Drivers of age-related inflammation and strategies for healthspan extension

Abstract

Aging is the greatest risk factor for the development of chronic diseases such as arthritis, type 2 diabetes, cardiovascular disease, kidney disease, Alzheimer's disease, macular degeneration, frailty, and certain forms of cancers. It is widely regarded that chronic inflammation may be a common link in all these age-related diseases. This raises the question, can one alter the course of aging and potentially slow the development of all chronic diseases by manipulating the mechanisms that cause age-related inflammation? Emerging evidence suggests that pro-inflammatory cytokines interleukin-1 (IL-1) and IL-18 show an age-dependent regulation implicating inflammasome-mediated caspase-1 activation in the aging process. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome controls the caspase-1 activation in myeloid-lineage cells in several organs during aging. The NLRP3 inflammasome is especially relevant to aging as it can get activated in response to structurally diverse damage-associated molecular patterns (DAMPs) such as extracellular ATP, excess glucose, ceramides, amyloids, urate, and cholesterol crystals, all of which increase with age. Interestingly, reduction in NLRP3-mediated inflammation prevents age-related insulin resistance, bone loss, cognitive decline, and frailty. NLRP3 is a major driver of age-related inflammation and therefore dietary or pharmacological approaches to lower aberrant inflammasome activation holds promise in reducing multiple chronic diseases of age and may enhance healthspan.

Keywords: IL-1; IL-18; NLRP3; adipose tissue; cytokines; inflammasome; macrophage; sarcopenia; senescence.

Fig. 1. Aging, disease burden, and mortality statistics

Incidences and causes of death in the elderly are shown. (A) Numbers of deaths, stratified by age group, in developed countries worldwide. (B) All causes of death in both males and females over age 70 in developed countries. (C) Further breakdown of the non-communicable causes of death in elderly males and females in developed countries. All data was obtained from the Global Health Data Exchange (89).

Fig. 2. Inflammasome activation by metabolic DAMPs is NLRP3-dependent

Representative Western blot of wildtype and Nlrp3^−/− bone marrow-derived macrophages stimulated with LPS + the indicated DAMP. Arrowheads demarcate the p48 pro-caspase-1 and the catalytically cleaved p20 caspase-1 subunit. The p20 subunit of caspase-1 is a marker of activation. All DAMPs shown here are NLRP3-dependent, as no active caspase-1 p20 band is present in the Nlrp3^−/− cells.

Fig. 3. Aging-induced increase in complement pathway in hippocampus is regulated by NLRP3

The basic complement activation cascade is shown. Molecules in green had increased expression (greater than 1.5 fold) in the hippocampus during aging that was prevented in old Nlrp3^−/− mice. Results shown are a graphical representation of findings that have been previously published (33).

Fig. 4. Crystal containing macrophages in aging thymus

Scanning electron microscopy image of a macrophage isolated from a mouse thymus (12 months old). Arrowheads indicate a crystal structure in the cytoplasm. This cell was not activated or induced in any way, but rather, was isolated from a naturally aged, standard chow-fed C57BL/6 mouse that had been maintained in a specific pathogen-free facility and unmanipulated until the time of sacrifice.

Fig. 5. Proposed mechanism of age-related inflammasome activation

Schematic representing a proposed mechanism of inflammasome activation during aging and how this leads to increases in chronic diseases.