rePresenting SENS

Started by , Apr 11 2005 03:23 PM

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#1

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Posted 11 April 2005 - 03:23 PM

I initially was going to post this on the Curing Aging scientist open letter topic but have decided to incorporate it as a more generalized point of discussion.

As many here know I have criticised SENS in various ways, and in my adversarial approach have managed to evoke considerable annoyance amongst some of you. What you may not be aware of, are my motives for doing so and how these motives relate to the discussion at hand.

Whilst I've been captivated by SENS since I first clicked onto Aubrey's site (I think 4 or 5 years ago) and have been pleasantly surprised at how such an evidently busy man can respond intelligently and honestly to a diverse and substantial number of inquiries (ranging from the curious to the manic), I have in parallel become troubled by the lack of data on implementation. Disappointingly, the more I pondered on the technology to achieve the core SENS objectives (AE and WILT), the further into the future I had to look for the answers.

Consequently, when the opportunity presented itself and ironically just as Aubrey envisages himself as a catalyst amongst the biogeronotological community, I decided to similarly attempt to stimulate him (and others within this community) towards a more serious consideration of the implementation problem. In seeking to do so, however, what emerged was an underlying set of prospective anti-senescence targets and theoretical solutions designed to support or replace some of the existing components of SENS. With Aubrey's refusal to consider their incorporation into the SENS framework I termed this solution subset as NeoSENS (which includes enhanced DNA repair, enhanced autophagy, and rDNA replacement). Unlike most, I dont view cancer as such an intractable problem if it considered in the context of tissue specific promoters as a means of targeting it and DNA repair as a means of preventing it.

The ideological contrast I have tried to make between SENS and NeoSENS is in the execution - the primary criterium is that the technology of implementation and the background knowledgespace must be available. In other words, there are no requirements for unavailable as yet technology or unknown as yet biology. What this means is that whilst NeoSENS may not take us as far SENS suggests it can, it will get us on the road much sooner. This, of course, is not to take anything away from SENS which is a set of solutions that if implemented, could have a dramatic effect on lifespan. Neither is it a promotion of NeoSENS which is no more than a logical set of conclusions that most would arrive to given sufficient time to ponder the problem in the context of available technology and knowledge space. What I wish to draw attention to is the possibility for a solution to address the concern expressed by those in the scientific community, who for better or for worse, have been indoctrinated with the characteristic evidence-based mode of thought that typifies senior scientists.

It must be appreciated just how difficult it is for a scientist, who having been trained from undergraduate school to meticulously scaffold hypotheses using substantiated research, to venture into the speculative world of the inventor and intellectual pioneer. SENS is this light, is an anathema to the conservative professional. This is why SENS's greatest strength, its independance from having to know everything about aging in order to modulate it, is its very weakness when it comes to gaining accreditation in the scientific community.

In my view, a synergistic reconciliation between an endorsement of SENS and the letter proposed would be to include the clusters of relevant studies that establish a pattern that paves the path to the promise of SENS. In other words a scientificaly credible platform that unifies the prospect for substantial lifespan extension and its foremost candidate, SENS, as the means by which it may be accomplished. Evidently, this has not as yet been done sufficiently to move the biogerontology community. In endeavors where it is scientists who must be convinced then this is something that necessitates the presence of a scientific substrate no matter how much the fanfare of activism.

This is not a task that necessarily requires original research (at the bench), but more so original thinking and a recontextualization of the information that is already at hand. It is time for the vision of SENS to be articulated in a palatable fashion for the scientific community.

If they need to have the "dots connected" then lets connect them.

#2 manofsan

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Posted 12 April 2005 - 05:53 AM

Cool, I hear what you're saying. A bird in the hand is worth two in the bush. This SENS thing will be an evolutionary process anyway. Even if it starts off with only rudimentary methods and marginal advances, as long as they can generate proven benefits, they can be the stepping stones to greater achievements.

For example, even if one does work on genemods of mouse zygotes rather than on treatments of middle-aged mice, as long as it generates lifespan improvements then you may have some proofs-of-concept which could potentially be the basis for re-designing into treatments for middle-aged senescent mice.

