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Chronic, low-grade inflammation increases with aging, contributing to functional declines and diseases that reduce healthspan. Growing evidence suggests that transcripts from repetitive elements (RE) in the genome contribute to this "inflammaging" by stimulating innate immune activation, but evidence of RE-associated inflammation with aging in humans is limited. Here, we present transcriptomic and clinical data showing that RE transcript levels are positively related to gene expression of innate immune sensors, and to serum interleukin 6 (a marker of systemic inflammation), in a large group of middle-aged and older adults. We also: (1) use transcriptomics and whole-genome bisulfite (methylation) sequencing to show that many RE may be hypomethylated with aging, and that aerobic exercise, a healthspan-extending intervention, reduces RE transcript levels and increases RE methylation in older adults; and (2) extend our findings in a secondary dataset demonstrating age-related changes in RE chromatin accessibility. Collectively, our data support the idea that age-related RE transcript accumulation may play a role in inflammaging in humans, and that RE dysregulation with aging may be due in part to upstream epigenetic changes., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer's disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. In this study, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-κB and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old (aged 19 months) wildtype mice, and in rTg4510 tau pathology mice (aged 2 months). We found that 4 weeks of NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and rTg4510 mice. These effects of NF-κB/NLRP3-targeting Nanoligomers were also associated with reduced glial cell activation and pathology, favorable changes in transcriptome signatures of glia-associated inflammation (reduced) and neuronal health (increased), and positive systemic effects. Collectively, our results provide a basis for future translational studies targeting both NF-κB and NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegeneration., (© 2024. The Author(s).)

Aging is the greatest non-modifiable risk factor for most diseases, including cardiovascular diseases (CVD), which remain the leading cause of mortality worldwide. Robust evidence indicates that CVD are a strong determinant for reduced brain health and all-cause dementia with advancing age. CVD are also closely linked with peripheral and cerebral vascular dysfunction, common contributors to the development and progression of all types of dementia, that are largely driven by excessive levels of oxidative stress (e.g., reactive oxygen species [ROS]). Emerging evidence suggests that several fundamental aging mechanisms (e.g., "hallmarks" of aging), including chronic low-grade inflammation, mitochondrial dysfunction, cellular senescence and deregulated nutrient sensing contribute to excessive ROS production and are common to both peripheral and cerebral vascular dysfunction. Therefore, targeting these mechanisms to reduce ROS-related oxidative stress and improve peripheral and/or cerebral vascular function may be a promising strategy to reduce dementia risk with aging. Investigating how certain lifestyle strategies (e.g., aerobic exercise and diet modulation) and/or select pharmacological agents (natural and synthetic) intersect with aging "hallmarks" to promote peripheral and/or cerebral vascular health represent a viable option for reducing dementia risk with aging. Therefore, the primary purpose of this review is to explore mechanistic links among peripheral vascular dysfunction, cerebral vascular dysfunction, and reduced brain health with aging. Such insight and assessments of non-invasive measures of peripheral and cerebral vascular health with aging might provide a new approach for assessing dementia risk in older adults.

One of the best strategies for healthy brain aging is regular aerobic exercise. Commonly studied "anti-aging" compounds may mimic some effects of exercise on the brain, but novel approaches that target energy-sensing pathways similar to exercise probably will be more effective in this context. We review evidence in support of this hypothesis by focusing on biological hallmarks of brain aging., (Copyright © 2021 by the American College of Sports Medicine.)

