A Look Back at 2016 in Longevity Science

Well, another year passes and here we are again, one step closer to the defeat of aging and age-related disease. Ours is an era of revolutionary progress in biotechnology, and it is starting to show. The past year was characterized by both significant fundraising and significant progress towards the clinical translation of the first complete SENS rejuvenation therapy: clearance of senescent cells from aged tissue. This is hopefully the first of numerous other SENS therapies based on repair of molecular damage to arrive over the next few years. I recently updated my predictions for the near future, looking over the parts of the field that are very close to the making the leap into for-profit startups. These are exciting times.

Regarding senescent cell clearance, I have to open by talking about fundraising. The two topics go hand in hand. Oisin Biotechnologies is the senescent cell clearance company closest to our community of supporters, seed funded back at the end of 2014 by the Methuselah Foundation and SENS Research Foundation, and led by one of the earliest donors to the Methuselah Foundation, someone who has been involved in this community for longer than I have. I've been talking about the need to extend our support for research beyond the laboratory and into startup companies, and in the tradition of doing rather than just talking about doing I participated in one of the funding rounds for Oisin Biotechnologies this year, joined by a number of other supporters. The money is going to good use, but that wasn't the big news in senescent cell clearance funding for 2016, of course. The big news was that UNITY Biotechnology landed one of the largest biotechnology industry funding rounds of recent years: $116 million in order to bring senolytic drugs to the clinic. That and the efforts that led to it will shape this field for years to come.

Over the course of the year, more evidence for the effectiveness of senescent cell clearance rolled in. Teams associated with UNITY Biotechnology showed 25% life extension in normal mice resulting from removal of senescent cells. Other work has shown restoration of function in aged lung tissue, and improved vascular health. New evidence reinforces a role of senescent cells in osteoarthritis, as well as in atherosclerosis, immunosenescence, and diabetic retinopathy. Many other papers have emerged in which researchers link senescent cells in some way to their particular areas of interest in aging. It is safe to say that the broader research community has been well and truly woken up on this topic, and are now engaged in producing a great weight of specific evidence in support of senolytic therapies as a way to delay and reverse numerous processes contributing to age-related disease. The tipping point has passed and things are moving very rapidly now in comparison to past years. How soon before the first senolytic therapies become available via medical tourism, immediately following the first human trials? Not more than a few years, I'd say. A lot of people are running, not walking, to enter this area of development at the moment.

When it comes to fundraising for SENS rejuvenation research, well, there has been a lot of that this year as well. In fact I think the long-standing grassroots of our community is reaching the point of exhaustion on this front. There is only so much water in the well when it comes to charitable support from a single community - and we've certainly given a great deal to the cause. Our community must grow to match the opportunity, but given what is happening for senescent cell clearance, I think this is a very real possibility. In crowdfunding initiatives this year, the Major Mouse Testing Program raised $50,000 for a senescent cell clearance study, and that happened back to back with the SENS Research Foundation raising $70,000 for work on one component of a universal cancer therapy based on blocking telomere lengthening. While that fundraiser was still running, Michael Greve of the Forever Healthy Foundation stepped up to pledge $10 million to SENS research and funding for the startup companies that will emerge from that research. This is the founding donation for the new SENS Project|21 initiative, seeking $50 million to bring significant segments of the SENS portfolio of rejuvenation therapies into readiness for the clinic by 2021. Somehow, in the midst of all of that excitement, the SENS Research Foundation staff found time to once again run the acclaimed Rejuvenation Biotechnology conference in August, bringing together industry and academia to build the necessary bridges for tomorrow's rejuvenation therapies.

Along the way, Ichor Therapeutics raised a funding round to build a therapy from the LysoSENS work of past years: bacterial enzymes turned into drugs to break down specific forms of harmful metabolic waste that contribute to age-related disease. BioViva recieved support from Deep Knowledge Ventures and allied with Sierra Sciences to set up a clinic in their gene therapy efforts. Ambrosia pulled in funds to run a trial of the transfer of young blood plasma to old individuals. The Methuselah Foundation launched their $500,000 research prize for tissue engineering in collaboration with NASA. Further, the founders of CellAge, one of the newer groups to enter the senescent cell clearance space, are currently running a crowdfunding initiative in order to produce better cellular senescence assay and identification technology for the research community.

