The impact of social partners: investigating mixed-strain housing effects on aging in mice

doi:10.21203/rs.3.rs-4820360/v1

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The impact of social partners: investigating mixed-strain housing effects on aging in mice

https://doi.org/10.21203/rs.3.rs-4820360/v1

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Aging is a multifaceted process characterized by the gradual decline of physiological functions and can be modulated by various internal and external factors. While social interactions have been shown to affect behaviors and physiology in different species, the impact of social partners on aging-related phenotypes and lifespan in mice remains understudied. To address this question, we investigated various aging-related traits and lifespan in two mouse strains, C57BL/6J and BALB/c, under two different housing conditions: mixed-strain and same-strain housing. Analyses using a Generalized linear model revealed significant differences between the two strains in several phenotypes, including metabolic, anxiety-like, and electrocardiographic traits. However, surprisingly, housing conditions did not significantly affect most of the examined parameters, but only 2 out of 19 traits, body weight change in a metabolic cage and running wheel activity. Lifespans were also similar between mixed- and same-strain housing in both C57BL/6J and BALB/c mice. Together, our study suggested a minimal influence of co-housing with social partners from different genetic backgrounds on aging-related phenotypes. This result demonstrates the feasibility of mixed housing for mouse husbandry and, more importantly, provides valuable insights for future research on the social influences on the aging process in mice.

Mixed-strain housing

aging

lifespan

Aging is an inevitable biological process characterized by declines in physical^1,2, physiological^3,4, and cognitive functions^5,6. Common age-related changes include increased blood pressure⁷, increased body fat⁸, and reduced physical activity⁹. Several factors can influence the aging process, including exercise¹⁰, diet¹¹, and stress¹². For instance, regular physical activity is associated with reduced cognitive decline and a lower risk of dementia¹³. In many species, dietary restriction has been shown to significantly extend lifespan^14,15. Additionally, chronic stress is known to accelerate the aging process through mechanisms such as inflammation and oxidative stress¹⁶. Understanding the interaction of these factors is crucial for developing strategies to promote healthy aging and improve the quality of life in older populations.

The social environments play crucial roles in modulating behaviors, physiology and, potentially, aging. Research across various species highlights the profound influence of social interactions on health outcomes. In humans, social isolation is associated with detrimental effects, including increased risks of cardiovascular disease¹⁷, decreased immune response¹⁸, and higher mortality rates¹⁹. Conversely, supportive social ties are beneficial, contributing to reduced blood pressure, heart rate, and stress hormones²⁰. The importance of social partners in maintaining physiological function can be seen not only in humans, several studies in model organisms also demonstrate the critical role of social environments on health. For instance, in C. elegans, different pheromones have been shown to extend or shorten animal lifespans^21,22. While in Drosophila melanogaster, living with younger or older social partners changed their lifespan and stress resistance^23,24. These findings highlight the significant impact of social environments on health across species. Despite the profound influence of social interactions on aging, understanding how social environments affect health and aging poses significant challenges due to their complexity and still needs further investigation.

Research exploring social interactions in house mice reveals significant impacts on both behavioral and physiological parameters. Studies with C57BL/6J and DBA/2N strains demonstrated increased agonistic behaviors and decreased socio-positive behaviors following cohousing for several weeks²⁵. Mice paired with unfamiliar partners exhibit higher metabolic rates during social interaction, indicating increased energy expenditure in socially unstable environments²⁶. There was also evidence in mice that social interactions alter health conditions and lifespan. Social isolation in male mice increases diet-induced obesity and peripheral inflammation, contributing to diabetes^27,28. Cohousing wild-type mice with R6/2 mice, a model for Huntington’s disease, extended lifespan in the R6/2 mice population²⁹. These findings highlight the critical role of social interactions in shaping behaviors, stress responses, and cognitive functions within complex social environments, essential for understanding health and aging in mice.

Despite extensive research on how social environments affect individuals in physiological and behavioral responses, most studies in mice have focused on short-term cohousing effects^25,30,31, often failing to explore long-term social influences on health or aging processes. In this study, we aimed to investigate the impact of social partners with different genetic backgrounds on various physiological and behavioral traits in aged mice following prolonged cohousing using C57BL/6 and BALB/c. We focused on female mice to minimize fighting during social interaction. Specifically, we hypothesized that long-term mixed-strain housing would significantly change multiple aging-related phenotypes, such as body composition, metabolic parameters, cardiovascular health, anxiety levels, locomotor activity, and lifespan. By addressing these questions, our research sought to provide a deeper understanding of how social environments modulate the aging process. Our findings may provide important information for housing strategy in mouse management and new insight into future research regarding the social modulation of aging.

