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Olfactory perception of food abundance regulates dietary restriction-mediated longevity via a brain-to-gut signal

Abstract

The role of food nutrients in mediating the positive effect of dietary restriction (DR) on longevity has been extensively characterized, but how non-nutrient food components regulate lifespan is not well understood. Here, we show that food-associated odors shorten the lifespan of Caenorhabditis elegans under DR but not those fed ad libitum, revealing a specific effect of food odors on DR-mediated longevity. Food odors act on a neural circuit comprising the sensory neurons ADF and CEP, and the interneuron RIC. This olfactory circuit signals the gut to suppress DR-mediated longevity via octopamine, the mammalian homolog of norepinephrine, by regulating the energy sensor AMP-activated protein kinase (AMPK) through a Gq-phospholipase Cβ-CaMKK-dependent mechanism. In mouse primary cells, we find that norepinephrine signaling regulates AMPK through a similar mechanism. Our results identify a brain–gut axis that regulates DR-mediated longevity by relaying olfactory information about food abundance from the brain to the gut.

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Fig. 1: Food odors suppress the lifespan of worms under dietary restriction but not those fed AL, and this requires neurotransmission.
Fig. 2: Food odors act on an olfactory circuit, comprising ADF, CEP and RIC neurons, to suppress DR longevity.
Fig. 3: The molecular basis by which the olfactory circuit senses and processes odor signals from food.
Fig. 4: The olfactory circuit signals the intestine to regulate the energy sensor AAK-2/AMPK via Gq-PLCβ-CaMKK-dependent norepinephrine signaling.
Fig. 5: Octopamine signaling in the intestine promotes lifespan and stimulates AMPK phosphorylation via a Gq-PLCβ-CaMKK-dependent mechanism.
Fig. 6: Activation of norepinephrine signaling stimulates AMPK via a Gq-PLCβ-CaMKK-dependent mechanism in mouse primary cells.

Data availability

The datasets generated and analyzed during this study are either included within the manuscript or are available from the corresponding author on reasonable request.

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Acknowledgements

We thank J. Gong, S. Zhang and H. Chen for assistance. Some strains were obtained from the Caenorhabditis Genetics Center. J.L. received funding support from the National Natural Science Foundation of China (81872945 and 81720108031). J.W. received funding support from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107583). X.Z.S.X. received funding support from the National Institute of General Medical Sciences (R35GM126917).

Author information

Authors and Affiliations

Authors

Contributions

B.Z. conducted the experiments and analyzed the data. H.J., B.Z. and J.W. performed mouse experiments and analyzed the data. B.Z., J.L. and X.Z.S.X. wrote the paper with assistance from other authors.

Corresponding authors

Correspondence to Jianfeng Liu or X. Z. Shawn Xu.

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The authors declare no competing interests.

Additional information

Peer review information Nature Aging thanks Andrew Dillin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Additional data related to food odor suppression of DR longevity without increasing food ingestion.

a, b, Food odors do not change the pumping rate of worms under DR. Pumping rate was counted at 24 hr (a), and 96 hr (b), after worms were transferred to the DR assaying plates. 2 × DR: twice amount of bacterial food, which stimulated the pumping rate. n = 30 (DR), 30 (DR + odor), 16 (2xDR) and 16 (2xDR + odor) biologically independent animals in (a). n = 30 (DR), 30 (DR + odor), 15 (2xDR) and 14 (2xDR + odor) biologically independent animals in (b). Data are presented as mean ± s.e.m. P values were calculated with one-way ANOVA with Bonfferroni’s test. See Fig. 1c for data of the pumping rate counted at 1 hr post-transfer. c, Feeding worms with twice amount of bacteria food (2x DR) does not affect DR longevity, but food odors can still suppress the lifespan of these worms.

