More Than You Ever Wanted to Know About Sirtuin Research

Research into sirtuins comprised the bulk of the last decade's wave of interest and funding for calorie restriction research. Sirtuin levels were found to be associated with the metabolic alterations produced by calorie restriction quite early on, and so scientists proceeded from there to work with compounds known to alter sirtuin levels in the body. Numerous research groups aimed to produce a drug candidate to recapitulate at least some of the benefits to health and longevity produced through the practice of calorie restriction. As is often the case, nothing of any great practical value has resulted for these years of work and probably in excess of a billion dollars in funding, through a lot more is known of the metabolism and genetics of calorie restriction as a result.

So sirtuins look like something of a dead end at the current point in time, or at least a place where more years of work are required to understand why early promise didn't carry through into mammals. Nonethless, sirtuin research continues apace with ambiguous results: some signs of life extension and improved long-term health in laboratory animals such as flies, but nothing that is reliably shown to extend life in mammals. There remain many optimists in the research community, people who think that there is some useful therapy in the future of sirtuin studies. Better and brighter drug candidates for slowing aging are emerging nowadays, however, such as rapamycin and similar items, and I would expect that interest and funding will tend to migrate to fields in which there are more reliable signs of extension of healthy life in mammals.

That said, we shouldn't expect anything better than the past decade of sirtuin and resveratrol research to emerge from present studies of mTOR and rapamycin. Trying to build drugs to slightly slow aging is inherently hard, and yet will produce only marginal therapies even if successful. The researchers who take this path do so because they don't believe that repair based strategies such as SENS are in actual fact a much more efficient path towards extending healthy life and eliminating the diseases of aging. I think that they are wrong in that view, of course.

A recently published edition of Methods in Molecular Biology is entitled "Sirtuins," and contains more than most of us ever wanted or needed to know about the nuts and bolts of sirtuin research. Obviously it is to a large extent written by sirtuin optimists:

Introduction: Sirtuins in Aging and Diseases

Over the past 15 years, the number of papers published on sirtuins has exploded. The initial link between sirtuins and aging comes from studies in yeast, in which it was shown that the life span of yeast mother cells (replicative aging) was proportional to the SIR2 gene dosage. Subsequent studies have shown that SIR2 homologs also slow aging in C. elegans, Drosophila, and mice. An important insight into the function of sirtuins came from the finding that yeast Sir2p and mammalian SIRT1 are NAD+-dependent protein deacetylases. In mammals, there are seven sirtuins (SIRT1-7). Their functions do not appear to be redundant, in part because three are primarily nuclear (SIRT1, 6, and 7), three are mitochondrial (SIRT3, 4, and 5), and one is cytoplasmic (SIRT2). The past decade has provided an avalanche of data showing deacetylation of many key transcription factors. In this chapter, I will address the evidence that sirtuins mediate the effects of CR on physiology and will then turn to the evidence of a relationship between sirtuins and aging and life span. Finally, I will discuss the roles of sirtuins in diseases of aging and the prospects of translating these findings to novel therapeutic strategies to treat major diseases.

The Emerging Links Between Sirtuins and Autophagy

Evidence suggests a role for acetylation and deacetylation in regulating autophagy. In this chapter, we describe the methods useful for understanding this important connection. In particular, we discuss methods for the measurements of sirtuin deacetylase activity, in vivo acetylation detection, and the common assays used to monitor both autophagy and the more selective process of mitophagy.

Utilizing Calorie Restriction to Evaluate the Role of Sirtuins in Healthspan and Lifespan of Mice

Calorie restriction is the most powerful method currently known to delay aging-associated disease and extend lifespan. Use of this technique in combination with genetic models has led to identification of key metabolic regulators of lifespan. Limiting energy availability by restricting caloric intake leads to redistribution of energy expenditure and storage. The signaling required for these metabolic changes is mediated in part by the sirtuins at both the posttranslational and transcriptional levels, and consequently, sirtuins are recognized as instigating factors in the regulation of lifespan.

This family of class III protein deacetylases is responsible for directing energy regulation based on NAD+ availability. However, there are many effectors of NAD+ availability, and hence sirtuin action, that should be considered when performing experiments using calorie restriction. The methods outlined in this chapter are intended to provide a guide to help the aging community to use and interpret experimental calorie restriction properly. The importance of healthspan and the use of repeated measures to assess metabolic health during lifespan experiments are strongly emphasized.

Comments

Speaking of "present studies of mTOR and rapamycin"... You can kickstart one here:

http://www.indiegogo.com/projects/i-am-a-little-mouse-and-i-want-to-live-longer/x/3643554

A Russian lab just discovered about a hundred aged 20 month-old mice that didn't have any experiment assigned to them, simply going to waste.

So they aren't wasted (raising mice to old age is expensive and takes time), the lab is crowdfunding a study into lifespan extension of old mice (applying for funding the conventional way would take too long). They are planning on testing the following combination treatment, but you can suggest any other therapies if you have other ideas:

* An α-adrenergetic receptor blocker (metoprolol). Potential action: Prevents too fast heart beats.
* An mTOR inhibitor (everolimus, similar action as rapamycin). Potential action: Puts cells in an active and resistant mode.
* Metformin. Potential action: Normalizes blood and IGF-1 values at low levels. It also has potential similarities with everolimus.
* Simvastatin. Action: Decreases the amount of LDL cholesterol (considered as 'bad' by some) in the blood.
* Ramipril: an ACE inhibitor. Action: Prevents hypertension.
* Aspirin. When small doses are used, it is believed to have reduced side effects while improving blood flow and therefore reducing cardiovascular risks, and potentially also preventing incidence of some cancers.

Aubrey de Grey and the SENS Foundation are helping out a little (but not with funding), and you can get an autographed copy of Ending Aging.

This Indiegogo campaign needs more advertising to be successful, so let other people or sites know. Even if you don't think these studies are the best use of funding, if an Indiegogo campaign is successful, it could help to start a paradigm shift in the way medical research is funded. And it would be a shame to waste the free aged mice.

http://www.indiegogo.com/projects/i-am-a-little-mouse-and-i-want-to-live-longer/x/3643554

Posted by: Carl at September 11th, 2013 9:11 PM

How many sirtuins are in humans?

Posted by: Jose jimenez at July 30th, 2014 12:08 PM

What would you say are the key researchers/research papers in sirtuin research?

Posted by: Emily at September 19th, 2014 11:55 AM

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