141 replies to this topic

[DJS]

[Jay, just to let you know, if you pull the names out of the quote tag the software bug goes away]

So you didn't mean tenable, you meant required?

No, I meant tenable.

neoSENS is the advocacy of SENS with a strong DNA repair component incorporated into it. As such, it is arguing for a redesign/repackaging of SENS. Such a repackaging could come at considerable cost, both in terms of PR and possible loss of credibility within the scientific community.

What I am contending is that SENS should not be tampered with unless there is solid evidence that it is in some way deficient. By your own admission...

Is DNA repair "required" for SENS to effect escape velocity? No.

SENS, as proposed, could work. IOW, it is a respectable scientific proposal.

One must remember that, with 10 to 20 years before the relevant technologies start to become feasible, the most important function of SENS is as a PR vehicle. Trying for a partial redesign only muddies the waters.

Therefore IMHO, without DNA repair being *required*, your position is untenable.

Again though, to make my position clear, I am not arguing against the development of DNA repair. I am only arguing against the inclusion of your proposed strong DNA repair component within SENS.

[DJS]

Jay

Concrete?

It's no more speculative than allotopic expression of mtDNA. Recet work (2003) has shown that such expression is both toxic in the cytosol and ineffective at import, and what few proteins make it into the mitochondria don't seem to affect the bioenegertic state. Sounds about as effective as anti-oxidant and DNA repair research so far. Entirely speculative.

Yeah, you're right. Concrete was a poor choice of words, but if you look at the post I just made I think it will clarify the idea I was trying to express (ie, my conservative persuasion regarding modifications to SENS) .

[ag24]

I'm going to try this quote thing at last. I bet I will totally mess it up. No laughs please.

Jaydfox

If nuDNA damage is not responsible for anything significant other than cancer, and if cancer rates rise significantly faster than DNA damage rates, and if indeed those cancer rates have a doubling period approximating most of the other age-related causes of death, and if all these age-related causes of death have their roots in non-nuDNA damage causes (primarily oxidaditive damage and accumulation of intra- and extra-cellular junk and crosslinks, as well as defective/inadequte cells and cells with aberrant hormonal output or function; i.e. the other 6 of 7 aspects of SENS), then shouldn't we see an appreciable drop in both the rate and doubling rate of cancer incidence?

Good question. No, but not for any of the reasons yet raised. The reason we shouldn't see that is because cancers take a very long time to get from a single angry cell to a clinically relevant cancer, as we can tell by, for example, the fact that people only die of lung cancer a long time after they started smoking. The reason age-related problems rise exponentially is that they are the result of a large number of independent events that have a low probability of all happening at an early age because of simple statistics.

I should also say, however, that it's not impossible that the rate of growth of pre-existing cancers would be slowed by the thorough implementation of the other six SENS strands. There is still some debate, but it's likely that a large part of why caloric restriction and growth hormone deficiency extend mouse lifespan so much is that they slow down the rate of growth of cancers rather than their age of initiation. In my book in 1999 I estimated a 10% chance that we would halve the rate of everything else just by the single intervention of complete allotopic expression. I would still say there's at least a 5% chance that that would occur. But a more likely scenario is that the interdependence of the seven strands is less than that, and in particular that cells that are already most of the way to being clinically relevant cancers are not going to be slowed down very much by doing the rest of SENS in middle-aged people.

Edit: Quote tag correction -- DS

[ag24]

Humph. OK, can one do this quote business without going to the other screen via the "add reply" button?

[Bruce Klein]

4 Step to Quote:


1. in topic view, click "Quote" button


2. in advanced edit mode, cursor highlight paragraph text..


3. in advanced edit mode, click "Quote" in top edit bar (while text is black highlighted) and quote code will wrap around text.


4. You may wish to copy and move paste the text to different location and reply from there.

Result from above example:

Humph. 

OK, can one do this quote business without going to the other screen via the "add reply" button?

OK, can one do this quote business without going to the other screen via the "add reply" button?

[jaydfox]

...cells that are already most of the way to being clinically relevant cancers are not going to be slowed down very much by doing the rest of SENS in middle-aged people.

I'll buy that (for cells that are most of the way there).

