The Near Horizon for Visions of Slowing Aging

The mainstream of the aging research community, or at least that fraction of it that is interested at all in increasing healthy longevity by intervening in the aging process, is almost entirely focused on the use of drugs to alter metabolism to slightly slow the onset of frailty and ill-health in later life. There isn't even much effort to find new drugs: candidates are largely existing drugs. Many of these researchers exclusively discuss compression of morbidity, the goal of extending healthy life without extending overall life span. There is still an aversion in many circles to any talk of extending overall human life spans, no matter how realistic the prospects, and the boundaries of the possible for these folk stops at slowing aging modestly. These are researchers who look ahead to another twenty years of research and development that looks exactly like the last fifty: a slow mining of the natural world in search of compounds that can be used as drugs to alter the operation of the human body to produce marginal benefits. No revolution, no great advances, just a continuation of the present trends.

This is an exceedingly narrow horizon, a box even. These researchers believe it will be challenging and expensive and slow to generate benefits, and if standard issue drug development after the 1970s model that is still with us today is all they plan to do, then that seems about right. Despite great advances in biotechnology, the research community is still only in the initial stages of of mapping the complexities of metabolism, epigenetics, and their changes with aging. There is little in the way of a clear path forward to actually slow aging in humans, and where there are potentially promising areas of study, such as calorie restriction, large amounts of funding and time have so far failed to produce meaningfully beneficial therapies based on calorie restriction mimetics.

This dismal situation is why we need a disruption of the entire field in favor of research approaches that might actually work to greatly extend healthy and overall human life, that have much more in the way of straightforward and defined research plans leading to therapies, and wherein the scientists involved are not afraid to stand up and state that the end of frailty and disease in aging, indeed the end of aging itself, is the goal. The present mainstream is not getting the job done: their primary focus is on gaining knowledge of metabolism and the fine details of aging, not of taking all that is known so far and building the best therapies possible.

The Strategies for Engineered Negligible Senescence (SENS) approach typifies the sort of reaction to the mainstream you'll find among more visionary researchers who see that much more can be done about aging in the near future. There are much better paths to a future of longer lives than the tired road of drug development. If all that happens over the next twenty years is more messing with metabolism in the vague hope that small and expensive benefits will be realized, than that will be a waste of a great opportunity. Enough is known to make real progress in treatments for aging today - the only thing missing is large-scale funding and widespread public support.

The open access paper quoted below provides a very clear and detailed look at the viewpoint of those who think that only marginal gains are possible, and that researchers shouldn't talk about or try to achieve extension of overall human life span. You should compare it with a reading of the introduction to the SENS research program. On the one hand a manifesto that has as an important strand of work digging through existing drugs in search of something, anything, that might do more good than harm. On the other, a call for taking the best of present knowledge to deliberately target the known root causes of aging with the aim of turning back the progression towards disability and disease. Night and day.

Translational Geroscience: Emphasizing function to achieve optimal longevity

Investigators working in fields related to the biology and biomedicine of aging ("Geroscientists") are among those at the forefront for creating solutions to the impending impact of global aging. Several strategies have been identified, the most well-known of which is the "compression of morbidity" paradigm advanced by Fries over 30 years ago. This approach is based on the idea that because most illness today is in the form of chronic diseases, if the onset of these disorders can be delayed to an older age, and the delay is greater than any associated increase in life expectancy, then illness, disability and their sequelae can be restricted to a shorter period at the end of life.

The key issue is how to best achieve compression of morbidity. Presently there is considerable support for the tactical approach of slowing the fundamental biological processes of aging, as opposed to treating (or even preventing) individual chronic diseases. Much of the momentum for this approach has been created by the tremendous advances made over the last 25 years in what is now the routine manipulation of lifespan in model systems such as Drosophila or C. elegans. The idea is that targeting specific 'upstream' pathways, originally identified in model systems, holds promise for delaying the age of onset of multiple age-associated comorbidities as a group, whereas delaying the clinical manifestation of a particular disease may simply result in some other age-related disorder "backfilling" the consequent reduction in risk. Slowing aging at the molecular and cellular levels would, theoretically, increase "healthspan", i.e., the period of life free from serious chronic diseases and disability, thus compressing morbidity and facilitating attainment of optimal longevity.

In the area of promising dietary and pharmacological strategies, the National Institute on Aging (NIA) Interventions Testing Program (ITP) has become a highly successful source of potential treatments to reduce age-associated pathologies and extend lifespan in mice. Moreover, independent laboratories working in basic aging biology recently have produced a remarkable number of potential targets and associated target-modulating treatments worthy of translational consideration. Overall, it seems likely that identification of candidate therapies from preclinical models will not be the major limitation for establishing effective interventions to slow the effects of aging and delay the onset of age-associated co-morbidities.

