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The effect of glycine administration on the characteristics of physiological systems in human adults: A systematic review.
Soh, J, Raventhiran, S, Lee, JH, Lim, ZX, Goh, J, Kennedy, BK, Maier, AB
GeroScience. 2024;(1):219-239
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Abstract
Functional decline of physiological systems during ageing leads to age-related diseases. Dietary glycine increases healthy lifespan in model organisms and might decrease inflammation in humans, suggesting its geroprotective potential. This review summarises the evidence of glycine administration on the characteristics of eleven physiological systems in adult humans. Databases were searched using key search terms: 'glycine', 'adult', 'supplementation'/ 'administration'/ 'ingestion'/ 'treatment'. Glycine was administered to healthy and diseased populations (18 and 34 studies) for up to 14 days and 4 months, respectively. The nervous system demonstrated the most positive effects, including improved psychiatric symptoms from longer-term glycine administration in psychiatric populations. While longer-term glycine administration improved sleep in healthy populations, these studies had small sample sizes with a high risk of bias. Larger and long-term studies with more robust study designs in healthy populations to examine the effects of glycine administration on preventing, delaying or reversing the ageing process are warranted.
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A Comprehensive, Multi-Modal Strategy to Mitigate Alzheimer's Disease Risk Factors Improves Aspects of Metabolism and Offsets Cognitive Decline in Individuals with Cognitive Impairment.
Schechter, G, Azad, GK, Rao, R, McKeany, A, Matulaitis, M, Kalos, DM, Kennedy, BK
Journal of Alzheimer's disease reports. 2020;(1):223-230
Abstract
BACKGROUND Alzheimer's disease (AD) is a chronic condition that progresses over time. While several therapeutic approaches have been developed, none have substantially altered disease progression. One explanation is that the disease is multi factorial. OBJECTIVE Using the Affirmativ Health Personal Therapeutic Program (PTPr), we sought to determine whether a comprehensive and personalized program could improve cognitive and metabolic function in individuals diagnosed with subjective cognitive impairment, mild cognitive impairment, and early stage AD. METHODS 35 individuals submitted blood samples and Montreal Cognitive Assessment (MoCA) scores, and answered intake questions. Individuals and caregivers participated in a four-day immersion program, which included Personal Therapeutic Plans (PTP), consultations with clinical practitioners, and explanations of the PTPr and PTP. Participants had follow-up by telemonitoring, with repeat blood sample analysis, updates regarding lifestyle choices, current medications and supplements, and MoCA testing at least once between 3 and 12 months after the PTPr. RESULTS By comparing baseline to follow-up testing, we determined several risk factor scores, including blood glucose and insulin levels, and levels of vitamins B12, D3, and E, improved either in the entire participant pool or specifically in individuals with measures outside the normal range for specific factors. MoCA scores were stabilized in the entire participant pool and significantly improved in individuals scoring 24 or less at baseline. CONCLUSION Our findings provide evidence that a comprehensive and personalized approach designed to mitigate AD risk factors can improve risk factor scores and stabilize cognitive function, warranting more extensive and placebo-controlled clinical studies.
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Does eNOS derived nitric oxide protect the young from severe COVID-19 complications?
Guan, SP, Seet, RCS, Kennedy, BK
Ageing research reviews. 2020;:101201
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Abstract
The COVID-19 pandemic poses an imminent threat to humanity, especially to the elderly. The molecular mechanisms underpinning the age-dependent disparity for disease progression is not clear. COVID-19 is both a respiratory and a vascular disease in severe patients. The damage endothelial system provides a good explanation for the various complications seen in COVID-19 patients. These observations lead us to suspect that endothelial cells are a barrier that must be breached before progression to severe disease. Endothelial intracellular defences are largely dependent of the activation of the interferon (IFN) system. Nevertheless, low type I and III IFNs are generally observed in COVID-19 patients suggesting that other intracellular viral defence systems are also activated to protect the young. Intriguingly, Nitric oxide (NO), which is the main intracellular antiviral defence, has been shown to inhibit a wide array of viruses, including SARS-CoV-1. Additionally, the increased risk of death with diseases that have underlying endothelial dysfunction suggest that endothelial NOS-derived nitric oxide could be the main defence mechanism. NO decreases dramatically in the elderly, the hyperglycaemic and the patients with low levels of vitamin D. However, eNOS derived NO occurs at low levels, unless it is during inflammation and co-stimulated by bradykinin. Regrettably, the bradykinin-induced vasodilation also progressively declines with age, thereby decreasing anti-viral NO production as well. Intriguingly, the inverse correlation between the percentage of WT eNOS haplotype and death per 100K population could potentially explain the disparity of COVID-19 mortality between Asian and non-Asian countries. These changes with age, low bradykinin and NO, may be the fundamental reasons that intracellular innate immunity declines with age leading to more severe COVID-19 complications.