Extended Data Fig. 2 Additional data related to the olfactory circuit.

a, ADF dendrite, soma and axon from DR, but not AL worms, all respond robustly to medium containing food odors. GCaMP6f was expressed as a transgene in ADF neurons under tph-1(L) promoter. DsRed was co-expressed to enable ratiometric imaging. Shades along the traces represent error bars (SEM). b, NSM neurons (dendrite/soma/axon) from DR and AL worms do not respond to medium containing food odors. GCaMP6f was expressed as a transgene in the NSM neurons using tph-1(s) promoter. DsRed was co-expressed to enable ratiometric imaging. Shades along the traces represent error bars (SEM). c, Bar graph summarizing data in (a) and (b). n = 11 (ADF dendrite - AL), 10 (ADF dendrite - DR), 8 (ADF soma - AL), 9 (ADF soma - DR), 11 (ADF axon - AL), 10 (ADF axon - DR), 11 (NSM soma - AL), 14 (NSM soma - DR), 13 (NSM processes - AL), and 10 (NSM processes - DR) biologically independent animals. d, CEP dendrite from DR worms, but not AL worms, responds robustly to medium containing food odors. GCaMP6f was expressed as a transgene in CEP neurons using dat-1 promoter. DsRed was co-expressed to enable ratiometric imaging. Shades along the traces represent error bars (SEM). e, CEP soma and axon from both DR and AL worms respond to medium containing food odors, showing no specificity towards DR. Shades along the traces represent error bars (SEM). f, Bar graph summarizing data in (d) and (e). n = 6 (CEP dendrite - AL), 8 (CEP dendrite - DR), 13 (CEP soma - AL), 20 (CEP soma - DR), 12 (CEP axon - AL) and 17 (CEP axon - DR) biologically independent animals. g, h, ADE and PDE neurons (soma and processes) from DR and AL worms do not respond to medium containing food odors. GCaMP6f was expressed as a transgene in ADE and PDE neurons using dat-1 promoter. DsRed was co-expressed to enable ratiometric imaging. Shades along the traces represent error bars (SEM). i, Bar graph summarizing data in (g) and (h). n = 11 (ADE soma - AL), 10 (ADE soma - DR), 13 (ADE processes - AL), 15 (ADE processes - DR), 10 (PDE soma - AL), 11 (PDE soma - DR), 10 (PDE processes - AL) and 11 (PDE processes - DR) biologically independent animals. j, RIC soma and processes from DR worms, but not AL worms, respond robustly to medium containing food odors. GCaMP6f was expressed as a transgene in RIC neurons under tbh-1 promoter. DsRed was co-expressed to enable ratiometric imaging. Shades along the traces represent error bars (SEM). The soma traces are duplicates of those presented in Fig. 2i, as these experiments were performed at the same time. k, RIM soma and axon from both DR and AL worms respond to medium containing food odors, showing no specificity towards DR. GCaMP6f was expressed as a transgene in RIM neurons using cex-1 promoter. DsRed was co-expressed to enable ratiometric imaging. Shades along the traces represent error bars (SEM). l, Bar graph summarizing data in (j) and (k). n = 11 (RIC soma - AL), 14 (RIC soma - DR), 11 (RIC processes - AL), 12 (RIC processes - DR), 12 (RIM soma - AL), 12 (RIM soma - DR), 12 (RIM processes - AL) and 10 (RIM processes - DR) biologically independent animals. m, n, RNAi knockdown of odr-3 and ocr-2 specifically in ADF neurons eliminates food odor-evoked calcium responses in these neurons. dsRNA against odr-3 and ocr-2 gene was expressed as a transgene specifically in ADF neurons using the bas-1(prom7) promoter. (m) Calcium imaging traces. Shades along the traces represent error bars (SEM). (n) Bar graph summarizing the data in (m). n = 10 (WT - AL), 9 (WT - DR), 10 (ADF odr-3(RNAi) - AL), 10 (ADF odr-3(RNAi) - DR), 10 (ADF ocr-2(RNAi) - AL) and 10 (ADF ocr-2(RNAi) - DR) biologically independent animals. (o) NSM neurons are not required for food odors to suppress DR longevity. tph-1(s) promoter was used to drive the expression of TeTx transgene specifically in NSM neurons. (p) Blocking the output of RIC neuron shortens DR longevity. tbh-1 promoter was used to drive the expression of TeTx transgene in RIC neurons. Data are presented as mean ± s.e.m. P values in c, f, i and l: two-tailed student’s t test. P values in n: one-way ANOVA with Bonfferroni’s test.