I'm all for articulating it in more plausible less-than-infinity terms, but experimental results speak loudest. People must find ways to generate hard data under conditions that withstand scrutiny. Hey, the scientific community will buy into your Cold Fusion, Anti-Gravity, Perpetual Motion, Faster-than-Light, Time Travel and Zero-Point Energy, as long as you can rigorously prove it under reproduceable conditions that they can verify for themselves.

If the Methuselah Mouse Prize effort can produce even a 20% improvement of lifespan in a mouse, you know that people will be stampeding to set up a Methuselah Chimp Prize. Rich old billionaires will be hammering down your door.

#3 manofsan

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Posted 12 April 2005 - 11:25 PM

Disclaimer: I don't really believe in Cold Fusion, Anti-Gravity, Perpetual Motion, Faster-than-Light, Time Travel and Zero-Point Energy -- I was just using outlandish examples to emphasize that whatever concept you're pitching to the scientific community, ultimately its acceptance into the mainstream rests on the ability to satisfy the standard rigorous tests of proof, which are themselves established and mainstream.

#4 Michael

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Posted 14 April 2005 - 06:59 PM

prometheus:
The ideological contrast I have tried to make between SENS and NeoSENS is in the execution - the primary criterium is that the technology of implementation and the background knowledgespace must be available. In other words, there are no requirements for unavailable as yet technology or unknown as yet biology. What this means is that whilst NeoSENS may not take us as far SENS suggests it can, it will get us on the road much sooner.

I don't see that the proposals which you've advocated actually meet this criterion. Most such proposals rely on gene therapy, and if it is to be effective "in those of us unfortunate enough to be already alive," that means somatic gene therapy. This technology is cleary not available for safe use in humans today, so that these proposal do indeed have "requirements for unavailable as yet technology."

Moreover, while several of the SENS interventions also require somatic gene therapy, (a) several either do not, or may not (xenohydrolase; immunization against extracellular garbage; stem cell therapy; AGE breakers), and seem likely to be good to go long before we have mastered somatic gene therapy; and (b) the additional technologies required to implement several other SENS interventions seem likely to be in good control before somatic gene therapy. This may mean that all -- or nearly all -- of the SENS interventions could be available in first iteration before, or more or less as soon as, any proposal which only requires somatic gene therapy, simply because it is the most difficult single step in the process.

Moreover, since most of the alternative proposals which you suggest involve "messing with metabolism" in ways that may or may not prove beneficial under normal conditions of aging (as opposed to eg the expectations one might form for the benefits of increased DNA repair based on experiments in cells or organisms exposed to acute, supranormal stressors such as high UV, oxidant stress from xanthine oxidase, etc), whereas SENS by definition attacks targets which are, by their nature, accumulating, pathological lesions, it seems much clearer that SENS interventions (a) will actually have beneficial effects on age-related pathology and on aging itself, and (b) will be of benefit to people who have already suffered a significant level of aging damage.

-Michael

#5 Mark Hamalainen

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Posted 15 April 2005 - 05:49 PM

What I wish to draw attention to is the possibility for a solution to address the concern expressed by those in the scientific community, who for better or for worse, have been indoctrinated with the characteristic evidence-based mode of thought that typifies senior scientists.

It must be appreciated just how difficult it is for a scientist, who having been trained from undergraduate school to meticulously scaffold hypotheses using substantiated research, to venture into the speculative world of the inventor and intellectual pioneer. SENS is this light, is an anathema to the conservative professional. This is why SENS's greatest strength, its independance from having to know everything about aging in order to modulate it, is its very weakness when it comes to gaining accreditation in the scientific community.

I think the situation is a bit different. I don't think you can change these people's minds by giving them a description or platform for SENS in more detail. As you say, then information is already out there to be recontextualized. It seems to me that the vast majority of scientists just follow the field dogma and aren't interested in breaking out of it. All of the scientists researching aging that I have dealt with have dismissed SENS without even bothering to study it.

