Highlights • Roles are emerging for natural killer (NK) cells beyond removing transformed cells. • These include immune regulation and the elimination of senescent cells. • Human ageing is associated with a decline in NK cell function. • We propose some aspects of human ageing are due in part to reduced NK cell function. • These include reduced vaccination efficacy and delayed resolution of inflammation.
Impaired immune function has been implicated in the declining health and higher incidence of cancer in the elderly. However, age-related changes to immunity are not completely understood. Neutrophils and macrophages represent the first line of defence yet their ability to phagocytose pathogens decrease with aging. Cytotoxic T lymphocytes are critical in eliminating tumors, but T cell function is also compromised with aging. T cell responses can be regulated by macrophages and may depend on the functional phenotype macrophages adopt in response to microenvironmental signals. This can range from pro-inflammatory, anti-tumorigenic M1 to anti-inflammatory, pro-tumorigenic M2 macrophages. Macrophages in healthy elderly adipose and hepatic tissue exhibit a more pro-inflammatory M1 phenotype compared to young hosts whilst immunosuppressive M2 macrophages increase in elderly lymphoid tissues, lung and muscle. These M2-like macrophages demonstrate altered responses to stimuli. Recent studies suggest that neutrophils also regulate T cell function and, like macrophages, neutrophil function is modulated with aging. It is possible that age-modified tissue-specific macrophages and neutrophils contribute to chronic low-grade inflammation that is associated with dysregulated macrophage-mediated immunosuppression, which together are responsible for development of multiple pathologies, including cancer. This review discusses recent advances in macrophage and neutrophil biology in healthy aging and cancer. (C) 2017 Elsevier B.V. All rights reserved.
Innate and adaptive immunity are the major defence mechanisms of higher organisms against inherent and environmental threats. Innate immunity is present already in unicellular organisms but evolution has added novel adaptive immune mechanisms to the defence armament. Interestingly, during aging, adaptive immunity significantly declines, a phenomenon called immunosenescence, whereas innate immunity seems to be activated which induces a characteristic pro-inflammatory profile. This process is called inflamm-aging. The recognition and signaling mechanisms involved in innate immunity have been conserved during evolution. The master regulator of the innate immunity is the NF-kB system, an ancient signaling pathway found in both insects and vertebrates. The NF-kB system is in the nodal point linking together the pathogenic assault signals and cellular danger signals and then organizing the cellular resistance. Recent studies have revealed that SIRT1 (Sir2 homolog) and FoxO (DAF-16), the key regulators of aging in budding yeast and Caenorhabditis elegans models, regulate the efficiency of NF-kB signaling and the level of inflammatory responses. We will review the role of innate immunity signaling in the aging process and examine the function of NF-kB system in the organization of defence mechanisms and in addition, its interactions with the protein products of several gerontogenes. Our conclusion is that NF-kB signaling seems to be the culprit of inflamm-aging, since this signaling system integrates the intracellular regulation of immune responses in both aging and age-related diseases. (c) 2007 Elsevier Ireland Ltd. All rights reserved.
Highlights • This review focuses on the behavioral and histopathological signature of AD in SAMP8 mice. • The behavioral and pathological features detected by the different methods in SAMP8 mice at different ages were listed. • The preclinical trials of potential therapeutic modalities using SAMP8 mice were summarized. • We compared the merits and limitations of SAMP8 mice with the transgenic mouse as AD animal model.
Cardiac -iodobenzylguanidine (MIBG) uptake on I-MIBG cardiac scintigraphy is reduced in patients with Lewy body disease such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and pure autonomic failure, and has been reported to be useful for differentiating PD from other parkinsonian syndromes, as well as DLB from Alzheimer disease (AD). Postmortem studies have shown that the number of tyrosine hydroxylase (TH)-immunoreactive nerve fibers of the heart was decreased in pathologically-confirmed Lewy body disease, supporting the findings of reduced cardiac MIBG uptake in Lewy body diseases. Now, reduced cardiac MIBG uptake can be a potential biomarker for the presence of Lewy bodies in the nervous system. I-MIBG cardiac scintigraphy can allow us to determine the presence of Lewy bodies.