One of the main obstacles for translation of treatments to improve function with aging lies in the initial steps from assessments in animal models to testing for safety and efficacy in human subjects (phase I and II clinical trials). The process for bringing new prescription agents targeting aging to market has been described in detail by Kirkland, and the steps, time lines and costs involved are extensive. However, development of drugs for older patients with geriatric syndromes such as frailty, as well as clinical disorders that are antecedents of these syndromes, clearly is an important goal and area of interest for the pharmaceutical industry.

Complementary options to new proprietary prescription drug development also exist, and may represent, in some cases, a nearer-term source for new therapies with function-enhancing effects for older adults. For example, widely used FDA approved drugs with established safety and efficacy for treating age-associated clinical disorders such as cardio-metabolic diseases (e.g., metformin, statins, renin-angiotensin system inhibitors, recent generation beta-blockers) could undergo repurposing for treatment of at risk older adults or patients with aging syndromes. Although such agents could be prescribed presently for their off-label effects in cases in which the existing evidence supports likely efficacy, broad use of these drugs likely will require new trials with appropriate subject groups and clinical endpoints recognized by drug regulatory authorities.

On the one hand it is good that ever more of the research community and its supporters are waking up to the idea of treating aging and speaking in public on that topic, rather continue with the past course of patching its consequences in silence. On the other hand, the specific research and development strategies advocated by most factions are just not good at all. They will produce knowledge, certainly, but nothing in the way of treatments that might be expected to add even a decade to human life spans. We can and should do far better than this, and the way to do so is via SENS and other repair-based approaches to the damage of aging. Only repair can lead to a future of actual rejuvenation and the prospect of unlimited healthy life spans.

Comments

Oh my. The "Figure 6. Sources of new treatments for slowing effects of aging." chart in that paper is such a depressing sight...

On a brighter note, their identification of the "Processes of aging" seems more in touch with that of SENS.
So again there's that common ground obfuscated by diverging goals.

Posted by: Nico at October 21st, 2014 11:38 PM

Sadly, the title of the paper might well be "Traditional Geroscience" rather than "Translational Geroscience."

Posted by: Gary at October 21st, 2014 11:57 PM

The thing to always keep in mind about SENS is that it is still speculative, which is why more scientists can't yet give it vocal backing.

Yeah there are proposed technological solutions for each of the classes of damage. But most of the doubt is around the timeframe and eventual comprehensiveness of any of these therapies coming to market. Everyone loves to cite the example of powered flight being written off, but could SENS be closer to another technology in search of a demonstration - fusion power?

One of the visiting professors at my uni was a critic of SENS (and even wound up debating Aubrey at oxford). But I was skeptical of his claims that SENS was a waste of time and resources... with technological demonstrations the naysayers don't have much more chance of predicting a successful outcome than the boosters.

I think the real unease for a lot of scientists out there is that SENS would need maybe all damage repair technological solutions to work in fairly short order, and for there not to be any unknown unknowns as to why repairing all the known damage still doesn't prevent degeneration and death (e.g. epigenetic instability).

Posted by: Jim at October 22nd, 2014 3:26 AM

Jim:

I agree. Everyone is acting like SENS is so obvious, but there hasn't been a single demonstration of it at all. We haven't even reverse aged a single mouse. So people are right to be skeptical. Maybe we're the ones engaging in wishful thinking.

Posted by: InternetStranger at October 22nd, 2014 5:29 AM

Well it is still definitely worth spending big bucks on investigating, which is not yet happening. However a demonstration of repair of one type of damage would probably unlock a lot more vocal support and funding. Senescent cell removal experiments are being repeated in non progeria model mice currently at the Mayo clinic. So that will probably be the first pebble moving and starting the eventual.landslide.

Posted by: Jim at October 22nd, 2014 7:26 AM

They're already doing cell removal experiments? I didn't know that. But then again I haven't been following this for very long. I do know that, not too long ago, the blood of young mice was used to make old mice functionally youthful. Hopefully this will pan out in humans.

Posted by: InternetStranger at October 22nd, 2014 5:15 PM

I'm a frequent visitor to this website, and I totally agree that finding ways to repair the damage from adding is very much needed. However, if natural substances like GDF-11 and GHK can induce the body to naturally repair many forms of damage, it seems to me that such substances could be valuable and help reverse aging.

