Medical Hypotheses 76 (2011) 547–549
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Erythrocyte plasma membrane redox system may determine maximum life span Syed Ibrahim Rizvi ⇑, Dileep Kumar, Shilpa Chakravarti, Prabhakar Singh Department of Biochemistry, University of Allahabad, Allahabad 211002, India
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Article history: Received 2 June 2010 Accepted 18 December 2010
a b s t r a c t There is great variation in the maximum life span of different species. The rate of living theory provides an explanation for the inter species difference in life span but falls short in accounting for the long life span of humans and flying birds. Although the membrane pacemaker theory given by Hulbert provides a viable explanation but there are still some unanswered questions. We propose that long living species have abnormally high activity of erythrocyte plasma membrane redox system which provides an effective armament to combat oxidative stress. The elevated PMRS hypothesis combined with Hulbert’s ‘membrane pacemaker’ theory provides a better explanation for the observed long life span of humans and flying birds. Ó 2010 Elsevier Ltd. All rights reserved.
Different mammalian species age in broadly similar ways but their longevity varies greatly. Some very small mammals live for 120 years. Earliest attempts to explain this inter species differences in life span revolved around the ‘rate of living’ theory which was based on the concept that the pace of life and the length of life were inversely related. In other words, species with high metabolic rates exhibited shorter life spans [1]. The ‘rate of living’ theory complimented the ‘free radical theory’ of aging proposed by Harman in 1956 [2]. The free radical theory or the ‘oxidative stress’ theory proposes that normal aerobic metabolism results in production of free radicals and reactive oxygen species which progressively damage biomolecules, this ‘oxidative damage’ accumulates and causes loss of function. The free radical theory of aging is currently the most accepted mechanistic explanation of the aging and variation in longevity. Despite a large body of evidence in its favour, the rate of living theory harbours within itself several unsolved questions. Flying birds have a higher rate of living than similar sized mammals yet generally are much longer-living; caloric restriction increases longevity however it does not do so by decreasing mass-specific metabolic rate; and within a species there is no inverse correlation between rate of living and longevity of individuals. As part of the explanation for species difference in maximum life span, Hulbert [3,4] proposed the ‘membrane pacemaker theory of aging’. According to this theory the membrane fatty acid composition may provide an explanation to the differences in longevity among endothermic vertebrates; mammals and birds. Longerliving flying birds were shown to contain a higher percentage of ⇑ Corresponding author. Tel.: +91 9415305910. E-mail address:
[email protected] (S.I. Rizvi). 0306-9877/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2010.12.014
saturated fatty acids in their membranes compared to mammals. The saturated fatty acids are relatively resistant to peroxidation and thus have a lower peroxidation index (PL). Hulbert provided evidence that there existed an inverse correlation between maximum life span of mammals and birds and the peroxidation index of skeletal muscle and liver mitochondrial phospholipids [5]. It was calculated that every doubling of maximum life span is associated with a 19% decrease in the PL of skeletal muscle phospholipids and a 22% decrease in the PL of liver mitochondrial phospholipids. Despite various arguments and explanations, the mechanisms that operate to determine maximum life span of different species remain hazy. The ‘abnormally’ large life span of humans compared to their body mass is not explained. We propose the involvement of erythrocyte plasma membrane redox system (PMRS) in determining the life span of different species and specifically the long life span of flying birds and humans. This hypothesis is based on our previous report of an increase in the erythrocyte PMRS activity during human aging [6]. Eukaryotic cells display a plasma membrane redox system (PMRS) that transfers electrons from intracellular substrates to extracellular electron acceptors [7,8] (Fig. 1). Although the exact physiological function of this PMRS remains elusive, proposed functions include: maintenance of redox state of sulfhydryl residues in membrane proteins [9], neutralization of oxidative stressors outside the cells [10], stimulation of cell growth [11], recycling of a tocopherol [11], reduction of lipid hydroperoxides, reduction of ferric ion prior to iron uptake by a transferring-independent pathway [11], and the maintenance of the extracellular concentration of ascorbic acid [12]. There is growing evidence that there is a strong correlation between oxidative stress and human aging [13]. Oxidised
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Fig. 1. Schematic representation of the functioning of the plasma membrane redox system (PMRS). AA-ascorbic acid, AFR-ascorbate free radical.
