Treating Aging in Advance of Fully Understanding Aging
Engineering is in essence the business of producing good, workable solutions in absence of complete knowledge. The Romans could construct excellent bridges with a tiny fraction of the knowledge of materials science, mathematics, and modeling possessed by today's architects. Medical technologies today are in much the same position: we might know about as much of the fine details of biology as the Romans did of the deeper sciences underlying architecture. A vast scope of discovery and cataloging is yet to be accomplished in the life sciences. Yet we can still produce good therapies well in advance of a full understanding of human biochemistry.
Pure science as practiced today is the polar opposite of engineering. The goal is to produce complete understanding, and only then hand over that knowledge to those who will apply it to produce technologies. This is an ideal rather than the reality, of course: at some point in the development process there are always those who will make the last leap to clinical application because it is more cost effective to take a chance than to grind to the very end of the research process. The last stages of medical research are ever a compromise between the ethic of science, full understanding first, and the ethic of engineering, let's just get it done when there's a reasonable chance of success. Building proposed therapies and trying them out is sometimes the best path forward for both learning and application of knowledge.
In aging research the archetype of the engineering approach is the SENS program, scientific projects aimed at moving as rapidly as possible towards practical rejuvenation therapies. The SENS vision for development is explicitly a way to use our present knowledge of forms of cellular and tissue damage that cause aging in order to work around our present lack of knowledge regarding how exactly metabolism and aging interact over time. The damage is comparatively simple, but the details of how that damage spreads and interacts, and how it forms age-related disease, are intricate and poorly understood. We are very complex self-adjusting biochemical factories, so it is a given that even simple malfunctions have complicated outcomes. Because the malfunctions are simple, however, they themselves are the best and most cost-effective point of intervention: the first step towards treatment of aging should be to repair the breakages known to cause it.
The very readable open access paper linked below is a similar argument for engineering (take action now) over science (wait for full understanding), but for less ambitious efforts to intervene in the aging process. These are drug development programs aimed at manipulating the operation of metabolism so as to gently slow the accumulation of damage, and thus slightly slow the pace of degenerative aging. The expected outcome here in terms of additional healthy life delivered per billion dollars invested is not great; you might look at the past decade of sirtuin research to see the median expected outcome, which is to say a lot of data on a tiny slice of metabolism and aging, but no practical therapies. In comparison given a billion dollars and ten years there is a reasonable shot at implementing prototype SENS rejuvenation treatments in mice. The challenge for now is to persuade enough people that this is the best path forward to have a hope of expanding the SENS funding and research community to this scale.
Why Is Aging Conserved and What Can We Do about It?
Aging is something everyone can relate to. From grandparents, to parents, and ultimately our own bodies, we are intimately familiar with the declines in form and function that accompany old age. Yet, we don't all appear to age at the same rate. Many individuals are healthy and active well into their 70s, 80s, or even 90s, while others will suffer from chronic disease and disability by the time they reach their 40s or 50s. Those of us that have companion animals also observe that different animal species or even subspecies, as in the case of dog breeds, age at profoundly different rates. Defining the factors that influence individual rates of aging is a major focus of aging research.From a biomedical perspective, it is critically important to gain a better understanding of the mechanisms that drive biological aging, as age is the single greatest risk factor for the leading causes of death in developed nations. The fact that aging influences so many different conditions is particularly curious. What is it about aging that creates an environment within our cells, tissues, and organs that is permissive for all of these seemingly disparate pathological states?
In order to understand the biological mechanisms of aging, scientists have turned to laboratory model organisms such as rats and mice, fruit flies, nematodes, and even yeast. While some have questioned the utility of these systems as models for human aging, it is now clear that similar pathways and processes affect longevity in each of these species. These studies have resulted in the identification of interventions that slow aging in taxa spanning broad evolutionary distances. Although it is still unknown whether these interventions will slow human aging, the potential impact on human health, if they do, is enormous.
In general, the known conserved modifiers of longevity tend to mediate the relationship between fundamental environmental and physiological cues (i.e., temperature, nutrient status, and oxygen availability) and the regulation of growth and reproduction. One school of thought holds that this relationship results from the ability of organisms to forgo reproduction and invest in somatic maintenance during times of adversity. In other words, based on the quality of the environment, the organism has evolved to make the appropriate choice between allocating its limited resources toward reproducing rapidly, and hence aging more quickly, versus delaying reproduction and allocating resources toward maintaining the soma, thereby aging more slowly.
Although conserved longevity pathways clearly exist, it has been challenging to identify their primary molecular mechanisms of action or even to definitively determine whether they directly modulate the rate of aging. This is true, in part, because there are no generally accepted molecular markers of aging rate in any organism. In mammals, several phenotypes are known to correlate with chronological age, and a handful have been suggested to have some predictive power for future life expectancy; however, none have been demonstrated convincingly in prospective studies.
