Stop smelling the roses – and live longer ?


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.


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?

Drosophila melanogaster

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))


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) ?

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