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BackgroundPhysical inactivity and a sedentary lifestyle among community-dwelling older adults poses a greater risk for progressive physical and cognitive decline. Mixed reality technology-driven health enhancing physical activities such as the use of virtual coaches provide an emerging and promising solution to support healthy lifestyle, but the impact has not been clearly understood.Methods and analysisAn observational explanatory sequential mixed-method research design was conceptualized to examine the potential impact of a user-preferred mixed reality technology-driven health enhancing physical activity program directed toward purposively selected community-dwelling older adults in two senior centers in the Philippines. Quantitative components of the study will be done through a discreet choice experiment and a quasi-experimental study. A total of 128, or 64 older adults in each center, will be recruited via posters at community senior centers who will undergo additional screening or health records review by a certified gerontologist to ensure safety and proper fit. Treatments (live coaching with video-based exercise and mixed reality technology-driven exercise) will be assigned to each of the two senior center sites for the quasi-experiment. The participants from the experimental group shall be involved in the discreet choice experiment, modeling, and usability evaluations. Finally, a qualitative sample of participants (n = 6) as key informants shall be obtained from the experimental group using purposive selection.DiscussionThis study protocol will examine the health impact of a promising mixed reality program in health promotion among older adults. The study utilizes a human-centered mixed method research design in technology development and evaluation in the context of developing nations.Clinical trial registration: ClinicalTrials.gov, identifier NCT06136468.

Abstract Background Dementia and frailty are common age-related syndromes often linked to chronic inflammation. Identifying the biological factors and pathways that contribute to chronic inflammation is crucial for developing new therapeutic targets. Circulating cell-free mitochondrial DNA (ccf-mtDNA) has been proposed as an immune stimulator and potential predictor of mortality in acute illnesses. Dementia and frailty are both associated with mitochondrial dysfunction, impaired cellular energetics, and cell death. The size and abundance of ccf-mtDNA fragments may indicate the mechanism of cell death: long fragments typically result from necrosis, while short fragments arise from apoptosis. We hypothesize that increased levels of necrosis-associated long ccf-mtDNA fragments and inflammatory markers in serum are linked to declines in cognitive and physical function, as well as increased mortality risk. Results Our study of 672 community-dwelling older adults revealed that inflammatory markers (C-Reactive Protein, soluble tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 [sTNFR1], and interleukin-6 [IL-6]) positively correlated with ccf-mtDNA levels in serum. Although cross-sectional analysis revealed no significant associations between short and long ccf-mtDNA fragments, longitudinal analysis demonstrated a connection between higher long ccf-mtDNA fragments (necrosis-associated) and worsening composite gait scores over time. Additionally, increased mortality risk was observed only in individuals with elevated sTNFR1 levels. Conclusion In a community dwelling cohort of older adults, there are cross-sectional and longitudinal associations between ccf-mtDNA and sTNFR1 with impaired physical and cognitive function and increased hazard of death. This work suggests a role for long ccf-mtDNA as a blood-based marker predictive of future physical decline.

The renin–angiotensin system (RAS) was initially considered to be part of the endocrine system regulating water and electrolyte balance, systemic vascular resistance, blood pressure, and cardiovascular homeostasis. It was later discovered that intracrine and local forms of RAS exist in the brain apart from the endocrine RAS. This brain-specific RAS plays essential roles in brain homeostasis by acting mainly through four angiotensin receptor subtypes; AT1R, AT2R, MasR, and AT4R. These receptors have opposing effects; AT1R promotes vasoconstriction, proliferation, inflammation, and oxidative stress while AT2R and MasR counteract the effects of AT1R. AT4R is critical for dopamine and acetylcholine release and mediates learning and memory consolidation. Consequently, aging-associated dysregulation of the angiotensin receptor subtypes may lead to adverse clinical outcomes such as Alzheimer’s disease and frailty via excessive oxidative stress, neuroinflammation, endothelial dysfunction, microglial polarization, and alterations in neurotransmitter secretion. In this article, we review the brain RAS from this standpoint. After discussing the functions of individual brain RAS components and their intracellular and intracranial locations, we focus on the relationships among brain RAS, aging, frailty, and specific neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and vascular cognitive impairment, through oxidative stress, neuroinflammation, and vascular dysfunction. Finally, we discuss the effects of RAS-modulating drugs on the brain RAS and their use in novel treatment approaches.

Chronic inflammation is associated with physical frailty and functional decline in older adults; however, the molecular mechanisms of this linkage are not understood. A mouse model of chronic inflammation showed reduced motor function and partial denervation at the neuromuscular junction. Metabolomic profiling of these mice and further validation in frail human subjects showed significant dysregulation in the tryptophan degradation pathway, including decreased tryptophan and serotonin, and increased levels of some neurotoxic kynurenines. In humans, kynurenine strongly correlated with age, frailty status, TNF-αR1 and IL-6, weaker grip strength, and slower walking speed. To study the effects of elevated neurotoxic kynurenines on motor neuronal cell viability and axonal degeneration, we used motor neuronal cells treated with 3-hydroxykynurenine and quinolinic acid and observed neurite degeneration in a dose-dependent manner and potentiation of toxicity between 3-hydroxykynurenine and quinolinic acid. These results suggest that kynurenines mediate neuromuscular dysfunction associated with chronic inflammation and aging.