Aubrey has already presented SENS in great detail and it has withstood the criticism of all who have bothered to try. The problem is, many scientists either just don't want to hear it, or aren't interested. The important thing now is to facilitate those people who are interested in doing the research, with projects such as the M Prize. Once I finish university and have my own income I'll definitely be contributing, hell I may even try to win it

On the other hand, a technically detailed / recontextualized platform for SENS may be a useful resource for researchers of many kinds. Its a big project though, and as the 'science-corner' has made apparent, nothing will happen without someone willing to dedicate the time to leading it. If you can put together a draft or outline to be filled in, I'll definitely contribute my knowledge through suggestions/criticisms/editing.

#6 Mark Hamalainen

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Posted 15 April 2005 - 06:02 PM

When explaining SENS to newbies, I like to make an analogy between mathematical proofs, similar to Aubrey de Grey's SENS, and formal proofs, similar to the tedious detail that the gerontology field unrealistically (and unnecessarily) demands.

"Formal proofs, however, never gained a foothold in the mainstream mathematical community because they are tedious—they take many steps to prove something in cases in which a mathematician might just take one."
The Economist

Edited by osiris, 15 April 2005 - 09:53 PM.

#7 Da55id

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Posted 15 April 2005 - 06:38 PM

Osiris...When I explain SENS to newbies I use the analogy of knee replacement. Of course it would be better to understand everything there is to know about what causes knees to wear out and perhaps to prevent it.

But that DOESN'T mean we have to understand all this in order to replace the knee with an engineered substitute. And there are 10's of THOUSANDS of people right now who would be in wheelchairs or worse if the "get all the research done first" crowd had prevented the use of knee replacements.

#8 Mark Hamalainen

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Posted 15 April 2005 - 08:53 PM

Exactly, thats what I meant. In a standard mathematical proof, logic is often used in a less formal sense since a formal proof could be so long as to be incomprehensible, in which case its hardly a proof at all! Incomplete knowledge can be perfectly sufficient depending on your goals.

#9 John Schloendorn

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Posted 16 April 2005 - 01:28 AM

Yes, it's all about goals. Every single senior life scientist has more than enough of the mental faculty to understand, or hell, even derive strategies like SENS on their own if they wanted to. Wherever some of these guys get together, I just love to see their minds cut through any complicated problem like a blade through air. What is missing is really the goal that massively preventing human suffering is massively better than postponing it a little bit.
Here, the ability to achieve goals really seems inversely correlated with the ability to set goals.
But we're pretty off topic, maybe someone move this elsewhere?

#10

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Posted 16 April 2005 - 01:57 AM

Most such proposals rely on gene therapy, and if it is to be effective "in those of us unfortunate enough to be already alive," that means somatic gene therapy. This technology is clearly not available for safe use in humans today, so that these proposal do indeed have "requirements for unavailable as yet technology."

Yes, all NeoSENS proposals rely on some sort of gene therapy to alter gene expression to induce anti-senescence. The point, however, is that all other things being equal - with gene therapy becoming increasingly efficacious with acceptable safety in the context of its use - then NeoSENS hypotheses can be tested more rapidly than SENS since their assumptive framework is more firmly grounded in contemporary science and is dependent on less variables. This is particularly of relevance to SENS's telomerase ablation component of WILT and AE which address age related decreases in genomic stability in contrast to NeoSENS's enhancement of DNA repair (nuclear, mitochondrial and ribosomal) and autophagy.

while several of the SENS interventions also require somatic gene therapy, (a) several either do not, or may not (xenohydrolase; immunization against extracellular garbage; stem cell therapy; AGE breakers)

I cannot see how you will be able to avoid gene therapy in SC treatments. There is the problem of allogeneic sources for which I can only envisage gene therapy technologies as providing a solution for. Even if all the SC originate from the patient then I imagine that they still would need to be reprogrammed for safety and efficacy reasons to tissue-specific regeneration and for maximal proliferative potential. Whilst we are seeing numerous examples of transdifferentiation and dedifferentiation in research reports the numbers are not high enough to support therapeutic strategies. So the SCs will likely have to be modified - by gene therapy - to optimize their state for therapeutic use.
(I agree with you, and hope, that extracellular junk and crosslinking can be addresses by non-genetic strategies)

... the alternative proposals which you suggest involve "messing with metabolism" in ways that may or may not prove beneficial under normal conditions of aging (as opposed to eg the expectations one might form for the benefits of increased DNA repair based on experiments in cells or organisms exposed to acute, supranormal stressors such as high UV, oxidant stress from xanthine oxidase, etc), whereas SENS by definition attacks targets which are, by their nature, accumulating, pathological lesions ...

