In Cell Reports Medicine, researchers have published a detailed review on the relationship between cardiovascular disease and the age-related inflammation known as inflammaging.
The immune system itself ages
Inflammaging occurs in both the cells sending out signals and in the cells receiving them. The numbers of specific immune cell types become imbalanced; the bone marrow begins producing more myeloid than lymphoid cells [1], leading to an alteration in the neutrophil-to-lymphocyte ratio, which itself is associated with frailty [2].
This imbalance even occurs in the heart. The self-sustaining population of CCR2- macrophages, which promote muscle growth and fight inflammation, is gradually replaced with CCR2+ macrophages, which have a different bodily origin and promote inflammation instead [3].
The thymus is where immune cells are trained, and thymic involution is the age-related process that gradually deteriorates this organ into fat. Mitochondrial dysfunction occurs in the T cells as well, causing further immune dysfunction [4].
Immune dysfunction leads directly to cardiovascular disease
Causing mitochondrial dysfunction in the T cells of mice gave them severe heart disease [5]. The contribution of T cell dysfunction to vascular problems is strong enough that depleting CD8+ T cells in aged mice reduced their atherosclerosis [6]. Similarly, T cells are modified in heart failure, and not for the better; mice that lack CD4+ T cells have better outcomes when subjected to artificial heart attacks [7], and a different study demonstrated that taking T cells from mice subjected to these heart attacks and giving them to other mice causes heart problems in the other mice [8]. Further work confirmed that dysregulated T cells cause long-term damage in this way [9].
T cells even appear to be responsible for the damage caused by well-known inducers of heart disease. As expected, feeding mice a high-fat diet and inducing hypertension causes a form of heart failure in mice, but this does not occur if the mice had their T cells depleted [10].
Inflammation also leads to problems in the vasculature. High levels of circulating inflammatory cytokines lead to endothelial dysfunction, a core contributor to atherosclerosis [11]. This immune overactivation encourages the formation of blood clots (thrombosis) [12], thus increasing the risk of heart attack and stroke [13].
Potential solutions
Unsurprisingly, reducing inflammation is being explored as a method of decreasing the likelihood of thrombotic events [14]. In the 2000s, trials of anti-inflammatory drugs specifically for preventing heart failure did not yield good results [15], but later on, colchichine was found to be successful [16], and a meta-analysis provided enough data for its effectiveness [17] that the FDA has approved it for the prevention of cardiovascular disease in people with multiple risk factors. However, even this drug does not help immediately after a heart attack [18].
Affecting cellular senescence has also been investigated as a potential solution. The link between senescence and inflammation is well-known; the circulating cytokines that can lead to dysfunction are part of the senescence-associated secretory phenotype (SASP), the signals that senescent cells emit [19]. However, fighting senescence to reduce heart problems can carry its own risks; for example, while the combination of dasatinib and quercetin is well-known as a senolytic that destroys senescent cells, dasatinib has been linked to heart problems [20]. Navitoclax, another well-known senolytic, can cause uncontrolled bleeding [21].
The researchers suggest that other drugs that modulate rather than kill senescent cells (senomorphics) may be more promising. Metformin, for example, has been found to reduce the SASP in this way [22]. This may be due to its effects on mitochondrial dysfunction; a study with a different drug suggests that reducing mitochondrial dysfunction by increasing mitochondrial turnover (mitophagy) has beneficial effects in this regard [23].
Some inflammation comes from the gut. The researchers consider well-known interventions such as probiotics, which directly provide healthy gut bacteria [24], along with prebiotics, which feed only these beneficial bacteria [25]. Combining these approaches has demonstrated benefits in pigs with cardiometabolic syndrome [26]. Directly transferring gut bacteria through fecal microbiome transplantation has demonstrated benefits in mice with heart problems [27].
Personalized medicine
The researchers suggest that the detailed relationship between inflammaging and vasculature makes personalized medicine the most preferable approach. Not all preventatives work on everyone with cardiovascular risk factors; for example, one study found that statins don’t offer benefits for people who do not show calcium on CT scans [28]. Similarly, while reducing blood pressure is a common choice to prevent cardiovascular events, antihypertensive drugs can have negative effects on some older people [29]. Advanced imaging and more in-depth examination of biomarkers may allow for more targeted treatments that lead to better outcomes.
Literature
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