Okay, let me put it this way, and see if you think my logic is reasonably sound.

nuDNA rates were found in Barja's study (1) not to be affected by CR, yet we know that cancer is appreciably affected by CR. So, why do those rates drop? I've assumed that it's because cancer defenses can be upregulated significantly, and hence that cancer incidence can be sharply curtailed. In other words, if it hasn't gone cancerous yet, then a significant barrier is thrown up which lowers the incidence rate, and slightly lowers the doubling rate (or, increases the doubling period).

However, I'll buy the idea that it's merely a severe slowing of progression of existing cancers and near-cancers.

In that light, or assuming that's true, I suppose another way to view it is from reliability theory. If 12 redundant cancer defenses have to be overcome (or, perhaps, 12 mutations must occur to circumvent the checks and balances and allow metastasis), then upon instituting 6/7 SENS, the cells that had 9 of 12 or 11 of 12 defenses circumvented will still have 9 or 11 of 12 circumvented. If the mean failure rate is then cut in half (in other words, if 6/7 SENS cuts relevant oxidative and DNA damage rates in half), then it should take twice as long for those last 1 or 3 defenses to be circumvented.

The interesting thing is that if all cells were pristine, then this should double the doubling period (or halve the doubling rate). The really interesting thing, however, is that for cells that have 9 of 12 independent systems circumvented already, the doubling rate would only increase by about 25% (because the other 75% is for systems that are already circumvented). I haven't done the maths, but intuitively I think this is what will happen. So I'm guessing that 6/7 SENS will actually have a non-linear benefit, such that a 40-year-old might have his remaining life expectancy doubled, but a 65-year-old might have his remaining life expectancy increased 50%.

Dr. de Grey, or Prometheus for that matter, would you say that 6/7 SENS would likely have more affect on the cancer incidence doubling rate in younger patients than in older?

(1) Gredilla, R.; Sanz, A.; Lo´pez-Torres, M.; Barja, G. Caloric restriction decreases mitochondrial free radical generation at Complex I and lowers oxidative damage to mitochondrial DNA in the rat heart. FASEB J. 15:1589–1591; 2001.

(edit, added the reference [1])

[jaydfox]

SENS, as proposed, could work. IOW, it is a respectable scientific proposal.

Sure. I have no problem programming death into mice, or dogs, or monkeys, or chimps. For controlled studies with human patients, I'm not even against it. Yes, as a scientific proposal, it's quite respectable.

But I don't think it's a good idea for society as a whole, for societies, for all of human civilization, given all the possible scenarios where it can cause as much or more death than it fixes (and precisely among that segment of society necessary to continue medical research, the early- and mid-adopters, not the poor masses), and given that its sheer cost can prevent rapid widespread adoption by a large percentage of earth's population.

It's still a hell of a good backup option, but there's still so much time between now and 2030 to research and develop the primary plan. And since I'm contending that the primary plan will build on 80%-90% of WILT anyway—the WILT scaffolding—there's no need to scrap WILT. It's not so much a modification as an addition. DNA damage causes cancer, so de Grey is curing cancer with WILT. But there's still the DNA damage, and we'll need to address it, either to increase the effectiveness of WILT if it's still found to be necessary by 2030, or to replace WILT if it's not.

Scientifically, is it required? No, in the engineering sense, shoddy damage prevention is obviated by frequent repair.

Pragmatically, it is definitely required. Capacity for frequent repair of 250 million patients or infrequent repair of 500 million patients, and suddenly a much higher cancer rate becomes acceptable, because it saves more lives overall (even assuming we take the pessimistic view of the prospects for DNA repair, which I think are unwarranted, but we'll take that view for the sake of argument; with a more optimistic view, the cancer rates won't be appreciably higher except in the extremely elderly [70-80 years old or more], for whom I already accept the utility of WILT; in the merely middle aged, 50-60, the cancer rates should be impacted much more by effective DNA repair).

[ag24]

I was always fonder of this quoting style anyway...

> for cells that have 9 of 12 independent systems circumvented already, the doubling rate
> would only increase by about 25% (because the other 75% is for systems that are
> already circumvented). I haven't done the maths, but intuitively I think this is what will
> happen. So I'm guessing that 6/7 SENS will actually have a non-linear benefit, such that
> a 40-year-old might have his remaining life expectancy doubled, but a 65-year-old might
> have his remaining life expectancy increased 50%.