My understanding is that the human body is genetically programmed to be able to reverse all age related damage. But as we age or bodies become less and less able to do so. Isn't letting or own bodies repair the damage just as good as using synthetic drugs? If we could take GDF-11, GHK, and other factors that allow our own bodies to repair the damage there might be less need for synthetic drugs.

Posted by: Me at October 23rd, 2014 1:27 AM

@Me - I don't know where you get the idea that the body is genetically programmed to reverse all age related damage?

Some types of damage are reversed perfectly. If you suffer blood loss your body will produce more blood. And the linings of your intestines are replaced regularly due to damage from digestive juices. But the human body can't or doesn't bother to repair the damage that eventually causes the appearance and diseases of aging. It seems likely that GDF-11 merely temporarily reverses some of the secondary effects of this underlying damage (which is still accumulating). It does not remove that damage.

What evolutionary pressure would cause humans to evolve repair mechanisms that they could never use?

Posted by: Jim at October 23rd, 2014 5:54 AM

One does not need to support SENS specifically to know that something like it is what's necessary. It's true that no single SENS research stream has demonstrated results as yet, but it's very clear that regenerative reversal of age related damage is what's called for, far above and beyond any pharmaceutical intervention that would slow down some aspects of aging. Yet it is this very obvious conclusion which seems to lack support, and not just SENS itself. This would seem to suggest it's not SENS and it's failings that are the problem, but people's attitude to the idea of reversing aging itself. It's not the particulars of SENS people object to. It's the goal.

Nothing would make me happier than were SENS to achieve success across all seven research platforms, but even should they fail in the particulars of their research, their role as advocates for an idea that ought simply be common sense would still be invaluable.

Posted by: Ben at October 24th, 2014 12:02 AM

@ Jim -

"It seems likely that GDF-11 merely temporarily reverses some of the secondary effects of this underlying damage (which is still accumulating)."

Please can you point out the studies that show this? I'm interested to read more on this subject.

Thanks.

Posted by: Adrian Crisan at October 24th, 2014 7:09 AM

@Adrian Crisan: That's a big picture view type of comment. I doubt enough work has been done on GDF-11 specifically at this point to build a complete picture of what is going on. However we can draw some conclusions as to what to expect, which is that GDF-11 is waking stem cells, which will do little or nothing to help the state of accumulated cross-links in tissues, lysosomal aggregates, and other metabolic waste. It also won't address nuclear mutations leading to raised risk of cancer. It may or may not have any effect on levels of senescent cells, but if it does that will likely be unrelated to its effect on stem cell activity.

The high level debate in such matters is often effectively between people who hold the view of aging as caused by damage versus those who see aging as a program. To programmed aging adherents, changing circulating levels of proteins is exactly and all that needs to be done to reverse aging, as they would say it is an evolved program of such changes that is causing the damage of aging. To the majority position of aging-as-damage, that is backwards, and changing circulating protein levels that are different because metabolism is reacting to the state of damage is just another type of compensatory medicine that fails to address the root causes of the problem.

You can search Fight Aging! for many of these terms and find useful commentary and links.

Posted by: Reason at October 24th, 2014 7:30 AM

@ Reason - thanks for reply. Indeed I was looking for a study that Jim can point out where was shown GDF-11 does the rejuvenation in a "temporary" mode. But even so, would be very interesting to fund some serious studies to understand what is the result. Isn't the community able to crowdfunding such studies? I'm pretty sure there will be lots of people genuine interested in seeing the results of GDF-11 (one it's me!).
Probably (as usual) the solution lies in between: programmed aging vs. damaged caused aging, as both shows valuable arguments. It is like in quantum mechanics where there is the duality of wave-particle at the same time, unable to differentiate one completely from the other one. So probably we will achieve some rejuvenation using GDF-11 factor (and similar factors) and use something else to remove the cellular junk.

Posted by: Adrian Crisan at October 26th, 2014 6:42 PM

Hi Adrian,

I think Reason actually already answered your question.

I'm hypothesizing that GDF-11 is affecting the downstream effects of damage, assuming that there are seven or so classes of damage as per SENS. Under that assumption anything that doesn't remove, repair, or obviate the original damage would probably only have a temporary effect, as that damage would still be accumulating to levels that the body would be increasingly unable to deal with.

If you are assuming that aging is programmed and not due to damage, then as Reason said, all you'd have to do is change the circulating levels of proteins back to a youthful setting. I personally don't believe that GDF-11 would do a great deal, particularly for an individual who is already aged, as I agree with the assumption of aging as damage. Perhaps it could have a similar effect on aged muscle as selective androgen receptor modulators?

Posted by: Jim at October 31st, 2014 2:02 AM

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