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SRT1720 is a sirt1 activator and the new hope for a calorie restriction mimicker, which may lead to an increase in human lifespan.

Resveratrol (which I have written about several times, here, here and here) is also a sirt1 activator, which is found (in very small quantity) in red wine,  is also a sirt1 activator and has been tested multiple times to see what it can do for animal’s health and survival (see below). The interesting thing about SRT1720 is that it works at a 1,000 times lower dose than resveratrol.

A new paper examining SRT1720 was published in cell metabolism and covered at eurakalert and wired.

In mice fed a high fat diet (very similar to the resveratrol study) SRT1720 spared the animals from gaining as much weight (even though they ate the same amount) and becoming insulin resistant. Additionally, the animals fed SRT1720 had greater running endurance (no great surprise since they were not overweight). Overall, the authors providing supporting data for the mechanism behind these affects is due to increased fatty acid oxidation (which should help endurance beyond just being a lighter weight) (the same thing exercise does).

Hmmm this sounds just like the recent paper I did on human exercise. Exercise in humans leads them to become less energy efficient at rest - as there was a decoupling of food intake and energy output (occurs in the mitochondria) and hence the extra energy is burnt off as heat. That is why you can eat more if you are on an exercise program and not gain weight (compared to your twin that is not exercising). This goes beyond just the extra calories you are burning while actually exercising. Your entire muscle metabolism becomes less efficient and you need more food to get the same amount of ATP. And while this sounds bad - there are obvious benefits once your muscles have to start working.

Back to RST1720 you must remember the results reported are for mice on a high fat diet. Resveratrol when tested on mice on a high fat diet improved health and survival (meaning the mice on this diet lived longer). When resveratrol was tested for its effect on lifespan on mice fed a ‘normal’ diet there was no effect (but the diet was not started until 12 months of age - it would be interesting to see if it would work when started earlier).

Take home message:

SRT1720 holds promise as it did prevent excessive weight gain and improved endurance, and appears to be an advance over resveratrol as it is 1,000 times more potent (hence I am guessing would be more economically viable). And combined with previous resveratrol studies is likely to increase the lifespan of animals on a high fat diet. The big question is will SRT1720 extend the lifespan of animals on a ‘normal diet’? This is the holy grail of calorie restriction mimickers. Time will tell.

In this case I don’t mean stop living life to its fullest – soaking it all up – but rather the possibility of ceasing your ability to smell to increase your life span (hopefully you can continue living life to its fullest without the ability to smell – open question).

Now one problem with almost all longevity papers is the question: will it work in humans? And the human question is actually a two step problem: 1) are the same longevity pathways we observe in lower organism similar in humans (see Ouroboros piece on the IGF-1 pathway), 2) are we ever going to really be able to test intervention ‘X’ in humans (be it calorie restriction (CR) , every-other-day fasting, resveratrol, etc.), because of the length and cost of the study.

I will propose that the olfaction/longevity results of a new paper (and the previous papers reporting similar results) unlike many of the other life extension intervention could ‘easily’ be tested in human in a relatively short time – but first I will discuss the new findings and a bit of the background.

New October 2008 Olfaction - longevity paper

A new paper (Collins et. al., PLOS Genetics, 2008) (freely available) adds to the growing story (at least in lower organism) of how smell (chemosensory) plays a large role in determining life span. They found an anticonvulsant drug (ethosuximide) approved for human use, which had previously reported (by the same group) to extends mean lifespan of C. elegans (by 17%) (Evason et. al., Science 2005) (Evason et al., also found that trimethadione, another human approved anticonvulsant drug – though rarely used due to side effects, extended mean life span by 47%), works via blocking the chemosensory system (which for argument sake I am calling the olfactory system). The group did a fairly exhaustive set of studies which I won’t go into all the details. However, it appears ethosuximide ability to increase this organisms lifespan is mediated via blocking the chemosensory-olfaction system.

