Hyponatremia is common in older people, most often of multifactorial origin, and can be associated with poor clinical outcomes. The aim was to analyze the frequency of severe hyponatremia (sodium concentration below 125 mmol/L), risk factors and mortality association in hospitalized older patients. A retrospective study was performed in older patients (over 65 years) with hyponatremia, diagnosed at admission in an Internal Medicine Department during one year. A control group of 127 older patients without hyponatremia was considered. Statistical analysis of the data gathered was made with SPSS Statistics 20. The main results were: a group of 1060 patients with age superior to 65 years was identified (representing 72.26% of total admissions); incidence of hyponatremia in those patients was 27.55% and severe hyponatremia was 5.94%; diagnosis of hyponatremia was mentioned in the discharge note in 66.67% of cases; mortality was 27.0%, against 16.0% in the control group (p=0.057, Odds Ratio (OR)=1.940); drugs were a significant risk factor (p<0.001), specially thiazide diuretics (p=0.029, OR=2.774), angiotensin receptor blockers (ARB) (p=0.001, OR=4.097), proton-pump inhibitors (PPI) (p=0.007, OR=2.561) and spironolactone (p=0.011, OR=4.473); other relevant risk factors were: increased water intake (p=0.004), tube feeding (p<0.001), vomiting (p=0.032, OR=2.492), cirrhosis (p=0.008, OR=10.862) and hyperhidrosis (p=0.017, OR=2.542). We conclude that, although this group of patients had a high mortality, hyponatremia is often not investigated and not always mentioned as a diagnosis. Clinicians should have a clear appreciation of the roles that iatrogenic interventions and lapses in nutrition frequently play in upsetting the homeostatic balance in older patients.

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Several chemical compounds including natural products have been suggested as being effective against age-related diseases or as beneficial for a healthy life. On the other hand, forkhead box O (FOXO) proteins are emerging as key cellular components associated with extreme human longevity. FOXO proteins are mainly regulated by posttranslational modifications and as these modifications are reversible, activation and inactivation of FOXO are attainable through pharmacological treatment. Here, we questioned whether a panel of compounds with known health-beneficial properties has the capacity to induce the activity of FOXO factors. We show that resveratrol, a phytoalexin present in grapes and other food products, the amide alkaloid piperlongumine found in the fruit of the long pepper, and the plant-derived β-carboline compound harmine induced nuclear translocation of FOXO3. We also show that piperlongumine and harmine but not resveratrol activate FOXO-dependent transcription. We determined the half maximal effective concentration (EC50) values for resveratrol, piperlongumine, and harmine for FOXO translocation, and analyzed their inhibitory impact on chromosomal maintenance 1 (CRM1)-mediated nuclear export and the production of reactive oxygen species (ROS). We also used chemical biology approach and Western blot analysis to explore the underlying molecular mechanisms. We show that harmine, piperlongumine, and resveratrol activate FOXO3 independently of phosphoinositide 3-kinase (PI3K)/AKT signaling and the CRM1-mediated nuclear export. The effect of harmine on FOXO3 activity is at least partially mediated through the inhibition of dual-specificity tyrosine (Y) phosphorylationregulated kinase 1A (DYRK1A) and can be reverted by the inhibition of sirtuins (SIRTs).

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