211 replies to this topic

[John Schloendorn]

I can't really judge that. From what I hear it seems that almost any senior biogerontologist would be welcome to do it and able to do the necessary study, but very few would have enough interdisciplinary experience to do it without some extra study. See also the SENS challenge thread.

[John Schloendorn]

This is a decent dictionary if you're after a quick definition. If you need to know more there is no way around google or pubmed :-) Most of the time you can replace greek characters by latin ones, or generate the symbol in word and copy it where you need it...

[opales]

Methylation inhibition as a means to extending life span

I was browsing through the SENS 2 abstracts and this particular work caught my eye

http://www.gen.cam.a...2/abs/Kroll.htm

Chaperones of longevity

J. Krøll
Hafnia Unit of Biogerontology, Godthåbsvej 111,3, DK 2000, Freberiksberg, Denmark

The inherent immortality of the embryonic stem cells imply that replicative senescence as possibly aging and longevity are epigenetic phenomena, probably resulting from changes in the expression of relatively few regulatory genes. Among those it is suggested that emphasis is placed on the genes that determines the level of expression of the "housekeeping" molecular chaperones. Thus evidence is presented that the longevity of species and cells correlates to the constitutive level of expression of the molecular chaperones, as do the stress resistance and the cellular resistance against malignant transformation. Possibly the epigenetic phenonena of aging and longevity are influenced by the progressive age related changes in promotor methylation, that have the potential to permanently silence gene expression. Evidence is presented that methylation inhibitors as 5-Aza-CdR can recover the expression of silenced genes.

Key words: Molecular chaperones, longevity, aging, methylation, cancer

Is this 5-Aza-CdR a general methylation inhibitor, or does it work on some specific aging related methylation patterns (perhaps related to those "housekeeping" molecular chaperones expressing genes)? Surely, a general inhibition of methylation would have dertimental effects to an organism, right? I mean, that just sound too simplistic to ever to work as a serious anti-aging strategy? Or should I just start popping up those pills ASAP[lol]

Or is the author just trying to prove a point that methylation can be halted, but is not saying that this 5-Aza-CdR could be used to enhance longevity (I am not sure because I can't get to the full text)?

Edit: fixed quote tags

Edited by prometheus, 25 September 2005 - 09:51 AM.

[John Schloendorn]

I'm serious: How do different antibodies and/or T-cell receptors avoid recognizing each others' variable domains as "non-self", thus continually neutralizing each other?

[John Schloendorn]

is not saying that this 5-Aza-CdR could be used to enhance longevity

I do not remember the poster, but I think it is fairly safe to assume that he is not saying this. (Although we did have one or two rather dodgy poster people there ;-) It sounds to me more like an in-vitro thing to clear methylation in cloned ES cells, something like that.

[kerrage25]

Is there a list of bio-tech companies that I can invest in to help further research?

[Lazarus Long]

Is there a list of bio-tech companies that I can invest in to help further research?

That list is generally reserved for Full Member discussion but you are welcome to ask about specific companies in the general fora rather than here in the science section. But that would be simply open discussion not any kind of recommendation from this organization.

[tenaya]

Hello friends and allies,

I am a freshman-year college student who is still very green in the subject of research that could prevent inevitable death. However, this subject is one that I have quietly felt very passionate about throughout my entire life, and I’m very glad to find such a resourceful, thriving community here. I went to college in the hopes that I could personally contribute to the efforts of this research, but am having difficulty knowing where to begin. Having completed most of my liberal education I am already being faced with the decision of which path to take. At first I thought I would be aiming for a bachelor degree in biological science, but now I’m considering a bachelor degree in biomedical engineering.

Can anyone give me advice? Is there a field of research that currently seems most promising in yielding results soon? What career would be most helpful within the next few years? What bachelor degree would I need to pursue it? (I will eventually be working toward a Master’s degree, then a Ph.D.) Any recommended colleges? I’m currently planning on transferring to the University of Minnesota. My natural talents are in biology, reading, writing, and ethical philosophy, but I am willing to learn whatever I must for the sake of this cause.

I apologize for failing to spend more time looking for the answers on my own before asking this question, but I’m very busy with my current classes, and I hope my desire to not waste the next semester on indecisiveness will be understood by those who are also racing against time. The advise of individuals who are already involved with research would be especially appreciated, but I could definitely also use the advice of anyone who is more up-to-date with articles and books on anti-aging/reverse-aging research being done by others.

Edited by tenaya, 12 November 2005 - 10:33 AM.