Does ethosuzimide block olfaction in humans:

I wonder if there are human thinking about attaining ethosuzimide to test on themselves for longevity purpose. Not necessarily the smartest thing to do. But one question I am sure longevity researchers are wondering is could this drug also extend the lifespan of humans. Well, I would argue there is a simple test they could run tomorrow to give them at least a hint: does ethosuzimide also block the ability to smell in humans. Interestingly, one side effect mentioned for ethosuzimide is the potential loss of taste (but this was included in a host of not so great common side effects). Loss of taste is obviously fairly closely related to loss of smell and I wonder if the loss of olfaction has just gone largely unreported. Interesting possibility at least.

(side note calorie restriction (CR) (at times also called dietary restriction) has also been shown to reduce seizures in animals models (Bough et. al., 2003) and fasting was the inspiration for the testing of a ketogenic diet (KD) (1921) on seizures, and KD is now used for refractory epilepsy in children, and also shown to be effective in adults – though adults find it difficult to stay on the ketogenic diet (Stafstrom et. al., 2003). Overall, a ketogenic diet is argued to be as effective as any current pharmaceutical treatment for children with seizures.

Background:

The first paper I am aware of that directly examined olfaction link with longevity is (Alcedo and Kenyon, Neuron, 2004). The researchers found that taking out specific gustatory or olfactory neurons can extend life span in C. elegans. Taking out (via laser ablation) of a very specific subset of olfactory neurons (AWA) extended life span, while removal of a different set of olfactory neurons (AWC) had no effect. However, taking out both the AWA and AWC together further extended the life span. Interestingly, after further testing they concluded that the olfactory AWA- organisms (or the AWA- and AWC-, or the AWA-, AWC-, ASI- (see below)) that lived longer ate as much as there wild type controls – hence they were not calorie restricted. They next found that a null mutation in odr-7, which is a nuclear hormone receptor that is required specifically for AWA function, lived longer than wild type.

However, the researchers had to remove the AWA and AWC olfactory neurons, along with the ASI gustatory neurons to produce the same longevity extension as is observed with CR. This would suggest that olfaction is not the entire story of CR.

Then one question would would the exposure to food odours reduce the life extension effects of CR?

Image via Wikipedia

When fruit flies (Drosophila melanogaster) on calorie restriction (CR) were exposed to food odorants the CR longevity effect was reduced 6 – 18% (Libert et al., 2007) (compared to the approx. 32% increase in lifespan with CR). Therefore, approxmatley 1/5 to 1/2 of the longevity effect of CR was lost with the simple exposure of the smell of food. Exposure of food odorants had no effect on life span in fully fed organisms.

To further explore the role of olfaction the researchers used a loss of function mutation in a specific odorant receptor (Or83b) (functional mutation form called Or83b2) and found organisms with this mutation had a 56% increase in median life span in fully fed females (less, but still significant affect in male fruit flies). So while the animal consumed the same amount of food their inability to smell via the Or83b2 mutation extended their lifespan. A ‘rescue’ experiment that involved the expression of the ‘normal’ version of the Or83b transgene resulted in normal life span (a loss of the increased life span).

They next tested the Or83b2 functional mutation on a variety of CR diets. All mutated Or83b2 groups lived longer than the controls over the various CR diets. But interestingly CR further increased the already dramatic increase in median life span of the Or83b2. (I had forgotten about this particular result from this paper – which has implications – see below. ). These result again (along with the above mentioned data) suggest that while olfaction plays an important role in CR’s life extension effect but it is not the sole mechanism.

(side note: the smell of food in humans is reported to increase insulin levels - which could drive the insulin-IGF-1 pathway (for review see Brand et. al., 1982))

Summary:

Now there are several papers (I did not mention them all here in this piece) that indicate the importance of smell, and not just food consumption on longevity – at least in lower organism. The question then becomes is this also true in higher organism, and most importantly to us egocentric humans, does it work in us (which is also true for all the potential longevity interventions even if they have been observed hundreds of times in multiple organism as seen with dietary restriction)?

Olfaction in humans and longevity – we can test this.

While I started out this piece pointing out the length and difficulty of ever testing the longevity effects of the various potential interventions. However, in regards to the olfaction effect on human longevity we should be able to ‘quickly’ and easily find out the answer. No we are not going to ask humans to come into the laboratory late one night and excise their olfactory system. There is already a group of humans that are unable to smell.