Last but far from least, the end of year fundraiser for the SENS Research Foundation is coming to a close as I write as well: there is still money left in the various matching funds supplied by Michael Greve, Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! This year, we decided to match a year of donations for anyone who signs up as a SENS Patron by pledging monthly donations. This is thinking in the long term, helping to build a steady flow of donations to SENS rejuvenation research, and you'll see more of this initiative in the year ahead.

While the two topics above generate the greatest excitement and attention, there was - of course - way more to the past twelve months in longevity science than senescent cells and fundraising. Gene therapies, for example, are rapidly coming closer to reality, and the first will be available via medical tourism soon enough. Reliable and comprehensive cell coverage remains an important hurdle, though there are promising signs of progress there. The BioViva human study of one reported results for the telomerase gene therapy and, later, the follistatin gene therapy. The only thing stopping you or I from undergoing those same therapies is a matter of knowing who to call and having the necessary funds, but costs will fall rapidly in the years ahead as the number of potential providers rises and data emerges. I'm very enthusiastic about myostatin and follistatin gene therapies, and less so when it comes to telomerase gene therapy. There, I'd like to see results in species other than mice, as their telomere dynamics are significantly different. Many people inside and outside the scientific community are pushing for the development of telomerase therapies to slow aging, however, and at the present adventurous pace we'll see more human data before data in other mammals.

2016 was a big year for the cryonics community, with a great deal of attention from the media, much of surprisingly good, including profiles of supporters and the Russian KrioRus group. Cryonics simply makes sense, and we can hope that more press attention translates into a larger community of supporters making material contributions to the end goal. On that topic, I finally stopped procrastinating and signed up. As it turns out, having a backup plan only works if you actually use it. There are other signs of growth, such as the CryoSuisse initiative, and continued efforts to produce reversible vitrification for the organ transplantation industry. The Brain Preservation Foundation's technology prize was won by a cryonics approach, though not the one currently in widespread use for reasons that have a lot to do with differences in end goal between various interested factions: restoration versus copying and uploading.

Work on the SENS strategy of cross-link breaking is also forging ahead. I wrote up a state of research article early in 2016, and it remains broadly correct for the end of 2016. This research is largely funded by the SENS Research Foundation, and has yet to spread all that far beyond this small number of research groups. In effect it is in much the same position as senescent cell research found itself prior to 2011, looking for the first drug candidate and the first impressive demonstration to gain more interest from outside sources. Fortunately, in this case there is a greater flow of philanthropic funding, so we should see that breakthrough arrive within the next few years. Meanwhile, evidence continues to accumulate for the role played by cross-links in degenerative aging beyond the obvious candidates, including blood vessel stiffening, such as impaired muscle regeneration

On the mitochondrial contribution to aging, this year the SENS Research Foundation in-house team achieved allotopic expression of mitochondrial genes ATP6 and ATP8 - a big advance. The newly public company Gensight Biologics was funded with tens of millions of dollars in venture capital on the basis of doing the same for just one gene, ND4. That work too was supported by the SENS Research Foundation in its earliest stages nearly a decade ago. This is a valuable technology. Now three of thirteen mitochondrial genes can be moved to the cell nucleus: only ten to go in order to remove the contribution of mitochondrial damage to aging. Also of note is research that demonstrates a link between mitochondrial DNA deletions and the progression of sarcopenia, age-related loss of muscle mass and strength - but I am glossing over a good dozen very interesting papers on mitochondrial aging from the past twelve months in order to point out that one.

A number of relevant new organizations have arrived on the scene in 2016. Beyond UNITY Biotechnology and CellAge, mentioned above, the Global Healthspan Policy Institute, focused on lobbying, launched early in the year. On the subject of lobbying, the considerable grassroots efforts among researchers to have aging formally defined as a disease continue, alongside similar efforts to put more of an emphasis on the treatment of aging in definitions provided by influential standards bodies. Separately, the Life Extension Advocacy Foundation continues to expand their footprint in the community. There is a lot of new material at their site; worth a look.