Nice argument. No, unfortunately, because the types of damage accelerate each other. Cancers that initiate early initiate in bodies that hardly have any of the damage that SENS removes -- they do so despite the absence of that damage. So yor calculation would have to take into account the basal level of tumorigenesis that exists even in the absence of any (non-nuDNA) damage.

[jaydfox]

Nice argument. No, unfortunately, because the types of damage accelerate each other. Cancers that initiate early initiate in bodies that hardly have any of the damage that SENS removes -- they do so despite the absence of that damage. So yor calculation would have to take into account the basal level of tumorigenesis that exists even in the absence of any (non-nuDNA) damage.

I thought I was taking that into account. I was assuming that non-nuDNA damage only accounted for (i.e. caused) half of the nuDNA damage that might lead to cancer. In any given individual, removing all non-nuDNA damage might not affect existing microtumors or cells that are one or two steps away from becoming tumors.

But across the population, in an actuarial sense, we'll have a distribution, and this distribution will respond in a predictable manner, even if any particular individual won't. I wasn't talking about any specific person's chances of getting cancer (though my wording may have implied such), I'm talking about cancer incidence rates as a function of the population. Cancers don't initiate early in everyone, only in a small subset, so that argument doesn't affect the overall argument. At higher age brackets in the population, the chance of a tumors or near-tumors rises, thus decreasing the ability to modulate the doubling rate.

Perhaps I was overoptimistic in saying a 40-year-old could have his remaining cancer-limited life expectancy doubled, but it seems there would be more benefit to such a person than to a 65-year-old, statistically speaking (as a function of the population), because that person is far less likely to have any cells that are 11/12 of the way to being cancer, and far fewer cells that are 9/12 of the way, or 7/12 of the way, than someone in the 65-year-old age bracket.

[ag24]

> supporting evidence vignette for DNA repair


But not specifically for non-cancer-related DNA repair...


> Perhaps I was overoptimistic in saying a 40-year-old could have his remaining
> cancer-limited life expectancy doubled, but it seems there would be more benefit
> to such a person than to a 65-year-old, statistically speaking

Yes - there would be some, I agree. I'm just saying it could easily be very minor.

[wall]

The architect comes up with the ambitious plans and the contractor tells him they can't be built.

[Michael]

supporting evidence vignette for DNA repair

I think it was Kevin who first posted the study linking the beneficial effects of caloric restriction to increased DNA repair (1). This is another key neoSENS supporting study since it demonstrates that normal DNA repair rate is sub-optimal because CR mediates its effects by increasing the rate of DNA repair (Michael take note).

However, when you dig further into the CR literature, you see that (as is the case with eg antioxidant enzyme activity) the effects of CR on DNA repair vary both by organelle and by tissue in ways that do not permit a simple "CR increases DNA repair" summary, let alone the conclusion that CR exerts its anti-aging effects via increased DNA repair or that those CR-induced increases in DNA repair which are observed exert benefits outside of reduced cancer incidence. The effect of aging is also inconsistent (but IAC see further on this below). Eg:

Repair of DNA strand breaks was efficient at all ages. Diet had little effect on these endpoints. Diet had no influence on 8-oxo-7.8- dihydroguanine levels in DNA from liver, testis and brain of 17 month old rats. Combining data from all four groups, the levels in brain and liver were significantly higher at 17 months compared with 1 month. Antioxidant enzyme activities tended to increase between 1 and 17 months; effects of diet were not so consistent. Conclusions: While DNA damage shows a modest increase with age in some organs, antioxidant status and DNA strand break repair do not decline with age. Restricted diets (including protein and calorie restriction) have no effect on any of these markers of genetic stability. (4)

Mitochondria isolated from CR mice had slightly higher uracil (UDG) and oxoguanine DNA glycosylase (OGG1) activities but marginally lower abasic endonuclease and polymerase gamma gap-filling activities, although these differences were tissue-specific. Uracil- initiated BER synthesis incorporation activities were significantly lower in brain and kidney from CR mice but marginally enhanced in liver. However, nuclear repair synthesis activities were increased by CR, indicating differential regulation of BER in the two compartments. The results indicate that a general up-regulation of mitochondrial BER does not occur in CR." (5)

What's even more striking is an earlier study  which looked at the relationship between aging and DNA repair rate where in all tissues tested of old (22 month) mice, including brain, heart and liver it was found that a 50 - 75% decline in base excision repair occurred (2).