Anosmics are unable to smell. There are congenital anosmics and non-congenital (via accident, or infection of the olfactory system, etc). According to the numbers there are approximately 2 million anosmics in America. I do not know the number of congenital anosmics (some preliminary data suggest around 30%).

What I am proposing is select out a large sample of anosmics that have no memory of every having the ability to smell (hence they at least have not been able to smell since the age of 4 to 5) and look at their life span compared to appropriately matched control group. Simple enough. There would be a wide range of ages including people close to the end of their lives, and we could possibly use data from those that are already deceased if we have clear enough evidence of when they lost (congenital or viral) their olfactory ability to speed up finding out the results. (I will volunteer to be part of the anosmic group since I have never had the ability to smell).

This way we can bypass 10 or 20 years of animal research on organisms above C elegans and fruit flies, and jump to the front of the line and see if knocking out olfaction in humans enable them to live longer.

(Another interesting question, but obviously more difficult to test, would be does the combination of olfaction KO and some form of dietary restriction cause a further increase in human life span?)

However - maybe we really want to smell the roses:

This won’t address the question of will humans willing choose to forgo olfaction for the chance to live longer (same can be said regarding dietary restriction other than we already know a vast majority of people would not choose this option – hence why it would be so lucrative for whatever company comes up with a CR mimicker).

I guess the questions is would you forgo the ability to smell the roses to live a longer life (assuming taking out human olfaction increases life span) ?

Anne C. has done a wonderful job (no pun intended) at Existence is Wonderful hosting the latest installment of the hourglass longevity blog carnival. She does a great job of writing bookends (introduction and postscript) to ease us in and out of exploring new frontiers.

Over the last 3-5 years you have probably come across the importance of visceral fat to your health. Visceral fat is not the fat you can pinch at your belly – that fat is subcutaneous fat. Visceral fat is inside the abdominal wall. It is the fat that is thought to be responsible for chronic inflammation (as measured by CRP, IL-6, and TNF-alpha levels), and is thought to be a major contributor to metabolic syndrome/diabetes along with cardiovascular diseases (CVD).

We had known for a long time that being overweight is detrimental to our long term health – but scientist started weeding out the culprit – it is not any fat, but rather the visceral fat which is the problem. In many ways you could argue it doesn’t really matter, the take home message is the same – don’t get too fat. But despite that, I will try to give you some knowledge about visceral fat.

That pot belly that we have all seen protruding out over the pants is more than likely caused by visceral fat, than simple subcutaneous fat. But the only way to really know is to get ‘scanned’. Now it is likely for most of us as we gain weight we first enlarge our subcutaneous fat stores and once they get full we start putting more into the visceral fat stores (of course it is not exactly that simple). But of course there are individual differences (like everything else – we are all special snowflakes) of our storage tendencies.

Visceral fat removal study:

A small study, which was not published in a high end journal (not that you should discount it for that reason), examined the relationship between visceral fat and lifespan in rats (Muzumdar et. al., 2008). They wondered what would happen if you surgically removed visceral fat (one time) and examined how long they would live.

Now the normal liposuction, which is one of the most popular surgeries in America, does not remove visceral fat – but rather subcutaneous fat.

Rats that had their visceral fat (VF group) removed at age 5 month lived longer than the control animals, but not as long as the third group of animals which were on calorie restriction (CR). The visceral fat removal group lifespan appeared in between the control group and the CR group – but the authors state that the VF group had approximately 20% of the longevity effect of CR. So while visceral fat is important CR still works considerably better.

So one problem with this study was they don’t have a time series measurement of the level of visceral fat (which can be done in rats with modern scanning techniques). Though at 20 weeks into the experiment they did measure body fat in a subset of animals (n = 8). Interestingly, the visceral fat removal group weighed slightly more than the control group (VF 610 g +/- 18 vs control 570 g +/- 16). The overall fat percentage did not differ between these two groups (VF 27.9% +/- 1.9 vs control 29.2% +/- 0.8, CR 13.3% +/- 1.8). However, in regards of visceral fat the VF group had 8.8 g +/- 1.2 which was significantly less than the control group 26.9 g +/- 2.3 (CR group = 5.9 g +/- 0.7). I was a little surprised at the lack of return of visceral fat in the VF group at 20 months of age as they had it removed at 5 months since this group gained considerable weight during this period and ended up weight slightly more than the control group. The authors point out that the VF group must have larger levels of subcutaneous fat to end up as the same percentage as the control group for overall body fat percentage.

