Melatonin and SIRT1

Let me open by saying that I rarely talk about supplements except to trash them. This is because (a) there are already plenty of people out there talking about nothing but supplements, and (b) there's no scientific evidence that demonstrates the sort of heavy-duty supplement packages advocated today to produce health and longevity benefits in any way comparable to those attained by exercise and calorie restriction. If you're fat and sedentary and you're feeling virtuous because you're taking expensive dietary supplements, you're most likely going to be disappointed in the trajectory of your future health.

Anyway. Today we're going to talk about melatonin because it looks like it triggers the sirtuin SIRT1 in a similar way to resveratrol, and a number of people are interested in following sirtuin research. You might recall that researchers presently believe SIRT1 to work by affecting heat shock proteins and thereby making cellular repair processes more efficient. This research is itself an outgrowth of calorie restriction studies, and it's worth reminding everyone that resveratrol itself hasn't been shown to produce any health benefit that is as effective as calorie restriction. On that basis, a number of researchers are looking elsewhere for the controlling mechanisms of calorie restriction.

Sirtuins remain interesting, however, given that they are connected to all sorts of triggers and switches inside metabolism that relate to longevity, cancer, energy generation, and so forth. Calorie restriction demonstrates that noteworthy benefits can be achieved through manipulation of these controls - the question is whether there is an even better setting that could be attained through drugs or gene manipulation, a setting that slows down aging further than calorie restriction.

A perhaps more pertinent question is whether that better metabolism can be developed and made commercially available before those of us reading this now get old. That's where I have my doubts, and think we'd all be better off if the research community focused more on SENS-like repair strategies and less on slowing down aging by manipulation of metabolism. Slowing aging is a wash if you're already old by the time the medical technology to achieve that goal arrives. Repairing the damage of aging on the other hand...

In any case, here's the paper that caught my eye today, published in the Journal of Pineal Research. A brief scan of past issues suggests this might as well be called the Journal of Melatonin Studies and Nothing Else. I'm impressed - or possibly appalled, I can't decide which - that we live in an age in which a research community exists that can reliably fill a bi-monthly journal with nothing but studies of melatonin:

Sirtuin 1 is a member of the sirtuin family of protein deacetylases, which have attracted considerable attention as mediators of lifespan extension in several model organisms. Induction of sirtuin 1 expression also attenuates neuronal degeneration and death in animal models of Alzheimer's disease and Huntington's disease.

In this study, an in vitro model of neuronal aging was used to test in several ways whether melatonin acts as a sirtuin 1 inducer and if this effect could be neuroprotective. It is shown that melatonin is able to increase the level of this deacetylase in young primary neurons, as well as in aged neurons. We also observed an increase in the deacetylation of several substrates of sirtuin 1, such as p53, PGC-1alpha, FoxO1, ADAM10 and NFkappaB.

Over the past years, you've probably seen all of those substrate genes mentioned here or in the Longevity Meme News. The biochemistry of metabolism is a tangled mess of a machine, and nothing operates independently. All of these genes and the mechanisms they participate in are legitimate areas of study until someone finally sorts it all out with a verifiable grand unified theory of metabolic mechanisms.

ResearchBlogging.orgTajes, M., Gutierrez-Cuesta, J., Ortuño-Sahagun, D., Camins, A., & Pallàs, M. (2009). Anti-aging properties of melatonin in an in vitro murine senescence model: involvement of the sirtuin 1 pathway Journal of Pineal Research DOI: 10.1111/j.1600-079X.2009.00706.x


Rather than vent my spleen, I would refer all readers of this blog to an article in New York Magaziine in which one Michael Rae opines that Actuarial Escape Velocity will be achieved in 50-100 years. ("he hopes").
I have been an advocate for SENS and CR after reading the book that de Grey and Rae authored. I will still be an advocate for CR (health benefits) but it now feels that they are taking people for a ride. (A very very long ride).
Donating money to SENS is as near to pissing money away as you will ever get.
A Hundred years! For fuck's sake - we'll all be long dead.
No wonder you two can't get any serious funding - you're speaking out of both corners of your mouths.
Research projects with a 100-year resolution/payback are simply childishness.
It is now blindingly clear to me that SENS is a religion for atheists. Scaredy-cat ones at that. D'oh!

