Inflammaging: The Chronic Inflammation Hypothesis

Overview

The Chronic Inflammation Hypothesis, more commonly referred to as “inflammaging,” represents a fundamental concept in aging research that links systemic, low-grade inflammation to the aging process and age-related diseases. This hypothesis proposes that chronic, persistent inflammation is a hallmark of aging and serves as a significant risk factor driving the development of many age-related conditions.^[1] 

Core Definition and Characteristics

Inflammaging is characterized by an age-related increase in circulating levels of pro-inflammatory markers and cytokines, occurring in the absence of active infection.^[2] This chronic, low-grade inflammatory state represents a 2- to 4-fold increase in plasma concentrations of pro-inflammatory mediators in healthy elderly people compared to younger adults.^[3]  Unlike acute inflammation, which is essential for fighting infections and promoting healing, inflammaging persists systemically, contributing to progressive physiological decline without providing protective benefits.^[4] 

Mechanisms Underlying Inflammaging

The development of inflammaging involves multiple interconnected mechanisms. Cellular senescence plays a central role, with senescent cells acquiring a senescence-associated secretory phenotype (SASP) characterized by the production of numerous inflammatory molecules.^[5] Additionally, oxidative stress and redox imbalance activate pro-inflammatory pathways, particularly through the upregulation of nuclear factor-kappa B (NF-κB) signaling.^[6] Dysregulation of the innate immune system, including altered toll-like receptor signaling and inflammasome activation, further perpetuates the inflammatory state.^[7]  The gut microbiota composition also changes with age, contributing to increased intestinal permeability and systemic inflammation through dysbiosis.^[8] 

Connection to Age-Related Diseases

The Chronic Inflammation Hypothesis provides an integrated framework explaining why aging is the major risk factor for numerous chronic diseases. Inflammaging has been strongly associated with atherosclerosis, type 2 diabetes, obesity, Alzheimer’s disease, cardiovascular disease, cancer, and rheumatoid arthritis.^[9]  The chronic pro-inflammatory state exacerbates tissue damage and accelerates functional decline across multiple organ systems. For example, elevated interleukin-6 and C-reactive protein levels predict future disability and cognitive decline in older adults.^[10]  In the brain, inflammaging-driven neuroinflammation contributes to neurodegenerative processes underlying Alzheimer’s disease and Parkinson’s disease.^[11] 

Evolution of the Hypothesis

Originally discovered and named by Franceschi and colleagues around 2000, the inflammaging hypothesis has evolved to encompass more comprehensive understanding of age-related inflammatory networks. Recent research has refined this concept, proposing “senoinflammation” as an expanded framework that better describes the complex interplay between cellular senescence, inflammatory pathways, and aging.^[12]  This evolution reflects recognition that inflammation operates through multiple coordinated pathways rather than as a single phenomenon.

Therapeutic Implications

The Chronic Inflammation Hypothesis has transformed approaches to aging and age-related disease management. Rather than treating individual diseases separately, this framework suggests targeting fundamental aging mechanisms, including inflammation, could simultaneously address multiple age-related conditions. Interventions including senolytics, dietary modifications, exercise, and anti-inflammatory compounds are being investigated as potential strategies to mitigate inflammaging and improve healthspan.^[13]  Understanding inflammaging provides a biological basis for why such broad-spectrum interventions might effectively prevent or delay multiple age-related diseases simultaneously.

FAQs

What is Inflammaging and How Does It Differ From Normal Inflammation?

Inflammaging refers to chronic, systemic low-grade inflammation that develops during aging, occurring without active infection.^[14]  Unlike acute inflammation, which responds to immediate threats and resolves, inflammaging is a persistent state characterized by a 2- to 4-fold elevation in pro-inflammatory markers like IL-6 and TNF-α.^[15]  This sustained inflammatory environment causes progressive tissue damage, accelerates organ dysfunction, and increases vulnerability to age-related diseases including cardiovascular disease, diabetes, and Alzheimer’s disease.^[16]

What Cellular Mechanisms Drive Inflammaging?