It's important to remember that to show that something changes with aging is not to show that it is causally involved with aging rather than secondary to something else (as eg. oxidative stress, or some accumulating molecular damage caused by a primary aging process). Since BER is an enzymatic process, and since genetically "programmed aging" is contrary to evolutionary theory etc (6), the latter is the most parsimonious hypothesis (cf previous discussions re: age-related shifts in gene expression).

Finally a mouse study where a DNA repair protein was overexpressed found that the incidence of liver cancer was dramatically reduced (3).

Sure -- but of course, it's acknowledged by all that nuDNA damage is required for the development of cancer, and so reducing or repairing this damage might reasonably be expected to reduce cancer risk. (Even here we must be careful, however: "messing with metabolism" is always risky, as Aubrey emphasizes. For instance, since cell studies (7) have found that a constitutive process appears to exist to repress the lengthening of telomeres by ALT, this suggests that ALT itself may be a constitutive process -- such as, for instance, part of some essential DNA repair mechanism ...).

The question from the point of view of prioritizing interventions to reach "actuarial escape velocity" is not whether nuDNA mutations can be carcinogenic (which is uncontroversial), but whether they important to aging per se within a currently "normal" lifetime.

-Michael

(1) DNA Repair (Amst). 2003 Mar 1;2(3):295-307.
Caloric restriction promotes genomic stability by induction of base excision repair and reversal of its age-related decline.
Cabelof DC, Yanamadala S, Raffoul JJ, Guo Z, Soofi A, Heydari AR.

(2) Mutation Research 500 (2002)135–145
Attenuation of DNA polymerase -dependent base excision repair and increased dimethyl sulphate-induced mutagenicity in aged mice
Diane C. Cabelof , Julian J. Raffoul , Sunitha Yanamadala, Cirlette Ganir, Zhong Mao Guo, Ahmad R. Heydari (attached)

(3) Mech. Ageing Dev. 98 (1997), pp. 203–222
Analysis and modulation of DNA repair in aging.
C.A. Walter, D.T. Grabowski, K.A. Street, C.C. Conrad and A. Richardson

4. Gedik CM, Grant G, Morrice PC, Wood SG, Collins AR.
Effects of age and dietary restriction on oxidative DNA damage, antioxidant
protection and DNA repair in rats.
Eur J Nutr. 2004 Jul 28; [Epub ahead of print]
PMID: 15278370 [PubMed - as supplied by publisher]

5. Stuart JA, Karahalil B, Hogue BA, Souza-Pinto NC, Bohr VA.
Mitochondrial and nuclear DNA base excision repair are affected differently by
caloric restriction.
FASEB J. 2004 Mar;18(3):595-7. Epub 2004 Jan 20.
PMID: 14734635 [PubMed - indexed for MEDLINE]

6. Kirkwood TB, Austad SN.
Why do we age?
Nature. 2000 Nov 9;408(6809):233-8.

7. Perrem K, Bryan TM, Englezou A, Hackl T, Moy EL, Reddel RR.
Repression of an alternative mechanism for lengthening of telomeres in somatic
cell hybrids.
Oncogene. 1999 Jun 3;18(22):3383-90.
PMID: 10362359 [PubMed - indexed for MEDLINE]

[jaydfox]

since genetically "programmed aging" is contrary to evolutionary theory etc (6)

Michael Rae, I'm surprised you would say something so patently indefensible. Contrary how? There are dozens of not-yet-experimentally disputed evolutionary theories of aging, and while stochastic decay plays some role in all of them, genetic programming nonetheless has not been disproven, and evidence exists in some limited basis.

Please elaborate.

(Yes, I realize you cited a reference, but I don't have access to it, and at any rate it could hardly be definitive given the controversy around evolutionary theories of aging, controversies I don't see being settled for decades.)

[jaydfox]

Michael Rae, how do you define "programmed aging". Is that aging which is programmed to intentionally shorten lifespan, or simply aging that is programmed to impair function relative to youthful function? There is clear evidence for the latter, though the evidence for the former, outside of anamolies like salmon, is not as strong.

