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Fundraiser by Lifespan.io & CellAge: Targeting Senescent Cells With Synthetic Biology

Fundraiser by Lifespan.io & CellAge: Targeting Senescent Cells With Synthetic Biology

The New Renaissance HatCellAge
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Editor’s Note: The Rational Argumentator and the U.S. Transhumanist Party support Lifespan.io and CellAge in their work towards groundbreaking scientific life-extension research. Finding a way to repair age-related damage to senescent cells would be a fundamental breakthrough for transhumanism, and we offer our best wishes and support for those striving towards these new technologies.

               ~ Gennady Stolyarov II, Editor-in-Chief, The Rational Argumentator, December 11, 2016

From Lifespan.io and CellAge:

Our society has never aged more rapidly – one of the most visible symptoms of the changing demographics is the exponential increase in the incidence of age-related diseases, including cancer, cardiovascular diseases and osteoarthritis. Not only does aging have a negative effect on the quality of life among the elderly but it also causes a significant financial strain on both private and public sectors. As the proportion of older people is increasing so is health care spending. According to a WHO analysis, the annual number of new cancer cases is projected to rise to 17 million by 2020, and reach 27 million by 2030. Similar trends are clearly visible in other age-related diseases such as cardiovascular disease. Few effective treatments addressing these challenges are currently available and most of them focus on a single disease rather than adopting a more holistic approach to aging.

Recently a new approach which has the potential of significantly alleviating these problems has been validated by a number of in vivo and in vitro studies. It has been demonstrated that senescent cells (cells which have ceased to replicate due to stress or replicative capacity exhaustion) are linked to many age-related diseases. Furthermore, removing senescent cells from mice has been recently shown to drastically increase mouse healthspan (a period of life free of serious diseases).

Here at CellAge we are working hard to help translate these findings into humans!

CellAge, together with a leading synthetic biology partner, Synpromics, are poised to develop a technology allowing for the identification and removal of harmful senescent cells. Our breakthrough technology will benefit both the scientific community and the general public.

In short, CellAge is going to develop synthetic promoters which are specific to senescent cells, as promoters that are currently being used to track senescent cells are simply not good enough to be used in therapies. The most prominently used p16 gene promoter has a number of limitations, for example. First, it is involved in cell cycle regulation, which poses a danger in targeting cells which are not diving but not senescent either, such as quiescent stem cells. Second, organism-wide administration of gene therapy might at present be too dangerous. This means senescent cells only in specific organs might need to be targeted and p16 promoter does not provide this level of specificity. Third, the p16 promoter is not active in all senescent cells. Thus, after therapies utilizing this promoter, a proportion of senescent cells would still remain. Moreover, the p16 promoter is relatively large (2.1kb), making it difficult to incorporate in present gene therapy vehicles. Lastly, to achieve the intended therapeutic effect the strength of p16 promoter to drive therapeutic effect might not be high enough.

CellAge will be constructing a synthetic promoter which has a potential to overcome all of the mentioned limitations. A number of gene therapy companies, including uniQure, AGTC and Avalanche Biotech have successfully targeted other types of cells using this technology. With your help, we will be able to use same technology to develop tools and therapies for accurate senescent cell targeting.

UNITY Biotechnology Raises $116M for Senescent Cell Clearance Development – Article by Reason

UNITY Biotechnology Raises $116M for Senescent Cell Clearance Development – Article by Reason

The New Renaissance HatReason
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The whispers of late have had it that UNITY Biotechnology was out raising a large round of venture funding, and their latest press release shows that this was indeed the case. The company, as you might recall, is arguably the more mainstream of the current batch of startups targeting the clearance of senescent cells as a rejuvenation therapy. The others include Oisin Biotechnologies, SIWA Therapeutics, and Everon Biosciences, all with different technical approaches to the challenge. UNITY Biotechnology is characterized by a set of high profile relationships with noted laboratories, venture groups, and big names in the field, and, based on the deals they are doing, appear to be focused on building a fairly standard drug development pipeline: repurposing of apoptosis-inducing drug candidates from the cancer research community to clear senescent cells, something that is being demonstrated with various drug classes by a range of research groups of late. Senescent cells are primed to apoptosis, so a nudge in that direction provided to all cells in the body will have little to no effect on normal cells, but tip a fair proportion of senescent cells into self-destruction. Thus the UNITY Biotechnology principals might be said to be following the standard playbook to build the profile of a hot new drug company chasing a hot new opportunity, and clearly they are doing it fairly well so far.

