Hanafi Ahmad Damanhuri

Background: Tocotrienol, a naturally occurring form of vitamin E, has been extensively studied for its potent antioxidant, anti-inflammatory, and immune-stimulating properties. However, the clinical impact of tocotrienol supplementation on older adults’ overall health and well-being remains relatively unexplored. This research aims to investigate the efficacy of tocotrienol-rich fraction (TRF) on various health parameters associated with general well-being in individuals aged between 50 years and 75 years. Objective: It is hypothesized that TRF supplementation may exhibit positive outcomes on blood biochemistry and several physiological aspects, including lowered levels of oxidative stress and inflammation biomarkers; improvement in vascular age; and enhancement of skin condition, bone mineral density, and cognitive function. Methods: This randomized, double-blind, placebo-controlled trial was designed to investigate the effectiveness of TRF supplementation on overall health in healthy older adults. The study aims to assess the impact of a daily dosage of 200 mg of TRF over a period of 6 months. A total of 220 participants is enrolled in the study, with one-half receiving the placebo and the other one-half receiving TRF supplementation. The study comprises 3 time points: baseline, 3 months, and 6 months. At each time point, various measurements are taken to evaluate different aspects of health. The primary outcome measurements include blood biochemistry assessments, such as liver function tests, renal profile, lipid profile, and full blood count. Oxidative stress markers, including malondialdehyde, advanced glycation end products, protein carbonyl, and isoprostane, are also evaluated. Immune response markers such as interleukin-6 and tumor necrosis factor-α are assessed. Satiety regulation is examined through measurements of leptin and ghrelin. Body composition and skin health parameters, including wrinkling, pigmentation, elasticity, hydration, and sebum secretion, are evaluated. Additionally, arterial stiffness is assessed using arteriography at baseline and 6 months. For secondary outcome measures, bone mineral density is measured using dual x-ray absorptiometry, and cognitive function is assessed using the Montreal Cognitive Assessment, Rey Auditory Verbal Learning Test, and digital span test. Both bone mineral density and cognitive function are also measured at baseline and 6 months. Results: The study is progressing as planned, with 209 participants recruited as of April 2025. The research was funded in 2019, and data collection started in December 2020. Preliminary data analysis has been completed for the first 120 participants, and final results are expected upon completion of data collection and unblinding in 2026. Conclusions: By comprehensively evaluating these health aspects, this study seeks to provide valuable insights into the potential benefits of tocotrienol supplementation for promoting the overall health and well-being of the aging population. Trial Registration: National Medical Research Register (NMRR) NMRR-19-2972-51179; https://tinyurl.com/yy9yueer International Registered Report Identifier (IRRID): DERR1-10.2196/73039

Tocotrienol-rich fraction (TRF), a subtype of vitamin E, has recently been reported to demonstrate promising neuroprotective properties. However, it remains to be fully determined how it confers protection in the brain. This scoping review aimed to explore and understand the intricate role of TRF in promoting and preserving neuronal well-being. A systematic literature search, based on the framework by Arksey and O’Malley and adhering to the PRISMA-ScR guidelines, was conducted across several databases, including PubMed, Scopus, and Web of Science (WOS), using the following phrases and Boolean operators: (“tocotrienol-rich fraction”) AND ((“neuroprotect”) OR (“cognit”) OR (“brain”)). The search yielded a total of 24 eligible articles, shortlisted based on predetermined inclusion and exclusion criteria established at the outset of the study. The findings highlight a diverse array of TRF-related studies, both in vivo and in vitro, that revealed functional mechanisms through which TRF confers neuroprotection. These include, but are not limited to, antioxidant and anti-inflammatory effects via attenuation of superoxide dismutase (SOD) activity and pro-inflammatory mediators; regulation of metabolic pathways; regulation of neuronal genes, proteins, and maintenance of cellular functions; and subsequent improvements in memory and cognitive performance in animal models following TRF treatment. The convergence of these neuroprotective effects suggests that TRF holds potential as a supplement to support healthy ageing or, at the very least, slow neurodegeneration by mitigating pathological changes that often begin insidiously before the onset of symptoms associated with cognitive decline.

The brain plays a central role in controlling and regulating bodily activities. Given its significance, the brain needs to remain in optimal condition to function properly. Neurodegenerative diseases arise when the mechanisms maintaining brain homeostasis fail, resulting in prolonged and uncontrolled activation of cell death pathways. Increasingly, researchers are focusing on specific types of cell death, such as ferroptosis and pyroptosis, due to their potential as targets for preventing and treating neurodegenerative diseases. Brain-derived neurotrophic factor (BDNF) is a crucial growth factor for neurogenesis, neuronal survival, and maintenance, and is thus implicated in cell death mechanisms. This review aims to elucidate the role of BDNF in the ferroptosis and pyroptosis mechanisms that impact brain health. To achieve this, three databases – PubMed, Scopus, and Web of Science – were searched for relevant studies, yielding 95 articles, of which only 14 were aligned with the study’s aim. Ferroptosis (iron-dependent cell death) and pyroptosis (inflammatory cell death) are distinct modes of cell death; however, this review found both mechanisms are associated with oxidative stress. Consequently, the findings suggest that ferroptosis and pyroptosis collectively impact brain health conditions such as depression, cognitive deficiencies, and anxiety, which are notably linked to reduced BDNF levels.