Extended Data Fig. 3 Other serotonin receptors are not required for food odors to suppress DR longevity.

Food odors can still suppress DR longevity in ser-1 (a), ser-4 (b), ser-7 (c) and mod-1 (d) mutant worms. a-d, share the same control group, as these experiments were performed at the same time.

Extended Data Fig. 4 Other dopamine receptors are not required for food odors to suppress DR longevity.

Food odors can still suppress DR longevity in dop-1 (a) dop-2 (b) dop-3 (c) dop-4 (d) and dop-5 (e) mutant worms. (a) and (c) share the same control group, as these experiments were performed at the same time. (b), (d) and (e) share the same control group, as these experiments were performed at the same time.

Extended Data Fig. 5 Additional data related to regulation of DR longevity by AMPK and octopamine signaling.

a, DR can extend the lifespan of raga-1 mutant worms. b, Food odors can suppress DR longevity in raga-1 mutant worms. c, DR can extend the lifespan of rict-1 mutant worms. d, Food odors can suppress DR longevity in rict-1 mutant worms. e, Pan-neuronal expression of aak-2 gene only has a slight rescue effect on the longevity defect of aak-2 mutant worms. This aak-2 neuronal transgene also does not rescue the odor sensitivity defect of aak-2 mutant worms. rgef-1 promoter was used to drive the expression of aak-2 cDNA in neurons. f-g, Food odors can still suppress DR longevity in ser-6 (f) and octr-1 (g) mutant worms. (f) and (g) share the same control group, as these experiments were performed at the same time. h, Intestine-specific knock-down of par-4/LKB1 by dsRNA transgene (Pges-1::par-4(RNAi)) does not prevent food odors from suppressing DR longevity, though it partially inhibits DR longevity. i, Intestine-specific knock-down of mom-4/TAK1 by dsRNA transgene (Pges-1::mom-4(RNAi)) does not prevent food odors from suppressing DR longevity; nor does it affect DR longevity. j–l, Mutations in egl-30 (j), egl-8 (k), and ckk-1 (l) abolish the ability of food odors to suppress DR longevity, a defect that is rescued by transgenic expression of corresponding wild-type genes in the intestine using ges-1 promoter.

Extended Data Fig. 6 AAK-2/AMPK-dependent lifespan extension requires DAF-16/FOXO.

a, Lifespan extension mediated by intestinal expression of aak-2 requires daf-16. daf-16 RNAi blocked the lifespan-extension effect of the intestinal aak-2 transgene. b-d, Intestinal expression of aak-2 promotes sod-3 gene expression in multiple tissues in a daf-16-dependent manner. sod-3::gfp is a transgene reporting the expression level of sod-3 gene. (b) Sample images showing a low level of sod-3::gfp expression. Left: bright field image. Right: fluorescent image. (c) Sample images showing that the Pges-1::aak-2 transgene increased the expression of sod-3::gfp. Top left: bright field image. Top right: fluorescent image. Bottom: zoomed-in images showing sod-3::gfp expression in multiple tissues, including pharynx (head), neurons (head), body-wall muscles, vulval muscles (mid-body), intestine, etc. Scale Bar: 100 μm. (d) Bar graph summarizing the data in (b) and (c). n = 24 (WT), 20 (Pges-1::aak-2), 43 (daf-16(RNAi)) and 22 (daf-16(RNAi); Pges-1::aak-2) biologically independent animals. Data are presented as mean ± s.e.m. P values were calculated with one-way ANOVA with Bonfferroni’s test.

Supplementary information

Reporting Summary

Supplementary Table 1

Lifespan statistics related to Figs. 1–5.

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Source Data Fig. 5

Unprocessed western blots.

Source Data Fig. 6

Unprocessed western blots.

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Zhang, B., Jun, H., Wu, J. et al. Olfactory perception of food abundance regulates dietary restriction-mediated longevity via a brain-to-gut signal. Nat Aging 1, 255–268 (2021). https://doi.org/10.1038/s43587-021-00039-1

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