A Look at Some of the Aging Research of Irina Conboy

Irina Conboy is on the SENS Research Foundation's advisory board and is one of the more frequently noted scientists presently working on heterochronic parabiosis and related research. These scientific programs aim at identifying age-related changes in important signal proteins circulating in the bloodstream, with parabiosis being where it all starts: link the circulatory systems of an old and a young animal and observe benefits to measures of health in the elder of the two. This happens because old tissues are exposed to a young blood environment. Once specific proteins in the blood are identified as being of interest, then researchers move on to attempts to alter amounts of these proteins in circulation in old animals. They are in search of the basis for therapies that might make cells and tissues in an old individual behave as if they were younger, despite the damage they have suffered.

The main thrust of this research could probably be considered a branch of stem cell medicine. The signals that differ between young and old tissue appear to be involved in regulating the activity of stem cell populations, and thus the degree to which tissues are maintained, kept supplied with fresh new cells. It is well known that stem cell activity declines with age. Much of the present panoply of stem cell therapies consists of what are, when it comes down to it, ways to bolster regeneration and tissue maintenance in old people. Stem cells transplanted into patients appear to achieve at least some of their beneficial effects by altering the balance of signal proteins in their environment. So why not a future in which the cells are done away with and the therapy consists of directly manipulating protein levels? The only thing needed for that to come to pass is a much better understanding of the signals themselves and how they control cell behavior.

The caveat for all of this is that as an approach it really doesn't address the underlying causes of aging at all. It addresses a consequence of cellular damage without repairing the damage itself. Revving up the activity of a damaged engine obviously bears risks. The greatest risk from a theory point of view is cancer: that damaged cells are doing more has an obvious consequence. In practice, more has been achieved in the field of stem cell medicine and with less cancer as the outcome that was feared at the outset. There may be a fair degree of room in our evolved biology for more regeneration in a damaged system, who knows. Equally these bounds and balances may be very different for short and long-lived species, and so it is an open question as to the degree to which we can trust results in laboratory mice today, even following on from consistency in past results in laboratory mice now translated into human stem cell therapies.

Still, we need stem cell medicine for the old. Stem cell populations will need restoration and repair regardless of success in the rest of the rejuvenation toolkit, as there will be old people awaiting treatment when these therapies are introduced. It is another open question as to whether sufficiently good prevention of other forms of damage will mean that stem cell populations never decline in an individual who has undergone period use of repair therapies since childhood, but that is hardly the most pressing issue in front of us. The first and initial goal of building treatments for aging is to save the people who are old when those treatments arrive.

Engineering the End of Aging

For over a decade, Conboy and her colleagues at UC Berkeley have been searching for ways to slow down or even reverse aging. Their latest discovery - a small-molecule drug that restored brain and muscle tissues to youthful levels in old mice through stem cells - signalled that the prospect of anti-aging therapy for humans may be on the horizon. Published this May, the discovery has been called "fountain of youth" or the "secret to eternal youth" by the media. Comfortably clad in an oversized hoodie, Conboy burst the bubble in her high-pitch, Eastern European accent: Sorry, the drug won't keep us young forever, and we will all eventually die. But what her research hopes to accomplish, Conboy said, is a painless, cost-effective way to live when we are old.

Aging-related diseases like adult-onset diabetes, cancer, Alzheimer's, and Parkinson's disease kill millions every year while draining the economy of billions of dollars on health care costs, and a treatment that keeps people healthier in old age would cut the costs significantly down. A drug that tackles these diseases at its root would also give people more agency how they choose to live late in their lives. "Aging is a synonym with diseases," Conboy said. "When we are young, we don't have these diseases. But when we are old, it doesn't matter what background or gender or culture, we all have them. If we can better understand the aging process, then we don't need to have different hospitals, departments, and institutes that deal with each disease."

The drug, known as Alk5 kinase inhibitor, target a growth factor called TGF-beta1 pathway which, at old age, overproduce itself and inhibits other pathways to stimulate stem cells. As our body breaks down over time, stem cells - which are responsible for repairing the body and live huddled together in pockets called niches - are prevented by TGF-beta1 from doing its job. As the body ages, however, the TGF-beta1 begins to overexpress itself and become a deterrent for yet unknown reasons. What the Alk5 kinase inhibitor sought to do was not rid the body of the pathway but rather regulate it by attaching itself to the pathway and dulling its signal asking for more expression. Now with the TGF-beta1 down to youthful levels, stem cells are able to freely repair the body.

"I look at it as more promising than anything," said Hanadie Yousef, the lead author of the Oncotarget study and currently a postdoctoral scholar at Stanford University. "When I was starting graduate school five years ago, there was absolutely nothing known about how aging actually happened. The field is growing so rapidly that I would bet within the next decade we'll see effective anti-aging therapeutic methods." With the probability of anti-aging therapy on the horizon, death may take a different shape in the future. Death, as Conboy's team hoped to accomplish, would no longer come with pain or suffering at some hospital with wires and machines keeping the body alive. Instead, death will come by more natural causes such as cardiac arrest or a stroke - a relatively quick way to die than fighting years against cancer or similar diseases. "I hope we'll just die in our sleep with no cancer or disease eating up our organs," Yousef said. "The goals of my colleagues and I are not to live forever. Instead of becoming old and becoming a burden on society, we can age ourselves more with integrity."

Persuading researchers to work on treating aging at all has been the major battle of the past fifteen years. We've come a long way when postdocs can now talk in public about treating aging without fearing for their future careers. From here we can build, grow the number of researchers who are willing to aim higher - at rejuvenation, radical life extension, and a complete end to aging. No illness, no loss of vigor or health, and consequently no age-related deaths. That is the future we'd like to see more people working towards.