[John Schloendorn]

Hi Tenaya, great to have you here. No worries at all about asking questions, that's what we're here for. It's young students like you who may one day save the butts of everyone here when our own brains get to demented to finish the research, so we're really keen on helping you in whatever way is needed. The archives at imminst can be a bit large and confusing, so allow me save you some time on the searches. We have had one reference career counseling here, and also a few smaller ones here and here. If you've read that, you will have more questions, so by all means come back and ask ;-)

[tenaya]

My sincere thanks for the welcome and links, John. It’s because of everyone who has come before me in undertaking related research that myself and so many others have hope of ultimately surviving. If I can find a way to repay that favor, I certainly will. I’ve read through the archived threads and taken notes, but yes, I do still have more questions. I wish I had more knowledge than I currently do to refine them. I was recently caught off guard when I realized just how many different ways there were to go about addressing research to combat mortality, and how different the classes required for each are. For now, I had bettter concentrate on the final month of my current classes, but when they’re over, I’m going to attempt more reading on my own, possibly make a counseling appointment at the University I’m hoping to attend, and then post more questions.

In the meantime, if you can give me any information on biochemistry’s role in longevity research from your own experience, it might help me since majoring in some form of biology and getting a bachelor of science degree was my original plan. (Not that that plan isn’t subject to change.) A biochemistry, neuroscience, genetics, and general biology major would all be along the same track as far as the next year at my community college goes before transferring. Gene therapy and biomedical engineering would be at a separate institute. As would nanotechnology. There were other fields listed in the threads you linked for me that I’d never even heard of before. I can’t tell if I would be especially good at or enjoy these other fields yet, simply because I haven’t yet explored them personally. But I think I could be good at anything I devote enough effort to, and enjoy anything that provides a chance to save lives—my own and my loved ones included. The only question is where I could be most helpful.

[John Schloendorn]

But I think I could be good at anything I devote enough effort to, and enjoy anything that provides a chance to save lives

That's good, it means you're basically out of trouble. I think it would be unwise to try to predict now where you will be most useful when you finish your degree several years in the future. Luckily, the field is changing very rapidly. I did not know where I was going to work until the very end stage of my degree. What I like about my biochem degree is that it is in the middle of all the other fields. For example, in a nanotech degree you do not learn much about physiology, or a biologist may not get much experience in free radical chemistry. In biochemistry (I feel) you get some overlap with most relevant fields and thus know at least roughly what everybody is talking about. This gives you a basis to decide where to become active most productively, once you and the world are ready.

The currently most important skill in promoting life-extension is perhaps to forget your old plans that you have become attached to and pursue something more efficient once you learn what that is.

[Karomesis]

MY question to the learned is this, Will the advent of stem cell rejuvination therapies(which are obviously in trials as we speak) combined with the not too distant gene therapy to modify repair mechanisms ect effectively trump supplement usage and save me 9 million dollars a month in supplement bills?

[Cyto]

Well, from the theory. If I were to have an efficacious platform in development, like SSRs, I would find being able to get rid of supps feasible. If you could have a small section of skin secreting supps in a highly vascularized region, I would imagine a good amount of people cutting out supps to afford the one that’s grafted onto them. Or just buy an injection of the vectors. But this is still a ways away from being available to the public, so I’m not going to tell you to give them up...maybe donate to the MPrize...but not to give up all your supps.

I do say SSRs a lot, but I think that it’s warranted. Not perfect yet, but warranted.

[Cyto]

And Im making sure to try and keep an eye out as to how I can get the Jan 2006 paper talking about the use of recombinases in murine models. A portion of this spliced-out summary can be reworded in our positive outlook.

http://www.ncbi.nlm....6801&query_hl=1

In recent years, the emergence of site-specific recombinases as tools to engineer mammalian genomes has opened new avenues into the design of genetically modified mouse models. The original Cre and FLP recombinases have demonstrated their utility in developing conditional gene targeting, and now other analogous recombinases are also ready to be used, in the same way or in combined strategies, to achieve more sophisticated experimental schemes for addressing complex biological questions. The properties of site-specific recombinases in combination with other biotechnological tools (tet on/off system, siRNA mediated gene silencing, fluorescent proteins, et al.) make them useful instruments to induce precise mutations in specific cells or tissues in a time-controlled manner. This ability can be applied in functional genomics in several ways: from conditional and inducible gene targeting to controlled expression of transgenes and recombination-mediated cassette exchange in mouse models for the study of development or disease phenotypes. This review focuses on the use of site-specific recombinases for mouse genome manipulation. A historical perspective of site-specific recombinases is considered and a number of strategies for achieving inducible or conditional genomic manipulations are contemplated in the context of current techniques for producing genetically modified mice.

