In addition to age acceleration, our findings provide evidence of a pronounced escalation in entropy, notably around the age of 40 years. This observation suggests the potential presence of a progressively dysregulated mevalonate pathway, culminating in the accumulation of dolichol. It is noteworthy that individuals afflicted with neurological disorders typically exhibit values that fall beyond the statistical range of two standard deviations when compared with the entropy levels of their healthier counterparts below the age of 40. This implies that individuals with neurological disorders already manifest an elevated state of entropy. However, the precise underlying mechanistic basis for this phenomenon remains obscure, and it is anticipated that forthcoming research endeavors will yield greater insights into this matter.
Further, it was hypothesized that the strong correlation observed between entropy and chronological age reflects age-dependent dysregulation of pathways involving this lipid class. Dolichols, composed of a long-chain isoprenoid alcohol comprising saturated alpha-isoprene units, belong to the class of polyprenols, and are involved in intracellular molecular transport (68), N-glycosylation (69), and serve as a key product within the mevalonate pathway (70). The mevalonate pathway is responsible for the synthesis of cholesterol, dolichol, and ubiquinone among other molecules (71). Alterations in the concentration levels of these molecules, alongside an increase in dolichol during aging (72–76), suggest dysregulation of this pathway, potentially mediated by an age-related increase in HMG-CoA reductase, the rate-limiting enzyme of this pathway (77). These findings support the hypothesis of an association between entropy and age-dependent dysregulation of the mevalonate pathway.
In this study we show that Zol has properties of a geroprotector, an activity mediated by its inhibition of FPPS. We show that Zol extends the life span and health span of Drosophila in absence of mineralized bone-like structures and demonstrate that it confers resistance to oxidative damage via the inhibition of FPPS in the mevalonate pathway. The median extension of life span by Zol is in the same range of other geroprotectors including rapamycin, with Zol extending the median life span of females by 14%–18% when given from middle age.
By inhibiting FPP synthase, N-BPs prevent the synthesis of FPP and its downstream metabolite geranylgeranyl diphosphate (Fig. 3). These isoprenoid lipids are the building blocks for the production of a variety of metabolites, such as dolichol and ubiquinone (21), but are also required for post-translational modification (prenylation) of proteins, including small GTPases (22, 23).
So, using a statin along with zoledronate or alendronate seems like a good idea
Conclusions: Our study discovered dramatic age-related changes in dolichol in the retina. The age-related accumulation of dolichols and the shortening of dolichol length distribution could be used as quantifiable biomarkers for retinal aging.
The mevalonate/isoprenoids/cholesterol pathway has a fundamental role in the brain. Increasing age could be associated with specific changes in mevalonate downstream products. Other than age differences in brain cholesterol and dolichol levels, there has been little if any evidence on the short-chain isoprenoids farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), as well as downstream lipid products. The purpose of the present study was to determine whether brain levels of FPP, GGPP and sterol precursors and metabolites would be altered in aged mice (23 months) as compared to middle-aged mice (12 months) and young mice (3 months). FPP and GGPP levels were found to be significantly higher in brain homogenates of 23-months-old mice. The ratio of FPP to GGPP did not differ among the three age groups suggesting that increasing age does not alter the relative distribution of the two isoprenoids. Gene expression of FPP synthase and GGPP synthase did not differ among the three age groups. Gene expression of HMG-CoA reductase was significantly increased with age but in contrast gene expression of squalene synthase was reduced with increasing age. Levels of squalene, lanosterol and lathosterol did not differ among the three age groups. Desmosterol and 7-dehydroxycholesterol, which are direct precursors in the final step of cholesterol biosynthesis were significantly lower in brains of aged mice. Levels of cholesterol and its metabolites 24S- and 25S-hydroxycholesterol were similar in all three age groups. Our novel find ings on increased FPP and GGPP levels in brains of aged mice may impact on protein prenylation and contribute to neuronal dysfunction observed in aging and certain neurodegenerative diseases.
The isoprenoid pathway and its metabolites–digoxin, dolichol, and ubiquinone–were assessed in autism. The isoprenoid pathway and digoxin status was also studied for comparison in individuals of differing hemispheric dominance to determine the role of cerebral dominance in the genesis of autism. There was an upregulation of the isoprenoid pathway as evidenced by elevated HMG CoA reductase activity in autism. Digoxin, an endogenous Na±K+ ATPase inhibitor secreted by the hypothalamus, was found to be elevated and RBC membrane Na±K+ ATPase activity was found to be reduced in autism. Membrane Na±K+ ATPase inhibition can result in increased intracellular Ca2+ and reduced magnesium levels. Hypothalamic digoxin can modulate conscious and subliminal perception and its dysfunction may lead to autism. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarizing tryptophan catabolites–serotonin, quinolinic acid (NMDA agonist), strychnine (blocks glycinergic inhibitory transmission), and nicotine (promotes dopamine release) and decreased levels of hyperpolarizing tyrosine catabolites–dopamine, noradrenaline, and morphine–contributing to membrane Na±K+ ATPase inhibition.
Increased nicotine levels can produce increased dopaminergic transmission in the presence of low dopamine levels. NMDA excitotoxicity could result from hypomagnesemia induced by membrane Na±K+ ATPase inhibition and quinolinic acid, an NMDA agonist acting on the NMDA receptor. Hypomagnesemia and increased dolichol level can affect glycoconjugate metabolism and membranogenesis leading on to disordered synaptic connectivity in the limbic allocortex and defective presentation of viral antigens and neuronal antigens contributing to autoimmunity and viral persistence important in the pathogenesis. Membrane Na±K+ ATPase inhibition can produce immune activation, a component of autoimmunity. Mitochondrial dysfunction consequent to altered calcium/magnesium ratios and reduced ubiquinone levels can result in increased free radical generation and reduced free radical scavenging and defective apoptosis leading to abnormal synaptogenesis. Autism can thus be considered a syndrome of hypothalamic digoxin hypersecretion consequent to an upregulated isoprenoid pathway. The biochemical patterns including hyperdigoxinemia observed in autism correlated with those obtained in right hemispheric chemical dominance. Right hemispheric chemical dominance is a predisposing factor for autism.
