



Elsewhere in this issue, Marios Kyriazis articulates a sharply skeptical assessment of the feasibility of medical rejuvenation, otherwise known as the “damage repair” approach to postponing the ill health of old age. His critique incorporates many errors of fact and/or interpretation and/or logic, which I enumerate here. I recognize that many of these errors are by no means Kyriazis's alone but are shared by numerous observers across the full range of biological expertise. It is for that reason above all that I hope this exchange will be of value to readers. Additionally, Kyriazis raises a number of valid concerns that have not been systematically addressed, by myself or by others, in past publications; I will attempt to remedy that here. For clarity, I will not structure this response as an essay, but instead as a simple point-by-point list of comments concerning individual statements and inferences that Kyriazis makes.

Comments



Is it in fact practical to seek damage repair, “rejuvenation” therapies for aging that are sufficiently comprehensive to do the job? Kyriazis says no. Here I inspect his reasons as set out in an article appearing on pages 390–396 in this issue.



“Physical repair-only therapies fail to address the human body as a complex adaptive system, ignore emergent phenomena and self-organizational properties…”



I agree with this criticism insofar as it relates to proposed therapies that entail adjusting the mechanics of metabolism so as to lessen the amount of damage that the body does to itself as a side effect of its normal operation, but not insofar as it relates to SENS. Indeed, one of the main inspirations for the “damage repair” approach that SENS embodies was that the body is so vastly complicated and good at looking after itself that our only feasible approach to postponing the ill health of old age is to let it do what it has evolved to do, merely alleviating the increasing burden of damage in the context of which it does it.



“…and take no account of entropy”



Life is only possible at all because living systems are extremely good at exporting entropy to their environment. However, it is true that entropy provides a reasonable starting point for explaining why aging exists, because it helps to explain why there is such a wide variety of different types of damage (creation of entropy) that the body does to itself, and thus such a wide variety of different sets of genetic machinery that have needed to evolve to export it. This in turn explains why it is unlikely that we will ever have medicine that can completely eliminate all such damage from the body. However, as I have noted repeatedly over the past decade, that does not mean we cannot defeat aging with medicine, because the body's ability to function at full performance in the presence of a limited amount of damage leads to the concept of “longevity escape velocity,” whereby we only need to approach that ideal at a rate faster than damage is accumulating—a task that, when one looks at the numbers, appears extremely feasible once we have achieved only a few decades of postponement of age-related ill health.



“…or the ‘direction’ of evolution.”



There is no such thing as the direction of evolution. Populations of living systems adapt to changing environments by use of natural selection, but not necessarily by becoming more complex.



“…while there is ongoing research aiming at identifying specific agents that may have an effect on each and every one of the seven types of damages involved in the repair-only rationale, there is no consideration of the pharmacological or clinical consequences of this research.”



The argument that Kyriazis introduces here is predicated on the assumption that antiaging interventions would manipulate our metabolism, and thus would have the plethora of unintended side effects and interactions with each other that we know to be typical of today's pharmaceuticals. Again, however, this misses the whole point of SENS. The fact that physical and mental function does not begin to deteriorate significantly until the age of at least 40 tells us that the body is set up to tolerate a certain amount of damage—and, indeed, this should be no surprise because it is also the case for simple, man-made machines. What that means is that this subpathogenic damage is entirely passive: It is not participating in metabolism and only starts to do so when it becomes too abundant. Thus, there is far less risk of unintended side effects and interactions from therapies that target this damage than from typical therapies.



“There is no discussion, not even in tentative theoretical terms, about the frequency of the intervention and its duration.”



On the contrary, I have often noted that these therapies can be expected to be repeated about every decade, and that in some cases more frequent administration may become preferred if their mode of delivery becomes particularly convenient (such as oral).



“…the use of enzyme replacement therapy with Imiglucerase as a therapy for Gaucher's disease involves 2-hr sessions of intravenous administration of the compound, which need to be repeated every 2 weeks, at a cost of $200 000 per patient per year.”



