Chronic Inflammation and Longevity

Chronic inflammation and longevity

Several studies have identified a link between chronic inflammation and longevity [1]. Although inflammation, such as acute inflammation is an essential event in immune response and tissue homeostasis, chronic inflammation has been associated with chronic diseases, including diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer.

These diseases are the main causes of bad quality of life, and death, and therefore, significantly reduce individuals’ lifespan. A group of genes named Conserved Transcriptional Response to Adversity (CTRA) appears to play a key role in linking chronic inflammation and longevity.

What is the Conserved Transcription Response to Adversity (CTRA)?

The Conserved Transcriptional Response to Adversity (CTRA) gene expression pattern involves the expression of a group of genes (e.g., IL1BIL6, IL8/CXCL8, COX2/PTGS2, and TNF) that are involved in promoting chronic inflammation through the activation of pro-inflammatory cytokines [2].

How is CTRA Activated?

CTRA gene expression appears to be induced by a signaling pathway named the “social transduction pathway” that is controlled by evolutionary treats response systems in the central nervous system (CNS) and that are triggered by adverse environmental conditions, such as poverty, stress, loss, trauma, and instability.

What is the Mechanism of CTRA induction?

Mechanistically, adverse environmental conditions create chronic and uncertain conditions that prompt the peripheral neural signaling to secrete norepinephrine, which induces the beta-adrenergic receptor/cAMP/PKA signaling pathway, resulting in the activation of transcription factors, such as CREB, NF-kB, and AP1, that induce the expression of CTRA genes [2].

What is the Relation Between Stress and CTRA Activation?

Stress is a key activator of CTRA leading to chronic inflammation and potentially to reduced longevity. A study evaluated the correlation between stress, CTRA gene-expression profile, and survival in treated Breast cancer patients. Based on predicted statistical analysis, the researchers found that stress increases the expression of CTRA genes which may result in a shorter 11-year disease-free survival (DFS) in the treated breast cancer patients. They also show that cognitive-behavioral stress management (CBSM) can limit this effect [3].

What Is the Relation Between Anxiety and CTRA Activation?

Several studies demonstrated that stress is one of the main triggers of anxiety [4] and that video gaming reduces anxiety [5][6]. A study has shown that gamers with a strong social connection have a reduced CTRA expression profile compared to gamers with low-social well-being [7].

What Is the Relation Between Low Socioeconomic Status and CTRA Activation?

It has been shown that low socioeconomic status (SES) has negative effects on long-term health and longevity. By analyzing pilot data on 120 older adults from the health and retirement study in the United States (2002-2010), a study showed an association between increased CTRA expression in individuals from low socioeconomic status who had extended periods of threat, uncertainty, or adverse life circumstances, when compared with individuals from higher socioeconomic groups [8].

What Is the Relation Between Grief and CTRA Activation?

The relationship between widowhood and CTRA expression was evaluated by bioinformatics analyses of data from 36 widows and 27 nonbereaved married women (controls). The results showed an increased expression of some CTRA genes in widowed women compared to controls [9].

What Is the Relation Between Happiness and CTRA?

By studying the correlation between happiness and CTRA gene expression in a sample of 22 women who survived breast cancer, a study showed that eudaimonic well–being, a state of being happy and feeling healthy reduces the CTRA proinflammatory gene expression and increases the expression of the antiviral/antibody-related CTRA immune subcomponent [10].

What Is the Relation Between Cancer and CTRA?

It has been shown that beta-adrenergic receptor activates transcription factors, such as CREB, NF-kB, and AP1, through the cAMP/PKA signaling pathway leading to the expression of CTRA genes. A study reported that the inhibition of the beta-adrenergic receptor using the beta-adrenergic antagonist, propranolol, decreases CTRA gene expression in individuals that received autologous hematopoietic cell transplant for multiple myeloma [11].


Increasing longevity may rely on multi-layers interventions that could include lifestyle changes via improving living conditions, reducing stress, promoting positive attitudes and behaviors, but may also involve pharmacological approaches that can interfere with the pathways that trigger the CTRA gene expression.


[1]Zhong, Jixin, and Guixiu Shi. “Regulation of inflammation in chronic disease.” Frontiers in Immunology 10 (2019): 737.

[2]Furman, David, et al. “Chronic inflammation in the etiology of disease across the life span.” Nature medicine 25.12 (2019): 1822-1832.

[3] Antoni, M.H., Bouchard, L.C., Jacobs, J.M., Lechner, S.C., Jutagir, D.R., Gudenkauf, L.M., Carver, C.S., Lutgendorf, S., Cole, S.W., Lippman, M. and Blomberg, B.B., 2016. Stress management, leukocyte transcriptional changes and breast cancer recurrence in a randomized trial: an exploratory analysis. Psychoneuroendocrinology74, pp.269-277.

[4] McEwen, B.S., Eiland, L., Hunter, R.G. and Miller, M.M., 2012. Stress and anxiety: structural plasticity and epigenetic regulation as a consequence of stress. Neuropharmacology62(1), pp.3-12.

[5] Zayeni, D., Raynaud, J.P. and Revet, A., 2020. Therapeutic and preventive use of video games in child and adolescent psychiatry: a systematic review. Frontiers in psychiatry11, p.36.

[6] Viana, R.B. and de Lira, C.A.B., 2020. Exergames as coping strategies for anxiety disorders during the COVID-19 quarantine period. Games for health journal9(3), pp.147-149.

[7] McEwen, B.S., Eiland, L., Hunter, R.G. and Miller, M.M., 2012. Stress and anxiety: structural plasticity and epigenetic regulation as a consequence of stress. Neuropharmacology62(1), pp.3-12.

[8] Levine, M.E., Crimmins, E.M., Weir, D.R. and Cole, S.W., 2017. Contemporaneous social environment and the architecture of late-life gene expression profiles. American journal of epidemiology186(5), pp.503-509.

[9] O’Connor, M.F., Schultze-Florey, C.R., Irwin, M.R., Arevalo, J.M. and Cole, S.W., 2014. Divergent gene expression responses to complicated grief and non-complicated grief. Brain, behavior, and immunity37, pp.78-83.

[10] Boyle, C.C., Cole, S.W., Dutcher, J.M., Eisenberger, N.I. and Bower, J.E., 2019. Changes in eudaimonic well-being and the conserved transcriptional response to adversity in younger breast cancer survivors. Psychoneuroendocrinology103, pp.173-179.

[11] Knight, J.M., Rizzo, J.D., Hari, P., Giles, K.E., Pasquini, M.C., D’Souza, A., Logan, B.R., Hamadani, M., Chhabra, S., Dhaka, B. and Shah, N., 2019. Abstract# 2055 Beta-adrenergic blockade inhibits stress-related transcriptome profiles associated with worse cancer outcomes: A randomized controlled study of propranolol in hematopoietic cell transplantation recipients. Brain, Behavior, and Immunity76, p.e4.

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