In addition to gaining an understanding of the molecular mechanisms of aging, a primary goal of aging research is to identify interventions that will slow aging in people. Advanced age is the primary risk factor for the majority of diseases in developed nations, and there are enormous social and financial pressures associated with demographic shifts toward more elderly populations. Interventions that expand the period of healthy life and reduce the period of chronic disease and disability (referred to as "compression of morbidity") offer the potential to alleviate these pressures while simultaneously increasing individual productivity and quality of life.
In practical terms, it may not be necessary to understand in detail why aging is conserved in order to do something about it. In several cases, components of the insulin signaling / mTOR network, as well as the sirtuins, have been shown to be associated with longevity and age-associated disease risk in people. While it remains unclear how difficult it will be to develop interventions to improve healthy aging in humans, there is reason for optimism that this may not be far off. Drugs that target these pathways, including some already shown to increase life span and health span in rodents, are beginning to be tested for effects on age-associated phenotypes or disease in humans. Unfortunately, because of the glacial pace of human aging when compared to common animal models, it will likely take several decades to determine whether rapamycin or other such compounds generally improve age-associated outcomes in people.
Hello Reason & co.!
Does the discovery in the link fit in any of SENS's 7 causes of aging? Thanks!
http://time.com/3841620/scientists-discover-the-secret-to-keeping-cells-young/?xid=fbshare
@Josep: That research is related to a progeria-like disease (a disease that seems like aging in some aspects, but not others), not real aging.
Yes, but Juan Carlos Ispizúa (the main researcher) thinks it could be applied to humans with normal aging, and revert it. Is he wrong?
Progeria is similar to aging in various ways but not the same. Can we learn about aging from it and apply it? I think we can yes.
But does it fit in any of the 7 causes? If not, we sholud start to think that there is more in the aging problem that just this 7 causes ...
Josep - scurvy (vitamin C deficiency) looks like aging in some regards (teeth fall out) that does not mean that scurvy is aging.
Josep, IMO, the statement of the title of the paper, "A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging", is the typical hype that surrounds some scientific papers. That is, it seems to me that the claim that this research revealed a "driver of human aging" instead of simply a driver of Werner syndrome, is unfounded (at least, according to what is said in the abstract, because I don't have access to the full text).
Yeah, but people with Werner's syndrome seems to have many symptoms that old people also have: wrinkles, grey hair, baldness, diabetes type 2, arteriosclerosis ... It really seems as accelerated aging, not a disease similar to aging. At least Ispizua says so.
WS has some features that aging doesn't have (e.g. skin and gonad atrophy, among others) and aging has some features that WS doesn't have (e.g. sarcopenia, overspecialization of the immune system, dementia...).
WS is not the same as aging but it shares some similar mechanics which we can learn from. Personally I think this is a downstream effect and we should be looking to change things way before intervention at this point. But it should fit into one of the 7 deadly SENS as most damage does :)
Ok, we'll see. This research seems to me good news, but everytime I see some reversal of aging that I cannot fit in any of the 7 causes, I lose some faith in SENS plan. Is it correct?
Steve H said: "WS is not the same as aging but it shares some similar mechanics".
Do you have any proof of that?
@Josep: When looking at any possible new mechanism that falls outside the broad buckets of SENS as it stands today, and there are a number of them, the first things to ask are:
1) Is it likely a consequence of other damage, or the consequence of epigenetic and other changes that are a reaction to damage. At the moment this is frequently completely unanswerable, as too little is known of the chains of cause and effect. The fastest path to figure it out is to fix damage. The SENS position is pretty much "fix all the damage then see what's left" as a fast investigative path.
2) Is it meaningful in normal aging? This can be challenging to uncover. Look at progeria, for example, another so-called accelerating aging condition. Like WS, that appears to be a massively larger incidence of a particular form of breakage that is seen in tiny amounts in normal aging. Is it relevant in normal aging? Ten years in to knowing the mechanism, and that's still a question mark. You can search back in the Fight Aging! archives for "progeria" and see the development of that research at a high level.
3) Is it meaningful over the course of a longer than usual human life span? Nuclear DNA damage isn't on the SENS list to fix at the moment, but I suspect it'll need dealing with at some point out beyond present human life spans. Similarly for all sorts of other issues, such as damage to long-lived nuclear transport proteins, where there is no good data on the degree to which this is actually important across a century, but where you have to suspect that eventually, if all other things are fixed, it is going to have to be dealt with.
The SENS list as it stands is a starting point, and we'd expect it to grow with success in lengthening life spans, I would think. Eventually you start chasing down mechanisms that are ever more insignificant in a normal life span, but would add up over a thousand years or more. I suspect most of those will be associated with component parts in long-lived cells in the nervous system, but who knows at this point.
Lastly, there is the old saw about hammers and damage: you can shorten mouse life span with blunt trauma, but that doesn't mean that hammers are a cause of aging. This is why one should not pay too great an attention to any mechanism wherein the researchers have only so far demonstrated shortening of life span. You can make any machine die more quickly by breaking some of its vital components, but there is no necessary rule that any of that can lead to a way to make it work better and for longer. So I generally wait for a demonstration of extended life span before paying too much attention.
Ok Reason, thanks for your answer!
