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Does the sense of smell influence longevity?

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Shubhankar Kulkarni
Shubhankar Kulkarni Aug 18, 2020
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Does the sense of smell influence longevity? How do we test it?

Studies have associated loss of sense of smell with mortality in older individuals. Anosmic (those with loss of smell) older adults were three times likely to die in a 5-year period compared to normosmic individuals (Odds ratio 3.37). These odds were higher than and independent of the known leading causes of death like chronic obstructive pulmonary disease, diabetes, stroke, cancer, heart attack, and heart failure. Moreover, it was observed that death in anosmic individuals did not result from nutrition, cognitive function, mental health, smoking and alcohol abuse, or frailty. The authors, therefore assert that olfactory function is one of the strongest independent predictors of 5-year mortality. Another similar study showed that compared to participants with good olfaction, those with poor olfaction had a 46% higher risk of death in 10 years. Poor olfaction was associated with higher mortality from neurodegenerative and cardiovascular diseases. There were no differences between the sexes in both these studies. It is speculated that cognitive deficits may explain, although with less power, the effect of odor identification on mortality. Odor identification scores were highest in healthy older patients followed by in those with mild cognitive impairment and Alzheimer’s disease, in that order. This suggests that loss of smell may be one of the earliest symptoms of neurodegeneration leading to death.

However, whether there is a causal relationship or purely an association between loss of sense of smell and aging (or mortality) is not known. If at all there is a causal relationship, can we improve the olfactory function and hope to reduce the risk of age-related diseases? Odor identification can also be used as a non-invasive test (and index) to measure age and morbidity.

[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

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Link between olfaction, metabolism, and longevity

Apoorva Kulkarni Aug 18, 2020
Disrupting the olfactory neuron function by mutation or laser ablation in worms and flies extends their life spans. [1,2] Therefore, the smell of food decreases life span in these organisms but only when the animals are calorie restricted. [3] Two different underlying mechanisms have been suggested: [4] 1. Regulation of the “hunger neurons” in the hypothalamus via food odors: [5-7] The agouti-related protein (AgRP) neurons are activated by food deprivation. AgRP neurons are regulated by both nutrients and hormones circulating in the blood and the sensory cues associated with food. The smell of food alone inhibits the AgRP neurons of a hungry mouse, affecting food intake and energy metabolism. 2. Direct regulation of energy homeostasis: The olfactory system may have direct effects on energy homeostasis (and therefore, longevity) independent of its function in odor detection. Olfactory structures express a high density of receptors for hormones such as insulin, leptin, and ghrelin. [8] Evolutionarily, the olfactory system may have a dual role of detecting outside sensory cues and also internal nutrients. Although the exact mechanism/s is/are not clear and studies in humans are lacking, these results suggest that olfaction and longevity are connected via energy metabolism. References: 1. Libert S, Zwiener J, Chu X, VanVoorhies W, Roman G, Pletcher SD. Regulation of Drosophila Life Span by Olfaction and Food-Derived Odors. Science (80- ) [Internet]. 2007 Feb 23;315(5815):1133–7. Available from: https://www.sciencemag.org/lookup/doi/10.1126/science.1136610 2. Alcedo J, Kenyon C. Regulation of C. elegans Longevity by Specific Gustatory and Olfactory Neurons. Neuron [Internet]. 2004 Jan;41(1):45–55. Available from: https://linkinghub.elsevier.com/retrieve/pii/S089662730300816X 3. Smith ED, Kaeberlein TL, Lydum BT, Sager J, Welton KL, Kennedy BK, et al. Age- and calorie-independent life span extension from dietary restriction by bacterial deprivation in Caenorhabditis elegans. BMC Dev Biol [Internet]. 2008 Dec 5;8(1):49. Available from: https://bmcdevbiol.biomedcentral.com/articles/10.1186/1471-213X-8-49 4. Garrison JL, Knight ZA. Linking smell to metabolism and aging. Science (80- ) [Internet]. 2017 Nov 10;358(6364):718–9. Available from: https://www.sciencemag.org/lookup/doi/10.1126/science.aao5474 5. Mandelblat-Cerf Y, Ramesh RN, Burgess CR, Patella P, Yang Z, Lowell BB, et al. Arcuate hypothalamic AgRP and putative POMC neurons show opposite changes in spiking across multiple timescales. Elife [Internet]. 2015 Jul 10;4. Available from: https://elifesciences.org/articles/07122 6. Betley JN, Xu S, Cao ZFH, Gong R, Magnus CJ, Yu Y, et al. Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature [Internet]. 2015 May 27;521(7551):180–5. Available from: http://www.nature.com/articles/nature14416 7. Chen Y, Lin Y-C, Kuo T-W, Knight ZA. Sensory Detection of Food Rapidly Modulates Arcuate Feeding Circuits. Cell [Internet]. 2015 Feb;160(5):829–41. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0092867415000768 8. Julliard A-K, Al Koborssy D, Fadool DA, Palouzier-Paulignan B. Nutrient Sensing: Another Chemosensitivity of the Olfactory System. Front Physiol [Internet]. 2017 Jul 12;8. Available from: http://journal.frontiersin.org/article/10.3389/fphys.2017.00468/full
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Consequence rather than the cause?

jnikola Dec 04, 2020
Differences in odor recognition and perception can occur because of differences in receptor proteins. Receptor proteins are coded by specific genes . Consequently, observed differences in receptor proteins can be a result of an impaired posttranslational mechanism or the changes in the gene sequence. As we age, mutations accumulate and "hit" various genes within the genome.

Can it be that the loss of smell is a consequence of aging and thus can be used as a measure of a DNA-damage? Do people who seem to "age slower" have a less significant decline in olfactory sensitivity?

[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

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Shubhankar Kulkarni
Shubhankar Kulkarni3 years 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.
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jnikola3 years 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.

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Shubhankar Kulkarni
Shubhankar Kulkarni3 years 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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