Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

Abstract

Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty - which affect clinical manifestations, prognosis, and response to treatment - and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials.

Fig. 1 |. Potential causes of inflammageing.

Several genetic variants associated with high levels of inflammatory markers or increased response to inflammatory stimuli have been identified; the most relevant factors are indicated in parentheses. In central obesity, visceral fat tissue is infiltrated by T cells, macrophages, and monocytes. T cells secrete IFNγ, which stimulates the production of several chemokines by adipocytes, including C-C motif chemokine 2 (CCL2), CCL5, C-X-C motif chemokine 9 (CXCL9), and CXCL10, which further amplify tissue T cell infiltration. The number of B cells and macrophages in visceral adipose tissue from obese individuals is also increased and is correlated with BMI. A specific subset of B cells expressing the tumour necrosis factor (TNF) superfamily ligand superfamily member 9 and producing TNF, IFNγ, and granzyme B accumulates in the abdominal cavity of older individuals. Cytokines released by B cells contribute to the phenotypic change of adipocytes in the visceral cavity, causing them to release adipokines, other pro-inflammatory factors, and cell debris. Activated monocytes that give rise to M1 and M2 macrophages produce even more inflammatory compounds. Damaged mitochondria that cannot be repaired by repeated cycles of fission and fusion and are not recycled owing to defective autophagy release damage-associated molecular patterns (DAMPs) that trigger the NLRP3 inflammasome and lead to caspase 1-dependent production of IL-1β and IL-18. Oxidative stress is one of the possible triggers of cell senescence, which can be induced by several other stressors, including epigenetic alterations. Senescent cells, through the senescence-associated secretory phenotype (SASP), secrete large quantities of cytokines, chemokines, and other molecules, locally triggering more cell senescence (paracrine senescence) and contributing to inflammageing. Studies have emphasized the role of age-related changes in the microbiome and increases in the gut mucosa permeability that lead to bacterial product release into the blood and stimulate an inflammatory response, in part through the NLRP3 inflammasome. In addition, part of inflammageing is probably caused by chronic infections (for example, human immunodeficiency virus (HIV) or human Cytomegalovirus (CMV) infection) and intrinsic defective mechanisms in immune cells that might involve metabolic stress as well as age-related changes in microRNA transcription. Of note, other important triggers of cell senescence, such as genomic instability, the activation of oncogenes, and the inhibition of tumour-suppressor genes, are not shown in the figure but might be part of the same mechanism.

Fig. 2 |. Inflammageing is a risk factor for multiple chronic diseases.

Inflammageing, defined as an age-related increase in the levels of pro-inflammatory markers in blood and tissues, is a strong risk factor for multiple diseases that are highly prevalent and frequent causes of disability in elderly individuals but are pathophysiologically uncorrelated. Mild chronic inflammation is generally considered to be a biomarker of accelerated biological ageing or one of the mechanisms by which the ageing process is associated with increased global susceptibility to all diseases. Cardiovascular diseases, chronic kidney disease, cancer, depression, dementia, osteoporosis, sarcopenia, and anaemia are shown in the figure as examples because extensive evidence indicates that inflammation contributes to the development of these diseases in old age, but the list is far from exhaustive^,,,,,. Concordant with this view, elevated blood levels of pro-inflammatory markers (such as IL-6) are a powerful risk factor for multimorbidity (the number of coexisting diseases) and predict future rates of change in multimorbidity. Unsurprisingly, inflammageing is also a strong risk factor for typical geriatric conditions, such as physical and cognitive disability, frailty, and premature death. Although this effect is primarily mediated by multimorbidity, evidence also indicates that inflammation interferes with the maintenance and repair that constantly occur in all tissues, leading to accumulation of damage that contributes to frailty.

Fig. 3 |. Inflammageing induces a catabolic state.

Inflammation causes pathological states linked with frailty, cardiovascular disease, and ageing. Sarcopenia: the induction of anabolic resistance in muscle inhibits the perfusion adjustment to anabolic stimuli as well as insulin-like growth factor (IGF1) production and signalling^–. Anaemia: chronic elevation of IL-6 levels causes anaemia through the production of hepcidin, reduction of the transmembrane iron transporter ferroportin, and inhibition of iron absorption and recycling as well as interference with erythropoietin (EPO) production and signalling^,. Insulin resistance: tumour necrosis factor receptor superfamily member 1A (TNF-R1) and Toll-like receptor 4 (TLR4) block insulin signalling through Janus kinase (JAK) activation, which causes serine phosphorylation of insulin receptor substrate 1 (IRS1) and IRS2, contributing to insulin resistance. Osteoporosis: TNF, IL-1β, IL-6, and TNF ligand superfamily member 11 (RANKL) contribute to osteoporosis by stimulating osteoclast growth and activity and inhibiting the production of osteocalcin^,. Mitochondria biogenesis: studies in vitro show that TNF, IL-1β, and IL-6 induce mitochondrial dysfunction with reduced ATP synthesis-driven respiration, a reduced NAD+:NADH ratio, and reduced mRNA levels of PPARGC1A (encoding peroxisome proliferator-activated receptor-γ co-activator 1α; PGC1α), suggesting impairment in mitochondrial biogenesis. Neurogenesis: pro-inflammatory cytokines interfere with the biological activity of neuronal growth factors, such as brain-derived neurotrophic factor, thereby affecting neurogenesis and plasticity. Accordingly, the addition of IFNα to human hippocampal progenitor cells reduces neurogenesis. These are just few examples of how chronic inflammation promotes a catabolic state, suggesting a possible unifying hypothesis. During an acute bout of inflammation, induced for example by an infection, the surveillance of damage and continuous repair functions in multiple tissues are chronically inhibited, leading to accumulated damage in organelles and macromolecules. Over time, this damage accumulation across different tissues and organs could become so severe that it cannot be compensated for and causes irreversible frailty.