1. Introduction

Aging is inevitable. It is associated with time-dependent decline in physical activity and physiological function, and slow but steady decrease in organ function that eventually leads to death. With increasing age, aging associated diseases occur that include insulin resistance, type 2 diabetes mellitus, hypertension, hyperlipidemia or dyslipidemia, coronary heart disease, Alzheimer’s disease, and cancer. Aging induces perceptible and time-dependent changes in the immune system and gradual increase in plasma inflammatory markers interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) with a parallel decrease in anti-inflammatory cytokines IL-4 and IL-10. However, it is not known whether changes in the levels of cytokines are inevitable with aging or are a signal of the impending aging process or just a marker of aging. It is not clear whether changes in cytokines and associated events such as free radical generation (reactive oxygen species, nitric oxide, carbon monoxide, hydrogen sulfide) and antioxidants are as a result of aging. However, what is certain is that these biochemical and immunological changes can be postponed or delayed by regular exercise and diet control (especially calorie restriction and intermittent fasting). Good dietary practices and regular exercise can delay the development of aging associated diseases obesity, insulin resistance, type 2 diabetes mellitus, hypertension, metabolic syndrome, coronary heart disease and cancer.

Understanding the molecular events responsible for aging process may help to develop strategies to slow aging. Optimal cell response to both internal and external stimuli depends on the cell membrane integrity. This is so since; all stimuli need to be conveyed to the genome through the cell membrane. Similarly, all the responses elicited by the cell genome need to be conveyed to the cell external milieu through the cell membrane. Thus, cell membrane structure and consequently its functions are crucial to receive and send signals to the external environment. Since aging is a universal process (from single cell organisms to humans), it is possible that understanding the molecular events of this process may have implications for all. Some of the outlined biological mechanisms of the aging proposed are given in Figure 1. Thus, methods or strategies developed to act on these processes may lead to certain common management strategies of diseases associated with aging and eventually ensure delaying or postponing or even preventing aging itself.

Figure 1. Scheme showing possible changes that can occur during ageing. Changes that are likely to be primary events in the causation of ageing are given in blue; responses to damage are given in orange and hallmarks of the effect of the alterations in genomic stability, telomere attrition and epigenetic changes and loss of proteostasis is given in green. Kindly note that all these events can interact with each other. In all the events associated with aging are modulated by AA (arachidonic acid, 20:4 n−6) and its metabolites.

2. Cell Membrane Theory of Aging

Both lipids and proteins (and their associated carbohydrate molecules) are important constituents of the cell membrane. Proteins are like bricks of the wall and inflexible. In contrast, lipids are flexible, and they influence cell membrane fluidity. The presence of higher amounts of unsaturated fatty acids render the membrane more fluid whereas higher content of saturated fatty acids and cholesterol make the membrane more rigid. Alterations in the cell membrane fluidity influences the expression of receptors and their affinity to their respective molecules. Hence, the constitution of cell membrane and its lipid content is critical to cell function.

There are several excellent reviews about the composition of properties of cell membrane in the literature. Hence, no detailed description of the cell membrane is given here. However, it is sufficient to say the following:

1. The cell membrane is the physical and chemical barrier which separates the inside the cell from the outside environment.
2. The structure of the cell membrane can be described as liquid bilayer of lipid embedded with proteins called as a “fluid mosaic model”.
3. This bilayer of the cell membrane is formed by the amphipathic molecules (phosphate rich heads on the outside and hydrophobic lipid tails on the inside).
4. The cell membrane is impermeable to water-soluble molecules but not to water, is soft and flexible. The flexibility of the membrane could be attributed to its lipid content. It has the unique property of being able to spontaneously repair pores.
5. About the composition of the cell membrane: lipids form ~50% by weight, proteins another ~50% by weight and carbohydrate portions of glycolipids and glycoproteins form approximately about 10%.
6. The outer membrane is mainly consisting of phosphatidylcholine and sphingomyelin and the inner membrane is composed of phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol and variable amounts of cholesterol.
7. The transmembrane proteins and lipid-anchored proteins are generally confined to one of the membranes. Most of the receptors for various proteins are located on the outer surface though some receptors are inside the membrane.
8. Glycosylated components of glycolipids and glycoproteins form the carbohydrate component of the membrane and they form the cellular glycocalyx.
9. In general, water is present between lipid molecules in a highly organized form and bulk of the water content is present in the pores and channels.
10. Ions such as calcium, sodium, etc., are present in the membrane and are attracted to the membrane by the intrinsic negative charge of the phospholipid heads.
11. Cholesterol is also a major membrane component and is present in a variable amount, depending on the cell and species.

