Energy Restriction Impairs Natural Killer Cell Function and Increases the Severity of Influenza Infection in Young Adult Male C57BL/6 Mice

Abstract

Energy restriction (ER) without malnutrition extends lifespan in mice and postpones age-related changes in immunity. However, we have previously shown that aged (22 mo old) ER mice exhibit increased mortality, impaired viral clearance, and reduced natural killer (NK) cell cytotoxicity following influenza infection compared with aged mice that consumed food ad libitum (AL). To determine whether the detrimental effects of ER in response to influenza infection occur independently of advanced age, young adult (6 mo) male C57BL/6 mice consuming an AL or ER diet were infected with influenza A virus (H1N1, PR8). Young adult ER mice exhibited increased mortality (P < 0.05) and weight loss (P < 0.01) in response to infection. ER mice exhibited decreased total (P < 0.001) and NK1.1+ lymphocytes (P < 0.05) in lung and reduced influenza-induced NK cell cytotoxicity in both lung (P < 0.01) and spleen (P < 0.05). Importantly, the mRNA expression of interferon (IFN)alpha/beta (P < 0.05) was also reduced in the lungs of ER mice in response to infection, and in vitro stimulation of NK cells from ER mice with type I IFN resulted in cytotoxicity comparable to that in NK cells from AL mice. In contrast, NK cell activation was enhanced in ER mice, determined as an increase in the percentage of NK cells expressing B220 (P < 0.001) and increased intracellular production of IFNgamma (P < 0.01). These data describe an age-independent and detrimental effect of ER on the innate immune response to influenza infection and suggest that a decrease in NK cell number and alterations in the NK cell-activating environment may contribute to decreased innate immunity in ER mice.

Calorie restriction in rodents: Caveats to consider

“…Effros et al imposed ip injections of influenza virus, while the Gardner studies used an intranasal route of administration which was more consistent with the typical route of infection (Gardner et al, 2011). Gardner et al noted decreased survival of aged (22 mo) B6 mice on lifelong 40% CR following infection (Gardner, 2005), and Ritz et al (2008) noted the same even in young (6 mo) B6 mice on CR(Ritz et al, 2008). Both studies observed decreased natural killer (NK) cell activity in lungs of CR mice.…”

NK Cell Maturation and Function in C57BL/6 Mice Are Altered by Caloric Restriction

“…Several decades ago, Weindruch et al (12) reported that CR resulted in decreased splenic NK cell cytotoxicity compared with aged matched controls, although this could be ameliorated by polyinosinic:polycytidylic acid. More recently, we have shown CR results in increased susceptibility to primary influenza infection and decreased influenza-induced NK cell cytotoxicity in young and aged mice (13, 14). This was accompanied by the observation that NK cell numbers and frequency are decreased in the spleen of young CR mice (14).…”

Earlier and more rapid ageing: Does nutrition contribute?

“…On one hand, CR apparently attenuates age-related decline in the immune system of rodents (delayed immune-senescence) (Kristan, 2008;Pahlavani, 2004). On the other, studies using bacteria (Sun, Muthukumar, Lawrence et al, 2001), viruses (Gardner, 2005;Ritz and Gardner, 2006;Ritz, Aktan, Nogusa et al, 2008) and parasites (Kristan 2007) showed a significantly reduced capacity of long-term CR rodents to respond to and to survive such infections despite their better immune system. This happened because the response of the immune system to an infectious pathogen is very expensive in terms of energy and the body of CR rodents may fail to mobilize the energy needed (Ritz and Gardner, 2006).…”