Aging is a complex and multifactorial process characterized by the gradual accumulation of molecular damage, leading to age-related frailty, disability, disease, and eventual mortality. Macrophages, essential components of the immune system, play crucial roles in tissue development, homeostasis maintenance, and response to pathogens. However, dysregulation of macrophage functions has been implicated in various pathological processes associated with aging, including inflammatory diseases, cancer, fibrosis, and impaired tissue repair.
The Role of Macrophage Immune Receptors in Aging:
Recent research suggests that immune receptors on microglia/macrophages are key players in aging-related processes such as energy metabolism, inflammation, and cognitive decline. One prominent example is the TREM2 lipid-sensing immune receptor, which is strongly associated with Alzheimer’s disease (AD) and is also involved in adipose tissue and hepatic metabolism, as well as inflammation control.
CD300f: A Lipid-Sensing Immune Receptor with Diverse Functions:
CD300f, another lipid-sensing immune receptor, shares many properties with TREM2, including ligands, expression patterns, and involvement in the regulation of microglia/macrophage phenotype and metabolic fitness. This immune receptor is unique in that it triggers both activating and inhibitory intracellular signaling pathways, suggesting a complex regulatory role. Studies in mouse models have demonstrated CD300f’s protective and anti-inflammatory profile in various conditions, including multiple sclerosis, lupus, allergy, and acute brain damage.
Controversies Surrounding CD300f Function:
However, CD300f activation has been shown to potentiate microglial proinflammatory responses under certain conditions, indicating a nuanced and context-dependent role. In vivo studies have demonstrated the upregulation of CD300f in response to proinflammatory insults, such as LPS injection or spinal cord injury, linking it to neuroprotective responses against Tau pathology. Additionally, genetic variants of CD300f have been associated with human inflammatory and autoimmune diseases, highlighting its relevance in clinical contexts.
CD300f and Aging-Related Processes:
Despite the wealth of evidence implicating CD300f in various conditions associated with aging, its role in the age-dependent accumulation of tissue damage, frailty, disability, and reduced lifespan has not been explored. Immune receptors, including CD300f and TREM2, are upregulated with age, and their absence has been linked to shortened lifespan and various aging-related conditions.
Microglial and Macrophage Metabolic Alterations in Aging:
Aging induces metabolic alterations in microglia and macrophages, contributing to cognitive decline. Both TREM2 and CD300f are crucial for maintaining the metabolic fitness of these cells under different neuropathological conditions. Moreover, many genes associated with Alzheimer’s disease are involved in phagocytosis/lysosomal pathways, where lipid-binding immune receptors like CD300f play a central role.
Implications for Systemic Aging-Related Processes:
Analysis of genomic non-coding regions in AD points toward microglia, CNS barrier-associated macrophages (BAMs), and other tissue-resident macrophages as central players, linking these cell types and their phenotype to age-related conditions. The accumulating evidence raises the question of whether immune receptors expressed on myeloid cells, particularly CD300f, can regulate systemic aging-related processes, including metabolism, inflammation, neurodegeneration, cognitive decline, and ultimately, healthy lifespan.
The central finding of this study reveals that CD300f−/− male and female mice experience a shortened lifespan and healthspan. The complexity of aging is reflected in the multifactorial and variable nature of the underlying causes of death, which encompasses a spectrum of age-related conditions. CD300f deficiency is linked to extensive deficits in microglia/macrophage metabolic fitness, suggesting a potential mechanism for the observed effects on aging-related processes, including inflammaging, senescence, cognitive decline, proteostasis alteration, systemic metabolic changes, and frailty.
Healthspan and Longevity:
Traditionally, maximum lifespan has been a primary focus in aging research. However, this study underscores the importance of healthspan, emphasizing that merely extending lifespan is an incomplete metric for evaluating aging. CD300f−/− mice exhibit various hallmarks of aging and associated pathologies, including neoplasms, chronic low-grade inflammation, frailty, altered brain proteostasis, increased brain senescence, cognitive decline, and, in females, systemic metabolic alterations.
Challenges in Defining Healthspan:
The challenge in determining the specific cause of death during aging is compounded by the variability in biological age, which differs from chronological age among subjects. Despite a thorough analysis of relevant biological parameters, the wide variety of pathologies associated with aging, and the non-synchronous aging process, make it difficult to pinpoint a specific pathology associated with CD300f deficiency. The dispersion of data over time supports differences in chronological and biological age, contributing to the gradual and unsynchronized emergence of aging-associated pathologies.
Notably, sex-related differences are observed in aged CD300f−/− mice. Females display systemic metabolic alterations, altered macrophage metabolism, reduced brain glucose uptake, and earlier cognitive decline. These findings align with the known epidemiology of AD dementia, which affects females more frequently. Sex differences related to CD300f are also noted in psychiatric conditions, highlighting the importance of understanding these distinctions for improved care and treatment.
Microglial and Macrophage Phenotype:
CD300f has been identified as a regulator of microglial phenotype, with implications extending to other macrophage populations throughout the organism. As a potential damage-associated molecular pattern (DAMP) receptor, CD300f may collaborate with receptors like TREM2 to sense DAMPs and toxic lipids derived from chronic low-grade tissue damage, contributing to homeostasis. The absence of CD300f is associated with increased aging and neurodegenerative processes, suggesting its role in maintaining the microglial homeostatic phenotype during aging.
Metabolic Pathways in Aging:
Aging-related longevity pathways involving growth, metabolism, nutrient sensing, autophagy, and stress response are interconnected. CD300f deficiency affects macrophage and microglial metabolic fitness, influencing mitochondrial function and mTOR activation. This suggests that CD300f may function as a costimulatory molecule, sustaining transitions between different macrophage/microglia phenotypes triggered by various receptors in response to tissue injury or dysfunction.
Implications for Neurodegenerative Diseases:
Understanding CD300f function in the central nervous system (CNS) and its role in metabolic activation, autophagy, and phagocytosis of myelin debris could provide insights into the design of treatment paradigms for neurodegenerative diseases, including Alzheimer’s disease (AD). The intricate interplay between immune receptors and aging mechanisms highlights the potential for identifying therapeutic targets that could have a broad impact on global health by attenuating aging and mitigating age-related diseases.
In conclusion, this study offers valuable insights into the role of CD300f in aging-related processes, emphasizing its impact on healthspan, longevity, and various age-associated pathologies. The findings underscore the importance of considering the complex interplay between immune receptors, metabolic pathways, and aging mechanisms in the quest to develop novel predictors of health and lifespan. The broader perspective of targeting fundamental aging mechanisms for therapeutic intervention holds the potential to revolutionize approaches to global health by addressing the root causes of age-related diseases.
reference link: https://www.cell.com/cell-reports/fulltext/S2211-1247(23)01281-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124723012810%3Fshowall%3Dtrue