A High Level View of the State of SENS Rejuvenation Research

The Life Extension Advocacy Foundation (LEAF) volunteers caught up with Aubrey de Grey of the SENS Research Foundation at the recent International Longevity and Cryopreservation Summit held in Spain, and hence the publication of the high level view of current progress in SENS rejuvenation research that I'll point out today. The conference was an opportunity for members the overlapping European communities focused on longevity science, cryonics, and transhumanism to present their work, build their networks, and plan future initiatives. When it comes to longevity, the SENS research program looms large: its focus on repair of the known forms of molecular damage that cause aging so far appears to be the only approach to therapies for aging that can plausibly produce significant rejuvenation in our lifetime. Success here, meaning working rejuvenation therapies in the clinic, is conditional on continued growth in funding and support for this part of the field, however, and while a great deal has been accomplished, there is a lot of work yet to be done.

SENS: Where are we now?

RepleniSENS: Cell loss and tissue atrophy

Over the course of decades, long lived tissues like brain, heart and skeletal muscles gradually lose cells and as replacement dwindles their function becomes compromised. The brain also loses neurons which leads to cognitive decline and dementia as well as the loss of fine muscle movements. The immune system also suffers, with the thymus gradually shrinking and losing the ability to produce immune cells, leaving you vulnerable to diseases. Thankfully stem cell research and cell therapy is already a well advanced field. SENS has not needed to get involved in this area as it is well funded and moving along very rapidly. Only this month we have seen hematopoietic stem cells produced for the first time and research in this field is moving forward at a furious rate. It will be plausible in the near future that we will be able to produce every cell type within the body to replace age related losses.

OncoSENS: Cancerous cells

Cancer uses two pathways to uncontrolled growth: hijacking telomerase and using the Alternative Lengthening of Telomeres (ALT) mechanism. Both allow cancer to maintain its telomeres and grow out of control. Therapies that can inhibit these pathways could be combined and are therefore a potential way for us to defeat all cancers. ALT therapies are progressing following a successful fundraiser on Lifespan.io last year. SENS has been developing a high throughput assay for ALT allowing cost effective candidate evaluation for drugs that can inhibit or destroy cancer cells using ALT. Within the next year a company based on ALT should be possible. Telomerase inhibiting therapies are being developed by a number of organizations and companies so the SENS Research Foundation does not need to get involved with this. Therapies that inhibit telomerase in cancer cells are already in clinical trials and are well funded.

MitoSENS: Mitochondrial mutations

As mitochondria produce the chemical energy store ATP they also generate waste products as a byproduct, in this case highly reactive molecules called free radicals. Free radicals can strike and damage parts of the cell including the mitochondrial DNA (mtDNA), which, due to their close proximity to the source of free radicals, are very vulnerable to these damaging strikes. Damaged mutant mitochondria enter an abnormal metabolic state to remain alive. This leads to cells with damaged mitochondria that dump waste into the circulation causing system wide levels of oxidative stress to rise and driving the aging process.

The solution to this problem is gene therapy to move the mtDNA to the cell nucleus where it will have a far greater level of protection from free radical strikes. The SENS Research Foundation successfully fundraised for the MitoSENS project on Lifespan.io back in 2015. They then followed up with a publication in the prestigious Nucleic Acids Research journal showing their results in September 2016. Thanks to the support of the community the MitoSENS project succeeded in migrating not one but two mitochondrial genes to the cell nucleus, a world first. Since then progress has been rapid and they have now almost migrated 4 of the 13 mitochondrial genes. They are currently refining the process into a standardized therapy.

ApoptoSENS: Death-resistant cells

Our cells have a built-in safety device that causes cells that are dysfunctional and damaged to destroy themselves in a process known as apoptosis. However as we age cells increasingly fail to dispose of themselves in this manner and they enter a state known as senescence. As we age more of these cells build up leading to increasingly poor tissue repair and regeneration. There has been a huge level of interest in senescent cell removal therapies in the last year or two and a number of companies are currently developing senolytics. Unity Biotechnology is taking the first generation of senolytics into human clinical trials this year after being successfully funded by a number of big investors. However the heat is on as other companies are following up close behind with potentially more sophisticated approaches for removing senescent cells such as plasmid based solutions from Oisin Biotechnologies and a synthetic biology approach from CellAge who successfully fundraised on Lifespan.io last year.

