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Nov 27
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A new paper just out in Cell by the Sinclair group gives us some intriguing but sobering information about aging and genomic integrity.

The new twist to the ever evolving story is the Sirt1 protein might have at least two primary roles in the cell. The first role is to locate itself on DNA to inhibit these particular genes that it is situated on for they are not needed by this particular cell at this time. The second role though is to help repair DNA damage caused by such things as oxidative stress. Sirt1 leaves its original location in which it was suppressing specific genes to where the DNA is damaged and hence they are no longer doing their gene suppressing job.

As the short review article in Science pointed out - this is a catch-22 situation (the catch-22 of aging).

In the paper when they induced oxidative stress there was a Sirt1 dependent dsregulation of gene expression - which resembles that of an aging mouse brain (see below). With the oxidative stress Sirt1 was relocated (from its original sites of action) to the DNA double-strand breaks. If Sirt1 was reduced there was less efficient repair of these DNA breaks. Interestingly, overexpression of Sirt1 repressed 85%  of the formerly deregulated gene expression.

Next the researchers irradiated mice to induce cancer in a specific mouse strain prone to developing cancer (p53 +/-) and found the Sirt1 activator resveratrol if fed 3 weeks prior to the irraditation increased survival by 24%. Since resveratrol might not be just working through increased Sirt1 activity they used a transgenic aniamal that allowed temporal and tissue specific overexpression of Sirt1. A 2-4 fold increase of Sirt1 expression in bone marrow lymphocyte progenitors and mature B and T cells was induced 2 weeks prior to exposure of the mice to irradiation. Survival in the Sirt1 induced animals increased by 46%. Finally, they found that overexpression of Sirt1 in the mouse brain could repress the age related deregulation of certain genes.

I am only give you brief outline of the paper, I encourage you to read the full thing if you are a scientist for even if this is not your particular scientific interest it is thorough and involves many interesting techniques.

Take home messages:

Aging could be a catch-22 situation - Sirt1 steadfastly performs its normal function of suppressing inappropriate gene expression but when there is DNA damage it abandons the castle to fight off genomic instability - but at the cost of deregulation back on the home front. However, overexpression of Sirt1 (via resveratrol and/or more direct genetic manipulations) can at least partially rescue the adverse affects of the accelerated irradiation induced ‘aging’ (genomic instability - increased cancer). Think of it as if you have enough soldiers you can both defend the home castle and fight wars in far off lands (though I am not a big fan of war like analogies).

Remember dietary restriction (in the form of calorie restriction or every-other-day fasting) has been reported to increase Sirt1 expression and dramatically decrease the incidences of cancer (tested numerous ways including radiation induced cancer), and increase genomic stability. Sounds famliar doesn’t it.

Jun 17

An example of how it is hard to hack a hacked system follows.

Previously I mentioned a quote from Francis Crick (1962 Nobel prize winner for the co-discovery of the structure of DNA (1953)) that biology is a hacked together system rather than engineered from the ground up. This general idea makes sense at an evolutionary level – one tweak, or system, was hay-wired on top of the next for whatever evolutionary gain. Hence, the system is a hacked, ad-hoc assembly that works very well for its appropriate environment, but not easy to reverse engineer.

The great hope of health science is through the intervention of a drug (usually acting by a single mechanism) to alter the biological system to cure, or treat, various diseases. Now it is an open question with all the redundancy and irregular and/or overlapping systems how effective this paradigm can be.

For example purpose, one biological problem that is getting an increasing level of interest is in the general health field of improving the overall health of humans, which can lead to increased longevity or just an increase of health in aged humans – instead of a life with chronic illness and constant health challenges.

Calorie restriction (CR) in its various forms has proven to improve the health and extend the lifespan of numerous organisms. However, many people correctly argue that is unreasonable to expect a significant percentage of the human population to adopt such ‘will power’ driven diets (just have to look at the obesity epidemic to see the logic of this argument). Therefore, there is a large search for calorie restriction mimetics (CRM) to produce the same effects. So like other health scientists, these scientist are looking for a pill to treat the masses, and in this particular case they want to produce the same effect as CR.

Resveratrol (found in wine) is the great hope, which I have covered previously . The main proposed mechanism of resveratrol is to increase the protein Sirt1, (sirt1 is one member of the sirtuin family of proteins) which is reported to be increased with CR in many tissues. Ouborous has a couple of very good posts on resveratrol and sirtuins .

David Sinclair – one of the two big guns in the resveratrol/sirtuin field who co-founded Sirtris Pharmaceuticals, made big news recently when the company was bought by GlaxoSmithKline for 720 million dollars (meaning a stock price of $ 22.50, which is a nice tidy sum over the closing price of $ 12.23 – as of April 23, 2008 - just before the deal). What David Sinclair and company has developed (and GlaxoSmithKline bought, bet on) are potent inducers of Sirt proteins (potential calorie restriction mimetic). David believes when his drug hits the market in 4 or 5 years for diabetes that his pills will only cost 3 or 4 dollars each, and once it comes off-patent only pennies. Alright - a cheap calorie restriction mimietic is coming down the pipeline.

Now what is interesting is a new Sirt1 paper by the other big leader in the field of resveratrol/sirtuin and longevity, Guarente (former supervisor of Sinclair) was recently published. Normally it is thought that CR increases Sirt1 expression (at least protein level and activity, not necessarily at the mRNA level) and this is what Guarente’s group found in the muscle and fat tissue of CR animals. However, in the liver they found lower levels of Sirt1 compared to the control fed group. Therefore, a pill that systemically increases sirtuin levels in all tissues might not produce the same effects as CR – and could even potentially produce some opposite effects of CR. High calorie diets in this study increased Sirt1 levels in the liver. The final line in the abstract is: “Our findings suggest that designing CR mimetics that target Sirt1 to provide uniform systemic benefits may be more complex than currently imagined.”

I think this statement is a caution to the biological field in general and obviously the Sirt1/Resveratrol field specifically.

This example might point out why when you want to hack a hacked system that you need to worry about the devils in the details, and why relatively simple (CR), but highly effective global results (increased lifespan, etc) might not be so easily addressed by a single magic bullet.

I don’t want to sound like a broken record (and I will get off this topic tomorrow), but like yesterday you can wait 4 or 5 years for a pill to produce overall health benefits (that may not work as well as we expect - see above), or do something today to improve your health. None of us are getting any younger, as I understand how time works. Go and try something novel today, go exercise, go light on your lunch today, go learn something new.