Maximum life span differences among animal species exceed life span variation achieved by experimental manipulation by orders of magnitude. The differences in the characteristic maximum life span of species was initially proposed to be due to variation in mass-specific rate of metabolism. This is called the rate-of-living theory of aging and lies at the base of the oxidative-stress theory of aging, currently the most generally accepted explanation of aging. However, the rate-of-living theory of aging while helpful is not completely adequate in explaining the maximum life span. Recently, it has been discovered that the fatty acid composition of cell membranes varies systematically between species, and this underlies the variation in their metabolic rate. When combined with the fact that 1) the products of lipid peroxidation are powerful reactive molecular species, and 2) that fatty acids differ dramatically in their susceptibility to peroxidation, membrane fatty acid composition provides a mechanistic explanation of the variation in maximum life span among animal species. When the connection between metabolic rate and life span was first proposed a century ago, it was not known that membrane composition varies between species. Many of the exceptions to the rate-of-living theory appear explicable when the particular membrane fatty acid composition is considered for each case. Here we review the links between metabolic rate and maximum life span of mammals and birds as well as the linking role of membrane fatty acid composition in determining the maximum life span. The more limited information for ectothermic animals and treatments that extend life span (e.g., caloric restriction) are also reviewed.

The cost of living can be measured as an animal's metabolic rate. Basal metabolic rate (BMR) is factorially related to other metabolic rates. Analysis of BMR variation suggests that metabolism is a series of linked processes varying in unison. Membrane processes, such as maintenance of ion gradients, are important costs and components of BMR. Membrane bilayers in metabolically active systems are more polyunsaturated and less monounsaturated than metabolically less-active systems. Such polyunsaturated membranes have been proposed to result in an increased molecular activity of membrane proteins, and in this manner the amount of membrane and its composition can act as a pacemaker for metabolism. The potential importance of membrane acyl composition in metabolic depression, hormonal control of metabolism, the evolution of endothermy, as well as its implications for lifespan and human health, are briefly discussed.

The thyroid hormones are very hydrophobic and those that exhibit biological activity are 3',5',3,5-ltetraiodothyronine (T4), 3',5,3-l-triiodothyronine (T3), 3',5',3-l-triiodothyronine (rT3) and 3,5,-ldiiodothyronine (3,5-T2). At physiological pH, dissociation of the phenolic -OH group of these iodothyronines is an important determinant of their physical chemistry that impacts on their biological effects. When non-ionized these iodothyronines are strongly amphipathic. It is proposed that iodothyronines are normal constituents of biological membranes in vertebrates. In plasma of adult vertebrates, unbound T4 and T3 are regulated in the picomolar range whilst protein-bound T4 and T3 are maintained in the nanomolar range. The function of thyroid-hormone-binding plasma proteins is to ensure an even distribution throughout the body. Various iodothyronines are produced by three types of membrane-bound cellular deiodinase enzyme systems in vertebrates. The distribution of deiodinases varies between tissues and each has a distinct developmental profile. Thyroid hormones have many effects in vertebrates. It is proposed that there are several modes of action of these hormones. (1) The nuclear receptor mode is especially important in the thyroid hormone axis that controls plasma and cellular levels of these hormones. (2) These hormones are strongly associated with membranes in tissues and normally rigidify these membranes. (3) They also affect the acyl composition of membrane bilayers and it is suggested that this is due to the cells responding to thyroidhormone-induced membrane rigidification. Both their immediate effects on the physical state of membranes and the consequent changes in membrane composition result in several other thyroid hormone effects. Effects on metabolism may be due primarily to membrane acyl changes. There are other actions of thyroid hormones involving membrane receptors and influences on cellular interactions with the extracellular matrix. The effects of thyroid hormones are reviewed and appear to be combinations of these various modes of action. During development, vertebrates show a surge in T4 and other thyroid hormones, as well as distinctive profiles in the appearance of the deiodinase enzymes and nuclear receptors. Evidence from the use of analogues supports multiple modes of action. Re-examination of data from the early 1960s supports a membrane action. Findings from receptor 'knockout' mice supports an important role for receptors in the development of the thyroid axis. These iodothyronines may be better thought of as 'vitamone'-like molecules than traditional hormonal messengers. ABSTRACT The thyroid hormones are very hydrophobic and those that exhibit biological activity are 3h,5h,3,5--tetraiodothyronine (T4), 3h,5,3--triiodothyronine (T3), 3h,5h,3--triiodothyronine (rT3) and 3,5,--diiodothyronine (3,5-T2). At physiological pH, dissociation of the phenolic kOH group of these iodothyronines is an important determinant of their physical chemistry that impacts on their biological ...

Lipids play varied and critical roles in metabolism, with function dramatically modulated by the individual fatty acid moities in complex lipid entities. In particular, the fatty acid composition of membrane lipids greatly influences membrane function. Here we consider the role of dietary fatty acid profile on membrane composition and, in turn, its impact on prevalent disease clusters of the metabolic syndrome and mental illness. Applying the classical physiological conformer-regulator paradigm to quantify the influence of dietary fats on membrane lipid composition (i.e. where the membrane variable is plotted against the same variable in the environment--in this case dietary fats), membrane lipid composition appears as a predominantly regulated parameter. Membranes remain relatively constant in their saturated (SFA) and monounsaturated (MUFA) fatty acid levels over a wide range of dietary variation for these fatty acids. Membrane composition was found to be more responsive to n-6 and n-3 polyunsaturated fatty acid (PUFA) levels in the diet and most sensitive to n-3 PUFA and to the n-3/n-6 ratio. These differential responses are probably due to the fact that both n-6 and n-3 PUFA classes cannot be synthesised de novo by higher animals. Diet-induced modifications in membrane lipid composition are associated with changes in the rates of membrane-linked cellular processes that are major contributors to energy metabolism. For example, in the intrinsic activity of fundamental processes such as the Na+/K+ pump and proton pump-leak cycle. Equally, dietary lipid profile impacts substantially on diseases of the metabolic syndrome with evidence accruing for changes in metabolic rate and neuropeptide regulation (thus influencing both sides of the energy balance equation), in second messenger generation and in gene expression influencing a range of glucose and lipid handling pathways. Finally, there is a growing literature relating changes in dietary fatty acid profile to many aspects of mental health. The understanding of dietary lipid profile and its influence on membrane function in relation to metabolic dysregulation has exciting potential for the prevention and treatment of a range of prevalent disease states.

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