GlycoSENS: Extracellular matrix stiffening

Blood sugar and other molecules react with structural proteins in tissues and bond with them creating fused crosslinks. Crosslinks bind neighboring proteins together impairing their movement and function. In the case of the artery wall crosslinked collagen prevents the artery from flexing in time with the pulse leading to hypertension and a rise of blood pressure. The SENS Research Foundation proposes to find ways to break down these crosslinks to restore movement to the structural proteins and thus reversing the consequences of their formation. The problem for many years was obtaining enough glucosepane, the primary constituent of human crosslinks, to be able to test therapies on. Thanks to funding by the SENS Research Foundation progress at Yale University now allows the cheap production of glucosepane on demand, this means that researchers can now test directly on it and find antibodies and enzymes to dissolve the accumulated crosslinks. Yale already has some antibodies against glucosepane, it is anticipated that by the end of the year monoclonal antibodies will be available and there is strong evidence for the existence of bacteria with enzymes that can break down glucosepane.

AmyloSENS: Extracellular aggregates

Misfolded proteins produced in the cell are normally broken down and recycled within the cell, but as we age more and more misfolded proteins accumulate to form sticky aggregates. These misshapen proteins impair cell or tissue function with their presence. This extracellular junk is known as amyloid and comes in a number of types. The work SENS Research Foundation funded at UT Houston in Sudhir Paul's lab is now in the hands of his company Covalent Biosciences, hopefully we will hear some news from them in the near future. Fortunately a number of alternatives are in development such as the GAIM system that appears capable of clearing multiple types of amyloids included those associated with Alzheimer's, Parkinson's and amyloidosis. The AdPROM protein targeting system also holds promise for selectively degrading target amyloids and other undruggable proteins to treat age-related diseases.

LysoSENS: Intracellular aggregates

Cells have a number of systems for breaking down unwanted materials, the lysosome is one of them. The lysosome can be considered to be a kind of cellular garbage disposal unit which contains powerful enzymes for breaking down unwanted materials. However, sometimes materials are fused together so well that not even the lysosome can break them down. This leaves the unwanted material sitting there and over time more and more of this material accumulates until it starts to interfere with lysosomal function. The solution to this problem proposed by the SENS Research Foundation is to identify new enzymes able to digest these insoluble wastes and supply macrophages and other cells with them so they can break it down. Ichor Therapeutics is taking SENS Research Foundation technology to market for macular degeneration with a therapy that removes a Vitamin A derivative that accumulates in the eye and causes blindness. Ichor has successfully conducted a seed round and is now undertaking a 15 million dollar series A round. The company is less than a year away from human clinical trials.

It is true that the SENS initiative, the Strategies for Engineered Negligible Senescence, has come a long way from its turn of the century origins as a rallying point, a research proposal, and a few like-minded advocates and researchers. After fifteen years of earnest advocacy, fundraising, scientific work, and persuasion, some lines of SENS research are now in clinical trials and commercial development, numerous independent groups are working on SENS or SENS-like research, a great, sweeping, and positive change in the attitudes of the research community towards aging has taken place, and the SENS Research Foundation has a yearly budget of a few million dollars provided by philanthropic donations - a mix of grassroots support by our community, and the greater material support provided a few high net worth individuals. This progress is a big deal, make no mistake: collectively our community has bootstrapped something from nothing, and that something has made and continues to make a great difference to our odds of living to see aging brought under medical control.