Indeed—and this is one reason why SENS's proposal is not to emulate enzyme replacement therapy by injecting the enzyme, but rather to incorporate the gene encoding the enzyme into the cells that need it. In the case of atherosclosis, those cells are macrophages, and it should be sufficient to augment only a minority of them in this way, so this can be done ex vivo using genetic manipulation of hematopoietic stem cells followed by bone marrow transplant. In other cases, high-performance somatic gene therapy may be needed, but that is needed for many other medical applications too, and progress towards it is rapid (some of the relevant being performed by SENS Research Foundation).



“…the treatment is a replacement of a missing enzyme and not a total repair of the defective gene”



This statement seems to be posed as an argument that repairing the gene would be even harder, which is in conflict with Kyriazis's previous point that enzyme administration must be frequent.



“…the case of Gaucher's disease implicates just one gene mutation, a recessive gene on chromosome 1, whereas in the case of aging there are several mutations that need to be addressed, on many chromosomes, and this makes the enzyme replacement therapy even more complicated.”



Not much more, no, since only a few aspects of aging are proposed to be addressed by introducing new catabolic enzymes. (Also, of course, what is being addressed in this case is not mutations, but the simple failure of evolution to provide us with the relevant genes.)



“It has been suggested that lipofuscin can help express lysosome-stabilizing factors and improve the viability of the lysosome under stress, acting like a hermetically useful agent. A complete elimination of lipofuscin through a putative future pharmacological agent would have negative repercussions upon the function of the lysosome.”



First I feel it necessary to point out the facility with which Kyriazis follows a statement of the form “It has been suggested that X” with a statement that assumes the truth of X. There is, of course, very simple and incontrovertible evidence that lipofuscin's protective effects, if they exist at all, can only be to mitigate the impact of other changes due to aging (changes which, by definition, SENS seeks also to eliminate): Namely, that young adults don't have much lipofuscin and yet are healthy.



“…the therapeutic effect was a priori destined to fail due to the fact that the reaction was based upon an autocatalytic principle. In other words, as the methyl groups of 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride (ALT-711) were made available to cleave the carbohydrate–protein bond, the resulting adduct compound was then released and was free to re-interact with other free carbohydrate molecules, so the cross-links were again reformed.”



Clearly this cannot be the whole story, because ALT-711 was repeatedly reported to confer long-term benefits in a variety of animal models. Moreover, since the cross-links putatively broken by ALT-711 are not actually a SENS target (being, apparently, not the major cause of arterial stiffening in humans), this is a straw man.



“Another target for cross-link cleavage is glucosepan. In this case, development of an enzyme or similar compound sounds a promising way forward. However, on the whole, there is little clinical information on this product, making it difficult to suggest concrete therapies that can deal with this particular compound.”



The SENS Research Foundation exists precisely because some of the challenges posed by aging are difficult. Kyriazis seems to be espousing the view that because it's difficult we shouldn't try.



“This is confounded further by the fact that there are other cross-link compounds that will have to be eliminated, and it is evident that a wide range of cross-link breaker therapies need to be developed.”



No: This is a classic case where the “longevity escape velocity” concept comes into play. All such cross-links have the same effect, so their contribution is additive. If we can eliminate the most abundant one (glucosepane), we buy ourselves time to figure out how to eliminate the next one, and so on.



“To induce elimination of cells (so that these can subsequently be replaced with stem cells), there would be a need to use chemotherapeutic agents…How likely is it that the public at large will visit a clinic for regular weekly infusions?”



Here Kyriazis refers to whole-body interdiction of lengthening of telomeres (WILT's) requirement to eliminate stem cells with intact telomerase genes, which would be replaced with new ones lacking such genes. He overlooks the fact that such cells can also be eliminated by agents that simply kill cells that express telomerase (a straightforward example of suicide gene therapy, which is needed for other parts of SENS too), or else not eliminated at all but genetically modified in situ by gene-targeting techniques such as clustered regularly interspaced short palindromic repeats (CRISPR). Again, therefore, the allusion to “weekly infusions” is a straw man founded entirely on a basic misunderstanding of what SENS actually proposes.



