Vote May 2005

Abstracts and pubmed links are listed here.
The vote closes on 8th of June, 0.00 am.

[EDIT: the voting period has been extended.]

Edited by John Schloendorn, 08 June 2005 - 09:52 AM.

John,

Good initiative. It may help to explain the goal (in brief) and perhaps background of this vote in the first post... and also, more work for you, but to make more successful, post each (preferably shortened) abstract and link on this thread in the first post as well. Also, as this is quite a bit of information to digest, we may wish to lengthen the duration for time to vote if done in a similar nature in the future. I can also include in the ImmInst Email updates.

Everyone. Even if you only have time to briefly scan the papers/abstracts, please submit a vote.

Thanks for the suggestions and support guys. Let's see what I can do... The goal is explained here. Discuss the winning paper in detail and hopefully with the authors, that is.

Ok, here's my brief (and necessarily biased!) comment on each of the papers, which basically explains why I proposed them: (Maybe Prometheus make one for yours, as you already suggested?)

Bartke et al 2004: Life-extension in the dwarf mouse
Ames, Snell and Laron dwarf mice have impaired signalling in the hormonal GH / IGF-1 axis in one way or another (see abstract), which was found to substantially increase life-span (GH is for growth hormone and IGF-1 is for insuline-like growth factor 1). Although these mice are created by germ-line engineering, the findings might have significance for moderate human life-extension in the near future as a means to reach escape velocity. Pharmacological interventions in GH / IGF-1 axis are already being used in humans. Interestingly, both GH and IGF-1 are often supplemented for anti-aging purposes in humans, although it is their deficiency that increases longevity in these mice. For spontaneous human germ-line mutants in the same genes, a tendency has been reported to live into their 80s and 90s, but the data is not conclusive. It is not known whether adult onset disrupton of GH / IGF-1 signalling can have a similar effect. The paper in question provides in my opinion an excellent overview of the development and analysis of these mice that could be the basis for future human interventions.

Tiranathanagul et al 2005: Bioartificial kidneys
Tissue-engineering of structurally difficult organs, such as kidneys, has been a constant challenge for regenerative medicine. What Tiranathanagul et al. demonstrate is that life-sustaining functionality of their engineered transplant does not depend on the native structure of the human kidney. They used kindey cells, but simply designed their own structural arrangement. Almost transhumanistic, isn't it?

Evason et al 2005: Anticonvulsant medications extend worm
Yet another example of impressive life-extension in C.elegans using a very simple human-approved drug. Yet again, life-span data on the humans that used it is not available. Perhaps the effect on age-related diseases could be estimated from this past data (similar to what is being done on caloric restriction), but to my knowledge it has not been done. Have these hit the nootropics market yet?

Conboy et al 2004: Rejuvenation of aged progenitor cells
This experiment was designed to test the hypothesis that the systemic environment (hormones) are sufficient to cause certain aspects of aging. Muscle and liver stem cells shut down with age, which is thought to contribute directly to the age-related functional decline of these organs. In both organs it is pretty well known how they shut down, on the molecular level. When aged mice were connected to the blood circuit of young mice, Conboy et al. showed that these molecular changes were reversed, and the stem cells regained their proliferative capacity.
In another paper, the same authors found that the notch receptor is a key player in these processes. Artificially activating notch can rescue the age-related failure of muscle regeneration in old animals and inhibiting notch can compromise muscle regeneration in young animals.
Taken together, these results demonstrate that rationally designed interventions can control signalling-dependent aspects of aging. The transplantation of replacement cells should benefit from or even depend on getting the hormonal signalling right, so that they can properly proliferate. Work like Conboy's is paving the way for cell replacement based rejuvenation therapies.

Daya et al 2005: Ocular surface reconstruction
Patients with severe corneal damage (i.e. blindness or near-blindness) were transplanted with allogenic (somebody else's) adult stem cells, which resulted in the regeneration of the cornea and near complete restoration of sight. Intriguingly, this did not appear to be due to the engraftment of donor stem cells into the cornea. Donor stem cells were indeed undetectable after a few months (perhaps due to immune rejection), but they somehow managed to initiate the regeneration of the cornea from the patients own cells. This clearly demonstrates that the regenerative potential of the adult body is sometimes greater than what it would like to admit. While I think that a therapy that only stimulates the patient's own cells is not sustainable in the very long run due to accumulating damage in those cells, as above, it can still be a valuable means to escape velocity. However, what I liked most about this study was reading some of the patients' reports in the news. Restoring sight to the blind equals a miracle of biblical dimensions, and the demonstration that we humans can do it, if only we use stem cells, can hugely affect sociopolitical attitudes towards biomedical research.

