency-associated genes on a single-cell level, the researchers showed that such reversion does occur, even if briefly and/or partially, with the cells subsequently reacquiring their cellular identities. These subtle back-and-forth transitions might not have been picked up by previous studies that used less precise bulk analysis.

If cellular identity is indeed suppressed by transient reprogramming, this brings back the specter of oncogenic mutations. The whole idea of transient reprogramming is to rejuvenate cells in vivo, where such mutations cannot be controlled or weeded out.

Can we do with fewer factors?

Since some Yamanaka factors are known to be more oncogenic than others, the researchers analyzed the effects of various combinations of factors to determine whether any of them could be left out. Surprisingly, they found that none of the factors were indispensable – probably because of the way they interact with each other. Apparently, when a combination of factors is introduced to the cell, it activates endogenic transcription of the missing factors. As a result, leaving out any single factor, or even two, only weakens the reprogramming effect, sometimes moderately. As an example, the SO cocktail (half of OSKM), while still effective in transient reprogramming and rejuvenation, was found to suppress cellular identity considerably less than the full array of Yamanaka factors.

The researchers applied the factors both to young and aged cells. While the aged cells were significantly rejuvenated by the treatment, on the transcriptomic map created by the researchers, these aged cells clustered differently from the young reprogrammed cells. This remaining difference probably means that certain features of aging might not be affected by transient reprogramming, but additional research is needed.

Among the gene sets that showed the biggest amplitude of change following the reprogramming was the set that regulates cellular inflammatory response. The genes in this set were upregulated in aged cells and significantly downregulated by reprogramming. As aging is linked to excessive inflammation, a situation known as inflammaging, the ability of transient reprogramming to downregulate these genes is great news.

The amphibian connection

Finally, the researchers attempted an unorthodox approach to transient reprogramming using factors that are associated with multipotency. As opposed to pluripotent cells which can differentiate to almost any cell type, multipotent cells can only differentiate into a small subset of types.

The researchers treated aged murine myocytes (smooth muscle cells) with the multipotency factor Msx1, which also facilitates limb regeneration in some amphibians. This multipotency cellular reprogramming successfully restored youthful gene expression in aged myogenic cells. People probably will not be growing back limbs any time soon, but induced rejuvenation of muscle cells is an important result.

Conclusion

While holding great promise, transient reprogramming apparently is not risk-free. This important paper showcases what can be done with proper funding – such as tens of thousands of single-cell RNA profiles. It expands our understanding of the intricate processes of acquiring and losing cellular identity and of possible ways of using reprogramming techniques to develop therapies.

HELP SPREAD THE WORD

Please connect with us on social media, like and share our content, and help us build grass-roots support for healthy life extension:

Thank You!

Literature

[1] Roux, A., Zhang, C., Paw, J., Zavala-Solorio, J., Vijay, T., Kolumam, G., … & Kimmel, J. C. (2021). Partial reprogramming restores youthful gene expression through transient suppression of cell identity. bioRxiv.

[2] Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. cell, 126(4), 663-676.

[3] Abad, M., Mosteiro, L., Pantoja, C., Cañamero, M., Rayon, T., Ors, I., … & Serrano, M. (2013). Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature, 502(7471), 340-345.

[4] Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., … & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.

The post Calico Scientists Develop Safer Cellular Reprogramming first appeared on Lifespan.io.

View the article at lifespan.io