Growing evidence suggests chronic low-grade inflammation (LGI) as a possible mechanism underlying the aging process. Some biological and pharmaceutical compounds may reduce systemic inflammation and potentially avert functional decline occurring with aging. The aim of the present meta-analysis was to examine the association of pre-selected interventions on two established biomarkers of inflammation, interleukin-6 (IL-6), and C-reactive protein (CRP) in middle-age and older adults with chronic LGI. We reviewed the literature on potential anti-inflammatory compounds, selecting them based on safety, tolerability, acceptability, innovation, affordability, and evidence from randomized controlled trials. Six compounds met all five inclusion criteria for our systematic review and meta-analysis: angiotensin II receptor blockers (ARBs), metformin, omega-3, probiotics, resveratrol and vitamin D. We searched in MEDLINE, PubMed and EMBASE database until January 2017. A total of 49 articles fulfilled the selection criteria. Effect size of each study and pooled effect size for each compound were measured by the standardized mean difference. I was computed to measure heterogeneity of effects across studies. The following compounds showed a significant small to large effect in reducing IL-6 levels: probiotics (−0.68 pg/ml), ARBs (−0.37 pg/ml) and omega-3 (−0.19 pg/ml). For CRP, a significant small to medium effect was observed with probiotics (−0.43 mg/L), ARBs (−0.2 mg/L), omega-3 (−0.17 mg/L) and metformin (−0.16 mg/L). Resveratrol and vitamin D were not associated with any significant reductions in either biomarker. These results suggest that nutritional and pharmaceutical compounds can significantly reduce established biomarkers of systemic inflammation in middle-age and older adults. The findings should be interpreted with caution, however, due to the evidence of heterogeneity across the studies.
Cardiac meta-iodobenzylguanidine (MIBG) uptake on I-123-MIBG cardiac scintigraphy is reduced in patients with Lewy body disease such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and pure autonomic failure, and has been reported to be useful for differentiating PD from other parkinsonian syndromes, as well as DLB from Alzheimer disease (AD). Postmortem studies have shown that the number of tyrosine hydroxylase (TH)-immunoreactive nerve fibers of the heart was decreased in pathologically-confirmed Lewy body disease, supporting the findings of reduced cardiac MIBG uptake in Lewy body diseases. Now, reduced cardiac MIBG uptake can be a potential biomarker for the presence of Lewy bodies in the nervous system. I-123-MIBG cardiac scintigraphy can allow us to determine the presence of Lewy bodies. (C) 2016 Elsevier B.V. All rights reserved.
The extent to which chronic exercise training preserves age-related decrements in physical function, muscle strength, mass and morphology is unclear. Our aim was to conduct a systematic review of the literature to determine to what extent chronically trained master athletes (strength/power and endurance) preserve levels of physical function, muscle strength, muscle mass and morphology in older age, compared with older and younger controls and young trained individuals. The systematic data search included Medline, EMBASE, SPORTDiscus, CINAHL and Web of Science databases. i) master athletes mean exercise training duration ≥20 years ii) master athletes mean age of cohort >59 years) iii) at least one measurement of muscle mass/volume/fibre-type morphology and/or strength/physical function. Fifty-five eligible studies were identified. Meta-analyses were carried out on maximal aerobic capacity, maximal voluntary contraction and body composition. Master endurance athletes (42.0 ± 6.6 ml kg min 1) exhibited VO values comparable with young healthy controls (43.1 ± 6.8 ml kg min , P = .84), greater than older controls (27.1 ± 4.3 ml kg min , P < 0.01) and master strength/power athletes (26.5 ± 2.3 mlkg min , P < 0.01), and lower than young endurance trained individuals (60.0 ± 5.4 ml kg min , P < 0.01). Master strength/power athletes (0.60 (0.28–0.93) P < 0.01) and young controls (0.71 (0.06–1.36) P < 0.05) were significantly stronger compared with the other groups. Body fat% was greater in master endurance athletes than young endurance trained (−4.44% (−8.44 to −0.43) P < 0.05) but lower compared with older controls (7.11% (5.70–8.52) P < 0.01). Despite advancing age, this review suggests that chronic exercise training preserves physical function, muscular strength and body fat levels similar to that of young, healthy individuals in an exercise mode-specific manner.
Numerous studies examine the relationship between social stressors and telomere length (TL). Beyond considering methods and major findings, this scoping systematic review takes a novel approach as it groups studies according to the types of social stressor considered and by age groups. Following PRISMA guidelines, we searched PubMed, Web of Science, Embase, and Scopus. We included all English-language human subject research articles that modeled any measure of TL as a dependent variable and exposure to a social stressor as an independent variable. For the sample of 105 articles, we summarized methods and findings by type of social stressor (socioeconomic stressors, stressful life events, work-related stressors, and neighborhood stressors) and by age of the study population (infants/children, middle-aged adults, older adults, and mixed samples of middle-aged and older adults). We found more variation in TL measurement methodology in studies of infants/children and older adults than in studies focusing on middle-aged adults. The most consistent finding was a relationship between early-life stressors and shorter TL. Work and neighborhood stressors, and older populations, are currently understudied. Across all stressors, limited evidence suggests that the stress-TL relationship may be moderated by characteristics such as age, sex, and race/ethnicity. We conclude with specific suggestions for future research.