“The fact that an effective therapy against aging may theoretically be developed in the laboratory does not necessarily align with the actual use of this therapy by the public.”



This is an absolutely valid concern, which I have highlighted in a different way in innumerable talks and interviews. At present, preventative medicine, in general, is a very hard sell, because the public are not inclined to subject themselves to medical treatments (especially not new, experimental ones) when they are not yet sick. However, there are exceptions (such as statins and angiotensin-converting enzyme [ACE] inhibitors). We must learn from these examples; in my view, the main lesson is that there is a trade-off between the perceived benefit and the perceived risk (as there should be!), so we must communicate the huge potential benefit to maintenance of health that will result. Also, of course, the best way to communicate it will be by example: Even if only a few early adopters take this risk at first, their health improvements will rapidly persuade others to follow suit.



“An example comparable to therapies for aging rejuvenation is that of antiretroviral medication that can save a patient from certain death from acquired immunodeficiency syndrome (AIDS). In this case, it was found that up to 37% of patients may be noncompliant.”



This example is instructive, but not so compelling as Kyriazis implies. The reasons for noncompliance are many and varied, but one is surely the impact quality of life: If a given medication improves one's life expectancy but causes major side effects, many patients may choose not to adhere. The studies Kyriazis cites are more than a decade old and thus refer to therapies that were much less effective and much more debilitating than today's; it would be of great interest to repeat this investigation today.



“Subconsciously, we may downgrade the significance of our own death as long as the survival of the species is assured.”



Maybe so—but evidently this is not a decisive influence, or else the elderly would eschew medicine entirely.



“Finding ways to deal with this aspect of death-drive (i.e., in this case, noncompliance) is likely to be as difficult as finding ways to diminish human aggression”



Again, maybe so—but we are actually doing rather well with the latter problem, as exemplified by the past century's progress in reducing deaths in war, in implementing gun laws, in abolishing the death penalty, etc. Arguably, these developments have been substantially driven by our increasing success in controlling other causes of death, specifically infections, and thus may be further advanced if we additionally control death from old-age infirmity.



“A pre-existing illness such as, for example, liver or renal disease, may interfere with the pharmacodynamics of the therapy in any specific individual”



Again Kyriazis makes the mistake of thinking of SENS as a combination of pharmacotherapies. Regenerative medicine, or indeed damage repair in general, is rarely if ever best implemented using drugs. In the case of SENS, only one component (stiffening of the extracellular matrix) is likely to be drug based, and even that one may in fact be enzyme based. The impressive substrate specificity of enzymes is something without which life would be impossible, and it can work for us in medicine too.



“If we assume that an effective therapy suite based on engineered negligible senescence is available, it will need to be tested repeatedly in two separate broad groups. The first would be the “younger” healthy group, arbitrarily defined up to the age of 60. The intervention would, on the whole, aim to prevent future degeneration, and it will not be therapeutic. The second group would be the over 60s age group likely to have several co-morbidities, such as existing age-related illnesses that need “curing.” Extrapolating risk–benefit ratios is notoriously difficult when we compare young/healthy individuals with older/ill ones.”



Here Kyriazis again highlights a valid and major concern. However, the solution is not so elusive as he assumes. First, the divide-and-conquer nature of SENS provides the option to test each component as a simple disease therapy, applied initially only to those who are at risk of (or are already suffering) the particular aspects of aging to which the therapy in question is most relevant, and not (or not to the same extent) the rest of aging. Second, when an individual is already exhibiting symptoms, the value of damage-repair therapies will be to potentiate the effectiveness of the pathology-targeted conventional therapies that exist today. Accordingly, it will in fact be quite straightforward and quite rapid to obtain evidence for both safety and efficacy of these therapies. Kyriazis's error here (a very common one) is to start from the presumption of some kind of Chinese wall between the diseases of old age and some nebulous phenomenon called “aging itself,” when there is in fact no such distinction.