Mitochondrially targeted antioxidants as a means to address inflammatory conditions, and maybe modestly slow the progression of aging or specific age-related conditions, have been in the news. The development of the SkQ series of compounds started in Russia, where it is already used in treatments for inflammatory eye conditions, and has now made its way into European clinical development at MitoTech. There are other lines of mitochondrial antioxidant, such as SS-31, but these are not as far along towards the clinic.

The public view of longevity assurance therapies might be coming around to support for the topic, per a survey conducted this year, provided that such therapies produce extended healthy life rather than extended frailty. In the field, it seems there is a still a considerable need for education, however. People tend to exhibit many incoherent and inconsistent positions when it comes to death, aging, and doing something about both of those topics. The comment sections of social news sites are still filled with people decrying longevity science when news comes to their attention. It is still overall a challenge to raise funds, despite our gains in recent years, and despite the growing interest on the part of various deep pockets. I have to think that the people who claim to want to age and die are failing to think critically about their own personal futures.

In Alzheimer's research, a trial of amyloid clearance via immunotherapy in humans finally worked. The field is littered with failures from the past decade, so this is a big deal. Further, there has been progress towards therapies to clear tau protein from the brain as well, including results from an an initial human trial for safety of a potential immunotherapy. On a different topic, an intriguing study appears to show that memories lost to Alzheimer's pathology can be restored via dendrite regrowth, at last in the early stages. A number of other possibilities beyond immunotherapy have emerged to reduce amyloid levels, such as drawing it out from the brain by clearing it elsewhere, or revisiting the possibility of β-secretase inhibitors. Further, the idea that amyloid builds up because physical drainage channels atrophy will get a test soon, via Methuselah Foundation funding of Leucadia Therapeutics. There are many other types of amyloid in aged tissue, however, and all those will need clearance as well. We might watch Pentraxin Therapeutics as one example of progress in this area. Like so much of this work, it proceeds at a crawl, even following a successful trial back in 2015.

Research on regeneration of an aged thymus, thereby restoring some of the decline in the immune system, continues to move forward. A recent study provided confirmation of benefits resulting from transplantation of a young thymus into an old mouse, for example. In addition to ongoing work on FOXN1 signaling as a possible way to regrow thymus tissue, it was discovered that FGF21 may also be a relevant target. Another team demonstrated that thymic decline correlates with lifespan in dog breeds. Meanwhile, tissue engineers continue to work on the production of working thymus tissue and cell therapies, aiming for the same goal of restoration.

DNA methylation patterns are a promising basis for a biomarker of aging, a test that could be used before and after a putative rejuvenation therapy to evaluate its likely long-term performance. The use of DNA methylation patterns is spreading, and evidence for their potential utility accumulates. Researchers have examined changes early in aging, assessed aging in skin tissue, determined that stroke patients are biologically older than their peers, found that people measured as being biologically older have a greater risk of cancer, and showed that known statistical differences between the life expectancies of various communities also show up in DNA methylation.

Immune system clearance and recreation has tremendous potential as therapy for autoimmunity and many aspects of age-related immunosenescence. This year, researchers demonstrated the ability to cure multiple sclerosis via a fairly simple process of destroying mature immune cells, with no need to attack blood stem cells. This is very promising for the near term development of similar therapies. All that is needed is a less harmful method of targeted cell killing, one that can be safely used by older patients. Fortunately there has been some progress in that direction in the past year, and I think we'll see more in the years ahead. Many methods currently under development in the cancer research community might be converted to this use.

Lastly for this year, a number of short essays fell from the pen to the page. Some might even be worth reading again as we look forward to 2017 and further, faster progress towards therapies to treat the causes of aging:

Comments

A very inspiring summary, Reason.

BTW, I wonder when the next SENS annual report will be published. The 2015 report is really about 2014 work, so they are almost a year late.