Whether they prove beneficial or not will, of course, have to be determined by experiment. The experiments performed to date, have for reasons of expediency, focused on addressing extreme genomic stressors (it would take a considerably longer time to test if increased DNA repair, for example, results in increased lifespan, rather than testing that it results in increased capability to deal with an adverse ROS environment) . Therefore it would be erroneous to dismiss such interventions by assuming that they would *only* be of therapeutic benefit under such extreme conditions, until proven otherwise.

... it seems much clearer that SENS interventions (a) will actually have beneficial effects on age-related pathology and on aging itself, and (b) will be of benefit to people who have already suffered a significant level of aging damage.

I am not sure how it seems clearer that SENS interventions can more directly address senescence than NeoSENS. Perhaps you can explain this. In my view, gene regulation is more central to aging than any other factor. NeoSENS more directly seeks to address this issue.

... there are 10's of THOUSANDS of people right now who would be in wheelchairs or worse if the "get all the research done first" crowd had prevented the use of knee replacements.

Of course - I think you have misunderstood me. I am not advocating that we are obligated to know in precise detail the mechanisms of aging in order that we embark on the work towards a solution. I am underlining the importance, in respect to mobilizing the scientific community, of placing more effort in presenting the SENS solution set in a scientifically palatable fashion. For example, Aubrey published a paper on the use of inteins as a means of delivering hydrophobic proteins into mitochondria as support for AE. This is the sort of thing that we need more of - and perhaps where the energies of those with the benefit of relevant academic backgrounds - such as Michael and Osiris, who are both published in RR - should be directed to. I think it is worth thinking about to write a few papers on the possible implementations of SENS with particular focus on methodology and likely outcomes ("connecting the dots"). At the worst, it is possible that it will galvanize anti-SENS scientists to attempt to repudiate either by correspondence or by experiment. At best it may motivate some to conduct some experimental work of relevance. In either case it may serve to increase awareness and discussion of SENS further within the scientific community.

Just because I have my views on SENS does not mean I would be disinclined to contribute in the preparation of such manuscripts. Our efforts could then be spent synergistically in a way that serves to promote SENS as well as further refine the science behind it.

#11 Michael

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Posted 17 April 2005 - 05:37 AM

All:
[quote]
[quote]
Michael: Most such proposals rely on gene therapy, and if it is to be effective "in those of us unfortunate enough to be already alive," that means somatic gene therapy. This technology is clearly not available for safe use in humans today, so that these proposal do indeed have "requirements for unavailable as yet technology."[/quote]
prometheus:Yes, all NeoSENS proposals rely on some sort of gene therapy to alter gene expression to induce anti-senescence. The point, however, is that all other things being equal - with gene therapy becoming increasingly efficacious with acceptable safety in the context of its use - then NeoSENS hypotheses can be tested more rapidly than SENS since their assumptive framework is more firmly grounded in contemporary science and is dependent on less variables.[/quote]
Again, I don't think that that's accurate, particularly in cases not involving gene therapy. We already have prototype AGE breakers and extracellular-junk-removers (amyloid immunotherapy), and the first therapies for the xenohydrolase project would  essentially be extensions of existing therapies for the recognized lysosomal storage diseases.
[quote]
prometheus: This is particularly of relevance to SENS's telomerase ablation component of WILT and AE which address age related decreases in genomic stability in contrast to NeoSENS's enhancement of DNA repair (nuclear, mitochondrial and ribosomal) and autophagy.[/quote]
Allotopic expression of mt-coded proteins requires somatic gene therapy, but has AFAICS no more challenging aspects to its implementation, based on the recent rate of progress in identifying viable nuclear-coded versions of human mt-coded genes and successful cellular rescue therewith.

