• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo
- - - - -

The SENS Challenge - Calling all scientists


  • Please log in to reply
48 replies to this topic

#31 John Schloendorn

  • Guest, Advisor, Guardian
  • 2,542 posts
  • 156
  • Location:Mountain View, CA

Posted 31 July 2005 - 08:00 PM

Good idea, since we're all not eligible, let's play the what's wrong with SENS game on a small scale...My 2 and a half things:

(1) I think I have read everything you wrote on the "war on aging" and I'm still not as confident as you are that a mouse and some enthusiastic gerontologists on TV can effectively restore people's sense of proportion. It does make sense and might work, yes, but I'd still like to see the type of economic growth that only the for-profit route can allow up our sleeves, just in case. But this is not about the science of SENS and probably not useful for non-immortalists to hear...

(2) If you do WILT, then you would not need the molecular interventions that extend cellular life-span in those tissues where you do WILT, because cellular life-span is designed to be short at any rate. It may be a way out to insist that WILT (or WILT scaffold for that matter) will not be done in all tissues, so that organismal survival may in the end depend on the molecular interventions, too. This is getting very speculative though. As far as I'm aware of, this dilemma is not yet discussed anywhere in SENS and it might deserve being discussed. This is not critical all by itself, but might add to the argument.

(3) I think a more critical aspect is endocrine and other forms of signaling-mediated aging. The healthiest cell will shut down if the hormones tell it to shut down. So does signaling-mediated aging come from cell intrinsic age-related changes that might get fixed by SENS, or from an aged signaling environment that could cause even initially healthy cells to sustain the aged signaling environment? I think one could cite a few references that would support the latter not as a sole, but as a partially sufficient cause of aging. SENS makes no reference that I am aware of to changes of signalling networks as a potentially limiting factor in causing aging. How would your defense go on this one?

#32

  • Lurker
  • 1

Posted 01 August 2005 - 01:02 AM

If you do WILT, then you would not need the molecular interventions that extend cellular life-span in those tissues where you do WILT, because cellular life-span is designed to be short at any rate. It may be a way out to insist that WILT (or WILT scaffold for that matter) will not be done in all tissues, so that organismal survival may in the end depend on the molecular interventions, too.


Precisely. WILT would not be as directly impacting in brain or cardiac tissue. In this scenario the junk & crosslink strategies as well as allotopic expression would kick in. Which reminds me, there is no solution for chromosomal mutations in long lived cells like those of the brain and heart.

#33 DJS

  • Member
  • 5,797 posts
  • 10

Posted 01 August 2005 - 01:09 AM

Prometheus

Which reminds me, there is no solution for chromosomal mutations in long lived cells like those of the brain and heart.


I was waiting for you to mention this. Remember though, Aubrey is only presenting SENS as a path to escape velocity, not *absolute* negligible senescence. If one were going argue chromosomal mutations, then s(he) would have to demonstrate that genomic instability is a major contributor in the regular aging process.

#34

  • Lurker
  • 1

Posted 01 August 2005 - 01:29 AM

I was waiting for you to mention this. Remember though, Aubrey is only presenting SENS as a path to escape velocity, not *absolute* negligible senescence. If one were going argue chromosomal mutations, then s(he) would have to demonstrate that genomic instability is a major contributor in the regular aging process.


Chromosomal instability is the main reason WILT exists, therefore I would say that it is already considered to be a major contributor to aging.

The point of contention is in implementation. I have argued that WILT alone will not deal with all aspects of genomic instability, that cancer being the WILT target, is not the only pathological consequence of chromosomal instability and that other adverse effects associated with altered gene expression are not dealt by with WILT.

Supposing WILT works as advertised, managing to deal with the danger of chromosomal instability by replacing cells (say every 10 years or less) before perturbed gene expression can manifest, it can only do so in the cells that are not physiologically required to have a long lifespan. Cells in the tissue of brain and heart will not be have WILT protection since they are not subject to the same stem cell type replenishment observed in other tissues. In these tissues only the mitochondrial genome is protected by allotopic expression and then only so far as the nucleus itself can protect the chromosomes from DNA damage.

In my view neither WILT nor any other aspect of SENS addresses chromosomal instability in such long lived cells as those of brain and heart and this interventional gap presents a vulnerability.


Edit: increased grammatical palatability

Edited by prometheus, 01 August 2005 - 08:31 AM.


#35 John Doe

  • Guest
  • 291 posts
  • 0

Posted 01 August 2005 - 04:02 AM

This news makes me so happy.

#36 ag24

  • Topic Starter
  • Honorary Member, Advisor
  • 320 posts
  • 29
  • Location:Cambridge, UK

Posted 01 August 2005 - 11:14 AM

Hi John,

War on aging - yeah, I guess my confidence is rather subjective.