Yet this is still the beginning of the story, the opening of the age of rejuvenation, the very first portion of a much bigger picture. A great deal of necessary growth is yet to be achieved. Wherever we stand on the upward curve of bootstrapping and success, there is still a mountain ahead. The yearly funding needs to be hundreds of millions, not a few million. SENS must become the majority concern in the broader research community, not just a handful of labs and a few dozen lines of research. I believe that is is possible for us to create this future, as success in the SENS approach of senescent cell clearance will be proof enough to direct ever more researchers and funding sources towards repair and rejuvenation as a guiding strategy rather than their current approach of tinkering with metabolism to slightly slow down aging.

In any machine, biological or otherwise, repair will almost always have better and more cost-effective outcomes than trying to alter the way in which the machine operates: remove the rust and replace the worn parts rather than merely changing the oil while hoping for the best. This has already been quite adequately demonstrated in the case of aging: repair in the sense of targeted removal of senescent cells has achieved a greater and more reliable impact on aging in a few short years of animal studies, than has been achieved by the far greater, much more expensive, and longer-lasting efforts devoted to calorie restriction mimetic development.

The potential for SENS rejuvenation research is tremendous, and we are just getting started.

Comments

Thanks Reason for this particular article.

It is great to see status update on the various repairs needed for aging. I may have asked this question a while ago, but what do you (or others) think the next one or two repair area will be beyond clearing out the Senescent cells. And, maybe someone can hazard a guess on the timeline?:)

It is very good to see progress being make on many fronts. I am sure some will take a decade or more to get into clinical studies.

Posted by: Robert at June 1st, 2017 9:44 PM

Robert: Reason helpfully pointed to this article on the order of arrival of rejuvenation biotechnologies in the intro to this article, as he does almost once a day these days ;) .

You're certainly right that some will take a decade or more to get into clinical trials, but it's very heartening to realize how many are in trials now or getting very close to it.

Posted by: Michael at June 1st, 2017 10:31 PM

Hey Michael,

So we can assume that RepleniSENS will happen first, then OncoSENS, then MitoSENS, and then ApoptoSENS? I thought the first treatments coming on line would be ApoptoSENS. It would great to see these first three becoming available inside of a decade (assuming ApoptoSENS gets here under 10 years).

Posted by: Robert at June 2nd, 2017 12:05 AM

ApoptoSENS looks set to arrive first considering Unity is entering phase 1 this year. Anyway hope you enjoyed the article, it was a response to the question about SENS we get all the time so we decided to do a summary.

Posted by: Steve Hill at June 2nd, 2017 4:40 AM

I've been making small donations directly to SENS when I can. You mentioned the fund raising campaigns - would it be more productive to donate there? Or some other way?

Posted by: RRob at June 2nd, 2017 10:14 AM

RRob: It depends on the donation campaign. Fighaging campaigns are done directly through SENS Research Foundation website. Lifespan.io charges a 5% fee before sending the money to SRF, for website maintenance, marketing, etc.

It also depends on the payment method.

Also, at lifespan.io you have some extras, like t-shirts, etc.

But, in general, if you are interested only in sending the maximum of money to SRF, it's better to send it through SRF website. Also, for some payment methods, it's better to accumulate several donations and send a big sum at once instead of sending several small donations.

Posted by: Antonio at June 2nd, 2017 10:36 AM

Thanks so much Steve for that article. Its good to know where we are.. and we are further along than I thought!

If SENS can ever get a fund-matching program going, I'll be sure to save some financial ammo for an event like that. I'd love to watch it blow through the goal roof.

Posted by: mborbely at June 2nd, 2017 11:54 AM

Whilst it is correct we do charge 5% for campaigns it is a very modest fee given the media exposure, marketing, social media and other things we do as part of that. I would also highlight that these activies also help to popularize rejuvenation biotechnology and drive public engagement. We are seeing a considerable uptick in traffic and interest over the last year or so. Oh and yes projects hosted on lifespan.io tend to have accompanying rewards. I would say there are pros and cons to direct and lifespan.io based projects but both have their place.

@mborbely thanks glad you enjoyed it we are working hard to help SRF increase their support.