The menopausal transition has been proposed to put women at risk for undesirable neurological symptoms, including cognitive decline. Previous studies suggest that alterations in the hormonal milieu modulate brain structures associated with cognitive function. This structured review provides an overview of the relevant studies that have utilized MRI to report volumetric differences in the brain following menopause, and its correlations with the evaluated cognitive functions. We performed an electronic literature search using Medline (Ovid) and Scopus to identify studies that assessed the influence of menopause on brain structure with MRI. Fourteen studies met the inclusion criteria. Brain volumetric differences have been reported most frequently in the frontal and temporal cortices as well as the hippocampus. These regions are important for higher cognitive tasks and memory. Additionally, the deficit in verbal and visuospatial memory in postmenopausal women has been associated with smaller regional brain volumes. Nevertheless, the limited number of eligible studies and cross-sectional study designs warrant further research to draw more robust conclusions.

Changes in mitochondrial bioenergetics are believed to take place during osteoclastogenesis. This study aims to assess changes in mitochondrial bioenergetics and reactive oxygen species (ROS) levels during polyethylene (PE)-induced osteoclastogenesis in vitro. For this purpose, RAW264.7 cells were cultured for nine days and allowed to differentiate into osteoclasts in the presence of PE and RANKL. The total TRAP-positive cells, resorption activity, expression of osteoclast marker genes, ROS level, mitochondrial bioenergetics, glycolysis, and substrate utilization were measured. The effect of tocotrienols-rich fraction (TRF) treatment (50 ng/mL) on those parameters during PE-induced osteoclastogenesis was also studied. During PE-induced osteoclastogenesis, as depicted by an increase in TRAP-positive cells and gene expression of osteoclast-related markers, higher proton leak, higher extracellular acidification rate (ECAR), as well as higher levels of ROS and NADPH oxidases (NOXs) were observed in the differentiated cells. The oxidation level of some substrates in the differentiated group was higher than in other groups. TRF treatment significantly reduced the number of TRAP-positive osteoclasts, bone resorption activity, and ROS levels, as well as modulating the gene expression of antioxidant-related genes and mitochondrial function. In conclusion, changes in mitochondrial bioenergetics and substrate utilization were observed during PE-induced osteoclastogenesis, while TRF treatment modulated these changes.

This study aimed to determine the effect of age on CVLM C1 neuron glucoregulatory proteins in the feeding pathway. Male Sprague Dawley rats aged 3 months and 24 months old were divided into two subgroups: the treatment group with 2-deoxy-d-glucose (2DG) and the control group. Rat brains were dissected to obtain the CVLM region of the brainstem. Western blot was used to determine protein expression of tyrosine hydroxylase (TH), phosphorylated TH at Serine40 (pSer40TH), AMP-activated protein kinase (AMPK), phosphorylated AMPK (phospho AMPK), and neuropeptide Y Y5 receptors (NPY5R) in CVLM samples. Immunofluorescence was used to determine TH-, AMPK-, and NPY5R-like immunoreactivities among other brain coronal sections. Results obtained denote a decrease in basal TH phosphorylation levels and AMPK proteins and an increase in TH proteins among aged CVLM neurons. Increases in the basal immunoreactivity of TH+, AMPK+, NPY5R+, TH+/AMPK+, and TH+/NPY5R+ were also observed among old rats. Young treatment-group rats saw a decrease in TH phosphorylation and AMPK proteins following 2DG administration, while an increase in AMPK phosphorylation and a decrease in TH proteins were found among the old-treatment-group rats. These findings suggest the participation of CVLM C1 neurons in counter-regulatory responses among young and old rats. Altering protein changes in aged CVLM C1 neurons may attenuate responses to glucoprivation, thus explaining the decline in food intake among the elderly.

The mechanism of cognitive aging at the molecular level is complex and not well understood. Growing evidence suggests that cognitive differences might also be caused by ethnicity. Thus, this study aims to determine the gene expression changes associated with age-related cognitive decline among Malay adults in Malaysia. A cross-sectional study was conducted on 160 healthy Malay subjects, aged between 28 and 79, and recruited around Selangor and Klang Valley, Malaysia. Gene expression analysis was performed using a HumanHT-12v4.0 Expression BeadChip microarray kit. The top 20 differentially expressed genes at p < 0.05 and fold change (FC) = 1.2 showed that PAFAH1B3, HIST1H1E, KCNA3, TM7SF2, RGS1, and TGFBRAP1 were regulated with increased age. The gene set analysis suggests that the Malay adult’s susceptibility to developing age-related cognitive decline might be due to the changes in gene expression patterns associated with inflammation, signal transduction, and metabolic pathway in the genetic network. It may, perhaps, have important implications for finding a biomarker for cognitive decline and offer molecular targets to achieve successful aging, mainly in the Malay population in Malaysia.