Mice

C57BL/6J (C57) and BALB/cByJ (BALB/c) female mice, 8 weeks old, were obtained from the National Laboratory Animal Center in Taiwan and kept at the Taiwan Mouse Clinic. All experiments were conducted at Taiwan Mouse Clinic and in compliance with institutional guidelines approved by the Institutional Animal Care and Use Committee of National Tsing Hua University and Taiwan Mouse Clinic.

Experimental Procedures (Fig. 1)

Upon arriving at the Taiwan Mouse Clinic, C57 and BALB/c mice were divided into two housing conditions: same-strain housing and mixed-strain housing. In the same-strain housing, there were 5 cages containing 4 C57 mice each and 5 cages containing 4 BALB/c mice each. In the mixed-strain housing, each cage housed 2 C57 mice and 2 BALB/c mice, totaling 10 cages. All mice were maintained in a controlled animal room with a 12-h light/dark cycle (7am-7pm).

After 21 months (about 23-month-old), mice were subjected to the following tests, including the Minispec Body Composition Analyzer, Metabolic cage analysis, Open Field test, Blood Pressure Analysis and Electrocardiography (ECG). After the tests, mice were kept till natural death or euthanasia due to uncontrollable pain or distress according to the guidelines of Taiwan Mouse Clinic. The lifespans for each mouse were recorded.

Body Composition

Mice were placed into Minispec LF50 TD-NMR (Bruker, Germany) to analyze parameters related to body composition, including body weight, body fat, body lean, body free fluid and body total water, based on the NMR signals. After the analyses, mice were returned to their home cages.

Metabolic cage for 24 hours

Mice were placed into the PhenoMaster Next Generation 6528(TSE Systems, Germany) cage system to monitor the body weight change, food and water intake/output, as well as running wheel activity in a consecutive 24 hours of time frame. Mice were returned to their home cages after the analyses.

Blood Pressure measurement

Mice were placed into the BP-2000 Series II Blood Pressure Analysis System (Visitech Systems, Inc., USA). After 30-minute habituation, the systolic, diastolic blood pressure and pulse rate were recorded consecutively for 30 minutes. The average values for each parameter were calculated. Mice were returned to their home cages after the analysis.

Electrocardiography (ECG)

Mice were anesthetized with isoflurane (5% induction, 1% maintenance). The ECG electrodes with PowerLab 8/30 and Animal Bio Amp (AD Instruments, USA) were attached to mice to analyze ECG parameters, including RR, PR and QRS intervals, P duration and QTc. Mice were returned to their home cages after the analysis.

Open Field Assay

Mice were placed in the center of an open field box (50*50*50 cm) and allowed to explore the box freely. The center 25*25(cm) area in square shape was defined as an inner zone of the open field. Their movements were digitally recorded for 60 minutes. Mice were returned to their home cages after the analyses. The videos were analyzed by the EthoVision XT (Noldus, Netherlands) to obtain the time in the inner zone and the total distance traveled.

Statistic

The distribution of data was evaluated by the Shapiro-Wilk normality test using GraphPad Prism 8.0 (GraphPad). The effects of strain, housing condition, and the interaction between strain and housing conditions on the parameters collected by the Minispec Body Composition Analyzer, Metabolic Cage Analysis, Open Field Test, Blood Pressure Analysis, and Electrocardiography (ECG) were examined using a Generalized Linear Model (GLM) with SPSS 27.0 (IBM). A linear model was employed for normally distributed data, while a Gamma model was used for non-normally distributed data. Additionally, the comparisons of body weight change and running wheel activity were further analyzed by post hoc pairwise comparison using the Fisher's Least Significant Difference (LSD) Test. Lifespan difference was examined by the cox proportional hazards model using R (R Core Team, 2023). Data are presented as the mean ± standard error of the mean (SEM), along with individual data points.

No significant difference in body composition and blood pressure between strains or housing conditions

The Generalized Linear Model (GLM) detected no significant difference in traits related to body composition, including body weight, body fat, body lean, body free fluid and body total water, between strains, between housing conditions or under the interaction between strain and housing conditions (Table 1). Although C57 mice appeared to have higher body fat than BALB/c mice, this difference was not significant after Bonferroni correction.

