Circulating levels of monocyte chemoattractant protein-1 as a potential measure of biological age in mice and frailty in humans

Abstract

A serum biomarker of biological versus chronological age would have significant impact on clinical care. It could be used to identify individuals at risk of early-onset frailty or the multimorbidities associated with old age. It may also serve as a surrogate endpoint in clinical trials targeting mechanisms of aging. Here, we identified MCP-1/CCL2, a chemokine responsible for recruiting monocytes, as a potential biomarker of biological age. Circulating monocyte chemoattractant protein-1 (MCP-1) levels increased in an age-dependent manner in wild-type (WT) mice. That age-dependent increase was accelerated in Ercc1^-/Δ and Bubr1^H/H mouse models of progeria. Genetic and pharmacologic interventions that slow aging of Ercc1^-/Δ and WT mice lowered serum MCP-1 levels significantly. Finally, in elderly humans with aortic stenosis, MCP-1 levels were significantly higher in frail individuals compared to nonfrail. These data support the conclusion that MCP-1 can be used as a measure of mammalian biological age that is responsive to interventions that extend healthy aging.

Keywords: CCL2; biological age; biomarkers of aging; chemokine; geropathology; monocyte chemoattractant protein-1.

Figure 1

Circulating MCP‐1 levels correlate with biological age. (a) Detection of MCP‐1 in the serum of mice by ELISA. All mice were WT f1 of varying ages and gender. (b) Linear regression analysis of the same data showing a highly significant correlation between serum MCP‐1 and chronological age. (c) Graphing of the same date by gender (pink females; blue male mice). (d) MCP‐1 serum concentrations were quantified by ELISA in progeroid Ercc1 ^−/Δ and Bubr1 ^H/H mice and WT littermate controls. WT (blue), Ercc1 ^−/Δ (red), Bubr1 ^H/H (green) and WT controls (green with black slashes). (e) Genetic depletion of NF‐κB in p65 ^+/− ;Ercc1 ^−/Δ mice (yellow), which extends the healthspan of the progeroid mice, reduces MCP‐1 levels relative to Ercc1 ^−/Δ. Five to six mice were used per group except for Bubr1 and their respective wild‐type controls (n = 3). (f) 16‐week‐old Ercc1 ^−/Δ mice (5–6 per group) treated with vehicle (Veh) or a combination of the senolytic drugs dasatinib and quercetin (D+Q) weekly starting at 4–6 weeks, and (g) 26‐month‐old WT mice (6 per group) that were placed on a rapamycin (Rapa) or control (Ctrl) diet for 8 weeks prior to analysis of serum MCP‐1 by ELISA. Values represent the mean ± SD, two‐tailed t test. p < .05*, p < .01**, p < .001***, p < .0001****, p < .00001*****

Figure 2

Circulating MCP‐1 levels are elevated in frail older adults. Plasma MCP‐1 concentrations were quantified by a Luminex platform. Frail individuals possessed three or more of the following criteria: slow gait, weak grip, reduced physical activity, low endurance, and unintentional weight loss. Graphed are individual values. The black bars represent the mean ± SEM (nonfrail n = 27, frail n = 36, Mann–Whitney test, **p = .009)