Multi-omic profiling of primary mouse neutrophils predicts a pattern of sex and age-related functional regulation.

Neutrophils are the most abundant human white blood cell and constitute a first line of defense in the innate immune response. Neutrophils are short-lived cells, and thus the impact of organismal aging on neutrophil biology, especially as a function of biological sex, remains poorly understood. Here, we describe a multi-omic resource of mouse primary bone marrow neutrophils from young and old female and male mice, at the transcriptomic, metabolomic and lipidomic levels. We identify widespread regulation of neutrophil 'omics' landscapes with organismal aging and biological sex. In addition, we leverage our resource to predict functional differences, including changes in neutrophil responses to activation signals. To date, this dataset represents the largest multi-omics resource for neutrophils across sex and ages. This resource identifies neutrophil characteristics which could be targeted to improve immune responses as a function of sex and/or age.

Measuring Phagocytosis in Bone Marrow-Derived Macrophages and Peritoneal Macrophages with Aging.

The majority of age-related diseases share common inflammatory mechanisms, a phenomenon which has been described as "inflamm-aging," and genetic variants in immune and inflammatory genes are significantly associated with exceptional human longevity and/or age-related diseases. Consistently, aging is associated with increased macrophage infiltration into tissues. Macrophages are a key component of the innate immune system and the inflammatory response, which accomplish key tasks such as phagocytosis, antigen presentation, and cytokine production. Phagocytosis is the process by which specialized cells that can clear harmful foreign particles, pathogens, and dead or dying cells. Upon phagocytosis, foreign particles are internalized in vesicles, forming phagosomes. Phagosomes go on to fuse with lysosomes, and the ingested particles are neutralized by lysosomal enzymes. Macrophages have two main origins: tissue-resident macrophages differentiate from specific embryonic progenitors, whereas monocyte-derived macrophages differentiate from bone-marrow progenitors. Because of their key role in inflammation and damage repair, macrophages are a key cell type in age-related inflammatory diseases. Here, we describe an efficient method to quantify the phagocytotic ability of two types of primary macrophages in aging mice: bone marrow-derived macrophages (BMDMs) and tissue-resident peritoneal macrophages.

Widespread sex dimorphism in aging and age-related diseases.

Although aging is a conserved phenomenon across evolutionary distant species, aspects of the aging process have been found to differ between males and females of the same species. Indeed, observations across mammalian studies have revealed the existence of longevity and health disparities between sexes, including in humans (i.e. with a female or male advantage). However, the underlying mechanisms for these sex differences in health and lifespan remain poorly understood, and it is unclear which aspects of this dimorphism stem from hormonal differences (i.e. predominance of estrogens vs. androgens) or from karyotypic differences (i.e. XX vs. XY sex chromosome complement). In this review, we discuss the state of the knowledge in terms of sex dimorphism in various aspects of aging and in human age-related diseases. Where the interplay between sex differences and age-related differences has not been explored fully, we present the state of the field to highlight important future research directions. We also discuss various dietary, drug or genetic interventions that were shown to improve longevity in a sex-dimorphic fashion. Finally, emerging tools and models that can be leveraged to decipher the mechanisms underlying sex differences in aging are also briefly discussed.