Table 1

Results of GLM for the effects of strain, housing condition, and their interaction on body composition
Phenotype	Factor	Est.	SE	t-value	p-value	Bonferrino p-value
Body Weight	Strain	1.7879	0.9187	1.9462	0.0516	0.2582
	Housing	0.0245	1.0112	0.0243	0.9806	> 0.9999
	Interaction	-0.6579	1.3178	-0.4992	0.6176	> 0.9999
Body Fat	Strain	0.3639	0.1834	1.9840	0.0473	0.2363
	Housing	-0.1891	0.1989	-0.9506	0.3418	> 0.9999
	Interaction	0.1070	0.2611	0.4098	0.6820	> 0.9999
Body Lean	Strain	0.0221	0.0358	0.6169	0.5373	> 0.9999
	Housing	0.0264	0.0394	0.6701	0.5028	> 0.9999
	Interaction	-0.0450	0.0514	-0.8755	0.3850	> 0.9999
Total Water	Strain	0.0290	0.0358	0.8101	0.4180	> 0.9999
	Housing	0.0310	0.0395	0.7848	0.4310	> 0.9999
	Interaction	-0.0480	0.0514	-0.9339	0.3460	> 0.9999
Free Fluid	Strain	0.1780	0.1005	1.7714	0.0765	0.3825
	Housing	0.1462	0.1106	1.3211	0.1865	0.9323
	Interaction	-0.1730	0.1442	-1.1997	0.2290	> 0.9999
Note: C57 (same-strain), n = 15; C57 (mixed-strain), n = 15; BALB/c (same-strain), n = 11; BALB/c (mixed-strain), n = 10.

GLM also failed to detect the difference in traits related to blood pressure, including systolic, diastolic blood pressure and pulse rate (Table 2). Despite that BALB/c females tended to show higher systolic pressure than C57, and mixed-strain housing tended to increase the systolic blood pressure, none of these differences were significant after Bonferroni correction.

Table 2

Results of GLM for the effects of strain, housing condition, and their interaction on blood pressure measurement
Phenotype	Factor	Est.	SE	t-value	p-value	Bonferrino p-value
Systolic	Strain	-0.0620	0.0288	-2.1528	0.0320	0.0960
	Housing	-0.0630	0.0313	-2.0128	0.0430	0.1290
	Interaction	0.0890	0.0414	2.1498	0.0320	0.0960
Diastolic	Strain	-4.1077	2.1127	-1.9443	0.0519	0.1556
	Housing	-3.0092	2.3568	-1.2768	0.2017	0.6050
	Interaction	6.2460	3.0517	2.0467	0.0407	0.1221
Pulse	Strain	0.0589	0.0434	1.3594	0.1740	0.5220
	Housing	0.0073	0.0484	0.1510	0.8800	> 0.9999
	Interaction	0.0150	0.0626	0.2396	0.8070	> 0.9999
Note: C57 (same-strain), n = 14; C57 (mixed-strain), n = 14; BALB/c (same-strain), n = 11; BALB/c (mixed-strain), n = 10.

C57 and BALB/c showed significant differences in metabolic, anxiety-like and electrocardiographic phenotypes

After Bonferroni correction, significant differences were detected in metabolic, anxiety-like and electrocardiographic phenotypes between two strains of aged female mice. Metabolic cage analysis showed higher total water intake but less body weight changes in C57 than BALB/c (Table 3). In the open field test, C57 mice spent significantly longer time in the center area than BALB/c mice, indicating lower anxiety levels (Table 4). Regarding parameters examined by ECG, we observed significantly longer PR intervals and P durations in BALB/c than C57 mice while QRS intervals and QTc were relatively longer in C57 than BALB/c (Table 5).

Table 3

Results of GLM for the effects of strain, housing condition, and their interaction on metabolic cage analysis
Phenotype	Factor	Est.	SE	t-value	p-value	Bonferrino p-value
Food Intake	Strain	0.8047	0.5132	1.5678	0.1169	0.4677
	Housing	0.4255	0.5513	0.7717	0.4403	> 0.9999
	Interaction	0.1710	0.7258	0.2356	0.8140	> 0.9999
Water Intake	Strain	2.3480	0.4123	5.6949	< 0.0001	< 0.0001
	Housing	0.3950	0.4363	0.9053	0.3660	> 0.9999
	Interaction	-0.8050	0.5830	-1.3808	0.1680	0.6720
Body Weight change	Strain	-1.2841	0.2766	-4.6425	< 0.0001	< 0.0001
	Housing	-0.9082	0.2927	-3.1025	0.0019	0.0077
	Interaction	0.9168	0.3912	2.3436	0.0191	0.0764
Running Wheel Total	Strain	0.1570	0.4569	0.3436	0.7310	> 0.9999
	Housing	-1.3740	0.4955	-2.7730	0.0060	0.0240
	Interaction	2.1860	0.6551	3.3369	0.0008	0.0034
Note: In Food Intake, Water Intake, Body Weight Change, C57 (same-strain), n = 15; C57 (mixed-strain), n = 15; BALB/c (same-strain), n = 11; BALB/c (mixed-strain), n = 10. In Running Wheel Total, C57 (same-strain), n = 15; C57 (mixed-strain), n = 16; BALB/c (same-strain), n = 11; BALB/c (mixed-strain), n = 10.