Comments

Irina does fantastic work and Michael too. As Aubrey himself stated on here recently this research may help SENS by simplifying the things that need to be tackled. Same seven deadly SENS but less strands if a few key pathways are identified and manipulated.

FOXN1, TERT, TGF-Beta, Myostatin Inhibitor and NF-KB all seem good targets for intervention and will potentially simplify the work SENS has to do.

I also don't completely agree with the comparison made about revving a damaged engine. There have been studies showing that quiescent (dormant) stem cells that are awakened via a change in systemic environment repair any DNA damage they sustain. Here is an example of such:

http://www.ncbi.nlm.nih.gov/pubmed/24813857

I think eventually the entire system will be mapped and come under our control but as you suggest that is a considerable task and not really practical in the near term. Aubrey I think has it right when he says using some of these pathways could reduce the work SENS has to do and that may well speed up progress, it was nice to see the SENS approach being modified as new information comes in too.

As I have said before whilst I like SENS and the work it does I think the first pass solutions will be a mixture of approaches before it becomes anywhere near a comprehensive suite of treatments.

Posted by: Steve H at June 11th, 2015 4:37 AM

Steve,

I also have become interested in their work, and think it has some potential promise. I also agree that the first pass treatments will likely be a mix of approaches. It's a little off topic, but I know some people on longecity were already experimenting on themselves with the drugs they used in those senolytics. I wish there was an actual way to see the results of that, if there are any. If there were a way to see results that could be a first pass you could do yourself if you were daring enough.

I wish more people were into the engineering idea though, and I hope research starts heading more in that direction, and away from the metabolic approach. Calico is such a wild card in this field now, and I'm hoping they don't take the traditional slow route. It's been described as a "moonshot" company, so hopefully they swing for the fences and take a different approach.

Posted by: Ham at June 11th, 2015 7:23 AM

Little bit off topic, but I wanted to post because seems like lots of people "already know" where Calico is going ... in fact nobody from outside know anything for sure. But that is human nature, we like to believe that we know what others are thinking.
Anyway, more on the topic of this post, is that Calico started a partnership with QB3 to license technology from them:

"Calico and QB3 announce partnership to conduct research into the biology of aging and to identify potential therapeutics for age-related diseases"

http://www.calicolabs.com/news/2015/03/24/

... and Irina Conboy and her team are part of QB3 ... so it is easy to connect the dots:

http://qb3.berkeley.edu/qb3/noteworthy.cfm

Also, there at QB3 is Jennifer Doudna co-autor of CRISPR/Cas9. Keep in mind that George Church is working on reverse aging with his team, and they are also experts in CRISPR/Cas9.

... Calico also partner with Broad Institute.

These will give some clues where Calico is going and why they are going to leapfrog others.

Yes, they are a wild card, but my feeling is that they are going to make a huge impact (in good) in this field. Just be patient, they will use same strategy like they did for other of their projects. And you see where are they now.

Posted by: Adrian Crisan at June 11th, 2015 9:16 PM

Adrian considering who is involved with Calico I have no doubt whatsoever they will be "messing with metabolism" as is often mentioned on here.

I think you are right they are going for gene therapy including the FOXO pathways and probably the pathways Irina Conboy has found eg, TGF-Beta etc...

They have big money and big data and I suspect they will leapfrog others once they have the foundations in place.

Posted by: Steve H at June 12th, 2015 3:52 AM

You're right. Their connections do seem vast. I can't find the link, but on longecity they dissected one of Hal Barron's speeches, and it led some of them to speculate that they would be taking the slow road. I realize that doesn't mean anything, and no one knows for sure what it is. I'm hoping for a broad sweeping approach that covers multiple approaches... they certainly have the team and the funding for that. I like to think they will make a good impact too.

Posted by: Ham at June 12th, 2015 4:45 AM

Little bit off topic, but I wanted to post because seems like lots of people "already know" where Calico is going ... in fact nobody from outside know anything for sure. But that is human nature, we like to believe that we know what others are thinking.
Anyway, more on the topic of this post, is that Calico started a partnership with QB3 to license technology from them:

"Calico and QB3 announce partnership to conduct research into the biology of aging and to identify potential therapeutics for age-related diseases"

http://www.calicolabs.com/news/2015/03/24/

... and Irina Conboy and her team are part of QB3 ... so it is easy to connect the dots:

http://qb3.berkeley.edu/qb3/noteworthy.cfm

Also, there at QB3 is Jennifer Doudna co-autor of CRISPR/Cas9. Keep in mind that George Church is working on reverse aging with his team, and they are also experts in CRISPR/Cas9.

... Calico also partner with Broad Institute.

These will give some clues where Calico is going and why they are going to leapfrog others.

Yes, they are a wild card, but my feeling is that they are going to make a huge impact (in good) in this field. Just be patient, they will use same strategy like they did for other of their projects. And you see where are they now.

Posted by: Adrian Crisan at June 12th, 2015 5:23 AM

Yep Calico plans to "mess around with metabolism" by targeting key pathways. This is good news for SENS as ADG recently said it could make their task easier if some of the key pathways reduce the strands they need to work on.

My fear is how they will get any therapy through the FDA when firstly it wont consider aging a disease and secondly if they do apply for an IND status it will be only for a named disease and therefore not available off label as an anti-aging therapy.

I also worry that SENS will encounter exactly the same problem no matter how good any therapy they develop is.

Posted by: Steve H at June 13th, 2015 4:20 AM

Steve, I think the answer to the FDA blockade is to find a compliant country (Finland, Iceland?) that will jump at the chance to become the world leader in aging therapies and has the vision to contemplate the enormous monetary infusion that would have on its GNP.

Also, I'm sure Calico would appreciate the bonus of tax freedom such a collaboration would entail.

Posted by: manorborn at July 21st, 2015 11:46 AM

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