Intermittent fasting and caloric restriction interact with genetics to shape physiological health in mice - PubMed
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. 2022 Jan 4;220(1):iyab157.
doi: 10.1093/genetics/iyab157.
Intermittent fasting and caloric restriction interact with genetics to shape physiological health in mice
Guozhu Zhang 
1
, Andrew Deighan 
2
, Anil Raj 
1
, Laura Robinson 
2
, Hannah J Donato 
2
, Gaven Garland 
2
, Mackenzie Leland 
2
, Baby Martin-McNulty 
1
, Ganesh A Kolumam 
1
, Johannes Riegler 
1
, Adam Freund 
1
, Kevin M Wright 
1
, Gary A Churchill 
2
Affiliations
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Affiliations
1 Calico Life Sciences LLC, South San Francisco, CA 94080, USA.
2 The Jackson Laboratory, Bar Harbor, ME 04609, USA.
PMID:
34791228
PMCID:
PMC8733459
DOI:
10.1093/genetics/iyab157
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Intermittent fasting and caloric restriction interact with genetics to shape physiological health in mice
Guozhu Zhang et al.
Genetics.
2022.
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. 2022 Jan 4;220(1):iyab157.
doi: 10.1093/genetics/iyab157.
Authors
Guozhu Zhang 
1
, Andrew Deighan 
2
, Anil Raj 
1
, Laura Robinson 
2
, Hannah J Donato 
2
, Gaven Garland 
2
, Mackenzie Leland 
2
, Baby Martin-McNulty 
1
, Ganesh A Kolumam 
1
, Johannes Riegler 
1
, Adam Freund 
1
, Kevin M Wright 
1
, Gary A Churchill 
2
Affiliations
1 Calico Life Sciences LLC, South San Francisco, CA 94080, USA.
2 The Jackson Laboratory, Bar Harbor, ME 04609, USA.
PMID:
34791228
PMCID:
PMC8733459
DOI:
10.1093/genetics/iyab157
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AbstractPubMedPMID
Abstract
Dietary interventions can dramatically affect physiological health and organismal lifespan. The degree to which organismal health is improved depends upon genotype and the severity of dietary intervention, but neither the effects of these factors, nor their interaction, have been quantified in an outbred population. Moreover, it is not well understood what physiological changes occur shortly after dietary change and how these may affect the health of an adult population. In this article, we investigated the effect of 6-month exposure of either caloric restriction (CR) or intermittent fasting (IF) on a broad range of physiological traits in 960 1-year old Diversity Outbred mice. We found CR and IF affected distinct aspects of physiology and neither the magnitude nor the direction (beneficial or detrimental) of effects were concordant with the severity of the intervention. In addition to the effects of diet, genetic variation significantly affected 31 of 36 traits (heritabilities ranged from 0.04 to 0.65). We observed significant covariation between many traits that was due to both diet and genetics and quantified these effects with phenotypic and genetic correlations. We genetically mapped 16 diet-independent and 2 diet-dependent significant quantitative trait loci, both of which were associated with cardiac physiology. Collectively, these results demonstrate the degree to which diet and genetics interact to shape the physiological health of adult mice following 6 months of dietary intervention.
Keywords:
Diversity Outcross mice; caloric restriction; environment interaction; gene ×; intermittent fasting; physiological health.
© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.
PubMed Disclaimer
Figures
Figure 1
Study design. Dietary intervention starts…
Figure 1
Study design. Dietary intervention starts at 180 days of age. Experimental procedures take…
Figure 1
Study design. Dietary intervention starts at 180 days of age. Experimental procedures take approximately 1 week starting from given day.
Figure 2
Diet specific mean (SE) trait…
Figure 2
Diet specific mean (SE) trait values for all experimental procedures. All trait values…
Figure 2
Diet specific mean (SE) trait values for all experimental procedures. All trait values were z-score transformed following batch and generation correction. Red bars denote traits that were significantly different from AL diet at a Westfall-Young multiple tests adjusted P-value threshold of 0.05.
Figure 3
Trait specific heritability (95% Bayesian…
Figure 3
Trait specific heritability (95% Bayesian credible interval) values.
Figure 3
Trait specific heritability (95% Bayesian credible interval) values.
Figure 4
(A) Pairwise genetic (upper-triangle) and…
Figure 4
(A) Pairwise genetic (upper-triangle) and phenotypic (lower-triangle) correlations. Squares containing a back-slash highlight…
Figure 4
(A) Pairwise genetic (upper-triangle) and phenotypic (lower-triangle) correlations. Squares containing a back-slash highlight correlations with an FDR adjusted P-value < 0.05. (B) Hierarchical clustering of traits based on phenotypic correlation values. Each color represents a significantly distinct cluster.
Figure 5
(A) Manhattan plot of directly…
Figure 5
(A) Manhattan plot of directly measured bone composition traits: total bone area and…
Figure 5
(A) Manhattan plot of directly measured bone composition traits: total bone area and bone mineral content. Red circles denote markers with statistically significant (P < 0.05) LOD score based on genome-wide permutation analysis. (B) Manhattan plot of PC derived bone physiology traits. (C) Fine mapping of total bone area (DX_BARE) chromosome 5 locus using imputed variants. LOD scores of closed circles are statistically significant (P < 0.05) based on permutation analysis of all imputed variants with ± 5 Mb of lead genotyped marker. Variants in three FAP groups shown in red, orange, and yellow circles, ordered by maximum LOD score. (D) Mean founder allele effect (± standard error) for the lead genotyped variant for total bone area (DX_BARE). Panels E and F are the same as C and D for bone mineral content (DX_BOMC). Panels G and H are the same as C and D for the chromosome 17 bone composition-PC1 (PC_DXB1) locus.
Figure 6
(A) Fine mapping of chromosome…
Figure 6
(A) Fine mapping of chromosome 16 locus associated with PC2 of ejection fraction…
Figure 6
(A) Fine mapping of chromosome 16 locus associated with PC2 of ejection fraction and left ventricular inner dimension, systole (PC_ECE2). Rank 1, 2, and 3 FAP variants shown in red, orange, and yellow circles. LOD scores of closed circles are statistically significant (P < 0.05) based on permutation analysis of all imputed variants with ± 5 Mb of lead genotyped variant. (B) Mean diet-specific founder allele effects (± standard error) for the lead genotyped variant for PC_ECE2.
Figure 7
(A) Fine mapping of chromosome…
Figure 7
(A) Fine mapping of chromosome 2 locus associated with left ventricular posterior wall…
Figure 7
(A) Fine mapping of chromosome 2 locus associated with left ventricular posterior wall thickness, diastole (EC_LVPD). Rank 1, 2, and 3 FAP variants shown in red, orange, and yellow circles. LOD scores of closed circles are statistically significant (P < 0.05) based on permutation analysis of all imputed variants with ± 5 Mb of lead genotyped marker. (B) Fine mapping of chromosome 2 locus associated with PC1 of left ventricular posterior wall thickness, systole and diastole (PC_ECL1), details are the same as in A. Mean diet-specific founder allele effects (±standard error) for the lead genotyped variant for EC_LVPD (C) and PC_ECL1 (D).
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References
Ahmet I, Tae HJ, de Cabo R, Lakatta EG, Talan MI. 2011. Effects of calorie restriction on cardioprotection and cardiovascular health. J Mol Cell Cardiol. 51:263–271.
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