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Age-related decline in murine macrophage production of nitric oxide
E Kissin1, M Tomasi, N McCartney-Francis
1Department of Medicine, University of Alabama School of Medicine, and VA Medical Center, Birmingham 35294, USA.
Abstract:
Since certain functions mediated by nitric oxide (NO) decline with age, the age dependence of NO production by macrophages from BALB/c mice was investigated. Lipopolysaccharide-, peptidoglycan-polysaccharide-, or interferon-gamma-stimulated splenic and peritoneal macrophages from young (1 month old), middle-aged (4-5 months old), and old (6-20 months old) BALB/c mice showed a progressive and marked decline in NO production. This age-related decline in inducible NO extended to C57/BL6 and CB6F1 mice. mRNA for inducible NO synthase (iNOS), the enzyme responsible for inducible NO production by macrophages, also declined with age. Importantly, the reduced NO production by macrophages from old mice could be up-regulated by pretreating the mice with either cholera toxin or concanavalin A. These findings indicate that reduced production of NO by murine macrophages correlates directly with advancing age, likely due to deficient signals or signal transduction responsible for iNOS mRNA and protein generation.
Insights
Nitric oxide (NO) production by macrophages significantly decreases with age in mice. This age-related decline in NO synthesis is linked to reduced inducible NO synthase (iNOS) and can be partially restored by specific treatments.
Area of Science:
- Immunology
- Aging Research
- Cellular Biology
Background:
- Nitric oxide (NO) plays crucial roles in various physiological functions.
- Age-associated decline in NO production is observed in certain biological systems.
- Macrophages are key immune cells involved in NO synthesis.
Purpose of the Study:
- To investigate the age-dependent changes in nitric oxide (NO) production by macrophages.
- To determine the correlation between aging and the expression of inducible NO synthase (iNOS) in macrophages.
- To explore potential methods for restoring NO production in aged macrophages.
Main Methods:
- Macrophages from BALB/c mice of different age groups (young, middle-aged, old) were stimulated with lipopolysaccharide, peptidoglycan-polysaccharide, or interferon-gamma.
- Quantification of NO production and mRNA levels for iNOS were assessed.
- Mice were pretreated with cholera toxin or concanavalin A to evaluate the potential for up-regulation of NO production.
Main Results:
- A progressive and marked decline in NO production was observed in splenic and peritoneal macrophages with increasing age across multiple mouse strains (BALB/c, C57/BL6, CB6F1).
- mRNA levels for inducible NO synthase (iNOS) also showed a significant age-related decrease.
- Pretreatment of old mice with cholera toxin or concanavalin A successfully up-regulated NO production by their macrophages.
Conclusions:
- Reduced NO production by murine macrophages is directly correlated with advancing age.
- The age-related decline in NO production is likely due to impaired signaling pathways responsible for iNOS gene and protein expression.
- Strategies targeting signaling pathways may offer a way to restore NO production in aged individuals.