Why We Age

The surface area of HN is so broad, the number of readers interested in pretty low. This is a observable problem. I often see lots of votes and zero responses for interesting posts.

Interesting enough to click, glance over, but not enough to think about and comment.

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How long until life-extending medical therapies are developed?

How long is a piece of string? Questions of time depend on questions of money. Over the past decade the rough estimates for a fully funded crash research program to realize SENS in mice as rapidly as possible have floated around $1-2 billion over ten to twenty years. It might cost less than that now, given the rapid advance of biotechnology, but not enormously less. Unfortunately SENS is nowhere near as well funded as this: the current budget for the SENS Research Foundation has only recently reached $5 million / year. So it will certainly take time to increase funding to the optimal levels of $100 million / year or more; this is a major undertaking involving the creation of many new major programs of medical research throughout the world. That in and of itself might require decades, and it is hard to estimate the pace of growth in the early stages of a new industry. Any number of small, happenstance choices made by today's investors and researchers might gain or lose years of future progress.

Meanwhile on the other side of the fence drug discovery programs are undertaken in search of ways to modestly slow aging. We know that it can take a decade and $1 billion to push a good drug candidate through validation and regulatory hurdles, all the way from early tests to clinical use. There are no good candidates at this time, but every sign that some may emerge in the next few years based on analogs to rapamycin. So it's not unreasonable to think that a first generation drug that might slightly slow aging in humans could emerge in the mid to late 2020s. Even at that point the research community may not be able to say whether it in fact actually slows aging in humans, however, versus definitively knowing that it produces positive changes in short-term measures of health.

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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.

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.

Senescent cell clearance is there, so could be making in that direction in the years ahead. Nothing moves fast of course.

I'm not sure where the ITP stands on things like stem cell treatments. They are very focused on diet, drugs, supplements, and resulting complex changes in the operation of normal metabolism. i.e. things that don't matter if you want meaningful results in extended healthy life. Good for scientific rigor though, going back through all the studies in the past that failed to control for inadvertent calorie restriction and showing that they were wrong.