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• Research Paper Volume 11, Issue 21 pp 9901-9911

  Innate sensitivity to stress facilitates inflammation, alters metabolism and shortens lifespan in a mouse model of social hierarchy

  Relevance score: 7.914129

  Maryia Bairachnaya, Oryan Agranyoni, Marina Antoch, Izhak Michaelevski, Albert Pinhasov

  Keywords: social behavior, stress sensitivity, aging, chronic inflammation, IGF-1

  Published in Aging on November 9, 2019

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  It is known that stress alters homeostasis and may lead to accelerated aging. However, little is known about the contribution of innate susceptibility to stress to the deterioration of physiological functions, acceleration of aging and developing of age-related diseases. By using socially-submissive stress susceptible (Sub) and socially-dominant stress resilient (Dom) selectively bred mouse model we observed a marked reduction in the lifespan of both male and female Sub mice. We found that innate susceptibility to stress correlates with chronic inflammation, development of splenomegaly and a significant increase in the levels of circulating pro-inflammatory cytokines IL-1β and IL-6. Furthermore, Sub mice showed a marked hypoglycemia, reduction of insulin levels, increase in GSK3 activity and elevation of IGF-1 serum levels, as well as low skin surface temperature and body weight. Interestingly, lifelong exposure of Sub mice to chronic mild stress did not further reduce their lifespan, indicating a high level of intrinsic stress. Taken together, our data reveal that social submissiveness coupled with innate stress sensitivity coincides with inflammation, leading to the deterioration of physiological functions and early aging independent of whether an individual is exposed to stress or not.

  

  The lifespan of Dom, Sub and BS mice. The Kaplan-Meier survival curves of Dom, Sub and BS mice in (A) males (log-rank test, p<0.001;n=30 for Dom and n=34 for Sub, and n=10 for BS), and (B) females (log-rank test, p<0.05; n=13 for Dom and n=23 for Sub, and n=10 for BS), (C) Sub naïve (n=20) and exposed to CMS (n=20) males. * - p<0.05, *** - p<0.001.

  
  
  

  

  Body weight, blood glucose level and skin surface temperature in Dom and Sub mice. The body weight (males (A), females (B)) and blood glucose level (males (C), females (D) are significantly higher in Dom mice (two-way ANOVA, p<0.001). A significant decrease in body surface temperature (E) was observed in stress sensitive Sub male (Student unpaired two-tailed t-test, t=2.653, p<0.05) and female (Student unpaired two-tailed t-test, t=3.335, p<0.01) mice in comparison to their Dom counterparts. Dom males n=30, females n=15; Sub males n=20, females n=16. * - p<0.05, ** - p<0.01. Error bars indicate SEM.

  
  
  

  

  Insulin, IGF-1 and IGFBPs circulation levels. The insulin levels in male (A) and female (B) Dom and Sub mice at the age of 12 weeks (Dom males n=5, females n=5; Sub males n=5, females n=6) and 26 weeks (Dom males n=5, females n=4; Sub males n=5, females n=5). In 26-week-old Sub males the fasting insulin level was significantly lower than in Dom (t=3.803, p<0.01). (C) IGF-1, IGFBP-2, IGFBP-3 and IGFBP-6 serum levels in Dom and Sub male mice. In the serum of Sub mice a significant elevation of IGF-1 (t=20.11, p<0.01) and a significant reduction of its binding proteins IGFBP-2 (t=17.21, p<0.01), IGFBP-3 (t=6.474, p<0.05) and IGFBP-6 (t=4.569, p<0.05) was detected (n=5 per group). * - p<0.05, ** - p<0.01. Student unpaired two-tailed t-test was used. Error bars indicate SEM.

  
  
  

  

  Sub mice exhibited decreased Akt and GSK3 phosphorylation and glycogen content in liver. Western-blot analysis of phospho- and pan-Akt and GSK3 levels in the liver of Dom and Sub mice at the age of 12 (A) and 26 weeks (B). (C) Phosphorylation level of Akt (Ser473) in Dom and Sub mice at the age of 12 and 26 weeks (n= 5 for each group). (D) The phosphorylation level of GSK3α (Ser21) in Sub mice was significantly decreased at the age of 12 weeks (Student unpaired two-tailed t-test, t=4.091, p< 0.01; n=5 for each group). (E) The phosphorylation level of GSK3β (Ser9) in Sub mice was significantly decreased at the age of 12 weeks (Student unpaired two-tailed t-test, t=3.012, p<0.05; n= 5 for each group). The amount of glycogen in the liver of Dom (F) and Sub (G) mice, PAS staining, scale bar - 20μm. (H) PAS staining revealed reduced level of glycogen in liver of Sub mice (Mann-Whitney test, p<0,001). The staining intensity of PAS staining was scored as 0 (0-25%), 1 (26-50%), 2 (51-75%), or 3 (76-100%) according to the percentage of positively stained cells. * - p<0.05, ** - p<0.01, *** - p<0.001. Error bars indicate SEM.

  
  
  

  

  Age-dependent splenomegaly and increased pro-inflammatory status in Sub mice. A significant increase in spleen weight was observed in stress sensitive male animals at the age of 26 weeks (t =2.408, p<0.05; n=13 for each strain), 39 weeks (t=3.038, p<0.01; n=10 for Dom, n=7 for Sub), 52 weeks (t=11.82, p<0.001; n=8 for Dom, n=2 for Sub) and 65 weeks (t=7.072, p<0.001; n=16 for Dom, n=5 for Sub). The serum levels of pro-inflammatory cytokines (A) IL-1β (t=7.611, p<0.001) and (B) IL-6 (t=2.644, p<0.05) in 12-week-old male Dom and Sub mice (n= 21 for Dom, n= 26 for Sub). * -p< 0.05, ** - p<0.01, *** - p<0.001. Student unpaired two-tailed t-test was used. Error bars indicate SEM.