Posted by: Antonio at December 31st, 2016 1:54 AM

Re: Alzhiemers and Amyloids - As pointed out by Dr de grey in the December 2016 Commentary on Some Recent Theses Relevant to Combating Aging a technique for using directed evolution to create highly specific proteases for degrading proteins has now been achieved:

Intracellular FRET-based Screen for Redesigning the Specificity of Secreted Proteases

A protease against amyloid beta was created that should be non inflammatory (unlike current IgG antibody approaches) and also highly specific (unlike the IgM catabody approach previously sponsored by the SENSRF).

It might even possible to create a protease against glucosepane.

Posted by: Jim at December 31st, 2016 7:45 AM

Great post and great job along 2016 Reason!
Some ideas for your web for 2017:

1) You could add a photo about the topic in your posts. It will make it more visual, easy to remember and attractive (like the news webs).
2) You could add a subtitle below the title. A little summary for people (like me, and others) who doesn't have time to read all the article, but we want to know what's going on in the field (like the news webs).
3) You could add some hashtags to the post, to classify them in topics (like the news webs).
4) This is more personal: You could write with your real name. This may give more credibility to people who isn't yet familiar with longevity science (like the news webs).
5) You could do other things, like interviews to scientists, politicians, etc, videos (like the news webs).

Those are some ideas.
Anyway, thanks for your work, and good luck!! We'll keep reading you in 2017!

Josep

Posted by: Josep at December 31st, 2016 12:43 PM

@ Reason : thank you for your hard work this year and for this useful recap. As a SENS follower I did my duty and helped the movement as I could, which in my case meant donating to the ongoing funding campaign.

@ Josep : I believe that Reason took a nickname for a specific purpose. We should respect his choice, and focus on his message instead of trying to find his identity.

Posted by: Spede at December 31st, 2016 4:27 PM

@Reason,

I remember years past (I think, besides the link you just provided) comments about your name. I also think it is irrelevant and more important, the work you do for all of us, even for those whose lives will be impacted down the road.

Also, even though I have a Facebook, I don't do anything with it, not even a pic of myself. I have no idea why anyone would spend alot of time and details with their lives on it. I also have a linkedin site, and still, no pic.

So, Reason, I totally feel where you are coming from.

Again, I am very thankful for the work and time you put into this. I hope you have a great new year.

Myself, I hate new years eve, as it is my birthday and a reminder that I (along with everyone else) am getting older:(

Posted by: Robert at December 31st, 2016 5:23 PM

Thank you for the excellent coverage. I think something like Bill Gate's Breakthrough Energy fund is needed to accelerate progress. See https://m.youtube.com/watch?v=S5WJ11difCY

Posted by: Leon A at December 31st, 2016 5:45 PM

I prefer the old look and not-web-2.0 feel of this blog. Indeed, most "web 2.0" sites, like lifespan.io, don't work well with my usual browser (firefox 3) or don't work at all (Life Extension Advocacy Foundation, Youtube, etc.).

Posted by: Antonio at January 1st, 2017 4:56 AM

@Jim: I think you're confusing the relatively modest specificity of the first generation of catabodies targeting wild-type transthyretin amyloid (which work was funded by SENS Research Foundation) with the highly specific catabodies targeting beta-amyloid Dr. Paul developed previously (and on the basis of which we and Dr. Stanley Primmer recruited him to do the TTR work). On the former front: Watch This Space for the upcoming SRF Annual Report.

@Robert: gosh, I celebrate my birthday and those of others exactly because it is a milestone: another year of the miracle of being alive and of having those other people in my life (respectively), and maybe another year closer to rejuvenation and a boundless future.

Posted by: Michael at January 1st, 2017 1:33 PM

Good review Reason we are promoting this widely.

Posted by: Steve Hill at January 2nd, 2017 8:07 AM

Good review!
Just a couple of points for completeness.
1. One company is missing from the list - Everon Biosciences (www.everonbio.com) - studying senescence since 2011, and
2. Things are more complicated with senescent cells as a target than we all originally thought. Turns out that a special type of macrophages is also accumulating with age probably being a dominant contributor to poisoning aging tissues. A paper was published about it in 2016. Reference can be found on Everon website.

Posted by: Alexander Polinsky at January 4th, 2017 12:37 AM

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