WILT versus intracellular interventions - sure, but that's true already: it's precisely the postmitotic cells that accumulate mitochondrial mutations and intracellular aggregates. Decadal replenishment is for stem cells in continually renewing tissues.

Endocrine etc aging: this was actually a separate category in my early descriptions of SENS, but I realised it should be excluded when I took into account that all hormones and other circulating molecules are made by cells, and thus that if you rejuvenate all the cells (in terms of both number and function) you necessarily also rejuvenatn hormonal signalling. The "signalling environment" is entirely created by cells. This is the main reason why I say that we'll need to give postmenopausal women new ovaries (or repopulate the old ones), for example.

#37 ag24

  • Topic Starter
  • Honorary Member, Advisor
  • 320 posts
  • 29
  • Location:Cambridge, UK

Posted 01 August 2005 - 11:14 AM

prometheus wrote:

> there is no solution for chromosomal mutations in long lived cells
> like those of the brain and heart.

That's correct, so as Don says, I'm relying on the idea that these mutations don't hurt us in anything like a normal lifetime. You know the logic: DNA maintenance and repair is as good as it is in order to stop us dying of cancer before puberty, and that's a lot better than it needs to be to maintain tissue function in ways that are independent of cancer. One might think that DNA maintenance/repair quality would be less in postmitotic cell types because such cells can't become cancers, but that doesn't seem to be true (measurements of mutation levels are not much higher in such cells than in mitotically competent ones). This could be for Campisi-theory reasons, i.e. a cell that's very mutant can secrete toxins that cause a neighbouring cell to becone cancerous. So neurons could carcinogenise glia, cardiomyocytes could carcinogenise endothelial cells, etc.

#38

  • Lurker
  • 1

Posted 01 August 2005 - 12:48 PM

You know the logic: DNA maintenance and repair is as good as it is in order to stop us dying of cancer before puberty, and that's a lot better than it needs to be to maintain tissue function in ways that are independent of cancer.


Providing that the only way cell function could be compromised is due to cancer then the above rationale is fine. What if, however, pathological effects arise out of chromosomal instability other than cancer? You recall the 2004 Lu et al Nature paper on the changes in gene expression in human brains after the age of 40 and how these changes appear to be a consequence of DNA damage.

This type of cell function impairment may not be as dramatic as the effects of cancer but certainly plays an increasingly important role as we age and in a scenario of even moderately increased lifespan would be devastating if ignored. Imagine being able to engineer a 90 year old's physiology to be able to function like a 60 year old's in every organ except the brain and heart.

Supposing the heart can be replaced or regenerated by extensive stem cell treatments we would not be able to do the same with the brain - but nor would we need to if we were able to prevent or repair chromosomal damage there.

#39 Chip

  • Guest
  • 387 posts
  • 0

Posted 01 August 2005 - 05:14 PM

As far as I can see there is evidence that brain tissue may also be repaired/regenerated using stem cell therapy, http://msnbc.msn.com/id/8206108/ Since memory appears to be largely interstitial, I wouldn't be surprised if we could eventually come to regenerate whole brain tissue organs without impacting personality or memory except in a positive manner.

All in all though, I find this thread and many similar to ignore some major determinates in what gets funding. Here is a pie chart of US funding, http://www.warresist...rg/piechart.htm Notice that much education, all within the grey area, as well as NASA and other aspects of the grey area are military related. I suspect for SENS to get the appropriate funding and research it will not be a case of whether or not it is more or less worthy than other approaches. SENS, as well as all other human life furthering research, is seriously impacted by human preoccupation with developing the machinery of making death. I find it highly likely that these experiments known as nation-states will pass in preference to some viable social science that will of necessity be forthcoming. I consider the question as to whether or not humanity can find some rationality in its governing systems is a pressing question for the survival of humanity. I hope that question will be addressed successfully and very soon. The inordinate number of recent violent deaths of microbiologists and other scientists may be something worthy of consideration http://www.gnn.tv/fo...ead.php?id=5219 The most exhaustive and informative report on this might be this, http://www.fromthewi...2_microbio.html Not only is death dealing the main preoccupation of humanity, those who might be able to facilitate SENS and other enhancements to the furtherance of longevity may suffer more than just lack of monetary funding.

Edited by Chip, 01 August 2005 - 05:41 PM.


#40 Mark Hamalainen

  • Guest
  • 564 posts
  • 0
  • Location:San Francisco Bay Area
  • NO

Posted 01 August 2005 - 06:04 PM

Supposing the heart can be replaced or regenerated by extensive stem cell treatments we would not be able to do the same with the brain - but nor would we need to if we were able to prevent or repair chromosomal damage there.