“In medicine we consider three aspects of a condition: The primary cause, the damage resulting from this cause, and the final consequences resulting for this damage. … In aging, the cause is the evolutionary necessity for sexual reproduction and hence the imbalance of resources allocated for repairs. The damage is the actual organismal changes broadly described by the seven areas of SENS, and the consequences are all the clinical manifestations of age-related degeneration such as dementia, arthritis, etc. Clearly, the elimination of the primary cause is the gold standard of medicine, and repair of the damage or of its consequences are only of secondary importance.”



No, this is not “clear” at all—it is completely wrong. The gold standard is the elimination, or pre-emption, of the consequences (the pathologies). We should not start out with any bias whatsoever as between elimination of the cause versus elimination of the damage, since both result in pre-emption of the consequences. We should prefer whichever turns out to be easier to implement.



“Without eliminating the primary cause, the organism attempts to adapt to the extraneous repair therapies and, through mainly epigenetic mechanisms, it may develop tolerance to these external therapies. An example here is levodopa, in the case of Parkinson's disease, where this rejuvenating compound, which essentially replenishes dopamine/repairs the dopaminergic neurons, can have initial positive effects but, with prolonged use, the effects wane.”



Kyriazis instantly makes my point. The decline in efficacy of levodopa arises from (1) the continued loss of dopaminergic neurons, leading to the need for higher compensating doses, and (2) the crude methods currently available for administration, which only very roughly approximate the natural (and required) distribution of dopamine throughout the brain. SENS, on the other hand, proposes to address Parkinson's disease by stem cell therapies that replace the lost dopaminergic neurons, thus restoring not only the quantity but the distribution of dopamine to youthful levels (as well as doing everything else that we may still not know that those neurons do). Initial clinical trials of such an approach were mostly unsuccessful, but the minority of patients who responded well are still free of disease nearly 20 years later despite having had only one transplant and no levodopa treatment since. With our greatly improved ability to nudge stem cells into the appropriate state so that they will differentiate into dopaminergic neurons after transplantation, hopes are currently at an all-time high that this therapy can truly cure Parkinson's disease quite soon, and new clinical trials are already in progress.



“If the primary cause of aging remains untreated, it will continue to fuel the damage, a fact that necessitates repetitive (and uninterrupted) therapeutic interventions. The ongoing anatomical, morphological, and structural alterations to the human body resulting from a repeated and ongoing repair therapy are not known.”



Kyriazis seems to need to look up the word “repair” in the dictionary. If there are such ongoing alterations, that means, by definition, simply that the repair is not precise. I have never claimed that these therapies will be perfect from the outset; like all medicine, they will be progressively improved, and in this case that means that the ongoing alterations that Kyriazis mentions will be reduced (and themselves repaired).



“Reversing the damage and returning the network to its original state clearly obviates the need for additional repair. However, these approaches are often unrealistic in a practical sense. One alternative approach involves compensating for network damage by fixing the state of one or more initially unaffected nodes…e.g., through gene manipulations, constitutive activation, or pharmacological interventions. However, (as quoted by Kyriazis from ref. 1) these modifications have an effect on every signaling component with which the targeted component interacts.”1



Precisely. And that is why SENS stands back and asks whether in this case, the approach that “clearly obviates the need for additional repair” is in fact “unrealistic in a practical sense.” The SENS Research Foundation exists because I and others have examined the problem in detail and found that no, it is not unrealistic.

Conclusion



Kyriazis's article is a valuable reminder to those who understand the logic of SENS that many—even those like him who have been exposed to it for many years—still misunderstand it in really fundamental ways. I am grateful to him for setting out his position in print and thereby allowing me to respond; too often such misconceptions remain unexpressed and thus unresolved for too many years. I suspect that many readers will have shared these misconceptions and concerns, and that this response will have allayed them. To the extent that it has not, I urge readers to follow Kyriazis's lead and articulate their remaining doubts in writing; Rejuvenation Research always welcomes scientific correspondence.

Reference

1. C Campbell, R Albert. Stabilization of perturbed Boolean network attractors through compensatory interactions. BMC Systems Biology 2014; 8:53.



http://www.ncbi.nlm.nih.gov/pubmed/25072964