Human Ageing

Human Ageing: Fish Fats, Orotic Acid and Probiotics

Professor Luis Vitetta and Dr Samantha Coulson
Medlab Clinical Ltd

As a consequence, ageing in biological systems is a stochastic process that occurs systemically after reproductive maturity in animals that reach a fixed size in adulthood. It is caused by the escalating loss of molecular fidelity that ultimately exceeds repair capacity.1 This then increases the vulnerability to pathology or age-associated diseases. Further, that there is a finitude associated with ageing that eventually leads to death.1 Grimley Evans2 has defined senescent changes as de novo structural and functional alterations that are not part of the developmental programme.


Specifically we understand that ageing in humans is a progressive loss of cellular and tissue function and energy production that is accompanied by decreasing fertility and increasing mortality with advancing age. The most obvious and commonly recognised consequence of aging and energy decline is a decrease in skeletal muscle function which affects every aspect of human life from the ability to walk and run, chewing, swallowing and digesting food to playing games. This is hence recognised as an overall decline of an individual’s fitness for the environment that they occupy. In the 21st century and particularly in Westernised countries, the decline in function associated with the environment is a gradual process, and the signs become mostly noticeable after the 5th decade of life. As such the individual is observed to slowly progress to death over the next three to four decades. Given, that the ageing process is slow and gradual it presents with opportunities and options that may improve the overall functional capacity of cells / tissues, and therefore the organism as a whole. Small changes in function may be more amenable and likely to further slow down and possibly reverse some of the deleterious effects of ageing, rather, than when the incremental changes are large. This overall effect may then translate into a significant compression of the deleterious aspects of human ageing with a resultant beneficial increase in human life expectancy.


There is a vast array of scientific literature that concludes that lifestyle modification factors that optimize nutrition, physical activity and mental health have significant correlation with reducing the risks of disease in later life that translates into an increased mean life expectancy. Furthermore, the consumption of fish fats, probiotics and nutraceuticals such as coenzyme Q10 and orotic acid demonstrate promise in maintaining cellular health.


Inflammation-associated cellular-molecular damage and loss of repair mechanisms are recognized as major features in the ageing process.3 Inflammatory responses are recognised to be part of the host immune defenses to pathogens and tissue responses to injury. Inflammatory responses engage and operate at all levels of biological organization and these responses can be focal or systemic.


Heart Health Fish Fats: a recent study has demonstrated that fish oil–derived n–3 PUFA treatment slowed the normal decline in skeletal muscle mass and function in a study with older adults. As such these compounds should very much be considered a therapeutic approach for preventing sarcopenia and maintaining physical independence in older adults. Other data shed a mechanistic view on the effect that n–3 PUFAs may have in lowering the risk of chronic diseases such as cardiovascular disease.5 This study reported that there was a positive association between plasma n–6 PUFAs and arterial stiffness and went on to suggest that higher concentrations of plasma long–chain n–3 PUFAs were associated with less arterial stiffness. They posited that the underlying molecular mechanisms that associated plasma n–3 PUFAs with a lower risk of cardiovascular risk was due to enhanced regulation of pro– inflammatory mediators as evidenced by higher intake and higher circulation levels of PUFAs.


Brain Health Coenzyme Q10 (CoQ10): studies have reported on the scientific and clinical literature being replete with reports on the efficacy of CoQ10 for the treatment of a wide range of apparently unrelated diseases.6 The CoQ10 efficacy reports have embraced a diverse range of pathologies. For instance, CoQ10 has been used for the treatment of congestive heart failure, muscular dystrophy, chronic fatigue syndrome, breast cancer and primary biliary cirrhosis. CoQ10 has also been used in a number of amelioration therapies such as support for AIDS patients treated with AZT and improved immune function. With such a diverse range of apparent therapeutic effects, it has been difficult to reconcile the mechanism by which CoQ10 acts by the extant description of CoQ10 as simply being active in mitochondrial energy metabolism and its action as an antioxidant.3 In an RCT study of Linnane and colleagues6 they reported results obtained from a continuing clinical trial on the effect of CoQ10 administration on human vastus lateralis (quadriceps) skeletal muscle. Muscle samples, obtained from aged individuals receiving placebo or CoQ10 supplementation (300 mg per day for four weeks prior to hip replacement surgery) were analysed for changes in gene and protein expression and in muscle fibre type composition. The results led to the conclusion that CoQ10 is very much a gene regulator and consequently has wide–ranging effects on over–all tissue metabolism. As a consequence of these results the group postulated a comprehensive hypothesis that CoQ10 plays a major role in the determination of membrane potential of many, if not all, sub–cellular membrane systems and that H2O2 arising from the activities of CoQ10 acts as a second messenger for the modulation of gene expression and cellular metabolism.3-6 Furthermore, the control and the re–regulation of the oxido–reductase metabolism of the cell is primordial for cellular and tissue health.3