Even if we can't directly slow DNA mutations in the brain, addressing all of the other aspects of aging will certainly have a significant effect. Perhaps it can't be proven to be sufficient for achieving escape velocity, but neither can it be disproved (given our current knowledge), and that is the key. "What if's" are not going to win the prize, what they're looking for is a straight "this will not work because..."

DNA damage in post-mitotic cells will have to be addressed eventually and we should revive discussion of it here at ImmInst, but in this context, I think Aubrey is right, it is no slam dunk.

#41

  • Lurker
  • 1

Posted 02 August 2005 - 12:26 AM

As far as I can see there is evidence that brain tissue may also be repaired/regenerated using stem cell therapy, http://msnbc.msn.com/id/8206108/


This is an article that reports progress in brain stem cells have been cultured with the aim of using them as transplant material in diseases such as Parkinsons and Huntingtons - genetic disorders with early age onset where the pathology is associated with degeneration of the brain in specific regions. These type of disorders are not related to the age related neuronal functional decline - such as reduced neuroplasticity - associated with altered transcription patterns due to chromosomal instability.

DNA damage in post-mitotic cells will have to be addressed eventually and we should revive discussion of it here at ImmInst, but in this context, I think Aubrey is right, it is no slam dunk.


I would hope not. But it sounds awful if one looks at SENS and says - hey where's the bit about rejuvenating the brain! I know that it sounds rather histrionic considering that ROS levels etc would stand to be dramatically reduced by allotopic expression but will that be enough to prevent chromosomal instability in these cells? Would not a more robust solution seek to cover that base?

In the past I have focused on critiquing individual elements of SENS that I believed could be refined but on this occassion I made the assumption that all of SENS worked as proposed to see if any weak links could be identified. In such a consideration the only glaring weakness that appears in my view is that aging in the brain is not being addressed (where it could be by addressing chromosomal instability). The other danger is that it could be interpreted as suggesting that SENS is primarily designed for mice rather than humans.

#42

  • Lurker
  • 1

Posted 03 August 2005 - 07:38 AM

Aubrey (or Michael).. Could you comment on how SENS could accomplish brain rejuvenation on those over 40?

#43 ag24

  • Topic Starter
  • Honorary Member, Advisor
  • 320 posts
  • 29
  • Location:Cambridge, UK

Posted 05 August 2005 - 04:01 AM

hi - travelling, sorry
prometheus wrote:

> Could you comment on how SENS could accomplish brain rejuvenation on those over 40?

um, well, the usual - the seven things. I presume your focus is on chromosomal damage (both genetic and epigenetic). As I've said, I think there is good evidence that these changes are not rate-limiting for aging (whether in the brain or elsewhere) except insofar as they cause cancer, for which my core solution is WILT. There will certainly be an age at which chromosomal damage becomes pathogenic in non-cancer ways, and this will be prevented by cell replacement, possibly accompanied by a mild acceleration of cell removal (cell death), but that is something further in the future than the achievement of escape velocity.

#44 treonsverdery

  • Guest
  • 1,293 posts
  • 161
  • Location:where I am at

Posted 06 August 2005 - 03:03 AM

At imminst.org/forum/index.php?s=&act=ST&f=173&t=7543&hl= imminst.org/forum/index.php?s=&...=173&t=7543&hl= a gerontologist might press: organismal senescence programming nonrelated to Tissue up-vitality.

humans show developmental patterns not sourced from immediate area tissues at different times of life. brain growth, puberty, head hair patterns. These may also direct aging. Mosaic studies will test mechanisms with mice.

I apologize here about the quality of writing. um, I believe that if you name whole body ilt: Wbilt people will like the strategy better.

Treon

Edited by treonsverdery, 19 October 2006 - 06:15 AM.


#45

  • Lurker
  • 1

Posted 06 August 2005 - 11:42 AM

As I've said, I think there is good evidence that these changes are not rate-limiting for aging (whether in the brain or elsewhere) except insofar as they cause cancer, for which my core solution is WILT.


Are you taking into consideration the findings of the Lu (1) paper?