UNITY Biotechnology Announces $116 Million Series B Financing

Quote:

UNITY Biotechnology, Inc. (“UNITY”), a privately held biotechnology company creating therapeutics that prevent, halt, or reverse numerous diseases of aging, today announced the closing of a $116 million Series B financing. The UNITY Series B financing ranks among the largest private financings in biotech history and features new investments from longtime life science investors ARCH Venture Partners, Baillie Gifford, Fidelity Management and Research Company, Partner Fund Management, and Venrock. Other investors include Bezos Expeditions (the investment vehicle of Jeff Bezos) and existing investors WuXi PharmaTech and Mayo Clinic Ventures. Proceeds from this financing will be used to expand ongoing research programs in cellular senescence and advance the first preclinical programs into human trials.

The financing announcement follows the publication of research that further demonstrates the central role of senescent cells in disease. The paper, written by UNITY co-founders Judith Campisi and Jan van Deursen and published today, describes the central role of senescent cells in atherosclerotic disease and demonstrates that the selective elimination of senescent cells holds the promise of treating atherosclerosis in humans. In animal models of both early and late disease, the authors show that selective elimination of senescent cells inhibits the growth of atherosclerotic plaque, reduces inflammation, and alters the structural characteristics of plaque such that higher-risk “unstable” lesions take on the structural features of lower-risk “stable” lesions. “This newly published work adds to the growing body of evidence supporting the role of cellular senescence in aging and demonstrates that the selective elimination of senescent cells is a promising therapeutic paradigm to treat diseases of aging and extend healthspan. We believe that we have line of sight to slow, halt, or even reverse numerous diseases of aging, and we look forward to starting clinical trials with our first drug candidates in the near future.”

So this, I think, bodes very well for the next few years of rejuvenation research. It indicates that at least some of the biotechnology venture community understands the likely true size of the market for rejuvenation therapies, meaning every human being much over the age of 30. It also demonstrates that there is a lot of for-profit money out there for people with credible paths to therapies to treat the causes of aging. It remains frustrating, of course, that it is very challenging to raise sufficient non-profit funds to push existing research in progress to the point at which companies can launch. This is a problem throughout the medical research and development community, but it is especially pronrounced when it comes to aging. The SENS view of damage repair, which has long incorporated senescent cell clearance, is an even tinier and harder sell within the aging research portfolio – but one has to hope that funding events like this will go some way to turn that around.

From the perspective of being an investor in Oisin Biotechnologies, I have to say that this large and very visible flag planted out there by the UNITY team is very welcome. The Oisin team should be able to write their own ticket for their next round of fundraising, given that the gene therapy technology they are working on has every appearance of being a superior option in comparison to the use of apoptosis-inducing drugs: more powerful, more configurable, and more adaptable. When you are competing in a new marketplace, there is no such thing as too much validation. The existence of well-regarded, well-funded competitors is just about the best sort of validation possible. Well-funded competitors who put out peer-reviewed studies on a regular basis to show that the high-level approach you and they are both taking works really well is just icing on the cake. Everyone should have it so easy. So let the games commence! Competition always drives faster progress. Whether or not I had skin in this game, it would still be exciting news. The development of rejuvenation therapies is a game in which we all win together, when new treatments come to the clinic, or we all lose together, because that doesn’t happen fast enough. We can and should all of us be cheering on all of the competitors in this race. The quality and availability of the outcome is all that really matters in the long term. Money comes and goes, but life and health is something to be taken much more seriously.

Now with all of that said, one interesting item to ponder in connection to this round of funding for UNITY is the degree to which it reflects the prospects for cancer therapies rather than the prospects for rejuvenation in the eyes of the funding organizations. In other words, am I being overly optimistic in reading this as a greater understanding of the potential for rejuvenation research in the eyes of the venture community? It might be the case that the portions of the venture community involved here understand the market for working cancer drugs pretty well, and consider that worth investing in, with the possibility of human rejuvenation as an added bonus, but not one that is valued appropriately in their minds. Consider that UNITY Biotechnology has partnered with a noted cancer therapeutics company, and that the use of drugs to inducing apoptosis is a fairly well established approach to building cancer treatments. That is in fact why there even exists a range of apoptosis-inducing drugs and drug candidates for those interested in building senescent cell clearance therapies to pick through. Further, the presence of large numbers of senescent cells does in fact drive cancer, and modulating their effects (or removing them) to temper cancer progress is a topic under exploration in the cancer research community. So a wager on a new vision, or a wager on the present market? It is something to think about.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.
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This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.
A Speculative Order of Arrival for Important Rejuvenation Therapies – Article by Reason

