The Slow and Ineffectual Path to Aging Interventions for Humans

A point I frequently make is that while there exists a wide range of potential approaches to the development of therapies to treat aging, it is important to divide these approaches into two buckets. Firstly there are potential therapies that aim to repair the root cause cellular and molecular damage that leads to degenerative aging, and which are in principle capable of rejuvenation, indefinite prevention of all age-related disease, and indefinite extension of healthy life. Whether any particular package of implemented therapies achieves this or not is a matter of how much damage is repaired: it depends on the effectiveness and coverage of the treatments in question. Are they repairing all the types of damage that cause aging, and are they repairing enough of each type in all tissues that matter?

The larger second category contains all other potential therapies that do not aim to repair the fundamental damage that causes aging. These either aim to alter the operation of metabolism to slow down the accumulation of that damage, or try to adjust or repair secondary effects of the root cause damage - neither of which is going to be anywhere near as effective an approach, even though they may be far more troublesome and costly to implement. These therapies are not in principle capable of more than fleeting and partial rejuvenation, and definitely can't achieve indefinite prevention of disease or extension of healthy life.

Outside the stem cell research community there is far more ongoing work on the second type of treatment at this time. This might make little sense to an outsider who imagines that things proceed completely rationally in the scientific world. Developing drugs to tinker with metabolism based on the study of dysfunctional end states of disease is the modus operandi of much of modern medicine, and has been for a century. There is a lot of inertia in the institutions involved, and mere details such as this being a far worse approach to take in work on treating aging won't slow down this train all that much. Change must come from disruption of the entire status quo, and disruption must come from the newcomers and the iconoclasts and the rebels. It is happening, thanks to the work of organizations like the Methuselah Foundation and SENS Research Foundation, but in the highly regulated medical research and development community this sort of change is slow. It has taken a decade of persistent advocacy for even some of the most evident and easily explained of the SENS proposals, such as senescent cell clearance, to get a little traction in the last couple of years.

(Remember that the SENS proposals for the treatment of aging really aren't the SENS proposals at all: they are a consensus on aging and our biology derived from scores of research groups and publications from past years, drawn together and presented in a coherent fashion. The SENS proponents are organizers. Every field of science goes through periods of great diversity and expansion that must necessarily be followed by a process of synthesis, as the shards of the field have diverged too far for the researchers involved to have a good vision of the whole. The SENS view of aging is a part of an ongoing period of synthesis of all fields of medical research relevant to aging: a great deal was discovered over the past thirty years, but only in the past decade has an earnest reconciliation and exchange of knowledge begun for the purposes of building new technologies).

Meanwhile, even as researchers could be making significant progress on actual rejuvenation therapies were there the funding and the will, the mainstream continues to consider itself radical for initiating tests of existing drugs that might, maybe, cause some health benefits in humans, and possibly an extension of life by just a few years if taken over the long term. It is a terrible thing to watch, knowing that time is ticking away for all of us.

Aging interventions get human (PDF)

Over the last three decades, aging research has made great strides. At least in non-vertebrate animal models such as yeast and worms, it is possible to extend lifespan through reduced or ablated expression of hundreds of genes. The number of genes tested in mice are substantially less but the data so far is consistent with modulation of aging by numerous genes and pathways. More importantly, evidence exists that many of these genetic interventions extend healthspan and protect against the onset of age-associated chronic diseases. Recently, small molecules have entered center stage, with both natural products and clinically approved compounds reported to delay aging.

These findings raise the question of whether it is possible to forestall aging as an approach to maintain vitality and delay the onset of multiple chronic diseases simultaneously. However, there are significant hurdles to testing human aging drugs and many have been skeptical that aging interventions will ever enter the clinic. Among the foremost challenges, aging is not formally considered a disease by the FDA and the prospects of testing whether drugs extend human lifespan directly promises to be a long and exorbitantly expensive process. There is also the challenge of performing clinical trials in aging individuals who are still generally healthy. Foremost among these is the extra level of safety that will need to be incorporated since care must be taken not to do harm to healthy, older people. One potential solution is to test compounds against deleterious phenotypes associated with human aging - but which compound and which phenotype? This question has been debated extensively.

Sometimes the best approach is to start testing and let the results dictate the path forward. In this vein, Mannick et al. recently reported the results of the first human aging trial. They chose a first generation derivative of the drug rapamycin (known as everolimus or RAD001), which has been shown to extend lifespan in all four major animal models of aging: yeast, worms, flies and mice. Importantly, rapamycin, which is a direct inhibitor of the mTOR kinase, can extend lifespan by 25% in mice and even show efficacy when initiated in 20 month old mice. Most studies indicate that rapamycin extends healthspan as well. Rapalogs, or rapamycin derivatives, are approved for treatment of several disease indications, but also have a range of side effects.

Mannick et al. chose to administer RAD001 to healthy people 65 and older over a six week period, followed by flu vaccine inoculation two weeks after suspending drug treatment. The findings from the Mannick study are encouraging. Importantly, Mannick et al. found efficacy at both lower dose regimens of RAD001, demonstrating at least a 1.2 fold increase in the serologic hemagglutinin inhibition geometric mean titer ratio (HI GMT) of two of the three influenza viruses represented in the vaccine at four weeks after inoculation. This is a relevant target since prior studies have shown that a 20% increase in GMT ratio has been associated with reduced influenza illness. Interestingly, RAD001 also appeared to broaden the serologic response, causing enhanced seroconversion to heterologous influenza strains not in the chosen influenza vaccine. This finding is also suggestive of enhanced protection against influenza illness.

The study by Mannick et al. is groundbreaking but it sets the stage for testing drugs associated with delayed aging in healthy older human populations. Whether rapalogs are the right drugs and immunosenescence is the right marker for healthspan remains to be determined, but it is critical for aging research to enter the clinic and this study is a fascinating initial foray.

Comments

It would appear to me that purse strings seem to be controlling the flow of things, and they are understandably not very patient until it becomes clear that it would ultimately be more prudent in their would-be substantially lengthened lives to spend for real gains in health and life span rather than a profit developing slow-road drugs they can burn on a yacht today while they're in their sixties and not likely to see a return on the former investment.

Selling SENS is a problem of marketing as much as it is a problem of red tape. I bet if you find people young and rich enough (Hollywood, music/games industry, hotshot hedge fund managers), and sell them eternal youth and beauty (emphasis on this second, though I'm sure this has been discussed before), you will start to see change.

Sure, it might be possible that the FDA's red tape is harder to cut than my inexperience could appreciate, and maybe getting around it wouldn't yield the most ideal way of getting the ball rolling, but it will certainly happen somewhere the money can have effect.

Posted by: Seth at January 29th, 2015 1:41 AM

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