Multiple interconnected mechanisms generate inflammaging. Cellular senescence is central, with senescent cells secreting pro-inflammatory factors through their senescence-associated secretory phenotype (SASP).^[17]  Oxidative stress activates NF-κB signaling pathways, amplifying cytokine production.^[18]  Dysbiosis increases intestinal permeability, allowing bacterial lipopolysaccharides (LPS) to trigger systemic inflammation.^[19]  Additionally, dysregulation of innate immunity, including altered Toll-like receptor signaling and NLRP3 inflammasome activation, perpetuates chronic inflammatory states.^[20]

How Does Targeting Inflammaging Help Treat Age-Related Diseases?

Rather than treating individual diseases separately, the inflammaging hypothesis suggests targeting fundamental aging mechanisms offers greater therapeutic benefit.^[21] Since chronic inflammation contributes to multiple age-related conditions simultaneously, anti-inflammatory interventions—including senolytics, dietary modifications, and exercise—may prevent or delay numerous diseases at once.^[22]  This “geroscience” approach recognizes that conditions like atherosclerosis, diabetes, and neurodegeneration share common inflammatory drivers, making multi-targeted inflammation reduction more effective than disease-specific treatments alone.

Update History

References

1. Necroptosis contributes to chronic inflammation and fibrosis in aging liver.. Mohammed et al.. (Aging Cell. 2021.)
2. Hydroxytyrosol Interference with Inflammaging via Modulation of Inflammation and Autophagy.. Velotti.. (Nutrients. 2023.)
3. Cold‐inflammaging: When a state of homeostatic‐imbalance associated with aging precedes the low‐grade pro‐inflammatory‐state (inflammaging): Meaning, evolution, inflammaging phenotypes.. Giunta.. (Clinical and Experimental Pharmacology and Physiology. 2022.)
4. Aging and chronic inflammation: highlights from a multidisciplinary workshop.. Saavedra.. (Immunity & Ageing. 2023.)
5. New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms.. Tchkonia.. (The Journal of Clinical Endocrinology & Metabolism. 2020.)
6. The Molecular Inflammatory Process in Aging.. Chung et al.. (Antioxidants & Redox Signaling. 2006.)
7. Toll like receptor signaling in “inflammaging”: microRNA as new players.. Olivieri.. (Immunity & Ageing. 2013.)
8. Aged Gut Microbiota Contributes to Systemical Inflammaging after Transfer to Germ-Free Mice.. Fransen.. (Frontiers in Immunology. 2017.)
9. Inflamm-Aging, Cytokines and Aging: State of the Art, New Hypotheses on the Role of Mitochondria and New Perspectives from Systems Biology.. Salvioli.. (Current Pharmaceutical Design. 2006.)
10. Serum IL‐6 Level and the Development of Disability in Older Persons.. Ferrucci.. (Journal of the American Geriatrics Society. 1999.)
11. Alzheimer’s Disease and Inflammaging.. Kosyreva et al.. (Brain Sciences. 2022.)
12. Redefining Chronic Inflammation in Aging and Age-Related Diseases: Proposal of the Senoinflammation Concept.. Chung et al.. (Aging and disease. 2019.)
13. New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms.. Tchkonia.. (The Journal of Clinical Endocrinology & Metabolism. 2020.)
14. Hydroxytyrosol Interference with Inflammaging via Modulation of Inflammation and Autophagy.. Velotti et al.. (Nutrients. 2023.)
15. Cold‐inflammaging: When a state of homeostatic‐imbalance associated with aging precedes the low‐grade pro‐inflammatory‐state (inflammaging): Meaning, evolution, inflammaging phenotypes.. Giunta.. (Clinical and Experimental Pharmacology and Physiology. 2022.)
16. Aging and chronic inflammation: highlights from a multidisciplinary workshop.. Saavedra.. (Immunity & Ageing. 2023.)
17. New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms.. Tchkonia et al.. (The Journal of Clinical Endocrinology & Metabolism. 2020.)
18. The Molecular Inflammatory Process in Aging.. Chung.. (Antioxidants & Redox Signaling. 2006.)
19. Aged Gut Microbiota Contributes to Systemical Inflammaging after Transfer to Germ-Free Mice.. Fransen et al.. (Frontiers in Immunology. 2017.)
20. Toll like receptor signaling in “inflammaging”: microRNA as new players.. Olivieri.. (Immunity & Ageing. 2013.)
21. New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms.. Tchkonia et al.. (The Journal of Clinical Endocrinology & Metabolism. 2020.)
22. An Update on Inflamm-Aging: Mechanisms, Prevention, and Treatment.. Xia et al.. (Journal of Immunology Research. 2016.)