biomolecules accumulate with age in cells [14,15] and this accumulation of damaged biomolecules has been widely proposed to play a role in limiting life spans in mammals [16]. It has been observed that individuals having genetically compromised system for countering stress could age at higher rates compared to individuals with a more robust system when exposed to environmental or dietary oxidants [17]. Long lived species have been reported to exhibit lower ROS production than short lived species [18]. In view of the above it can be argued that the most effective strategy for natural selection towards long life span is to devise inherent mechanisms for countering oxidative stress. The erythrocyte PMRS plays an important role in maintaining the antioxidant status of the plasma during aging [6,19] and diabetes mellitus [20]. Mitochondria-deficient cells (q° cells) have been known to survive due to enhanced activity of PMRS which plays a key role in maintaining the levels of NAD/NADH and reduced coenzyme Q. Importantly up-regulation of PMRS activity has also been
associated with cell survival and membrane homeostasis under conditions of stress and dietary restriction [21]. In Fig. 2 we show our preliminary results on the activity of erythrocyte PMRS in different species (rat, goat, dog, pigeon and man) which have wide variation in their life spans (4–122 years). The PMRS activity of human and pigeon is significantly higher compared to other animals. This initial observation prompts us to hypothesize that species which possess an efficient system for maintaining plasma antioxidant status (higher PMRS activity) are better equipped to combat oxidative stress and display longer life. There is no scientific evidence to prove that the aging process is itself genetically programmed, however, studies in several model organisms have identified potent longevity genes which can extend the life span. Most longevity factors promote stress resistance and cellular survival. There are more than 100 candidate genes which have been shown to be involved in determining longevity. Of particular interest among longevity genes include the genes of the insulin/IGF-pathway, FOXO3A, FOXO1A, lipoprotein metabolism (APOE and PON1) and cell cycle regulators (TP53 and P21) [22]. The components of PMRS include cytochrome b5 reductase, NADH-quinone oxidoreductase 1, lipophilic antioxidants (Coenzyme Q and a-tocopherol) and cytosolic electron donors [21]. Although mature human erythrocytes lack protein synthesizing ability, up-regulation of PMRS enzymes have been reported in neural cells in response to mitochondrial dysfunction [23]. Thus the genes coding for the enzymes of PMRS may also be considered as longevity promoting genes. The elevated PMRS hypothesis combined with Hulbert’s ‘membrane pacemaker’ theory provides a better explanation for the observed long life spans of humans and flying birds. The pivotal role of erythrocyte PMRS in modulating life span presents an interesting approach for designing anti aging interventions. Determination of PMRS activity in large number of species as a function of life span is the only possible way to check this hypothesis. Conflict of interest There is no conflict of interest. Acknowledgement This work was supported by a research Grant to SIR from University Grants Commission, New Delhi MRP: F 37-392/2009 SR. References
Fig. 2. Erythrocyte PMRS activity in some selected species plotted against their maximum life span. PMRS activity was determined as described (6). Briefly, 0.2 ml RBC were suspended in phosphate buffered saline containing 5 mM glucose and 1 mM freshly prepared potassium ferricyanide. The suspension were incubated for 30 min at 37 °C and then centrifuged at 1800g at 4 °C. The supernatant collected was assayed for ferrocyanide content using 4,7 diphenyl-1,10 phenanthrolinedisulfonic acid disodium salt and measuring absorption at 535 nm (e = 20,500 M 1 cm 1). Results are expressed in micromole ferrocyanide/ml PRBC/ 30 min.
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