This 2018 review outlines how age-related chronic inflammation acts as a central mechanism driving cardiovascular disease, multimorbidity, and frailty. The authors detail how genetic susceptibility, visceral obesity, cellular senescence, and gut dysbiosis contribute to a systemic pro-inflammatory state, shifting the body into a catabolic state that impairs tissue repair and accelerates atherogenesis.
Inflammaging describes the progressive elevation of pro-inflammatory markers such as IL-6, C-reactive protein, and tumor necrosis factor in older adults. This immune activation occurs independently of acute infection and serves as a primary risk factor for cardiovascular disease, physical disability, and premature mortality.
The pathogenesis is multifactorial. Visceral obesity plays a critical role. Abdominal fat tissue becomes infiltrated by macrophages and T lymphocytes that secrete chemokines and cytokines. Cellular senescence amplifies this process. Senescent cells accumulate exponentially in aging tissues and develop a senescence-associated secretory phenotype. This phenotype releases interleukins and metalloproteinases into the circulation, degrading extracellular matrix components and spreading inflammation to neighboring cells.
Mitochondrial dysfunction is another driver. When damaged mitochondria are not cleared by mitophagy, they release reactive oxygen species and damage-associated molecular patterns. These molecules activate the NLRP3 inflammasome in innate immune cells, triggering the cleavage and release of IL-1 beta and IL-18. Age-related shifts in the gut microbiome also contribute. A reduction in beneficial commensal bacteria combined with increased intestinal permeability allows bacterial products to enter the bloodstream, constantly stimulating the immune system.
Intrinsic defects in immune cells and chronic viral infections sustain inflammaging. Latent cytomegalovirus and human immunodeficiency virus require constant immune surveillance, driving T cell exhaustion. In the cardiovascular system, continuous inflammatory signaling accelerates atherosclerosis.
Cholesterol crystals in the arterial wall activate the NLRP3 inflammasome within macrophages, converting them into foam cells and driving the formation of a necrotic core. Metalloproteinases secreted by senescent cells weaken the fibrous cap of atherosclerotic plaques, increasing the risk of rupture and acute thrombosis.
The systemic consequences extend beyond the vasculature to induce a widespread catabolic state. Chronic inflammation causes anabolic resistance in skeletal muscle by inhibiting insulin-like growth factor 1 production and signaling. This inhibition impairs muscle regeneration and directly drives sarcopenia. Inflammatory markers also interfere with insulin signaling via Janus kinase activation, promoting systemic insulin resistance.
Cardiovascular disease frequently co-occurs with multimorbidity and frailty. Suppressing chronic inflammation early in the aging process could simultaneously delay cardiovascular pathology and preserve physiological reserves. Preliminary clinical trials utilizing interleukin inhibitors demonstrate that targeting specific inflammatory nodes reduces cardiovascular events independent of lipid lowering.
Actionable Insights
Visceral fat reduction is a primary non-pharmacological strategy to lower systemic inflammation. Caloric restriction and targeted weight loss normalize inflammation-related gene expression in white adipose tissue and downregulate NLRP3 inflammasome activity.
The Mediterranean diet is linked to a lower risk of frailty.
For pharmacological interventions, off-label use of metformin demonstrates efficacy in counteracting inflammation and insulin resistance, reducing all-cause mortality independent of diabetic control. Rapamycin specifically inhibits the mechanistic target of rapamycin signaling pathway to provide potent anti-inflammatory activity, which improves survival and healthspan in animal models.
Low-dose aspirin and colchicine are identified as viable tools for the secondary prevention of cardiovascular events. Modulating the gut microbiome through prebiotics and probiotics may restore barrier integrity and restrict the influx of inflammatory bacterial products. The clinical magnitude of these variables is significant.
The presence of frailty in patients with cardiovascular disease is associated with a twofold increase in the risk of death, representing a 100 percent relative increase in mortality risk.
Additionally, a single gene transcript mapping to sodium-driven chloride bicarbonate exchangers accounts for up to 19 percent of the age-related variance in circulating IL-6 levels.
Context and Source
- Open Access Paper: Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. , Sept. 2018.
- Institution: Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA and Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
- Country: United States and Italy.
- Journal Name: Nature Reviews Cardiology.
- Impact Evaluation: The impact score of this journal is 33.7, evaluated against a typical high-end range of 0 to 60+ for top general science, therefore this is an Elite impact journal.