The most rapid progress in WILT will not require somatic gene therapy: it will use autologous stem cells which will be genetically manipulated ex vivo, clonally expanded, and then delivered to the patient. This is likely to be relatively trivial quite shortly, and certainly long before the same can be said of somatic gene therapy. If the manipulation of postmitotic cells in situ proves necessary, then again this appears to be the most difficult hurdle it faces.

Autophagy: see my previous post on restoring youthful autophagy within SENS.

But as I said:
[quote]
[quote]
Michael:while several of the SENS interventions also require somatic gene therapy, (a) several either do not, or may not (xenohydrolase; immunization against extracellular garbage; stem cell therapy; AGE breakers)[/quote]
prometheus: I cannot see how you will be able to avoid gene therapy in SC treatments. There is the problem of allogeneic sources for which I can only envisage gene therapy technologies as providing a solution for.[/quote]
First: I doubt that allogeneic sources will be favored for most applications: either direct use of autologous stem cells, or SCNT, will be chosen instead. However, even if allogeneic cells are used:
[quote]prometheus:Even if all the SC originate from the patient then I imagine that they still would need to be reprogrammed for safety and efficacy reasons to tissue-specific regeneration and for maximal proliferative potential.[/quote]
Again, the necessary genetic reprogramming for most SENS proposals, if required at all, can be accomplished ex vivo, a much less technically challenging technique than somatic gene therapy.

By contrast, somatic gene therapy would be an essential component of most "NeoSENS" proposals from the get-go.

[quote]
[quote]
Michael: the alternative proposals which you suggest involve "messing with metabolism" in ways that may or may not prove beneficial under normal conditions of aging (as opposed to eg the expectations one might form for the benefits of increased DNA repair based on experiments in cells or organisms exposed to acute, supranormal stressors such as high UV, oxidant stress from xanthine oxidase, etc), whereas SENS by definition attacks targets which are, by their nature, accumulating, pathological lesions[/quote]
prometheus: Whether they prove beneficial or not will, of course, have to be determined by experiment. The experiments performed to date, have for reasons of expediency, focused on addressing extreme genomic stressors (it would take a considerably longer time to test if increased DNA repair, for example, results in increased lifespan, rather than testing that it results in increased capability to deal with an adverse ROS environment) . Therefore it would be erroneous to dismiss such interventions by assuming that they would *only* be of therapeutic benefit under such extreme conditions, until proven otherwise.[/quote]
The examples of antioxidants, statins, and antiinflammatory drugs would seem to suggest this, however, as does the general thrust of evolutionary theory (pleiotropy).

[quote]
[quote]
Michael:it seems much clearer that SENS interventions (a) will actually have beneficial effects on age-related pathology and on aging itself, and (b) will be of benefit to people who have already suffered a significant level of aging damage.[/quote]
prometheus: I am not sure how it seems clearer that SENS interventions can more directly address senescence than NeoSENS. Perhaps you can explain this.[/quote]
The accumulating molecular lesions targeted by the SENS platform are intrinsically and entirely deleterious, and their removal or obviation intrinsically and entirely beneficial. The real questions at this point are the extent to which this will benefit aging per se as vs. age-related disease (eg. souped-up lysosomes might "only" cure atherosclerosis).
[quote]
prometheus:
In my view, gene regulation is more central to aging than any other factor.[/quote]
Well, of course, as you know I disagree; my position is that age-related shifts in gene expression are mostly or exclusively secondary to primary aging damage.
[quote]
prometheus: NeoSENS more directly seeks to address this issue.[/quote]
The dangers of making gene expression itself a therapeutic target follow from their secondary nature, and are also illustrated by recent experience with pharmaceuticals. To take some facile examples of the former: damping down the age-related increases in the expression of inflammatory signaling molecules and antioxidant enzymes will not improve, and may in some cases exacerbate, the underlying pathology. Addressing the underlying damage to which these inductions of genes are a response is both more effective and safer a priori.

As to the latter: again, pleiotropy. See the side effects of COX-2 inhibitors and of statin drugs (with the slight alteration that the proposed drugs would be COX-2 or HMG-CoA gene expression inhibitors instead of enzyme inhibitors). A gene expression Vioxx would be a questionable tradeoff in most cases of even the relatively severe inflammation for which it would normally be prescribed; the precise modulation of COX-2 to at once counteract the more subtle induction in inflammation due to aging yet avoid excessive reductions in PGI2 etc would be a significantly more challenging and ultimately fraught endeavor.