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The conundrum of human immune system "senescence".
Pawelec, G, Bronikowski, A, Cunnane, SC, Ferrucci, L, Franceschi, C, Fülöp, T, Gaudreau, P, Gladyshev, VN, Gonos, ES, Gorbunova, V, et al
Mechanisms of ageing and development. 2020;:111357
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Abstract
There is a great deal of debate on the question of whether or not we know what ageing is (Ref. Cohen et al., 2020). Here, we consider what we believe to be the especially confused and confusing case of the ageing of the human immune system, commonly referred to as "immunosenescence". But what exactly is meant by this term? It has been used loosely in the literature, resulting in a certain degree of confusion as to its definition and implications. Here, we argue that only those differences in immune parameters between younger and older adults that are associated in some definitive manner with detrimental health outcomes and/or impaired survival prospects should be classed as indicators of immunosenescence in the strictest sense of the word, and that in humans we know remarkably little about their identity. Such biomarkers of immunosenescence may nonetheless indicate beneficial effects in other contexts, consistent with the notion of antagonistic pleiotropy. Identifying what could be true immunosenescence in this respect requires examining: (1) what appears to correlate with age, though generality across human populations is not yet confirmed; (2) what clearly is part of a suite of canonical changes in the immune system that happen with age; (3) which subset of those changes accelerates rather than slows aging; and (4) all changes, potentially population-specific, that accelerate agig. This remains an immense challenge. These questions acquire an added urgency in the current SARS-CoV-2 pandemic, given the clearly greater susceptibility of older adults to COVID-19.
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The yeast replicative aging model.
He, C, Zhou, C, Kennedy, BK
Biochimica et biophysica acta. Molecular basis of disease. 2018;(9 Pt A):2690-2696
Abstract
It has been nearly three decades since the budding yeast Saccharomyces cerevisiae became a significant model organism for aging research and it has emerged as both simple and powerful. The replicative aging assay, which interrogates the number of times a "mother" cell can divide and produce "daughters", has been a stalwart in these studies, and genetic approaches have led to the identification of hundreds of genes impacting lifespan. More recently, cell biological and biochemical approaches have been developed to determine how cellular processes become altered with age. Together, the tools are in place to develop a holistic view of aging in this single-celled organism. Here, we summarize the current state of understanding of yeast replicative aging with a focus on the recent studies that shed new light on how aging pathways interact to modulate lifespan in yeast.
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Structural changes to monomeric CuZn superoxide dismutase caused by the familial amyotrophic lateral sclerosis-associated mutation A4V.
Schmidlin, T, Kennedy, BK, Daggett, V
Biophysical journal. 2009;(6):1709-18
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron degenerative disease, and the inherited form, familial ALS (fALS), has been linked to over 100 different point mutations scattered throughout the Cu-Zn superoxide dismutase protein (SOD1). The disease is likely due to a toxic gain of function caused by the misfolding, oligomerization, and eventual aggregation of mutant SOD1, but it is not yet understood how the structurally diverse mutations result in a common disease phenotype. The behavior of the apo-monomer fALS-associated mutant protein A4V was explored using molecular-dynamics simulations to elucidate characteristic structural changes to the protein that may allow the mutant form to improperly associate with other monomer subunits. Simulations showed that the mutant protein is less stable than the WT protein overall, with shifts in residue-residue contacts that lead to destabilization of the dimer and metal-binding sites, and stabilization of nonnative contacts that leads to a misfolded state. These findings provide a unifying explanation for disparate experimental observations, allow a better understanding of alterations of residue contacts that accompany loss of SOD1 structural integrity, and suggest sites where compensatory changes may stabilize the mutant structure.