Table 4

Results of GLM for the effects of strain, housing condition, and their interaction on open field assay
Phenotype	Factor	Est.	SE	t-value	p-value	Bonferrino p-value
Center time	Strain	0.8351	0.3447	2.4228	0.0154	0.0308
	Housing	0.6406	0.3776	1.6967	0.0897	0.1795
	Interaction	-0.4418	0.4441	-0.9949	0.3198	0.6386
Distance Moved	Strain	0.2590	0.2028	1.2771	0.2016	0.4032
	Housing	-0.1863	0.2232	-0.8345	0.4040	0.8080
	Interaction	0.0940	0.2909	0.3231	0.7480	> 0.9999
Note: C57 (same-strain), n = 15; C57 (mixed-strain), n = 15; BALB/c (same-strain), n = 11; BALB/c (mixed-strain), n = 10.

Table 5

Results of GLM for the effects of strain, housing condition, and their interaction on Electrocardiographic measures
Phenotype	Factor	Est.	SE	t-value	p-value	Bonferrino p-value
RR Interval	Strain	-0.0980	0.0485	-2.0206	0.0430	0.2150
	Housing	-0.0490	0.0534	-0.9176	0.3630	> 0.9999
	Interaction	0.0490	0.0696	0.7040	0.4850	> 0.9999
PR Interval	Strain	6.4827	1.9039	3.4050	0.0007	0.0033
	Housing	-0.4453	2.0956	-0.2125	0.8317	> 0.9999
	Interaction	4.1950	2.7311	1.5360	0.1250	0.6250
P duration	Strain	4.6920	1.4731	3.1851	0.0014	0.0072
	Housing	0.0530	1.6215	0.0327	0.9740	> 0.9999
	Interaction	0.9450	2.1132	0.4472	0.6550	> 0.9999
QRS Interval	Strain	-0.2470	0.0640	-3.8594	0.0001	0.0006
	Housing	-0.0830	0.0704	1.3930	0.2380	> 0.9999
	Interaction	0.1090	0.0918	1.3930	0.2360	> 0.9999
QTc	Strain	-0.2700	0.0782	-3.4527	0.0006	0.0028
	Housing	-0.0720	0.0861	-0.8362	0.4020	> 0.9999
	Interaction	0.2000	0.1122	1.7825	0.0740	0.3700
Note: C57 (same-strain), n = 15; C57 (mixed-strain), n = 15; BALB/c (same-strain), n = 11; BALB/c (mixed-strain), n = 10.

Housing conditions influence body weight change and running wheel activity

In the present study, housing conditions only affected two examined parameters, body weight change and running wheel activity. Mixed-strain housing significantly reduced the decrease in body weight after 24 hours in metabolic cage (Table 3, Fig. 2A). The interaction between strain and housing conditions with p-value close to significant (p = 0.0764) implied that the mixed-strain housing mainly affected BALB/c, while the effect on C57 was relatively smaller.

As for running wheel activity, while C57 and BALB/c showed similar activity, there was a strong interaction between stain and housing conditions (Table 3). Mixed-strain housing significantly decreased the activity in BALB/c but tended to increase the activity in C57 (p = 0.0934) (Fig. 2B). And this housing effect was mainly observed during the night time (Figs. 2C and D).

Housing conditions have no significant influence on the lifespan of both strains

Lastly, the lifespans were compared between strains and between the housing conditions. C57 mice showed significantly longer lifespan than BALB/c in both same-strain and mixed-strain housing conditions (Fig. 3A and B), suggesting the robust lifespan difference between C57 and BALB/c even under different housing environments. Housing conditions, however, did not alter the lifespan of either strain (Fig. 3C and D).

In this study, we aimed to investigate the influence of mixed-strain housing on aging-related phenotypes in mice. Surprisingly, even though the cohousing lasted for 21 months, we did not detect statistically significant differences in most phenotypes regarding body composition, food intake, behaviors, and lifespan. Only 2 out of 19 examined parameters showed significant differences between the two housing conditions after correction. Body weight change in BALB/c, but not in C57, showed a significant difference between the two housing conditions. Additionally, C57BL/6 mice displayed a higher trend of activity levels on running wheels in mixed housing conditions, while BALB/c mice displayed a lower trend of activity levels on running wheels in mixed housing conditions, suggesting a strain-dependent housing effect on these phenotypes.