The cell membrane is crucial for all the cellular functions. Hence, it is reasonable to propose that there could occur a close correlation between cell membrane integrity and changes in its composition to features of aging. This proposal implies that the lipid composition of the cell membrane is critical for the aging process. Of all the lipids that are present in the membrane, unsaturated fatty acids and their metabolites are important not only for cellular functions but also the aging process, implying that lipid composition of the membrane changes with aging and vice versa. At the same time, it is likely that the concentrations of various unsaturated fatty acids and their metabolism varies from cell to cell and is probably specific for each type of cell/tissue/organ. This is supported by the data given in Table 1, which shows that each type of cell/tissue has its own unique lipid composition. Similarly, the concentrations of antioxidants (superoxide dismutase, catalase, glutathione peroxidase), nitric oxide and lipid peroxides have also been reported to be different in various cells/tissues ^[1][2][1,2]. Thus, depending on the cell architecture, function, and its role in various cellular processes, the unsaturated fatty acid content and its metabolism varies. In other words, the composition of the cell membrane and its unsaturated fatty acid content and its metabolism determines the cell function and vice versa. This crosstalk between the cell architecture and function and its membrane composition are integrated with each other in such a way that cell membrane architecture determines the cell function and vice versa. Thus, changes in the lipid composition of the membrane determines the cellular function and its aging process. Since the membrane composition of each cell type is different and specific to it, this explains why different cells/tissues/organs show variation in their aging process. In this review, specific emphasis is given to the metabolism of unsaturated fatty acids and their metabolism (called as bioactive lipids: BALs) and this concept can be extended to other lipids present in the membrane such as phospholipids, cholesterol, glycolipids, phosphoglycerides, sphingolipids, etc. It is noteworthy that of all these lipids, perhaps, unsaturated fatty acids and their metabolism is critical to various cellular functions simply because most of the other lipids such as cholesterol, glycolipids, phosphoglycerides, and sphingolipids can influence the metabolism of unsaturated fatty acids either directly or indirectly.

In addition to the fact that unsaturated fatty acids composition of cells/tissues are specific to each type of cell/tissue, their concentrations change with aging as well. In a study, where age-related changes in phospholipid fatty acid composition in rat liver, kidney and heart were evaluated (in 3-, 12- and 24-month-old rats) it was noted that saturated fatty acids did not change significantly with age but a significant decrease in LA (18:2 n−6) in the liver and heart, DGLA (20:3 n−6) in the kidney in the organs studied. This change with age in the ratio between saturated and unsaturated n−6 and n−3 fatty acids with the balance tilted more towards the former is likely to produce a decrease in cell membrane fluidity (more rigid). It is noteworthy that dietary restriction significantly reverted these changes that lends support to the concept that decreased calorie intake is beneficial and prolongs lifespan ^[3][4][5][3–5]. Some of the pathways that mediate the beneficial effects of calorie restriction include insulin/insulin growth factor-1 (IGF-1), sirtuins, mammalian target of rapamycin (mTOR), 5′ adenosine monophosphate-activated protein kinase, decrease in ROS generation (reactive oxygen species), increase in antioxidant scavenging capacity, reduced damage to DNA and proteins, increase in autophagy and improvement in T cell function ^[6][7][6,7]. It is likely that all these changes reported with calorie restriction and its beneficial action in delaying aging process could be linked to alterations in the metabolism of essential fatty acids and their impact on cell membrane fluidity and other actions as discussed below.

BALs (bioactive lipids) produce extensive changes in the membrane fluidity that, in turn, can affect several cellular functions, including but not limited to carrier-mediated transport, the properties of membrane-bound enzymes, expression and binding characteristics of various receptors, phagocytosis, endocytosis, depolarization-dependent exocytosis, immunologic and chemotherapeutic cytotoxicity, prostaglandin production, and cell growth ^[8][9][8,9]. Thus, the actions of bioactive lipids are extraordinarily complex, and they vary from one type of cell to another. It is difficult to make any generalizations or to predict how a given system (cell, tissue, or organ) will respond to a lipid. However, it is likely that many of the functional responses are probably secondary to changes in the membrane structure. It is quite but natural that the conformation or quaternary structures of certain transporters, receptors, and enzymes are sensitive to changes in the structure of their lipid microenvironment, leading to alterations in their activity. The formation and nature of various types of prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs), lipoxins (LXs), resolvins, protectins and maresins is certainly modulated by the availability of their precursors that reside in the membrane phospholipids which are released from the membrane stores based on the type, nature, and strength of the stimulus which in itself can cause a change in membrane lipid structure. Thus, a close relationship exists between the membrane lipid compositional change and the concurrent functional perturbations. Since many aging associated diseases are pro-inflammatory in nature (mostly are characterized by low-grade systemic inflammation), it is relevant to delve into the metabolism essential fatty acids (EFAs) and note the various pro- and anti-inflammatory products formed from them.