Posted by: Steve Hill at June 2nd, 2017 12:01 PM

You are welcome Steve! Would you guys over at Leaf consider making this an annual thing? This is kinda important, we are trying to change the defining element of our species, you guys should be chronicling it.I can tell you that the community would appreciate it.

Posted by: mborbely at June 2nd, 2017 5:57 PM

We are already working on a roadmap to rejuvenation, an interactive system that shows progress and will be frequently updated. The more patrons we get the more content, events and features we can add to our repertoire. Wait till the roadmap is rolled out I think you will love it.

Posted by: Steve h at June 2nd, 2017 6:55 PM

Glad to hear about this upcoming project Steve, the summary that LEAF made and which is the object of this blog article is already tremendously useful. It really facilitates the transmission of information stemming from the complex rejuvenation field towards the public.

Posted by: Spede at June 3rd, 2017 3:25 AM

"It really facilitates the transmission of information stemming from the complex rejuvenation field towards the public."

This is the #1 aim of LEAF, to present the science in a public facing way that engages.

Posted by: Steve Hill at June 3rd, 2017 3:41 AM

Good to see we are rapidly moving forward with RepleniSENS, OncoSENS, MitoSENS, and ApoptoSENS. Let us hope that funding continues to flow in to SENS research otherwise that would be noneSENSe.

Posted by: Tj Green at June 3rd, 2017 6:32 AM

"plasmid based solutions from Oisin Biotechnologies".

I'm wondering how Oisin are going to overcome the delivery problem that has plagued all other attempts at using plasmids in gene therapy? I know they only need to achieve transient not long term expression in cells, but I don't think that alone will solve the problem.

Posted by: Jim at June 3rd, 2017 5:09 PM

@Steve Hill,

I greatly appreciate the work you and your team have done so far, and certainly for providing a status/progress report on repairing the causes of aging. It looks like the first four on the list should progress at such rate that they could be in clinical studies inside of a decade, IMO:)

What I am truly surprised at is the mainstream media provides zero attention to what is going on. Even riding our bodies of Senescient cells would be a big deal, yet little info in the media.

And, I wonder how someone could take advantage (investing) knowing that our lives will be greatly extended, even if just of couple of these "repairs" were to be available very soon.

Posted by: Robert at June 5th, 2017 2:06 AM

@ Robert : The mainstream media (and politicians) have long been known for either shunning SENS-related research and/or writing sensationalist articles about « immortality » and « overpopulation ». But as research progresses, they'll eventually be forced to address the matter half-properly. Money should also become less of an issue.

As for the investments, I would personally bet on land. It can currently be had for cheap, depending on where you live, and there's a chance that its value will mount in the next hundred years.

Posted by: Spede at June 5th, 2017 3:28 AM

Steve Hill,

Researching "senescient cells 2017" tonight, I came across an article written by Steve Hill titled "Billionaire Entrepreneur says Longevity is the Next 'money fountain". I assume this is you, Steve, who wrote the article. You wrote that Jim Mellon will have a book printed later this month, called Juvenescience. It sounds interesting, I may pick it up.

Posted by: Robert at June 5th, 2017 3:30 AM

On investments for centuries in the future: probably money will cease to exist much before that, due to automatization taking over almost all the jobs, so I think it's pointless to invest thinking in such long timeframes.

Posted by: Antonio at June 5th, 2017 3:51 AM

@Robert - Covalent Bioscience and Ichor Therapeutics are not publically listed companies yet, but might be interested in taking a private investment from individuals, provided it is a large enough amount to make it worth the effort, say USD 10,000.

A company not directly involved with the SENS Foundation, but with technology that might be applied to tackling Glucosepane is Bicycle Therapeutics who are developing small peptides that act like antibodies but penetrate tissues much better due to their small size. Their initial target is cancer. Again they might be amenable to a 10k or 100k investment.

Posted by: Jim at June 5th, 2017 4:00 AM

@Robert yes that was me.

Posted by: Steve Hill at June 5th, 2017 2:41 PM

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