Background & Aims
As individuals age, some endure persistent, unresolved pain that affects their quality of life. This chronic pain is more prevalent in adults over 65 (1,2) and is often underestimated or misdiagnosed, resulting in a decline in their overall well-being. Attributed to aging is a state of chronic, low-grade systemic inflammation called inflammaging (3,4). Operating systemically and involving immune cells, plasma proteins, lipids, and metabolites, this process contributes to various chronic diseases. Given the prevalence of inflammaging in the elderly, it is crucial to understand how modulations in systemic immune signal transductions connect to age-related chronic pain development. We hypothesize that the circulatory environment has a crucial role in regulating chronic pain and ultimately aim to delineate pathways integrated in age-associated systemic inflammation that precipitate the transition of pain from an acute to a chronic state.
Methods
Our study used C57/BL6 mice at the age of aged 3m (young), and >20m (geriatric). Both male and female mice were included to explore potential sex differences in serum proteomic signatures and chronic pain behaviors. Mouse pain behavior was assessed using von Frey and acetone tests. Pooled serum samples from both young and aging mice (n=3/group) at defined time points were processed through Mass Spectrometry (5,6) and pathway enrichment was analyzed with Metascape and IPA for activity prediction. The plantar incision model(7) was used to assess post-surgical pain and examined subsequent pain severity and duration in aging compared to young mice (n=8-10/group). Biweekly serum transfers (8) from young to aging mice were used to investigate whether young serum could ameliorate pain experiences and modify serum proteome in geriatric mice. Serum cytokine and chemokine profiles were detected using a protein profiler assay as well as Luminex.
Results
Our study found that ageing mice experience prolonged post-surgical pain compared to young mice. Treating aging mice with young serum normalized pain thresholds, alleviated post-surgical pain, and promoted recovery. We observed age-related and sex-dependent changes in serum composition, with differences in the complement system and cytokine/chemokine profiles between male and female young mice. Immunoglobin families did not show significant sex-dependent differences in young mice. However, in aging females, disturbances in immunoglobin chains were more pronounced, along with increased cytokine/chemokine expression in aging males. Rejuvenation studies showed a reduction in elevated cytokine/chemokine levels in aged male mice, potentially contributing to pain alleviation. In female mice, relief of post-surgical pain with young serum treatment may be linked to alternative immune system modalities.
Conclusions
Pain behavior is altered in aging mice, rejuvenation with young serum could rescue it. Systemic inflammation (inflammaging) develops with age, involving cytokines/chemokines, complement system, and immunoglobulins, with sex-dependent signatures. Understanding the dichotomy of immune signal transductions between male and female mice will not only delineate the mechanisms by which the immune system modulates pain behaviour but also provide insight into precision medicine by considering sex-dependent influences.
References
1. Domenichiello, A. F. & Ramsden, C. E. The silent epidemic of chronic pain in older adults. Prog Neuropsychopharmacol Biol Psychiatry 93, 284-290, doi:10.1016/j.pnpbp.2019.04.006 (2019).
2. Jones, M. R. et al. Pain in the Elderly. Curr Pain Headache Rep 20, 23, doi:10.1007/s11916-016-0551-2 (2016).
3. Franceschi, C. & Campisi, J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. The journals of gerontology. Series A, Biological sciences and medicalsciences 69 Suppl 1, S4-9, doi:10.1093/gerona/glu057 (2014).
4. Franceschi, C. et al. Immunobiography and the Heterogeneity of Immune Responses in the Elderly: A Focus on Inflammaging and Trained Immunity. Frontiers in immunology 8, 982, doi:10.3389/fimmu.2017.00982 (2017).
5. Whittaker, K. et al. Quantitative proteomic analyses in blood: A window to human health and disease. Journal of leukocyte biology 106, 759-775, doi:10.1002/JLB.MR1118-440R (2019).
6. Altelaar, A. F., Munoz, J. & Heck, A. J. Next-generation proteomics: towards an integrative view of proteome dynamics. Nature reviews. Genetics 14, 35-48, doi:10.1038/nrg3356 (2013).6. Villeda, S. A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90-94, doi:10.1038/nature10357 (2011).
7. Brennan, T. J. Postoperative Models of Nociception. ILAR J 40, 129-136, doi:10.1093/ilar.40.3.129 (1999).
8. Villeda, S. A. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature medicine 20, 659-663, doi:10.1038/nm.3569 (2014).
Presenting Author
Basma Abdelkader
Poster Authors
Basma Abdelkader
MRes Drug Discovery and Dev
McGill University
Lead Author
Wen Bo Sam Zhou
McGill University, Alan Edwards Center for Research on Pain
Lead Author
Xiang Qun Shi
MSc
Alan Edwards Center for Research on Pain, McGill University
Lead Author
Ji Zhang
MD PhD
Alan Edwards Center for Research on Pain, McGill University
Lead Author
Francis Beaudry
Université de Montréal
Lead Author
Topics
- Pain in Special Populations: Elderly