Trifunovic et al 2004: Defective mitochondrial polymerase
Artificially introducing random mutations in the mitochondrial DNA of mice caused a clear-cut premature aging phenotype. This is basically another point for mitochondrial mutations as a "limiting factor" in aging. Even if the rest of the mouse was genetically fine, the mitochondrial mutations alone were enough to make it appear aged. So it looks like, if we are to fix anything, the mitochondria have to be among it. Good to know.

Schriner et al 2005: Overexpression of mitochondrial catalase
Interestingly, the mitochondrial damage does not merely seem to be sufficient to cause aging in the mouse, as suggested by Trifunovic's et al work, but also within limits necessary. These authors here demonstrate that targeting the H2O2 detoxifying catalase to the mitochondria of mice extended their life-span by as much as 20%. This is a big plus for the free radical theory of aging, which holds that reactive oxygen species like H2O2, and the free radicals that can derive from it cause damage to DNA and other macromolecules, which in turn causes aging. Earlier than this work, the success of antioxidant interventions with small molecules and enzymes was meager, which was thought to be due to improper localization of the most often pharmacologically applied substances. The endogenos expression of catalase with a mitochondrial targeting signal apparently overcame some of these problems.

Following John's convention:

Espejel et al 2004: Analysis of the effects of telomerase ablation in mice lacking key DNA repair factors.

The most consistent observation in aging cells is the increasing level of genomic damage which results in a reduction of protein synthesis or sometimes, more catastrophically, in the aberrant production of proteins. The aging cell has one of three fates depending on how intact its regulatory mechanisms are: a) a progressive downmodulation of gene expression via senescence, b) an abrupt self-destruction via apoptosis (either a or b or both result in tissue atrophy) or c) escape into tumorigenesis. One well known modifier of cell replicative lifespan and chromosomal stability is the enzyme telomerase which is essential for maintaining telomere integrity following cell division. In the absence of this enzyme, a cell will only be able to divide for a limited number of times before its chromosomes become destabilized. Other proteins such as PARP-1, Ku86, and DNA-PKcs have also been implicated in the maintenance of telomeres. This paper looks at mice in respect to aging and cancer incidence that have been genetically modified to not express telomerase as well as the selected DNA repair and putative telomere maintenance proteins PARP-1, Ku86, and DNA-PKcs. The results: lack of telomerase activity alone results in atrophy of the intestinal epithelia and testes (two regions associated with high stem cell rate of division), lack of telomerase activity and either lack of Ku86 or DNA-PKcs exacerbates this effect, probably by accelerating the rate of telomere erosion. Interestingly, whilst the rate of aging was increased, the rate of cancer incidence was not, suggesting that so long as the p53 function is operational a reduction of genomic stability will not result in cancer.

This paper is especially interesting in respect to one of the 7 SENS pillars, WILT, which is reliant upon the systemic ablation of telomerase in order to prevent cancer. One is compelled to consider increased p53 and telomerase expression as an alternative to telomerase ablation. It could be that we are better off engineering cells to be more cancer sensitive (via increased p53) whilst having greater genomic stability and replicative lifespan (via increased telomerase).

How is an even score result decided?

Good question In general by a run-off ballot. But in this case I decided to extend the voting period by another week due to low but still steady participation. New deadline is june 8th, 0.00 am GMT.
As a rule of thumb, a voting period will be extended when the participation is lower than 20% of the current full membership (at this time 27.2 votes) and there is reason to believe that extending the period will change that.

I guess it will be the Espejel paper..

Sweet. The vote is closed and the award goes to Espejel et al. The results were:

Bartke et al 2004: Life-extension in the dwarf mouse [ 4 ] [25.00%]
Tiranathanagul et al 2005: Bioartificial kidneys [ 0 ] [0.00%]
Evason et al 2005: Anticonvulsant medications extend worm [ 1 ] [6.25%]
Conboy et al 2004: Rejuvenation of aged progenitor cells [ 4 ] [25.00%]
Daya et al 2005: Ocular surface reconstruction [ 0 ] [0.00%]
Trifunovic et al 2004: Defective mitochondrial polymerase [ 1 ] [6.25%]
Schriner et al 2005: Overexpression of mitochondrial catalase [ 1 ] [6.25%]
Espejel et al 2004: Telomerase ablation on organismal viability [ 5 ] [31.25%]

Congratulations to the winning authors! paper is now available in the current paper forum and the discussion is ongoing.