A Speculative Order of Arrival for Important Rejuvenation Therapies – Article by Reason

The New Renaissance Hat
Reason
October 6, 2012
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A toolkit for producing true rejuvenation in humans will require a range of different therapies, each of which can repair or reverse one of the varied root causes of degenerative aging. Research is underway for all of these classes of therapy, but very slowly and with very little funding in some cases. The funding situation spans the gamut from that of the stem cell research community, where researchers are afloat in money and interest, to the search for ways to break down advanced glycation endproducts (AGEs), which is a funding desert by comparison, little known or appreciated outside the small scientific community that works in that field.

While bearing in mind that progress in projects with little funding is unpredictable in comparison to that of well-funded projects, I think that we can still take a stab at a likely order of arrival for various important therapies needed to reverse aging. Thus an incomplete list follows, running from the earliest to the latest arrival, with the caveat that it is based on the present funding and publicity situation. If any one of the weakly funded and unappreciated lines of research suddenly became popular and awash with resources, it would probably move up in the ordering:

1) Destruction of Senescent Cells

Destroying specific cells without harming surrounding cells is a well-funded line of research thanks to the cancer community, and the technology platforms under development can be adapted to target any type of cell once it is understood how to target its distinctive features.

The research community has already demonstrated benefits from senescent cell destruction, and there are research groups working on this problem from a number of angles. A method of targeting senescent cells for destruction was recently published, and we can expect to see more diverse attempts at this in the next few years. As soon as one of these can be shown to produce benefits in mice that are similar to the early demonstrations, then senescent cell clearance becomes a going concern: something to be lifted from the deadlocked US regulatory process and hopefully developed quickly into a therapy in Asia, accessed via medical tourism.

2) Selective Pruning and Support of the Immune System

One of the reasons for immune system decline is crowding out of useful immune cells by memory immune cells that serve little useful purpose. Here, targeted cell destruction can also produce benefits, and early technology demonstrations support this view. Again, the vital component is the array of mechanisms needed to target the various forms of immune cell that must be pruned. I expect the same rising tide of technology and knowledge that enables senescent cell targeting will lead to the arrival of immune cell targeting on much the same schedule.

Culling the immune system will likely have to be supported with some form of repopulation of cells. It is already possible to repopulate a patient’s immune system with immune cells cultivated from their own tissues, as demonstrated by the limited number of full immune system reboots carried out to cure autoimmune disorders. Alternatives to this process include some form of tissue engineering to recreate the dynamic, youthful thymus as a source of immune cells – or more adventurous processes such as cultivating thymic cells in a patient’s lymph nodes.

3) Mitochondrial Repair

Our mitochondria sabotage us. There’s a flaw in their structure and operation that causes a small but steadily increasing fraction of our cells to descend into a malfunctioning state that is destructive to bodily tissues and systems.

There are any number of proposed methods for dealing with this component of the aging process – either repairing or making it irrelevant – and a couple are in that precarious state of being just a little more solidity and work away from the point at which they could begin clinical development. The diversity of potential approaches in increasing too. Practical methods are now showing up for ways to put new mitochondria into cells, or target arbitrary therapies to the interior or mitochondria. It all looks very promising.

Further, the study of mitochondria is very broad and energetic, and has a strong presence in many areas of medicine and life science research. While few groups in the field are currently engaged in work on mitochondrial repair, there is an enormous reservoir of potential funding and workers awaiting any method of repair shown to produce solid results.

4) Reversing Stem Cell Aging

The stem cell research field is on a collision course with the issue of stem cell aging. Most of the medical conditions that are best suited to regenerative medicine, tissue engineering, and similar cell based therapies are age-related, and thus most of the patients are old. In order for therapies to work well, there must be ways to work around the issues caused by the aged biochemistry of the patient. To achieve this end, the research community will essentially have to enumerate the mechanisms by which stem cell populations decline and fail with age, and then reverse their effects.