[DJS]

I really can not understand why you and Prometheus insist on using the term "programmed" when your conception of the term is clearly different from its traditional meaning in aging theory. I feel like this is ground hog day or something... [lol]

At some point along its aging trajectory, a species will arrive at peak reproductive fitness, after which extrinsic mortality factors will gradually erode away the selection pressure that kept repair mechanisms at an optimum. With no selection pressure being placed on repair, it will become an expendable biological function.

And usually with evolution, anything that is expendable is expended.

Evolution is all about efficiency. Why would it continue to divert resources to repair when it could make use of them some where else (where there is a selection pressure)?

But I do not believe that you disagree with this line of reasoning. Instead, you are maitaining that evolution is selecting for a diversion of resources away from repair. You call this programmed, others call this neglect.

[DJS]

Prometheus

Whilst I doubt the existence of aging genes per se, I believe in the existence of regulatory mechanisms that are designed to decrease their investment in somatic survivability after a period, with the germline following not far behind

You see Prometheus, this is thoroughly sensible to me, but why do you insist on calling it programmed? Surely you are aware that this gives many readers the wrong impression at first glance. It seems to me that your contention falls entirely within the disposable soma/pleiotropy theories of aging.

[jaydfox]

You see Prometheus, this is thoroughly sensible to me, but why do you insist on calling it programmed?

First of all, I didn't start using the term programmed, to my knowledge. I simply said that less than optimal DNA repair has evolved, been selected for, etc. I believe I used the appropriate terminology, at least in most of my posts.

But as long as we're on the topic of programming, if less-than-optimal DNA repair has been selected for, and if this results in aging, and if we can UNDO that, then why does it matter if I call it programmed. The point is, Michael Rae made the implicit statement that DNA repair is currently optimal for longevity (assuming we fix everything else), and that it cannot be increased significantly by manipulation of existing systems, because it isn't programmed to be deficient in the first place. Programmed, or "evolved" through selection, he contends it isn't less than what's possible for longevity.

Yet we see evidence from supercentenarians—whose DNA repair is arguably not much more "optimal" than ours is (the population can only be so heterogenous with only 6 billion data points, as statistical outliers become super-exponentially less common with each standard deviation we move away from the mean)—that DNA repair and cancer prevention (which to de Grey are one and the same thing, since nothing besides cancer matters) are exceedingly perturbable in humans.

And through manipulation of existing systems, we can engineer as many standard deviations as the genome will support, which given the number of variables involved—130 genes and probably a thousand or more regulatory systems (mRNA, etc.)—we should be able to perturb to our hearts' desire. DNA repair can only go so far without fixing the other problems of course (especially mitochondrial ROS production), but hey, that's why I'm not against 6/7 SENS being used in tandem. Which is why I advocate making the SENS platform more comprehensive by inclusion of a real DNA repair/maintenance strategy: the two are inherently complementary. Perhaps it's de Grey's responsibility, perhaps not, to make such an inclusion, but for ImmInst, this inclusion in discussions and presentations of escape velocity and SENS is essential!

Given the number of variables we're talking about manipulating, that's why I advocate the Fly Prize, to at least try to cull from our gene space all the axes of non-additive and/or incompatible gene perturbations, so that we have a greatly reduced subset that could reasonably be tested in mice for less than $10 million to $100 million, let alone less than a billion (which is what it would probably take to do a halfway thorough job without such an initial culling).

Yes, DNA repair would be fairly expensive to research through strict trial and error in lifespan studies in mice, but given the evolutionary implications of huge numbers of systems being preserved from at least as long ago as when yeast split from us (which predated the split of insects by a couple hundred million years or so, if I recall, but don't quote me), such a culling should be pretty efficient. It might miss some combinations of genes here and there, but there's more than likely more than just one or two or ten optimal combinations, given the number of variables, so it's an acceptable risk to lose a combination here and there.

At any rate, the Fly Prize is not proposed as a component of SENS, just DNA repair. The Fly Prize could be ImmInst's contribution to SENS, as the project should be small enough and inexpensive enough (compared to the M Prize) to be manageable by us. But like I said, DNA repair is what's before us for discussion, not the Fly Prize.

(Edit: fixed an HTML typo)

[jaydfox]

the implicit statement that DNA repair is currently optimal for longevity (assuming we fix everything else)

I suppose I should clarify, so Micharl Rae doesn't take offense.

