Aging augments the impact of influenza respiratory tract infection on mobility impairments, muscle-localized inflammation, and muscle atrophy

Bartley, Jenna M.; Pan, Sarah; Keilich, Spencer R; Hopkins, Jacob W.; Al-Naggar, Iman M.; Kuchel, George A.; Haynes, Laura

doi:10.18632/aging.100882

Cited by 37 publications

(31 citation statements)

References 51 publications

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“…These data suggest inhibiting atrogin-1 directly or the pathways required for its induction may preserve muscle mass during influenza A infection. These results should be interpreted with some caution, however, as others have observed increased expression of mRNA for both atrogin-1 and MuRF1 in the skeletal muscle following influenza infection (67). Further, it is not clear whether the IL-6-and atrogin-1-mediated degradation of muscle proteins is an adaptive process during influenza A infection.…”

Section: Discussionmentioning

confidence: 72%

Influenza A Virus Infection Induces Muscle Wasting via IL-6 Regulation of the E3 Ubiquitin Ligase Atrogin-1

Radigan

Nicholson

Welch

et al. 2019

The Journal of Immunology

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Muscle dysfunction is common in patients with adult respiratory distress syndrome and is associated with morbidity that can persist for years after discharge. In a mouse model of severe influenza A pneumonia, we found the proinflammatory cytokine IL-6 was necessary for the development of muscle dysfunction. Treatment with a Food and Drug Administration-approved Ab antagonist to the IL-6R (tocilizumab) attenuated the severity of influenza A-induced muscle dysfunction. In cultured myotubes, IL-6 promoted muscle degradation via JAK/STAT, FOXO3a, and atrogin-1 upregulation. Consistent with these findings, atrogin-1 +/2 and atrogin-1 2/2 mice had attenuated muscle dysfunction following influenza infection. Our data suggest that inflammatory endocrine signals originating from the injured lung activate signaling pathways in the muscle that induce dysfunction. Inhibiting these pathways may limit morbidity in patients with influenza A pneumonia and adult respiratory distress syndrome.

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Section: Discussionmentioning

confidence: 72%

Influenza A Virus Infection Induces Muscle Wasting via IL-6 Regulation of the E3 Ubiquitin Ligase Atrogin-1

Radigan

Nicholson

Welch

et al. 2019

The Journal of Immunology

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“…For these studies, we employed a sublethal infection dose and examined immune parameters at 7 days postinfection. At this time point, influenza-induced weight loss becomes more evident, however, is not different between ages ( 80 ) or CR and AL groups (unpublished experiments from the Haynes lab). Thus, percent weight loss should not be a confounding factor between groups and should not put CR mice at greater risk to succumb to infection ( 45 , 46 ).…”

Section: Resultsmentioning

confidence: 81%

Impact of Age, Caloric Restriction, and Influenza Infection on Mouse Gut Microbiome: An Exploratory Study of the Role of Age-Related Microbiome Changes on Influenza Responses

et al. 2017

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Immunosenescence refers to age-related declines in the capacity to respond to infections such as influenza (flu). Caloric restriction represents a known strategy to slow many aging processes, including those involving the immune system. More recently, some changes in the microbiome have been described with aging, while the gut microbiome appears to influence responses to flu vaccination and infection. With these considerations in mind, we used a well-established mouse model of flu infection to explore the impact of flu infection, aging, and caloric restriction on the gut microbiome. Young, middle-aged, and aged caloric restricted (CR) and ad lib fed (AL) mice were examined after a sublethal flu infection. All mice lost 10–20% body weight and, as expected for these early time points, losses were similar at different ages and between diet groups. Cytokine and chemokine levels were also similar with the notable exception of IL-1α, which rose more than fivefold in aged AL mouse serum, while it remained unchanged in aged CR serum. Fecal microbiome phyla abundance profiles were similar in young, middle-aged, and aged AL mice at baseline and at 4 days post flu infection, while increases in Proteobacteria were evident at 7 days post flu infection in all three age groups. CR mice, compared to AL mice in each age group, had increased abundance of Proteobacteria and Verrucomicrobia at all time points. Interestingly, principal coordinate analysis determined that diet exerts a greater effect on the microbiome than age or flu infection. Percentage body weight loss correlated with the relative abundance of Proteobacteria regardless of age, suggesting flu pathogenicity is related to Proteobacteria abundance. Further, several microbial Operational Taxonomic Units from the Bacteroidetes phyla correlated with serum chemokine/cytokines regardless of both diet and age suggesting an interplay between flu-induced systemic inflammation and gut microbiota. These exploratory studies highlight the impact of caloric restriction on fecal microbiome in both young and aged animals, as well as the many complex relationships between flu responses and gut microbiota. Thus, these preliminary studies provide the necessary groundwork to examine how gut microbiota alterations may be leveraged to influence declining immune responses with aging.

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“…Moreover, our results around neutrophil decaying responses must be taken in a larger context of age-related immune and host defense decline. Insufficient innate responses in aging may lead to longer, or even chronic, inflammatory episodes causing harm to tissues [ 34 , 35 ] and promoting inflam-mation further. Nonetheless, an ineffective inflammato-ry response is clearly at play in older subjects.…”

Section: Discussionmentioning

confidence: 99%

Age-related decline of the acute local inflammation response: a mitigating role for the adenosine A2A receptor

Laflamme

Mailhot

Pouliot

2017

Aging

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Aging is accompanied by an increase in markers of innate immunity. How aging affects neutrophil functions remains of debate. The adenosine A2A receptor (A2AR), essential to the resolution of inflammation, modulates neutrophil functions. We sought to determine whether or not A2AR protects against the effects of aging. We monitored neutrophil influx, viability, and activation as well as cytokine accumulation in wild-type (WT) and A2AR-knockout mice (KO) at three different ages.Several readouts decreased with aging: neutrophil counts in dorsal air pouches (by up to 55%), neutrophil viability (by up to 56%), elastase and total protein in exudates (by up to 80%), and local levels of cytokines (by up to 90%). Each of these parameters was significantly more affected in A2AR-KO mice. CXCL1-3 levels were largely unaffected. The effects of aging were not observed systemically. Preventing neutrophil influx into the air pouch caused a comparable cytokine pattern in young WT mice. Gene expression (mRNA) in leukocytes was affected, with CXCL1 and CCL4 increasing and with TNF and IL-1∝ decreasing.Conclusion: Aging has deleterious effects on the acute inflammatory response and neutrophil-related activities, and defective migration appears as an important factor. A functional A2AR signaling pathway delays some of these.

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Aging augments the impact of influenza respiratory tract infection on mobility impairments, muscle-localized inflammation, and muscle atrophy

Cited by 37 publications

References 51 publications

Influenza A Virus Infection Induces Muscle Wasting via IL-6 Regulation of the E3 Ubiquitin Ligase Atrogin-1

Influenza A Virus Infection Induces Muscle Wasting via IL-6 Regulation of the E3 Ubiquitin Ligase Atrogin-1

Impact of Age, Caloric Restriction, and Influenza Infection on Mouse Gut Microbiome: An Exploratory Study of the Role of Age-Related Microbiome Changes on Influenza Responses

Age-related decline of the acute local inflammation response: a mitigating role for the adenosine A2A receptor

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