Where stem cells themselves are damaged by age, stem cell populations will have to be replaced. This is already possible for many different types of stem cell, but there are potentially hundreds of different types of adult stem cell – and it is too much to expect for the processes and biochemistry to be very similar in all cases. A great deal of work will remain to be accomplished here even after the first triumphs involving hearts, livers, and kidneys.

Much of the problem, however, is not the stem cells but rather the environment they operate within. This is the bigger challenge: picking out all the threads of signalling, epigenetic change, and cause and effect that leads to quieted and diminished stem cell populations – and the resulting frailty as tissues are increasingly poorly supported. This is a fair sized task, and little more than inroads have been made to date – a few demonstrations in which one stem cell type has been coerced into acting with youthful vigor, and a range of research on possible processes and mechanisms to explain how an aging metabolism causes stem cells to slow down and stop their work.

The stem cell research community is, however, one of the largest in the world, and very well funded. This is a problem that they have to solve on the way to their declared goals. What I would expect to see here is for a range of intermediary stopgap solutions to emerge in the laboratory and early trials over the next decade. These will be limited ways to invigorate a few aged stem cell populations, intended to be used to boost the effectiveness of stem cell therapies for diseases of aging.

Any more complete or comprehensive solution for stem cell aging seems like a longer-term prospect, given that it involves many different stem cell populations with very different characteristics.

5) Clearing Advanced Glycation Endproducts (AGEs)

AGEs cause inflammation and other sorts of mischief through their presence, and this builds up with age. Unfortunately, research on breaking down AGEs to remove their contribution to degenerative aging has been a very thin thread indeed over the past few decades: next to no-one works on it, despite its importance, and very little funding is devoted to this research.

Now on the one hand it seems to be the case that one particular type of AGE – glucosepane – makes up 90% or more the AGEs in human tissues. On the other hand, efforts to find a safe way to break it down haven’t made any progress in the past decade, though a new initiative was launched comparatively recently. This is an excellent example of how minimally funded research can be frustrating: a field can hover just that one, single advance away from largely solving a major problem for years on end. All it takes is the one breakthrough, but the chances of that occurring depend heavily on the resources put into the problem: how many parallel lines of investigation can be followed, how many researchers are working away at it.

This is an excellent candidate for a line of research that could move upward in the order of arrival if either a large source of funding emerged or a plausible compound was demonstrated to safely and aggressively break down glucospane in cell cultures. There is far less work to be done here than to reverse stem cell aging, for example.

6) Clearing Aggregates and Lysomal Garbage

All sorts of aggregates build up within and around cells as a result of normal metabolic processes, causing harm as they grow, and the sheer variety of these waste byproducts is the real challenge. They range from the amyloid that features prominently in Alzheimer’s disease through to the many constituents of lipofuscin that clog up lysosomes and degrade cellular housekeeping processes. At this point in the advance of biotechnology it remains the case that dealing with each of the many forms of harmful aggregate must be its own project, and so there is a great deal of work involved in moving from where we stand today to a situation in which even a majority of the aggregates that build up with age can be removed.

The most promising lines of research to remove aggregates are immunotherapy, in which the immune system is trained or given the tools to to consume and destroy a particular aggregate, and medical bioremediation, which is the search for bacterial enzymes that can be repurposed as drugs to break down aggregates within cells. Immunotherapy to attack amyloid as a treatment for Alzheimer’s is a going concern, for example. Biomedical remediation is a younger and far less funded endeavor, however.

My expectation here is that some viable therapies for some forms of unwanted and harmful metabolic byproducts will emerge in the laboratory over the next decade, but that will prove to be just the start on a long road indeed. From here it’s hard for me to guess at where the 80/20 point might be in clearing aggregates: successfully clearing the five most common different compounds? Or the ten most common? Or twenty? Lipofuscin alone has dozens of different constituent chemicals and proteins, never mind the various other forms of aggregate involved in specific diseases such as Alzheimer’s.

But work is work: it can be surmounted. Pertinently, and again, the dominant issue in timing here is the lack of funding and support for biomedical remediation and similar approaches to clearing aggregates.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.  

This work is reproduced here in accord with a Creative Commons Attribution license.  It was originally published on FightAging.org.