Orotate (Orotic Acid): Supplemental orotic acid is converted to pyrimidines in the liver.7 Organisms ranging from yeast and humans possess the enzyme orotate phosphoribosyltransferase (OPRTase), which is responsible for catalyzing the first step in the conversion of orotic acid into uridine. It does so by facilitating the attachment of a ribose plus phosphate group to free orotic acid. The net result is the formation of a molecule named orotidine 5'–monophosphate, which in turn is the immediate precursor to uridine 5'–monophosphate. Uridine is a nutrient that is largely unknown as a dietary supplement and nevertheless, surprisingly has a well–established place in nutrition. Indeed, uridine is one of the reasons that fish is known as brain food and brewer’s yeast is recognized for its health benefits. Uridine, along with adenosine, guanosine, and cytidine, is one of the four components that comprise RNA. When RNA–rich foods are consumed, the RNA is broken down and releases its basic elements for absorption from the small intestine.

The uridine synthesized in this manner enters directly into the blood circulation, and as such can be transported across the blood–brain barrier and into brain neurons, serving as precursors for neuronal pyrimidines.8 Furthermore, cytidine nucleotides have an essential role in the synthesis of the neuronal membrane phospholipids. Researchers have suggested that efficient neuronal membrane biogenesis, by supporting formation of neurites and dendritic spines, aids the formation of new synaptic connections that is crucial for learning and memory formation.9 This group also demonstrated that administration of uridine and the omega-3 fatty acid DHA (a major component of neuronal membranes), with or without a supplemental source of choline, enhances the formation of dendritic spines and neurites in animal models, boosting their cognitive performance.10, 11


Probiotics: are organisms that have the capacity to impact human health and consequently have been defined as live microorganisms that when administered in adequate amounts confer a health benefit on the host.12 Bacteria are important because they comprise the earliest form of independent life on this planet. Bacterial development has included co-operative symbiosis with plants (e.g., Leguminosae family and nitrogen fixing bacteria in soil) and animals (e.g., the gut microbiome). A fusion event of two prokaryotes evolutionarily gave rise to the eukaryote cell in which mitochondria may be envisaged as a genetically functional mosaic, a relic from one of the prokaryote cells. Microbial interactions in the gastrointestinal tract provide the necessary cues for the development of regulated signals [in part by reactive oxygen species] that promote immunological tolerance, metabolic regulation and stability, and other factors, which may then help control local and extra-intestinal end organ (e.g., kidneys) physiology. As such, mucosal surfaces constitute a discrete compartment of the immune system that is autonomous from the systemic arm by virtue of several marked differences, including a different immunoglobulin isotype, immunoglobulin A. The mucosal compartment also has a unique process for generating an immune response and it is populated by an independent lymphocyte subpopulation. The mucosal immune system depends on the cooperation of lymphoid and intestinal epithelial cells to initiate and to maintain an immune response and homeostasis. An effective response in the intestines involves:

  1. Binding, uptake and transport of antigens at the mucosal surface via specialized epithelial cells (M cells) on the domes of lymphoid nodules (e.g., Peyer’s patches);
  2. Antigen presentation to immunologically competent cells (e.g., intestinal resident macrophages, dendritic cells) within the Peyer’s patches;
  3. Isotype switching, differentiation and migration (homing) of antigen-stimulated Peyer’s patch IgA B immunoblasts to the intestinal lamina propria,
  4. Local antibody production by IgA plasma cells in the lamina propria and (e) receptor–mediated transport of antibodies across the intestinal epithelium to the mucosal surface. These secreted antibodies (secretory IgA) neutralize toxins on the mucosa surface, block the adherence of bacteria to the epithelium and reduce the invasive penetration of antigens across the mucosa. Mechanism failure in this respect can induce pro–inflammatory responses and consequently disrupt homeostasis as often happens in the older age groups with the variation in intestinal microbiome species that have been reported (Figure 1. vide infra the dotted red line).