@Josep: Jim, Antonio, to some extent Steve H, and especially Reason have collectively done an admirable job of covering the issues here: see especially Reason's comments about hammers. The whole notion of "accelerated aging" is a slippery one and often used as a petitio principii. See a previous discussion on Hutchinson-Gilford Progeria Syndrome (HGPS)) for a similar case already cited by others.
The one thing I would add is that in this case, as with progerin mutations, there is a kind of converse side to Reason's Point #1 about kinds of apparent damage being downstream consequences of upstream phenomena — in this case, looking down the causal pathway, from metabolism to true, stable damage. Note that in the WS paper in question,
So, here WRN deficiency is causing MSC to undergo senescence. Of course, "wild-type" aging also involves cellular senescence, so it's at least reasonable to hypothesize that some of why WS looks like "normal" aging is because WS patients suffer an accelerated rate of cellular senescence.
But, first, that doesn't mean that the cause of the excess cellular senescence in WS is the same as the cause of senescence in the rest of us, and quite a few things cause cellular senescence in the rest of us for reasons that I do not see reason to expect are mediated through this mechanism.
Second, and more directly to your question: this also tells you how SENS would deal with this problem if it should turn out that this mechanism of aging does, indeed, also occur in the rest of us. remember, the beauty of the "damage-repair" strategy of SENS is that it works no matter what the metabolic causes of the targeted damage may be. In this case, WRN mutations causes a failure of heterochromatin maintenance and loss of H3K9me3, leading to an increase in senescent cells. We know that the rest of us don't have WRN mutations, but (hypothetically) we might have our wild-type gene downregulated in aging for some reason. Rather than trying to outsmart a hypothetical regulated downregulation of the wild-type gene (which may be happening for a perfectly good reason), or fix an epimutation in H3K9me3, the "damage-repair" approach to cells rendered senescent via WRN downregulation is exactly the same as the solution to cells rendered senescent via ionizing radiation, telomere attrition, or activation of proto-oncogenes: to clear out the senescent cells and then replace them with pristine new ones via cell therapy.
(Hm. In case that wasn't clear: the way that the WS phenomenon would fit into the seven categories of aging damage in the SENS platform is that, if it turned out to be reflected in a similar phenomenon in "normal" aging, it falls clearly under the "Death-Resistant Cells" category, and would be cleared via the same approach used to remove garden-variety senescent cells).
As much as I believe that there will be varying levels of success to a damage-control methodology at some point, one may need to step back to the bigger picture of it as a financially self-sustaining medical service that needs to get customers, provide fair value in money and time, and be a defensible procedure (legally, within the medical profession, and the highly-competitive/litigious for-profit corporate culture). To say that we can deal with all that when we are further along is to fail to realize is that one is producing a product/service that in all likelihood will not be covered by a gov't medical plan (if you live in such a country) or many very-extended private plans. What other industries need to work under such circumstances - cosmetic surgery, cryonics, types of alternative procedures/assessments not 'affected' as much by the FDA. The point is that these industries are some science, some engineering, but mostly developer, promotion, and technical advocate-type 'businesses'. This is not to say they are not very technical with large R&D. But, they are typically very private with operations and clientele, opaque about funding, heavily lawyered up, and very affected by the direction of investors and corporate services. Even the Google/Calico situation as much as it is perceived as a benevolent corporate entity, is likely very profit-driven. Where do we go to search out a culture that provides guidance - Silicon Valley and the like with apps and computer services - fraught with VCs, angel investors, etc. A high risk, high intensity, frustrating jungle of under-monied R&D and ruthless-pseudo-vision. As a system of procedures that are so early in their development, SENS may have to go this route (if it has not been trying for at least 5 - 10 years, which is still not enough of a go), to get the necessary large injections of fleeting capital to make the fits and starts of forward momentum. It is not enough to depend on the nobleness of the end goal or its rigorous science to those parts of society amenable previously; or more lately the engineering and 'down-to-earth' 'close enough' improvements as they come; but to move to an investor-driven 'human-improvement' service. Some of the sites that occasionally have their finger on the pulse of this VC culture is tech crunch. There one sees 50% funding news/rumors, 50% technical milestones and news - this mentality drives that industry way beyond the sum of its technical prowess and some grant-based bureaucracy. Before Silicon Valley 'disruption' culture, perhaps there was the 90s and early 00s of the pre-/early Craig Venter great bio-engineering/ bio-med start-up firms races. Why not again? But with improved funding methodologies - more money but higher risk and more volatility. This is the 'kick' needed not the outmoded 'kickstarter' or university-based/huge lab overhead models. What is the minimum lab set-up? What post-docs without full-time support are available? Who is monitoring this money flow and investment culture? What city/town can provide the tech cluster to attract that critical mind/money mass? Short of a DARPA program or an Elon Musk following, I see no other alternative to attract investment and talent. Which may mean a move to a non-G7 country or non-traditional research and proving procedures.
"in all likelihood will not be covered by a gov't medical plan (if you live in such a country)"
On the contrary, government should be most interested in having citizens that don't go to retirement and continue working.
Thank you Michael for your answer!