Now I would call this work preliminary but interesting, and deserves further experiments where a more thorough analysis of the effect of visceral fat removal can be obtained.

Neuronal control over visceral fat levels:

Now what controls visceral fat storage? Well that is a huge complicated series of checks and balances which I can’t begin to cover in this blog piece. But as you can imagine for something so important for survival evolution has provided an intricate system that works very well (unless you are in times of extreme abundance as seen in modern human society – developed countries).

But I will tell one part of fat control - motor and sensory innervations of fat. Interestingly, while way back in 1898 they ‘knew’ that fat was innervated it was either considered wrong or ignored until very recently (Bartness et al., 2005: very good review). I was stymied that it has only been in the last 5 or so years that this has really been studied (maybe because of the obesity epidemic and the final realization that fat is not an inert organ – but rather an active dynamic endocrine organ). Fat is innervated by sympathetic peripheral nervous system which sends signals to induce fat release (when needed for energy requirement). Additionally, sensory info from the fat is sent to the dorsal root ganglion and up the spinal cord. So as good thinking individuals what do you think would happen if the spinal cord is injured and the information is no longer sent?

What happens if you remove the innervations to visceral fat?

In humans that have a spinal cord injury (SCI) (either at the cervical or thoracic level) despite having similar BMI , waist circumference, and even higher activity level than age matched able bodied controls the SCI subjects have roughly 41-45% more visceral fat (Edwards et al., 2008, Maruyama et. al., 2008). Now the little you know about visceral fat and its effect on general health what do you think the lifespan is for SCI subjects – (looking at survival of those subjects that have lived beyond the initial 3 years after injury – so you get rid of the confounding variable of the acute trauma)? People with spinal cord injury die approximately 13 to 25 years earlier than able bodied counterparts (depends on the level – cervical vs thoracic, and how complete is the injury) (Strauss et. al., 2006). Since the confounding variable of the acute trauma complications is eliminated it appears that the spinal cord injury leads to quicker rate of death in people with SCI. People with a SCI appear to die from the same leading causes of death in able body subjects: heart disease, cancer, etc. Additionally, people with SCI have chronic inflammation similar to what is seen in people with high levels of visceral fat (CRP, IL-6, TNF-alpha).

Could the increase visceral fat play a role in the earlier death of SCI subjects? And why in general would SCI subjects despite being very active, healthy, and not a big waist still have such a high accumulation of visceral fat? It seems to make sense that it is due to the loss of information sent up and down the central nervous system – but surprisingly us scientist really don’t know. In reality spinal cord scientist have not bother to study animal models of reduced lifespan after SCI. In addition, this dramatic reduction of lifespan seen in people with SCI is rarely mentioned in the field.

It appears that the data from SCI subjects give further evidence (but not conclusive in anyways since there are so many other variable altered in SCI subjects) of the negative role visceral fat may play in lifespan.

Bottom line:

Do your best to control your fat level, specifically your visceral fat – which really means eat well and exercise – don’t become overweight.

Is visceral fat removal for a longer lifespan coming to a plastic surgery clinic in a mall near you? I am not sure how feasible this surgery is in humans - but if it is possible I can see the surgeons rubbing their hands.

And maybe, just maybe, we should be looking into why people with spinal cord injuries die 13 – 25 years earlier than able bodied subjects (nothing to do with acute effects of the trauma). Smokers die 8-10 years earlier than non smokers to give you a comparison – and anti smoking campaigns have been a high priority in developed nations for over 40 years. It appears that the loss of 8-10 years is considered a just cause for serious intervention then what about people with a spinal cord injury? While the number of people with SCI are obviously far less than the number of smokers - the loss of lifespan in greater.

While millions and millions have been spent on research in hope of making them walk again, with really no success, research investigating intervention to give them a more normal lifespan has been ignored.