Deactivation of the gene PLa2g7 partially mimics the anti-aging effects of caloric restriction (CR) in mice, researchers report. The findings could be used to develop CR-mimetic targets to enhance health span and potentially lifespan in humans.
Moderately decreased food intake that doesn’t result in malnutrition has shown to delay aging and the onset of age-associated diseases in a variety of model organisms, including nonhuman primates. However, understanding the mechanisms that underlie these observations and translating them into therapeutically relevant targets for humans has remained a challenge.
To better understand the factors and processes that are causal in the beneficial effects of CR, Olga Spadaro and colleagues evaluated immune function in humans who have undergone caloric restriction by ~14% over two years, as well as in mice under more severe (40%) caloric restriction. Cellular analyses and transcriptional profiling of adipose tissue in calorie-restricted humans showed that expression of PLa2g7 – an immune-associated gene encoding platelet-activating factor acetylhydrolase – was reduced. Deleting this gene in mice resulted in decreased age-related inflammation and also improved thymic and metabolic function in aging animals.
According to Spadaro et al., the findings suggest that the reduction of PLA2G7 may mediate some of the beneficial immunometabolic effects of CR and provide a molecular target that could be used to lower inflammation and improve health span without reducing caloric intake. “Spadaro et al. provide new insight into the biology of PLA2G7 and its important role in immunometabolic regulation and systemic homeostasis,” write Timothy Rhoads and Rozalyn Anderson in a related Perspective. “This work is a good example of what can be gained by focusing on the mechanisms underlying the beneficial effects of CR.”
Spadaro, O., et al. (2022) Caloric restriction in humans reveals immunometabolic regulators of healthspan. Science. doi.org/10.1126/science.abg7292.