This open access paper surveys what is known of age-related changes in the phospholipid composition of cell membranes, a feature that has been studied in a range of different species. As a mechanism of aging, this is likely downstream of deeper causes of aging, while also producing its own very complex set of consequences. Those consequences are poorly understood, and will likely remain poorly understood for the foreseeable future. There are only so many researchers and so much time and funding. Picking apart the fine details of aging at the level of cellular operations, particularly processes that can in principle influence near every aspect of cellular metabolism, is a very long-term prospect. This is why the better path forward towards lengthening the healthy human lifespan is to target the known root causes of aging, rather than studying their spreading, highly complex web of downstream consequences.
The relationship between lipids and aging has been well recognized. The contents, composition, and metabolism of fatty acid (FA) are altered in aged or long-lived humans and model organisms. Moreover, studies in model organisms such as Caenorhabditis elegans have revealed that various FA species could extend lifespan when supplemented in the diet. These unsaturated FAs function mainly through classic longevity factors, such as DAF-16/FOXO3, SKN-1/Nrf2, and HSF-1/HSF1, to regulate healthspan and lifespan.
Despite these advances linking FA to longevity regulation, little is known about their mechanisms of action. Generally, FAs function through several major mechanisms, including signaling molecules, energy resources, substrates for post-translational modifications, and the components of complex lipids. Take oleoylethanolamine for example, it acts as a signaling molecule and regulates animal lifespan by direct binding and activation of the nuclear hormone receptor NHR-80. But to date, only a few FAs were found to exert their functions directly as signaling molecules, or as substrates for post-translational modifications. The majority of FAs are incorporated into complex lipids such as membrane lipids as their acyl chains, thus affecting the structure, composition, and function of the membrane. Therefore, it is conceivable that FAs may regulate lifespan by acting as the important components of membrane lipids, potentially linking membrane homeostasis to lifespan regulation.
Membrane lipids, mainly phospholipids (PLs; also known as glycerophospholipids), consist of the lipid bilayer that acts as barriers between the cell and environment, and between different cellular compartments. However, numerous studies suggest that the lipid bilayer not only function as structural barriers but also play crucial roles in the regulation of multiple cellular processes. Also, this idea is supported by the diversity of membrane lipids (different membrane lipid species and different acyl chains within certain membrane lipids), which is far more beyond the need for barrier function. In regard to the aging process, studies in several model organisms have reported the association of the contents and compositions of many membrane lipids with animal age, supporting potential roles for the membrane lipids in aging modulation. In this review, we focused on PLs and summarized recent advances that link PL homeostasis to the aging process and discussed their potential mechanisms of action.