A Speculative Order of Arrival for Important Rejuvenation Therapies

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.

Comments

This was a great overview of developments that I hope to see in my lifetime.

Posted by: Kip at October 4th, 2012 7:12 PM

It's hard for me to understand the lack of commercial enthusiasm for developing drugs to break glucosepane cross-links. That's an eight figure blockbuster drug waiting to happen. Just think of all the money people spend on worthless cosmetic remedies for skin aging. It gets even better — because stiffening of ECM also plays a major role in heart disease, insurance companies would cover it. They would possibly even *want* to cover it considering the payments they could avoid by doing so. You have vanity, health impact and even the insurance companies all aligned in a rare conjugation.

Of course, every drug development effort is uncertain, but the upside here is *obscene* and for all anyone has done on it, it might turn out to be easy. Where are the calculated risk takers?

Posted by: José at October 4th, 2012 11:44 PM

Hello Reason,

Thanks for showing that status of each area that is being investigated in the name of ending ageing. It would also be nice to show which area is the most important, the 2nde most important, and so forth. It seems the aging communinity would work towards this sequence of importance to get the most bang for the buck.
Robert C.

Posted by: Robert Church at October 5th, 2012 7:16 AM

@Robert Church: Each and every one can kill you on its own, so they all have to be fixed. Mitochondrial damage is probably the most important contribution, based on comparisons of mitochondria between species with quite different life spans, but that's an opinion that could be argued either way until someone fixes mitochondria in an animal model to see what happens.

Posted by: Reason at October 5th, 2012 7:57 AM

Great Post

Posted by: JohnD at October 5th, 2012 1:45 PM

These developments are amazing.

There is a good chance that anyone born after 2000 or so might achieve near-immortality.

For those of us born before 2000 (anyone reading this)........ too bad.

Posted by: TTT at October 8th, 2012 9:09 PM

These approaches have the common denominator of signaling errors - correct those and you have your cake - but those cannot be addressed without full mapping of the epigene - and that is not even on the radar screen of most research - and is infinitely more complicated than the mapping of the genome. Give these ideas about 300 years if the present research trajectory does not change...

Posted by: judge arrow at October 9th, 2012 7:49 AM

What are safe therapies available to the public presently? I am always trying to glean from your updates if there is anything I can do with what is available to help my body age with less damage. For example, I review Life Extensions supplements, which often tries to address some of the issues discussed in this newsletter with supplements, but my concern is how safe are the supplements? It would be very helpful, when possible, if you could please add comments on what the public can do with what is available to help curb a damaging process, while more effective tools are hopefully developed.

Truly thankful for your passion, research and communication regarding curbing destructive components of biological aging.

Posted by: Foxglove at July 20th, 2014 1:14 PM

Thanks for update-I know its two years old, but is latest available I can find.

It may be my imagination but I sensed some frustration and disappointment at some points in your article? But I get a sense that any really tangible treaaaaaaatments or products are still a long way off. I think the 10-15 year horizons I have read look a bit optimistic.
Also, two areas I have been fascinated by are using nanotechnology- some amazing potential products being worked on and 3D printing of organs
Is there a recent update for either of those?
PS Congratulations to all of you - great things are never quick or easy and will always have the naysayers. What you are doing is going to change the world, lets hope its not too far away

best wishes

David Amer

Posted by: David at October 13th, 2014 12:20 AM

@David: For organ printing, the Methuselah Foundation efforts with the New Organ initiative are worth following. See their blog for interviews with researchers in the field:

http://www.mfoundation.org/blog

And the New Organ site for more:

http://neworgan.org

Posted by: Reason at October 13th, 2014 4:18 AM

"4) Reversing Stem Cell Aging"is most important i think

Posted by: hu ling at February 2nd, 2016 10:01 PM

El tema se complementaría con:
a) de evitar el acortamiento de los telómeros vía genética o TA65,
b) mantener la masa muscular vía bloqueo del gene de la miostatina,
c) el mantener la masa ósea vía inyección de células madres mesenquimales (MSC),
d) la detección temprana del cáncer vía biopsias liquidas
e) la aplicación de restricción calórica para disminuir riesgos
f) Mantener la energía cerebral con Piruvato
Habrá que ver como evoluciona todo esto en los próximos años

Posted by: eduardo at March 24th, 2016 7:46 AM

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