¶ Inflammaging Biomarkers
Inflammaging refers to the chronic, low-grade inflammation that develops with age and contributes to age-related diseases. Biomarkers of inflammaging help assess inflammatory status and monitor the effectiveness of anti-inflammatory interventions. This phenomenon represents one of the most significant hallmarks of aging and is a key target for longevity interventions.
¶ Overview
Inflammaging is characterized by elevated levels of pro-inflammatory cytokines and markers that persist throughout the aging process. These biomarkers provide insights into inflammatory status and disease risk. The concept of inflammaging was first introduced by Claudio Franceschi and represents a fundamental shift in understanding aging as a pro-inflammatory state.[1]
The inflammatory response, while essential for host defense in youth, becomes dysregulated with age, leading to chronic low-grade inflammation that contributes to tissue damage and functional decline.[2] This age-related inflammatory state is distinct from acute inflammation and is characterized by persistent elevation of inflammatory mediators without obvious infection or injury.
¶ Key Biomarkers
¶ Cytokines
- Interleukin-6 (IL-6)
- Tumor necrosis factor-alpha (TNF-α)
- Interleukin-1β (IL-1β)
- C-reactive protein (CRP)
IL-6 is considered one of the most reliable biomarkers of inflammaging, with levels increasing significantly with age and correlating strongly with mortality risk.[3] TNF-α plays a crucial role in the inflammatory cascade and has been associated with multiple age-related diseases including cardiovascular disease, diabetes, and neurodegenerative disorders.[4]
¶ Acute Phase Proteins
- C-reactive protein (CRP)
- Fibrinogen
- Serum amyloid A
- Haptoglobin
CRP is the most widely used biomarker of systemic inflammation and has been extensively validated as a predictor of cardiovascular events and mortality in older adults.[5] Elevated fibrinogen levels are associated with increased risk of thrombosis and cardiovascular disease in aging populations.[6]
¶ Cellular Markers
- Neutrophil-to-lymphocyte ratio
- Monocyte activation markers
- T-cell senescence markers
- Natural killer cell function
The neutrophil-to-lymphocyte ratio (NLR) has emerged as a simple but powerful biomarker of systemic inflammation and has been associated with increased mortality risk in various populations.[7] T-cell senescence markers, including CD28- T cells, are elevated in aging and contribute to immune dysfunction.[8]
¶ Clinical Significance
Inflammaging biomarkers are associated with:
- Increased mortality risk
- Age-related diseases
- Functional decline
- Cognitive impairment
Elevated levels of inflammatory markers such as IL-6 and CRP have been consistently associated with increased mortality risk and age-related diseases.[9] Chronic inflammation has been identified as a key driver of age-related functional decline and cognitive impairment.[10]
¶ Mortality and Longevity
Meta-analyses have demonstrated that elevated IL-6 levels are associated with a 2-3 fold increased risk of all-cause mortality in older adults.[11] The combination of multiple inflammatory biomarkers provides even stronger predictive value for mortality risk than individual markers alone.[12]
¶ Age-Related Diseases
Inflammaging contributes to the pathogenesis of multiple age-related diseases including cardiovascular disease, type 2 diabetes, Alzheimer's disease, and cancer.[13] The inflammatory milieu created by inflammaging promotes tissue damage and accelerates the progression of these conditions.[14]
¶ Functional Decline
Chronic inflammation is strongly associated with sarcopenia, frailty, and loss of physical function in older adults.[15] Inflammatory markers predict the development of disability and loss of independence in aging populations.[16]
¶ Measurement Methods
Common approaches include:
- Blood-based assays
- Multiplex cytokine panels
- Flow cytometry
- Gene expression analysis
¶ Standardized Assays
High-sensitivity CRP (hs-CRP) assays provide the most reliable measurement of low-grade inflammation and are widely available in clinical settings.[17] Multiplex cytokine panels allow for simultaneous measurement of multiple inflammatory markers, providing a comprehensive inflammatory profile.[18]
¶ Novel Approaches
Single-cell RNA sequencing has revealed cell-type specific inflammatory signatures in aging, providing new insights into inflammaging mechanisms.[19] Metabolomic profiling has identified inflammatory metabolites that may serve as novel biomarkers of inflammaging.[20]
¶ Therapeutic Implications
These biomarkers help:
- Assess intervention effectiveness