As SENS proposes, the favored route is to not attempt to outsmart metabolism, but to allow the organism's complex networks to operate normally, and clean up the mess that they make before it becomes pathological. To expand on the Mouse's point, knee replacement is to be favored over anti-inflammatory drugs.
[quote]
prometheus: I think it is worth thinking about to write a few papers on the possible implementations of SENS with particular focus on methodology and likely outcomes ("connecting the dots").[/quote]
Well, of course, Aubrey HAS done a lot of this -- not only in brief form in his core SENS papers (1-3), but in detail for allotopic expression of mtDNA (4), lysosomal enhancement with xenohydrolases (5), and WILT for cancer (6).
[quote]
prometheus: At the worst, it is possible that it will galvanize anti-SENS scientists to attempt to repudiate either by correspondence or by experiment. At best it may motivate some to conduct some experimental work of relevance. In either case it may serve to increase awareness and discussion of SENS further within the scientific community.[/quote]
Yes. It's quite embarrassing how willing many biogerontologists are to either ignore or pooh-pooh SENS without offering any basis for doing so, and often without any understanding of the platform.  In their debate, Dick  Sprott totally failed to address any of de Grey's actual proposals, choosing instead to wave his hands, but Sprott was at least willing to engage in an open debate as opposed to those gerontologists who refuse to go on the record with their critiques of de Grey or who snipe behind his back, as did an anonymous reviewer to my recent rebuttal to the excessive pessimisim of the Journals of Gerontology special edition on anti-aging medicine: "Rae laments that he 'has yet to hear a cogent rejoinder to these proposals from the "anti-aging" skeptics'; in my view it's because we skeptics have yet to see [anything] even remotely convincing from de Grey and his ilk [!], and don't wish to draw further public attention to this fringe movement" [emphasis mine].
[quote]
prometheus: Just because I have my views on SENS does not mean I would be disinclined to contribute in the preparation of such manuscripts. Our efforts could then be spent synergistically in a way that serves to promote SENS as well as further refine the science behind it.[/quote]
Prometheus, if you feel you have some ways to advance the SENS project in the peer-reviewed press -- either by way of concrete "connection of dots" or even via critique, as a gadfly -- I would strongly urge you to get some electrons humming!

-Michael

1. 8. de Grey AD.
An engineer's approach to the development of real anti-aging medicine.
Sci Aging Knowledge Environ. 2003 Jan 8;2003(1):VP1. Review.
PMID: 12844502 [PubMed - indexed for MEDLINE]
http://www.gen.cam.a...ens/focusPP.pdf

2. de Grey AD.
Challenging but essential targets for genuine anti-ageing drugs.
Expert Opin Ther Targets. 2003 Feb;7(1):1-5. PMID: 12556198 [PubMed - as supplied by publisher]
http://www.gen.cam.a...sens/manu21.pdf

3. de Grey AD, Ames BN, Andersen JK, Bartke A, Campisi J, Heward CB, McCarter RJ, Stock G.
Time to talk SENS: critiquing the immutability of human aging.
Ann N Y Acad Sci. 2002 Apr;959:452-62; discussion 463-5.
PMID: 11976218 [PubMed - indexed for MEDLINE]
http://www.gen.cam.a...sens/manu12.pdf

4. de Grey AD.
Mitochondrial gene therapy: an arena for the biomedical use of inteins.
Trends Biotechnol. 2000 Sep;18(9):394-9. Review.
PMID: 10942964 [PubMed - indexed for MEDLINE]
http://www.gen.cam.ac.uk/sens/allo.pdf

5. de Grey AD.
Bioremediation meets biomedicine: therapeutic translation of microbial
catabolism to the lysosome.
Trends Biotechnol. 2002 Nov;20(11):452-5.
PMID: 12413818 [PubMed - indexed for MEDLINE]
http://www.gen.cam.a...sens/manu15.pdf