Memory and the self have long been considered intertwined, leading to the assumption that without memory, there can be no self. This line of reasoning has led to the misconception that a loss of memory in dementia necessarily results in a diminished sense of self. Here, we challenge this assumption by considering discrete facets of self-referential memory, and their relative profiles of loss and sparing, across three neurodegenerative disorders: Alzheimer’s disease, semantic dementia, and frontotemporal dementia. By exploring canonical expressions of the self across past, present, and future contexts in dementia, relative to healthy ageing, we reconcile previous accounts of loss of self in dementia, and propose a new framework for understanding and managing everyday functioning and behaviour. Notably, our approach highlights the multifaceted and dynamic nature in which the temporally-extended self is likely to change in healthy and pathological ageing, with important ramifications for development of person-centred care. Collectively, we aim to promote a cohesive sense of self in dementia across past, present, and future contexts, by demonstrating how, ultimately, ‘All is not lost’.
Increasing evidence suggests an important role for light in regulation of aging and longevity. UV radiation is a mutagen that can promote aging and decrease longevity. In contrast, NIR light has shown protective effects in animal disease models. In invertebrates, visible light can shorten or extend lifespan, depending on the intensity and wavelength composition. Visible light also impacts human health, including retina function, sleep, cancer and psychiatric disorders. Possible mechanisms of visible light include: controlling circadian rhythms, inducing oxidative stress, and acting through the retina to affect neuronal circuits and systems. Changes in artificial lighting (e.g., LEDs) may have implications for human health. It will be important to further explore the mechanisms of how light affects aging and longevity, and how light affects human health.
Both cancer and Alzheimer’s disease (AD) are emerging as metabolic diseases in which aberrant/dysregulated glucose metabolism and bioenergetics occur, and play a key role in disease progression. Interestingly, an enhancement of glucose uptake, glycolysis and pentose phosphate pathway occurs in both cancer cells and amyloid-β-resistant neurons in the early phase of AD. However, this metabolic shift has its adverse effects. One of them is the increase in methylglyoxal production, a physiological cytotoxic by-product of glucose catabolism. Methylglyoxal is mainly detoxified via cytosolic glyoxalase route comprising glyoxalase 1 and glyoxalase 2 with the production of S-D-lactoylglutathione and D-lactate as intermediate and end-product, respectively. Due to the existence of mitochondrial carriers and intramitochondrial glyoxalase 2 and D-lactate dehydrogenase, the transport and metabolism of both S-D-lactoylglutathione and D-lactate in mitochondria can contribute to methylglyoxal elimination, cellular antioxidant power and energy production. In this review, it is supposed that the different ability of cancer cells and AD neurons to metabolize methylglyoxal, S-D-lactoylglutathione and D-lactate scores cell fate, therefore being at the very crossroad of the “eternal youth” of cancer and the “premature death” of AD neurons. Understanding of these processes would help to elaborate novel metabolism-based therapies for cancer and AD treatment.
Multicomponent interventions (MCT) combine physical exercises and cognitive training and seem to be most effective in improving cognition in elderly people. However, literature is inconclusive if MCTs are superior to active comparison interventions, if delivery modes matter, and if people can transfer achieved effects to instrumental activities of daily living (IADL). This network meta-analysis aimed to a) identify MCTs that were effective on physical capacity and/or cognitive function and able to transfer these effects into IADL in elderly people with normal cognition (NC) and mild cognitive impairment (MCI); b) provide a rating on the best interventions per outcome; c) evaluate MCTs’ mode of delivery. Eligible studies were randomized controlled trials comparing MCTs to active comparison or no treatments. Six studies in participants with MCI (n = 1088) and eleven studies in participants with NC (n = 670) were included. Five effective MCTs that were superior to physical exercises or cognitive training alone in improving physical capacity and/or cognitive function were detected, however none of these MCTs improved IADL. In people with NC MCTs performed separately or simultaneously were effective. However, in people with MCI MCTs performed separately were more effective. A framework needs to be developed to better understand the mediating effects of physical capacity and cognitive function on IADL and to design MCTs that effectively improve IADL.
Orthostatic hypotension (OH) may negatively affect physical functioning and aggravate morbidities, but existing evidence is contradictory. MEDLINE (from 1946), PubMed (from 1966) and EMBASE databases (from 1947) were systematically searched for studies on the association of OH and physical functioning in older adults, categorized as: balance, gait characteristics, walking speed, Timed Up and Go time, handgrip strength (HGS), physical frailty, exercise tolerance, physical activity, activities of daily living (ADL), and performance on the Hoehn and Yahr scale (HY) and Unified Parkinson’s Disease Rating Scale (UPDRS). Study quality was assessed using the Newcastle Ottawa Scale. Forty-two studies were included in the systematic review (29,421 individuals) and 29 studies in the meta-analyses (23,879 individuals). Sixteen out of 42 studies reported a significant association of OH with worse physical functioning. Meta-analysis showed a significant association of OH with impaired balance, ADL performance and HY/UPDRS III performance, but not with gait characteristics, mobility, walking speed, TUG, HGS, physical frailty, exercise tolerance, physical activity and UPDRS II performance. OH was associated with impaired balance, ADL performance and HY/UPDRS III performance, but not with other physical functioning categories. The results suggest that OH interventions could potentially improve some aspects of physical functioning.