Michael - prepare to die like a man.

PS. I dare you to publish this. I bet you truly are a scaredy-cat.

Posted by: Tom Chellew at August 6th, 2009 9:43 AM

I would like to respond to Tom's comment that, "Donating money to SENS is as near to pissing money away as you will ever get.
A Hundred years! For fuck's sake - we'll all be long dead." For my part, I am interested in extending and improving human healthspan, including my own. I think that SENS research, given adequate funding, might yield some valuable therapeutic techniques to help me and millions of other people my age (I'm 35) live longer, healthier lives. I would consider it a victory if SENS type therapies allowed me to gain even a couple of extra years of robust health.

At the same time, I understand that scientific research, even sans the FDA, is sometimes a slow, deliberate process. It can take decades for researchers to translate an idea into a medical/pharmacological intervention. Nonetheless, I do not think that this fact should stop us from investing money in such research. I feel that a majority of people, regardless of what they think of gerontological research in general or of SENS in particular, would agree with me on this point. To whit, both the federal government and individuals invest significant sums of money in medical research into cancer, heart disease, etc., which will not yield clinical results for decades.

If Tom believes that it is not worthwhile to invest money in basic research with a long-term event horizon, he should probably write to his or her representative and ask that his government stop funding its national health institute.

Posted by: Anthony at August 7th, 2009 12:34 AM

Yes, I will certainly do that.
Who knows - perhaps I will get all my tax contributions back and can stop them being "p****d away" on research that won't benefit me, my children or my grandchildren.

Look mate, I am on your side. However, one has to be honest about the technological environment we find ourselves in. We also have to be honest about this great white elephant called "basic research". When Nixon declared the War on Cancer, his own Surgeon General voiced doubts about the outcome saying he believed that many of the enabling factors were simply not in place. He was, of course, sacked for this impertinance. Anyway, two hundred and thirty billion dollars later - Public, Charitable and Corporate research (Source Wikipedia), - and cancer deaths are 4% lower than they were in 1974. Meanwhile, 245m people have died prematurely from a lack of potable water. IN AFRICA ALONE.
$230bn could have bought more than a few pumping stations.

My point, Anthony, is that this is about priorities. de Gray & Rae talk about a Manhattan Project to combat death in 50-100 years, but what about the deaths tomorrow? The awful, terrible truth is that this is all about them.
Sure, they have the right narrative for public consumption, but surely you can see through this? Their motivations are transparent narcissism, and the affectations that they both transport are obvious (to my simplistic mind anyway).


And yet both have joined the Methuselah 300. Modelelled on the 300 Spartans at Thermopylae. Give me a BREAK - Leonidas would have laughed his socks off at this pair. More honesty and less sophistry might be the order of the day.

Final point - should you be curious then, yes, I too am scared of oblivion. Life is simply too much fun for me to want to leave. I will not "go gently into that dark night".
However, perhaps de Gray and Rae (and you) ought to look into your souls - their/your skin is worth no more than that of the starving African - and him we can save tomorrow, not in 100 years.

PS. Again, I think it will be interesting to see if Michael Rae allows this to be published.


Good health & long life,


Posted by: Tom Chellew at August 7th, 2009 2:56 PM

Michael Rae is in no way associated with this blog. Nor is particularly polite to use another person's publishing platform for the purpose of ad-hominem attacks. Blogs are free; create one and vent there.

The argument that one shouldn't live a life any better than that of the worst off - the sackcloth and ashes view - isn't particularly helpful. Its advocates never practice what they preach, given that one finds them, say, engaged in work to make themselves money whilst there are homeless people on the street not half a mile from where they live.

If you believe in doing something for the worst-off in the world, then go forth and do it. You'll be taken more seriously when you've given up all you have to help those who have nothing. But of course you'll do nothing of the kind.

Posted by: Reason at August 7th, 2009 3:14 PM

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