-- For those unfamiliar with the paper see the following for a primer:
http://www.ncbi.nlm....brk.chapter.653
http://www.rndsystem...Expression.aspx




(1) Lu, T. et al. (2004) Nature 429:883

#46 ag24

  • Topic Starter
  • Honorary Member, Advisor
  • 320 posts
  • 29
  • Location:Cambridge, UK

Posted 06 August 2005 - 02:59 PM

Oh yes, I'm familiar with the Lu paper (and I feel sure it's been discussed here before). To summarise: these authors measured the levels of a particular oxidation product of DNA, namely 8oxo-dG (which they carelessly call 8-oxoguanine - that would be the equivalent in RNA) in the promoter regions of many genes and they identify a number of genes with important roles in neuronal function which (a) are downregulated in the elderly and (b) have more 8oxo-dG than most genes. They further demonstrate that the down-regulation is largely a consequence of the 8oxo-dG, by overexpressing OGG1, the enzyme that repairs 8oxo-dG, and observing a restoration of gene expression (though not with intermediate durations, 6 or 8 hours, of exposure to oxidative stress - very odd and not commented on). This is all very interesting, but in order to determine whether it's a concern for SENS we must ask whether the application of all the other SENS solutions (removal of aggregates, etc) would reverse this DNA damage. The best evidence that it indeed would is that complete absence of OGG1 in mice is totally without detrimental effect (unless those mice are also challenged in other ways), despite a sharp elevation in 8oxo-dG levels: evidently, normal levels of 8oxo-dG are well within tolerable range. Since the maturation of 8oxo-dG into a bona fide mutation requires DNA replication, which is not occurring in nuclear DNA of postmitotic cells such as neurons, the Lu paper does not constitute evidence that mutations are accumulating to the detriment of gene expression in these genes, though of course we would like to know whether mutations are indeed also accumulating. It may even be that the down-regulation of gene expression is a regulated response to sensing of 8oxo-dG damage, since transcription of DNA with 8oxo-dG would (I think) also be prone to give erroneous mRNA and hence protein (though of course only if there is 8oxo-dG in the genes' coding regions as well as promoters). But whether or not that's so, the simlest interpretation of the Lu paper is that 8oxo-dG is simply a harmless readout of oxidative stress levels in neurons and would be restored to youthful levels by the normal action of OGG1 if oxidative stress were relieved by removing aggregates etc.

#47

  • Lurker
  • 1

Posted 07 August 2005 - 01:12 AM

It may even be that the down-regulation of gene expression is a regulated response to sensing of 8oxo-dG damage, since transcription of DNA with 8oxo-dG would (I think) also be prone to give erroneous mRNA and hence protein (though of course only if there is 8oxo-dG in the genes' coding regions as well as promoters).


One could go further and suggest that the RNAP complex may not be able bind to DNA regions occluded with 8oxo-dg. Would it not be more likely that transcription is effectively shut off due to the conformational changes in DNA (just like when methylation occurs)? And having made this analogy with methylation type gene regulation that it would be worth investigating reversible DNA oxidation as another level of genetic regulation?

Also interesting is that the older neurons in the Lu study appear to be trying to fight off DNA damage (or attempt to maintain steady state) from the observation of increased OGG1 expression. One may ask what the maximal increase of OGG1 a cell can sustain naturally (observed 2 fold increase) and if greater OGG1 production would bring gene expression to a more youthful pattern.

Of course as you mention,

we must ask whether the application of all the other SENS solutions (removal of aggregates, etc) would reverse this DNA damage


The other SENS solutions may reverse this damage (by increasing innate DNA repair rate efficiency) or prevent it from increasing (by reducing the cause of damage) or both. However, I think it is equally important to ask from an interventional approach for those with limited time (literally) whether the other SENS solutions are as technically easy to implement as increasing selected DNA repair enzymes artificially.

#48 JonesGuy

  • Guest
  • 1,183 posts
  • 8

Posted 30 November 2005 - 08:41 PM

Do we have any actual links regarding this topic? Why isn't there something on the Technology Review site?

#49 gavrilov

  • Guest
  • 341 posts
  • 9
  • Location:Chicago, USA

Posted 14 February 2007 - 02:44 AM

I am worried by this idea.

It specifically motivates to discredit SENS offering  $20,000,
including the Methuselah Foundation money ($10,000 dollars) !

I believe that this money could be much better spent on objective
evaluation of the SENS project, rather than for making direct
invitation to discredit it.


He has a point. A 750 word article for $30K is pretty smart takings. A few days of work for an astute biologist and the possibility of a backfire to this plan since a cleverly worded article that is strongly referenced could effectively hamstring SENS to the sceptical portion of the public. Of course, Aubrey, like a dedicated athlete, has been waiting a long time for this and has presumably prepared for all permutations of attack. There are some vulnerabilities, however, which could be exploited and should be buffered against. This would be a good time to look at such weaknesses and devise appropriate strategies of defence. Who can see any holes in SENS?



It is nice that this story has a happy end for SENS.

However the victory was not decisive in perception of gerontologists, because there were no experts on aging in the jury.

The scientific community was further polarized over SENS, and more harsh criticism was published here and there.

On the other hand, we do not know, maybe the recent generous donations to SENS were in fact stimulated by this controversy.




1 user(s) are reading this topic

0 members, 1 guests, 0 anonymous users