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder for which no curative treatments, disease modifying strategies or effective symptomatic therapies exist. Current pharmacologic treatments for AD can only decelerate the progression of the disease for a short time, often at the cost of severe side effects. Therefore, there is an urgent need for biomarkers able to diagnose AD at its earliest stages, to conclusively track disease progression, and to accelerate the clinical development of innovative therapies. Scientific research and economic efforts for the development of pharmacotherapies have recently homed in on the hypothesis that neurotoxic β-amyloid (Aβ) peptides in their oligomeric or fibrillary forms are primarily responsible for the cognitive impairment and neuronal death seen in AD. As such, modern pharmacologic approaches are largely based on reducing production by inhibiting β and γ secretase cleavage of the amyloid precursor protein (APP) or on dissolving existing cerebral Aβ plaques or to favor Aβ clearance from the brain. The following short review aims to persuade the reader of the idea that APP plays a much larger role in AD pathogenesis. APP plays a greater role in AD pathogenesis than its role as the precursor for Aβ peptides: both the abnormal cleavage of APP leading to Aβ peptide accumulation and the disruption of APP physiological functions contribute to AD pathogenesis. We summarize our recent results on the role played by the C-terminal APP motif -the Y ENPTY motif- in APP function and dysfunction, and we provide insights into targeting the Tyr residue of APP as putative novel strategy in AD.
Peripheral biomarkers have shown significant value in predicting brain health and may serve as a useful proxy measurement in the assessment of evidence-based lifestyle behavior modification programs, including physical activity and nutrition programs, that aim to maintain cognitive function in late life. The aim of this systematic review was to elucidate which peripheral biomarkers are robustly associated with cognitive function among relatively healthy non-demented older adults. Following the standards for systematic reviews (PICO, PRIMSA), and employing MEDLINE and Scopus search engines, 222 articles were included in the review. Based on the review of biomarker proxies of cognitive health, it is recommended that a comprehensive biomarker panel, or , be developed as a clinical end point for behavior modification trials aimed at enhancing cognitive function in late life. The biomarker signature should take a multisystemic approach, including lipid, immune/inflammatory, and metabolic biomarkers in the biological signature index of cognitive health.
Since the first clinical case reported more than 100 years ago, it has been a long and winding road to demystify the initial pathological events underling the onset of Alzheimer's disease (AD). Fortunately, advanced imaging techniques extended the knowledge regarding AD origin, being well accepted that a decline in brain glucose metabolism occurs during the prodromal phases of AD and is aggravated with the progression of the disease. In this sense, in the last decades, the post-translational modification O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) has emerged as a potential causative link between hampered brain glucose metabolism and AD pathology. This is not surprising taking into account that this dynamic post-translational modification acts as a metabolic sensor that links glucose metabolism to normal neuronal functioning. Within this scenario, the present review aims to summarize the current understanding on the role of O-GIcNAcylation in neuronal physiology and AD pathology, emphasizing the close association of this post-translational modification with the emergence of AD-related hallmarks and its potential as a therapeutic target.
Executive function deficit is an indicator of Alzheimer's-type dementia and manifests as disruptions of attentional control, memory, cognitive flexibility, planning, and reasoning, among other cognitive problems. Physical exercise is suggested to have a protective effect on global cognition with aging. However, whether it influences executive function in people living with Alzheimer's-type dementia specifically is unknown. The current systematic review examined the efficacy of physical exercise on executive function performance in community-dwelling older adults living with Alzheimer's-type dementia. An electronic search of databases retrieved randomized and non-randomized controlled trials of community-dwelling older adults diagnosed with Alzheimer's-type dementia who completed a physical exercise intervention and who were assessed using an executive function outcome measure. Methodological quality of six studies meeting the inclusion criteria published between 2009 and 2016 was scored independently by two raters using the Physiotherapy Evidence Database and a Cochrane informed domain-based assessment of risk of bias. Trends toward improvement in executive function scores were seen across all six studies, and significant improvement was seen in four of the eligible studies. Future studies should explore the benefits of the American College of Sports Medicine recommended 150 min of physical exercise per week with select measures of executive function.