[Cyto]

There is also a paper...available in a location on this site, that talks about using SSRs somewhat. I could highlight the section and send it to you if youd like.

[Cyto]

Mep, one more plug...

Here is a good sum-up:

"Phage integrases are enzymes that mediate unidirectional site-specific recombination between two DNA recognition sequences, the phage attachment site, attP, and the bacterial attachment site, attB. Integrases may be grouped into two major families, the tyrosine recombinases and the serine recombinases, based on their mode of catalysis. Tyrosine family integrases, such as λ integrase, utilize a catalytic tyrosine to mediate strand cleavage, tend to recognize longer attP sequences, and require other proteins encoded by the phage or the host bacteria. Phage integrases from the serine family are larger, use a catalytic serine for strand cleavage, recognize shorter attP sequences, and do not require host cofactors. Phage integrases mediate efficient site-specific recombination between two different sequences that are relatively short, yet long enough to be specific on a genomic scale. These properties give phage integrases growing importance for the genetic manipulation of living eukaryotic cells, especially those with large genomes such as mammals and most plants, for which there are few tools for precise manipulation of the genome. Integrases of the serine family have been shown to work efficiently in mammalian cells, mediating efficient integration at introduced att sites or native sequences that have partial identity to att sites. This reaction has applications in areas such as gene therapy, construction of transgenic organisms, and manipulation of cell lines. Directed evolution can be used to increase further the affinity of an integrase for a particular native sequence, opening up additional applications for genomic modification.*"

*Groth, Amy C. Calos, Michele P. Journal of Molecular Biology, 2003, 335, 667-678.


Its was from several years ago, but the idea is the same.

[Cyto]

One more...one more. And John, you remembered correctly (hazaa!), it was for the liver. And Im finding that this guy has a long history with people unable to produce phenylalanine (phenylketonuria). Interesting.

Im sure most saw this on Betterhumans but they didn't say anything about the method!! So, for everyone, phages are helping.

http://www.pnas.org/...RMAT=&fulltext=



Complete and persistent phenotypic correction of phenylketonuria in mice by site-specific genome integration of murine phenylalanine hydroxylase cDNA

Li Chen and Savio L. C. Woo *

Department of Gene and Cell Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1496, New York, NY 10029

Edited by Yuet Wai Kan, University of California School of Medicine, San Francisco, CA, and approved August 22, 2005 (received for review May 16, 2005)

We explored the potential of using a bacteriophage integrase system to achieve site-specific genome integration of murine phenylalanine hydroxylase cDNA in the livers of phenylketonuric (PKU) mice. The phiBT1 phage integrase is an enzyme that catalyses the efficient recombination between unique sequences in the phage and bacterial genomes, leading to the site-specific integration of the former into the latter in a unidirectional manner. Here we showed that this phage integrase functions efficiently in mouse cells, and several naturally occurring pseudo-attP sites located in the intergenic regions of the mouse genome have been identified and molecularly characterized. We further demonstrated that the addition of nuclear localization signal sequences to the C terminus of the phage integrase enhanced the efficiency for transgene integration into the mouse genome. Using this phage integration system, we delivered mouse phenylalanine hydroxylase cDNA to the livers of PKU mice by hydrodynamic injection of plasmid DNA and showed that the severity of the hyperphenylalaninemic phenotype in the treated mice decreased significantly. After three applications, serum phenylalanine levels in all treated PKU mice were reduced to the normal range and remained stable thereafter. Their fur color also changed from gray to black, indicating the reconstitution of melanin biosynthesis as a result of available tyrosine derived from reconstituted phenylalanine hydroxylation in the liver. Thus, the phiBT1 bacteriophage integrase represents an effective site-specific genome integration system in mammalian cells and can be of great value in DNA-mediated gene therapy for a multitude of genetic disorders.

Next topic that may be on its way, enlistment of Unnatural Amino Acids and 4-nucleotide "codons" of the future. Do we have what it takes?
More, later...

[John Schloendorn]

If you could have a small section of skin secreting supps in a highly vascularized region

There is no foreseeable way SSR-based vectors could carry the payload necessary for a whole enzymatic pathway to synthesize nootropics if that's what you're having in mind ;-) Nice idea though. Stem cells and artificial chromosomes, maybe.

[Cyto]

Yea, my bad for not asking exactly what he was talking about. And I don't know anything about the Nootrop synth, or even Nootrop use.

So, endogenous antioxidants yes. Something really wacky, not anytime soon.

Thanks for being more analytical John.

