Welcome to part 3 of ODX's "Biological Age Biomarkers" Series. In the third post, you'll learn how elevated CRP is a sign of systemic inflammation that can accelerate biological aging, especially when combined with metabolic dysfunction.
C-reactive protein is a key inflammation biomarker and an independent risk factor for ischemic cardiovascular diseases. It contributes to atherosclerosis through various mechanisms, including activation of vascular cells, accumulation of monocytes and lipids, apoptosis, and promotion of coronary artery thrombosis. Elevated CRP levels exacerbate ischemic damage by activating the complement system, leading to increased necrosis. CRP promotes monocyte mobilization into atheromatous plaques, suppressing nitric oxide release and causing endothelial dysfunction. CRP increases the expression of plasminogen activator inhibitor-1 and adhesion molecules and enhances cholesterol uptake by macrophages, directly contributing to atherosclerosis (Banai 2022). In peripheral tissues, CRP can dissociate from its native pentameric (pCRP) form to a monomeric form (mCRP) that can be synthesized de novo outside the liver. Both forms promote atherosclerosis: pCRP binds to oxidized LDL and apoptotic cells, and mCRP induces platelet aggregation and thrombosis (Salazar 2014).
Chronic inflammation can impair immune function and lead to significant alterations in cell and organ physiology, ultimately contributing to hyperglycemia, hypertension, depression, sarcopenia, osteoporosis, and cancer. Inflammation can cause a diversion of energy and nutrients away from maintenance metabolic processes and toward an activated immune system. This shift can lead to “sickness behaviors,” including fatigue, sadness, anhedonia, decreased libido, reduced food intake, altered sleep patterns, social withdrawal, insulin resistance, increased blood pressure, and dyslipidemia (Furman 2019).
Increasing evidence shows that CRP is not only an inflammatory biomarker but also a significant risk factor associated with aging-related diseases, including cardiovascular disease, hypertension, diabetes mellitus, and kidney disease. Recent studies have demonstrated that CRP is pathogenic in numerous diseases, such as hypertensive cardiovascular and kidney complications, diabetic nephropathy, and acute and chronic kidney diseases. CRP is known to activate the NF-κB signaling pathway, mediate tissue fibrosis, impair cell regeneration, and promote aging via a Smad3-dependent p21/p27 mechanism (Tang 2017).
Inflammatory markers, such as high-sensitivity C-reactive protein (hs-CRP), are closely associated with cognitive impairment (CI) and mortality. CRP, an acute-phase reactant, is a strong indicator of systemic inflammation and has been linked to both the initiation and progression of atherosclerosis. Elevated CRP levels, particularly those above 3.0 mg/L, are associated with an increased risk of cardiovascular events and mortality. Cognitive decline, commonly associated with aging, is also linked to increased mortality in the elderly. In patients with dementia or CI, CRP has been found in β-amyloid plaques and neurofibrillary tangles, suggesting that inflammation contributes to cognitive decline (Chen 2019)
Data from 1447 elderly adults in the 2012 Chinese Longitudinal Healthy Longevity Survey (CLHLS) demonstrated a graded association between higher hs-CRP levels and increased mortality, even after considering cognitive function. Hs-CRP and cognitive function were found to be independent predictors of all-cause mortality, with significant interaction effects observed, highlighting the critical role of inflammation in cognitive decline and mortality risk. Participants in the highest hs-CRP quartile (3.06 mg/L or above) had nearly double the risk of death compared to those in the lowest quartile (< 0.41 mg/L) (Chen 2019).
Chronic systemic inflammation underlies many chronic diseases, including CVD, cancer, diabetes, chronic kidney disease, non-alcoholic liver disease, and autoimmune and neurodegenerative disease. These disabling disorders are often associated with “aging” but can primarily be related to unhealthy lifestyle choices (Furman 2019).
Elevated CRP is a sign of systemic inflammation that can accelerate biological aging, especially when combined with metabolic dysfunction. A study of 41,634 adults examined the impact of C-reactive protein (CRP) levels and diabetes mellitus (DM) on biological aging and mortality. Key points include (Tang 2024):
Elevated hs-CRP levels are linked to obesity and smoking, as expanded adipose tissue secretes proinflammatory cytokines that boost CRP synthesis. Moderate alcohol consumption and high physical activity are associated with lower hs-CRP levels, though evidence is not conclusive. While CRP is suggested as an independent marker of cardiovascular disease risk, its predictive capacity is debated. However, many studies show a higher risk of type 2 diabetes with elevated CRP, independent of obesity and other risk factors. Diet also influences CRP levels; high intakes of carotenoids and vitamin C, and high consumption of vegetables and fruits are linked to lower CRP levels, potentially due to their anti-inflammatory effects (Nanri 2007)
Lifestyle factors associated with the relative absence of chronic systemic inflammation include increased physical activity, fresh or minimally processed foods, limited exposure to toxins and pollution, circadian rhythms in sync with sunlight exposure, and limited social stressors (Furman 2019).
Banait, Tanvi et al. “Role of High-Sensitivity C-reactive Protein (Hs-CRP) in Non-communicable Diseases: A Review.” Cureus vol. 14,10 e30225. 12 Oct. 2022, doi:10.7759/cureus.30225
Chen, Chen et al. “Combined associations of hs-CRP and cognitive function with all-cause mortality among oldest-old adults in Chinese longevity areas: a prospective cohort study.” Immunity & ageing : I & A vol. 16 30. 17 Nov. 2019, doi:10.1186/s12979-019-0170-y
Furman, David et al. “Chronic inflammation in the etiology of disease across the life span.” Nature medicine vol. 25,12 (2019): 1822-1832. doi:10.1038/s41591-019-0675-0
Nanri, Akiko et al. “Impact of C-reactive protein on disease risk and its relation to dietary factors.” Asian Pacific journal of cancer prevention : APJCP vol. 8,2 (2007): 167-77.
Salazar, Juan et al. “C-Reactive Protein: An In-Depth Look into Structure, Function, and Regulation.” International scholarly research notices vol. 2014 653045. 15 Dec. 2014, doi:10.1155/2014/653045
Tang, Ying et al. “C-reactive protein and ageing.” Clinical and experimental pharmacology & physiology vol. 44 Suppl 1 (2017): 9-14. doi:10.1111/1440-1681.12758
Tang F, et. al. Joint association of diabetes mellitus and inflammation status with biological ageing acceleration and premature mortality, Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 2024, https://doi.org/10.1016/j.dsx.2024.103050.