- Monitor treatment response
- Identify high-risk individuals
- Guide personalized approaches
¶ Intervention Monitoring
Inflammaging biomarkers serve as crucial endpoints in clinical trials of Longevity Interventions, allowing researchers to assess the effectiveness of treatments targeting chronic inflammation.[21] Reductions in inflammatory markers following intervention are associated with improved health outcomes and reduced disease risk.[22]
¶ Personalized Medicine
Individual inflammatory profiles can guide personalized treatment approaches, with high-risk individuals potentially benefiting from more aggressive anti-inflammatory interventions.[23] Biomarker-guided therapy has shown promise in improving outcomes in age-related diseases.[24]
¶ See also
¶ References
Franceschi C, Bonafè M, Valensin S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244-254. https://pubmed.ncbi.nlm.nih.gov/10911963/ ↩︎
López-Otín C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell. 2013;153(6):1194-1217. https://www.cell.com/cell/fulltext/S0092-8674(13)00645-4 ↩︎
Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med. 2000;51:245-270. https://pubmed.ncbi.nlm.nih.gov/10774463/ ↩︎
Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444(7121):860-867. https://www.nature.com/articles/nature05485 ↩︎
Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342(12):836-843. https://www.nejm.org/doi/full/10.1056/NEJM200003233421202 ↩︎
Kannel WB, Wolf PA, Castelli WP, D'Agostino RB. Fibrinogen and risk of cardiovascular disease. The Framingham Study. JAMA. 1987;258(9):1183-1186. https://pubmed.ncbi.nlm.nih.gov/3625968/ ↩︎
Templeton AJ, McNamara MG, Šeruga B, et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst. 2014;106(6):dju124. https://academic.oup.com/jnci/article/106/6/dju124/1012390 ↩︎
Effros RB, Dagarag M, Spaulding C, Man J. The role of CD8+ T-cell replicative senescence in human aging. Immunol Rev. 2005;205:147-157. https://pubmed.ncbi.nlm.nih.gov/15882350/ ↩︎
Franceschi C, Garagnani P, Parini P, et al. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576-590. https://www.nature.com/articles/s41574-018-0059-4 ↩︎
Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018;15(9):505-522. https://www.nature.com/articles/s41569-018-0064-2 ↩︎
Krabbe KS, Pedersen M, Bruunsgaard H. Inflammatory mediators in the elderly. Exp Gerontol. 2004;39(5):687-699. https://pubmed.ncbi.nlm.nih.gov/15130663/ ↩︎
Varadhan R, Yao W, Matteini A, et al. Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults. J Gerontol A Biol Sci Med Sci. 2014;69(2):165-173. https://pubmed.ncbi.nlm.nih.gov/23682161/ ↩︎
Chung HY, Cesari M, Anton S, et al. Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev. 2009;8(1):18-30. https://pubmed.ncbi.nlm.nih.gov/18692159/ ↩︎
Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473(7347):317-325. https://www.nature.com/articles/nature10146 ↩︎
Visser M, Pahor M, Taaffe DR, et al. Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women: the Health ABC Study. J Gerontol A Biol Sci Med Sci. 2002;57(5):M326-M332. https://pubmed.ncbi.nlm.nih.gov/11983728/ ↩︎
Penninx BW, Kritchevsky SB, Newman AB, et al. Inflammatory markers and incident mobility limitation in the elderly. J Am Geriatr Soc. 2004;52(7):1105-1113. https://pubmed.ncbi.nlm.nih.gov/15209645/ ↩︎
Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107(3):499-511. https://www.ahajournals.org/doi/full/10.1161/01.cir.0000052939.59093.45 ↩︎
Ray S, Britschgi M, Herbert C, et al. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med. 2007;13(11):1359-1362. https://www.nature.com/articles/nm1653 ↩︎
Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377(2):111-121. https://www.nejm.org/doi/full/10.1056/NEJMoa1701719 ↩︎
Menni C, Kastenmüller G, Petersen AK, et al. Metabolomic markers reveal novel pathways of ageing and early development in human populations. Int J Epidemiol. 2013;42(4):1111-1119. https://pubmed.ncbi.nlm.nih.gov/24038796/ ↩︎
Justice JN, Nambiar AM, Tchkonia T, et al. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019;40:554-563. https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(19)30094-0/fulltext ↩︎
Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-1131. https://www.nejm.org/doi/full/10.1056/NEJMoa1707914 ↩︎
Belsky DW, Caspi A, Houts R, et al. Quantification of biological aging in young adults. Proc Natl Acad Sci U S A. 2015;112(30):E4104-E4110. https://www.pnas.org/doi/10.1073/pnas.1506264112 ↩︎
Ridker PM, MacFadyen JG, Everett BM, et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet. 2018;391(10118):319-328. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32814-3/fulltext ↩︎