Although most examined phenotypes were similar between the two housing conditions, our experiments identified several differences between aged female C57BL/6 and BALB/c mice. Specifically, C57BL/6 mice exhibited higher total water intake and less body weight change. A previous study suggested lower anxiety levels in C57BL/6 mice³², which was also identified in this study. Most importantly, consistent with a previous report³³, we showed a longer lifespan in C57BL/6 mice under both housing conditions, suggesting the robustness of the lifespan difference between these two strains. It is also worth noting that, while earlier studies reported no differences in PR interval and QRS interval between 6-month-old C57BL/6 and BALB/c mice³⁴, our research identified significant differences in these parameters in aged mice. This suggests that age may reveal distinct electrocardiographic characteristics between the strains that are not apparent in younger mice.

Several studies have used C57 and DBA/2 mice to explore the influence of mixed-strain housing on physiology and behavior. Although a few phenotypes, such as social behaviors, were affected, most studied phenotypes remained unchanged^25,30,31. Notably, the cohousing duration in these studies was relatively short. In contrast, our research extended the cohousing period to almost two years, focusing on outcomes in aged mice. However, despite this long-term cohousing, our studies still found no significant differences in most examined phenotypes, including lifespan, suggesting minimal influence of cohousing on mouse health and aging. These results align well with previous studies and support the feasibility of a mixed-strain housing strategy, which can potentially benefit individual identification for mouse management and split-plot design for experimental purposes.

Despite our study detecting insignificant differences between same- and mixed-housing conditions in most parameters, we cannot exclude the possibility that some limitations in our experimental design may have diminished the observed influence of social partners. For example, other aging-related phenotypes, such as cognition or hormonal regulation, may be more sensitive to social environments but were not investigated in this study. Additionally, the genetic differences between these commonly used research strains may not be large enough to create a significant social influence, especially in a stable mouse facility with consistent factors such as temperature, lighting, and food quality, which further reduced potential influences from social partners. Moreover, long-term cohousing may lead to adaptation, normalizing behavioral and physiological responses over time, potentially explaining the pronounced differences observed in some studies but not in ours. To better understand the social influence on aging, future research should consider these limitations and optimize the experimental design to maximize the effect of social partners.

In summary, our studies using C57 and BALB/c mice revealed limited influence of mixed-strain housing on lifespan and several age-related phenotypes. These results support the possibility of cohousing different strains during mouse husbandry, which can be advantageous in certain circumstances. More importantly, our studies provided valuable insights for future research on social effects on aging. While we explored several physiological outcomes, many parameters still require further investigation. Additionally, extending the scope of research to include different age groups, genders, and other commonly used mouse strains may help create a more diverse environment, potentially leading to more striking differences after cohousing. Future studies exploring this aspect may enhance our understanding of the complex interplay between social environments and aging processes, shedding light on how varying social conditions can modulate health outcomes, disease progression, and overall longevity. These insights could inform strategies to improve laboratory animal welfare and management, provide translational benefits for understanding social influences on aging in humans, and potentially, develop more effective interventions to promote healthy aging and improve quality of life across species.

Data availability

The data supporting the findings of this study are available within the paper and upon request from the corresponding authors.

Author Contribution

CL Lee, YC Lin, and TH Kuo designed the experiments; CL Lee, YC Lin, and TH Kuo analyzed the data; and CL Lee, YC Lin, and TH Kuo wrote the manuscript.

Acknowledgement

We thank the Taiwan Mouse Clinic, Academia Sinica and Taiwan Animal Consortium for the technical support in behavioral, metabolism and cardiovascular services. We also thank the members of the Kuo labs for experimental help and discussion. The work was supported by the National Science and Technology Council (NSTC 112-2636-B-007-007 Young Scholar Fellowship), and by the Higher Education Sprout Project funded by Ministry of Education and the Ministry of Science and Technology to the Brain Research Center (to T-H Kuo).

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No competing interests reported.

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The impact of social partners: investigating mixed-strain housing effects on aging in mice

Status:

Version 1

Abstract

Figures

Introduction

Materials and Methods

Mice

Experimental Procedures (Fig. 1)

Body Composition

Metabolic cage for 24 hours

Blood Pressure measurement

Electrocardiography (ECG)

Open Field Assay

Statistic

Results

No significant difference in body composition and blood pressure between strains or housing conditions

C57 and BALB/c showed significant differences in metabolic, anxiety-like and electrocardiographic phenotypes

Housing conditions influence body weight change and running wheel activity

Housing conditions have no significant influence on the lifespan of both strains

Discussion

Declarations

Data availability

Author Contribution

Acknowledgement

References

Additional Declarations

Status:

Version 1