[Karomesis]

A mutation in one of kenyons C.elegans produced a six fold increase in lifespan, in theory is this possible for humans?Why/ why not? This is one of the reasons I think gene modifications should be first on the list after stem cells to radically extend our lives. Admitedly, there have been mishaps in gene therapy and its dangers are profound, then again so was going to the moon.

[John Schloendorn]

A mutation in one of kenyons C.elegans produced a six fold increase in lifespan, in theory is this possible for humans?Why/ why not?

Not for the purpose we're having in mind. The intervention in the worms was germ-line (there is no way of administering the therapy to adult organisms and it is not known whether that would be effective), the effectivity of these interventions in short-lived mammals is much less than in worms and testing (i.e. developing) the intervention in humans would probably imply the death of the experimenter and anyone alive today by aging before a result is obtained.

[Karomesis]

At what stage does speciation occur? and what defines it for the future of homo sapiens? Also would you as biologists define a true psycopath a a different species of human? why/why not? THe africanized honey bee is physically indistinguishable from its docile relative the european strain, this would seem to suggest that phychological charachteristics can define a species, true? not true?

[John Schloendorn]

A species is most often defined as a group of organisms that can have fertile offspring with each other. Other definitions use genomic sequence similarity in one way or another. Human psychopaths cannot be excluded from our species on any of these grounds. I do not know about the bees.

[Karomesis]

Thanks again john [thumb] What is preventing us from inducing a gene knockout in an adult human? If massive increses in maximum LS can be achieved with gene modifications, what is preventing this from being applied to humans? It seems a much quicker way to achive ENS. I realise we are not C. elegans complexity wise, but don't we have similar pathways, mechanisms ect?

How would I go about removing an unwanted/ pesky gene?

[randolfe]

John, what is the term for animals like Mules. Mules are produced by breeding a horse and a donkey. However, Mules can't reproduce themselves.

Are there otheer examples of this kind of thing, perhaps happening in nature?

[John Schloendorn]

What is preventing us from inducing a gene knockout in an adult human?

It is at this time too hard to achieve the necessary effectivity and specificity for useable human applications. You have some 10 to the 14 cells and if in a single one of them a tumor suppressor gets knocked out due to a single unfortunate jitter of your enzyme, it can kill you. If ideally 10 to the 9 humans wanted the therapy that would make an error threshold of 10 to the 23, which is, well, kinda hard to do. (Note though that this is a wacky extrapolation...) Not to mention our 200 different cell types, many with elaborate and variable defenses to keep suspicious things out of the cell and the nucleus.
But more importantly, it is not known whether knocking in or out any gene extends life span in any animal substantially more long-lived than the rat. Extrapolating from life span percentage gained in several short lived species versus total life span of the same species would in fact suggest that each of these interventions would be as good as ineffective in very long lived animals. (Yeast 600%), Worms 500%, flies 300%, mice 50%, rats 30%, you get the idea... The only true alternative is to target the damage, rather than metabolism.

animals like Mules

I bet nature does this more often than once. I have no idea if there is a consensus classification as a species or debate about that. Feel free to google ;-)

[jays]

Extrapolating from life span percentage gained in several short lived species versus total life span of the same species would in fact suggest that each of these interventions would be as good as ineffective in very long lived animals. (Yeast 600%), Worms 500%, flies 300%, mice 50%, rats 30%, you get the idea...

Isn’t it that depending of the metabolic rate there’s a proportional response to DNA/cellular damage? For instance normal DNA/cell protection in humans is not actually better than in mice.

[John Schloendorn]

For instance normal DNA/cell protection in humans is not actually better than in mice

Yes, it is way better. For example, human cells have much higher genomic DNA repair activity than mouse cells [1], have lower mitochondiral mutation rates than can be explained by metabolic rate differences [2], have more active [3], and more specific [4] tumor suppressor pathways, and the list goes on. Nonetheless, metabolic rate appears to be a factor in many, but not all vertebrate species (parrots, bats have high metabolic rates and are long lived). (though this would not affect the above argument -- the extrapolation still holds)
It is not known what causes the differential effect of certain gene knockouts and cr on life span percentage gained in different species. All that is known is a strong inverse correlation with total life span.

[Karomesis]

prometheus, according to a recent article I read the likelyhood of RNAi becoming clinically available within 10 years is very likely, do you agree? disagree? with this statement. I am also under the impression that RNAi can silence many genes experimentally within a very short timeframe, does this mean we can compare mammilian models so as to correlate genes quickly as well?

John and prometheus, what is your educated guess as to the benefits/consequences of mimicking the silencing if SIRt1/2 in humans? or perhaps another gene you have had your eyes on?