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Does the sense of smell influence longevity?

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Shubhankar Kulkarni
Shubhankar Kulkarni Aug 18, 2020

[1]Pinto JM, Wroblewski KE, Kern DW, Schumm LP, McClintock MK. Olfactory Dysfunction Predicts 5-Year Mortality in Older Adults. Hummel T, editor. PLoS One [Internet]. 2014 Oct 1;9(10):e107541. Available from: https://dx.plos.org/10.1371/journal.pone.0107541

[2]Liu B, Luo Z, Pinto JM, Shiroma EJ, Tranah GJ, Wirdefeldt K, et al. Relationship Between Poor Olfaction and Mortality Among Community-Dwelling Older Adults. Ann Intern Med [Internet]. 2019 May 21;170(10):673. Available from: http://annals.org/article.aspx?doi=10.7326/M18-0775

[3]Quarmley M, Moberg PJ, Mechanic-Hamilton D, Kabadi S, Arnold SE, Wolk DA, et al. Odor Identification Screening Improves Diagnostic Classification in Incipient Alzheimer’s Disease. Velayudhan L, editor. J Alzheimer’s Dis [Internet]. 2016 Dec 20;55(4):1497–507. Available from: https://www.medra.org/servlet/aliasResolver?alias=iospress&doi=10.3233/JAD-160842

Creative contributions

Link between olfaction, metabolism, and longevity

Apoorva Kulkarni Aug 18, 2020

Consequence rather than the cause?

Juran Dec 04, 2020

[1]C. Trimmer, A. Keller, N. R. Murphy, L. L. Snyder, J. R. Willer, M. H. Nagai, N. Katsanis, L. B. Vosshall, H. Matsunami, J. D. Mainland. Genetic variation across the human olfactory receptor repertoire alters odor perception. Proceedings of the National Academy of Sciences, 2019; 201804106 DOI: 10.1073/pnas.1804106115

Shubhankar Kulkarni
Shubhankar Kulkarni3 months ago
Juran K.What you are saying is true. Aging will affect the sensitivity to smell the same way it affects other organs. So, let us assume the causality from longevity to smell sensitivity.

I found some evidence suggesting that the other-way-round causality might also be true.
We know that caloric restriction positively affects longevity. As I mentioned in another contribution in this session, the agouti-related protein (AgRP) neurons in the hypothalamus are activated by food deprivation. Moreover, the smell of food alone inhibits the AgRP neurons of a hungry mouse. This means that there exist neuronal connections between the olfactory sensory neurons and the hypothalamus relaying signals from the former to the latter. Also, deficiency of the AgRP neurons is known to lead to an increased lifespan (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1771482/). The same paper also suggests that "the involvement of AgRP in the process of aging may be independent from its role in feeding behavior". This is because the authors did not observe any significant changes in the food intake and metabolism between the AgRP-null and the wild-type mice.

Therefore, what I think is - if there is no loss in the sensitivity to smell, the olfactory neurons might relay a "satisfied" signal to the hypothalamus and the AgRP neurons will not be activated, mimicking a caloric restriction response, and that might affect longevity positively. On the other hand, if there is a loss in the sensitivity to smell, the olfactory neurons might relay a "hunger" signal to the hypothalamus and the AgRP neurons will be activated, and thereby, negatively affecting longevity.

Although the difference in the loss of sensitivity might be small, the loss is permanent and will be effective in perpetuity. This means that every time a healthy nose smells x amount of food, the aged nose will smell x/age (the constant divided by some factor of the organism's age) amount of food. However small the amount, since it is active continuously (neuronal firing based on the smell of food), the effect might be larger.

This is a hypothesis though. Just like you have suggested, the hypothesis might be true if there is evidence suggesting that people who seem to "age slower" have a less significant decline in olfactory sensitivity. Here is one reference that agrees with the previous statement. Centenarians did better in an odor perception test and the certainty of their response than what was expected at their age (https://pubmed.ncbi.nlm.nih.gov/11461724/). More detailed studies using neuro-imaging techniques are necessary to conclude.
Juran3 months ago
Shubhankar Kulkarni The Agouti paper is very interesting. With no statistically significant impact on measured body metrics and, at the same time, prolonged life span, AgRP sounds incredible in fighting the late visceral obesity in humans! As they suggested, the sample size should be increased in further experiments, but as a pilot study, the research is very promising.
(The only thing that puts a small question mark is a cold sensitivity. Since no comparison of the immune response to common pathogens was observed in the study, this seems like the next step of the AgRP research.)

I see the logic that you follow. If a person/mouse smells food normally and the smell of food is known to inhibit the AgRP (probably because the smell of food relays the "satisfied" signal to the hypothalamus), it can affect longevity positively. With the things from the fourth paragraph being said, I really think it could be true.

The only thing that can make the effect of this kind of "AgRP inhibition" smaller is the fact that loss of smell is often associated with the loss of appetite and vice versa (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759725/), which can, as mentioned above, trigger the activation of AgRP.

The second paper you cited is exactly what we need. The only question is why they have their olfaction ability preserved.

Shubhankar Kulkarni
Shubhankar Kulkarni2 months ago
Juran K. I agree with the loss of smell being associated with the loss of appetite. However, the agouti mice paper suggests otherwise. They found no significant loss in food intake (ad libitum). However, this gets complicated when we talk about humans. Humans have peculiar and sometimes strong desires (eating habits) based on the smells, texture, and appearance of the food. All of these play a role along with the known taste of the food. Since the appetite depends on smell (more so in humans), that might be a problem.

Right! The question of "why" still remains.

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