6.  de Grey AD, Campbell FC, Dokal I, Fairbairn LJ, Graham GJ, Jahoda CA, Porterg AC.
Total deletion of in vivo telomere elongation capacity: an ambitious but
possibly ultimate cure for all age-related human cancers.
Ann N Y Acad Sci. 2004 Jun;1019:147-70. Review.
PMID: 15247008 [PubMed - indexed for MEDLINE]
http://www.gen.cam.ac.uk/sens/WILT.pdf

7. Rae MJ.
All hype, no hope? Excessive pessimism in the "anti-aging medicine" special sections.
J Gerontol A Biol Sci Med Sci. 2005 Feb;60(2):139-40. No abstract available.
PMID: 15814852 [PubMed - in process]
http://biomed.geront...t/full/60/2/139

Edited by caliban, 27 August 2012 - 07:54 PM.
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#12

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Posted 17 April 2005 - 03:35 PM

prometheus: I am not sure how it seems clearer that SENS interventions can more directly address senescence than NeoSENS. Perhaps you can explain this.

The accumulating molecular lesions targeted by the SENS platform are intrinsically and entirely deleterious, and their removal or obviation intrinsically and entirely beneficial. The real questions at this point are the extent to which this will benefit aging per se as vs. age-related disease (eg. souped-up lysosomes might "only" cure atherosclerosis).

In my view, the only SENS solution that can more directly address senescence would be the "scaffold" component of WILT (systemic stem cell replenishment) for those cells that are beyond repair.

The dangers of making gene expression itself a therapeutic target follow from their secondary nature, and are also illustrated by recent experience with pharmaceuticals. To take some facile examples of the former: damping down the age-related increases in the expression of inflammatory signaling molecules and antioxidant enzymes will not improve, and may in some cases exacerbate, the underlying pathology. Addressing the underlying damage to which these inductions of genes are a response is both more effective and safer a priori .

I don't think using the experiences of pharmaceuticals is a suitable argument against genetic interventions for aging. Pharmaceutical approaches are generally designed to provide symptomatic relief rather than attempt to repair or correct the cause of pathology which in some cases may not be well understood or known. Genetic approaches seek to deal with the cause as specifically as possible, and aging is very strongly correlated with genetics. The fact remains that some humans have a lifespan of 115 years whilst others are limited to only 45 years within the same environment. Cells in the lab, with certain genetic modifications can be made to be immortalized. Cancer as a form of cellular immortalisation, achieves this state due to specific genetic changes.

The solution of increasing DNA repair in the nucleus and particularly in the nucleolus (ribosomal DNA) as well as in mitochondria is easier for now to implement, at least experimentally, than AE or WILT, by means of overexpression (or youthful expression) and targeting. The DNA repair factors chosen to be enhanced do not have to be associated with those that increase mutagenicity or could otherwise be possibly deleterious ("messing with metabolism") but those that are known to have no side effects such as OGG1. Furthermore, the reality that an age related general drop in rate of transcription is occurring cannot be ignored (as it seems to be), as well as consequences such as reduced autophagy.

As SENS proposes, the favored route is to not attempt to outsmart metabolism, but to allow the organism's complex networks to operate normally, and clean up the mess that they make before it becomes pathological. To expand on the Mouse's point, knee replacement is to be favored over anti-inflammatory drugs.

Whilst I appreciate the elegance of a solution that can ignore metabolic complexity whilst decoupling metabolism from pathology (SENS) I am sure you can appreciate the notion that enhancing genomic stability by simple genetic interventions (NeoSENS) may decrease senescence. Naturally this solution set relies on the assumption that genomic instability is the seat of senescence. Which brings us to what causes the instability...

..my position is that age-related shifts in gene expression are mostly or exclusively secondary to primary aging damage.

You are of the view that it is aging damage that causes changes to gene expression. With the possible exception that some aging is due to a developmental program of altered methylation patterns, I largely agree. It is damage that causes changes in gene expression. It is this damage that NeoSENS seeks to prevent/repair. Any solution that aspires to extend lifespan will have to deal with reengineering the inherent limits placed on somatic cells due to evolutionary contraints. One of these constraints, in my view, is a reduced investment in genomic stability.

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