Obviously, DNA repair is not optimal for indefinite or even greatly increased lifespans, even if we assume the only negative consequence of suboptimal DNA repair is cancer. This was the reason for the birth of WILT, because it was assumed that DNA repair could not be enhanced enough to solve the cancer problem (by solve, I don't mean cure completely, because for escape velocity, we don't need a total, perfect cure, just a really good one).

What I meant was, Michael Rae made the implicit statement that DNA repair is currently optimal or very nearly optimal for what is physically possible through evolution alone, even if evolution were selecting solely for longevity, regardless of the negative impact of such selection on individual fitness (e.g. increased DNA repair comes at a metabolic cost that reduces fitness in the real world of predators and limited resources, etc.).

Or in other words, increasing DNA repair sufficiently to increase longevity is not a trivial matter of modulating the expression of existing genes (something that can be tweaked in a few hundred or few thousand generations by evolution), but would require the nontrivial evolution of new systems and genes (which would require millions or tens of millions of years and a great deal of luck), similar to the concept of moving mtDNA genes to the nucleus or creating a new SOD for the MIMS, both of which have apparently turned out to be nontrivial evolutionary tasks.

I contend that the former is indeed the case: that with an adequate selective pressure for longevity, human lifespan could be extended by a very large percentage in a few hundred or few thousand generations, without the creation of nontrivial new systems or genes. And if this is the case, then genetic engineers should be able to accomplish the same thing without performing such super-multi-generational studies. But the best part is, the genetic engineers don't have to tweak all MLSP-limiting factors, which would involve handling tons of feedback issues and metabolic tradeoffs. They'd only have to address the DNA issue, as 6/7 SENS will handle the other MLSP-limiting factors.

Hence, achieving the feat of doubling lifespan in a few score generations that Michael Rose achieved with Drosophila would actually be easier in humans and mice, because 6/7 SENS would allow geneticists to focus exclusively on DNA repair/maintenance, cancer prevention, and cancer defenses, and ignore issues like trying to reduce mitochondrial inner and outer membrane oxidizability, reducing leakage, increasing mitochondrial ROS scavanging, protecting mtDNA, breaking down and preventing extracellular crosslink buildup, etc., etc.

We can attack the problem piecemeal, with a group focussed on mitochodria, a group focused on intracellular junk, a group focussed on extracellular junk, a group focussed on crosslinks, a group focussed on stem cell therapies, and a group focused on greatly enhancing DNA repair/maintenance.

That's the beauty of SENS. It's just incomplete, as it stands today, without that last component.

[ag24]

Aside: shortly after my paper came out it was found that there actually is a SOD in the MIMS. Conveniently, around the same time Florian Muller improved on my hypothesis by noting that HO2 may be formed within the inner membrane itself (in the lipid phase) thereby allowing it to zap a lipid before even a MIMS SOD can get to it.

I think it's entirely possible that human DNA repair could be very much improved by evolution within a few dozen (or a few hundred anyway) generations, if the selection pressure were applied (though conditions that would give such pressure are not all that obvious -- perhaps a sharply raised exposure to carcinogens). What I don't agree with you about is, I claim that to do this we would need to improve our enzymes, not just their level of expression, and we don't know how to do that -- not just we don't know the details (as with allotopic expression), we don't know where to start. Conceivably enzymes from other organisms might be useful (radiation-resistant ones, e.g.), but more likely those enzymes would just not work (because the chromatin is packed with different proteins, e.g.)

I have said this several times now and I don't recall an answer. You've repeated your hunch that raising expression would suffice, but no data supporting this has been cited, only data showing that raising expression protects against igh exposure to mutagens (which is no surprise but irrelevant). I've pointed out that enzymes that are needed to respond to highly unpredictable events (spikes in ROS production, e.g.) are typically present in considerable excess because it's better not to have to wait for them to be synthesised in response to need. This is why heterozygous knockouts for all the mouse antioxidant enzymes have a normal lifespan, for example.

[jaydfox]

Aside: shortly after my paper came out it was found that there actually is a SOD in the MIMS. Conveniently, around the same time Florian Muller improved on my hypothesis by noting that HO2 may be formed within the inner membrane itself (in the lipid phase) thereby allowing it to zap a lipid before even a MIMS SOD can get to it.

Neat!