Change in intestinal flora with age

Figure 1. Mitsuoka T 1978. Intestinal Bacteria and Health. Harcourt Brace Javanovich Japan Inc.


Pharmacobiotics, the administration of live probiotic cultures is an exciting growth area of potential therapeutics, developing together with an increased scientific understanding of gastrointestinal microbiome symbiosis in health and disease. The beneficial effects of probiotics are likely to result from several complex and interacting mechanisms that differ for different strains and sites of action.

The mechanism of probiotic efficacy may include competition for binding sites to the intestinal wall, competition for essential nutrients, production of antimicrobial substances, stimulation of mucin production, stabilization of the intesti¬nal barrier, improvement of gut transit, metabolism of nutrients to volatile fatty acids, and immunomodulation (immune stimulation and immunoregulation).13 Clinical trials that translate these effects to efficacy in humans require further warranted studies.13

In this selective and brief review we have summarized the scientific evidence that may prevent disease and maintain the molecular integrity of the organism, thus expanding the mean life expectancy whilst operating within the framework of normal physiological function and repair. We find that whilst aging is not irreversible and inevitable, certain key factors may add significant benefits to human mean life expectancy such as when lifestyle interventions of prudent nutritional and physical activity practices are combined with the supplementation of fish fats, CoQ10, magnesium orotate and probiotics.



References

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  2. Grimley Evans J. 21st Century: Review: Ageing and medicine. Journal of internal medicine. 2000;247(2):159-67.
  3. Linnane AW, Kios M, Vitetta L. The essential requirement for superoxide radical and nitric oxide formation for normal physiological function and healthy aging. Mitochondrion. 2007;7(1-2):1-5.
  4. Smith GI, Julliand S, Reeds DN, Sinacore DR, Klein S, Mittendorfer B. Fish oil-derived n-3 PUFA therapy increases muscle mass and function in healthy older adults. The American journal of clinical nutrition. 2015;102(1):115-22.
  5. Reinders I, Murphy RA, Song X, Mitchell GF, Visser M, Cotch MF, et al. Higher Plasma Phospholipid n-3 PUFAs, but Lower n-6 PUFAs, Are Associated with Lower Pulse Wave Velocity among Older Adults. The Journal of nutrition. 2015;145(10):2317-24.
  6. Linnane AW, Kopsidas G, Zhang C, Yarovaya N, Kovalenko S, Papakostopoulos P, et al. Cellular redox activity of coenzyme Q10: effect of CoQ10 supplementation on human skeletal muscle. Free radical research. 2002;36(4):445-53.
  7. Dileepan KN, Kennedy J. Rapid conversion of newly-synthesized orotate to uridine-5-monophosphate by rat liver cytosolic enzymes. FEBS letters. 1983;153(1):1-5.
  8. Cansev M, Watkins CJ, van der Beek EM, Wurtman RJ. Oral uridine-5'-monophosphate (UMP) increases brain CDP-choline levels in gerbils. Brain research. 2005;1058(1-2):101-8.
  9. Wurtman RJ, Cansev M, Sakamoto T, Ulus I. Nutritional modifiers of aging brain function: use of uridine and other phosphatide precursors to increase formation of brain synapses. Nutrition reviews. 2010;68 Suppl 2:S88-101.
  10. Wurtman RJ, Cansev M, Ulus IH. Synapse formation is enhanced by oral administration of uridine and DHA, the circulating precursors of brain phosphatides. The journal of nutrition, health & aging. 2009;13(3):189-97.
  11. Sakamoto T, Cansev M, Wurtman RJ. Oral supplementation with docosahexaenoic acid and uridine-5'-monophosphate increases dendritic spine density in adult gerbil hippocampus. Brain research. 2007;1182:50-9.
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