Aging is a powerful risk factor for the development of many chronic diseases including dementia. Research based on disease models of dementia have yet to yield effective treatments, therefore it is opportune to consider whether the aging process itself might be a potential therapeutic target for the treatment and prevention of dementia. Numerous cellular and molecular pathways have been implicated in the aging process and compounds that target these processes are being developed to slow aging and delay the onset of age-associated conditions. A few particularly promising therapeutic agents have been shown to influence many of the main hallmarks of aging and increase life span in rodents. Here we discuss the evidence that some of these antiaging compounds may beneficially affect brain aging and thereby lower the risk for dementia., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aging is the greatest risk factor for most diseases including cancer, cardiovascular disorders, and neurodegenerative disease. There is emerging evidence that interventions that improve metabolic health with aging may also be effective for brain health. The most robust interventions are non-pharmacological and include limiting calorie or protein intake, increasing aerobic exercise, or environmental enrichment. In humans, dietary patterns including the Mediterranean, Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) and Okinawan diets are associated with improved age-related health and may reduce neurodegenerative disease including dementia. Rapamycin, metformin and resveratrol act on nutrient sensing pathways that improve cardiometabolic health and decrease the risk for age-associated disease. There is some evidence that they may reduce the risk for dementia in rodents. There is a growing recognition that improving metabolic function may be an effective way to optimize brain health during aging., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Calorie restriction (CR) increases lifespan and improves brain health in mice. Ad libitum low-protein, high-carbohydrate (LPHC) diets also extend lifespan, but it is not known whether they are beneficial for brain health. We compared hippocampus biology and memory in mice subjected to 20% CR or provided ad libitum access to one of three LPHC diets or to a control diet. Patterns of RNA expression in the hippocampus of 15-month-old mice were similar between mice fed CR and LPHC diets when we looked at genes associated with longevity, cytokines, and dendrite morphogenesis. Nutrient-sensing proteins, including SIRT1, mTOR, and PGC1α, were also influenced by diet; however, the effects varied by sex. CR and LPHC diets were associated with increased dendritic spines in dentate gyrus neurons. Mice fed CR and LPHC diets had modest improvements in the Barnes maze and novel object recognition. LPHC diets recapitulate some of the benefits of CR on brain aging., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Nutrition influences both hepatic function and aging, but mechanisms are poorly understood. Here, the effects of lifelong, ad libitum-fed diets varying in macronutrients and energy on hepatic gene expression were studied. Gene expression was measured using Affymetrix mouse arrays in livers of 46 mice aged 15 months fed one of 25 diets varying in protein, carbohydrates, fat, and energy density from 3 weeks of age. Gene expression was almost entirely influenced by protein intake. Carbohydrate and fat intake had few effects on gene expression compared with protein. Pathways and processes associated with protein intake included those involved with mitochondrial function, metabolic signaling (PI3K-Akt, AMPK, mTOR) and metabolism of protein and amino acids. Protein intake had variable effects on genes associated with regulation of longevity and influenced by caloric restriction. Among the genes of interest with expression that were significantly associated with protein intake are Cth, Gls2, Igf1, and Nnmt, which were increased with higher protein intake, and Igf2bp2, Fgf21, Prkab2, and Mtor, which were increased with lower protein intake. Dietary protein has a powerful impact on hepatic gene expression in older mice, with some overlap with genes previously reported to be involved with regulation of longevity or caloric restriction.

Evaluation of behavior and cognition in rodent models underpins mechanistic and interventional studies of brain aging and neurodegenerative diseases, especially dementia. Commonly used tests include Morris water maze, Barnes maze, object recognition, fear conditioning, radial arm water maze, and Y maze. Each of these tests reflects some aspects of human memory including episodic memory, recognition memory, semantic memory, spatial memory, and emotional memory. Although most interventional studies in rodent models of dementia have focused on pharmacological agents, there are an increasing number of studies that have evaluated nutritional interventions including caloric restriction, intermittent fasting, and manipulation of macronutrients. Dietary interventions have been shown to influence various cognitive and behavioral tests in rodents indicating that nutrition can influence brain aging and possibly neurodegeneration., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Old age is the greatest risk factor for most neurodegenerative diseases. During recent decades there have been major advances in understanding the biology of aging, and the development of nutritional interventions that delay aging including calorie restriction (CR) and intermittent fasting (IF), and chemicals that influence pathways linking nutrition and aging processes. CR influences brain aging in many animal models and recent findings suggest that dietary interventions can influence brain health and dementia in older humans. The role of individual macronutrients in brain aging also has been studied, with conflicting results about the effects of dietary protein and carbohydrates. A new approach known as the Geometric Framework (GF) has been used to unravel the complex interactions between macronutrients (protein, fat, and carbohydrate) and total energy on outcomes such as aging. These studies have shown that low-protein, high-carbohydrate (LPHC) diets are optimal for lifespan in ad libitum fed animals, while total calories have minimal effect once macronutrients are taken into account. One of the primary purposes of this review is to explore the notion that macronutrients may have a more translational potential than CR and IF in humans, and therefore there is a pressing need to use GF to study the impact of diet on brain aging. Furthermore, given the growing recognition of the role of aging biology in dementia, such studies might provide a new approach for dietary interventions for optimizing brain health and preventing dementia in older people., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Nutrition has profound effects on ageing and lifespan. Caloric restriction is the major nutritional intervention that historically has been shown to influence lifespan and/or healthspan in many animal models. Studies have suggested that a reduction in protein intake can also increase lifespan, albeit not as dramatically as caloric restriction. More recent research based on nutritional geometry has attempted to define the effects of nutrition on ageing over a broad landscape of dietary macronutrients and energy content. Such studies in insects and mice indicate that animals with ad libitum access to low-protein, high-carbohydrate diets have longest lifespans. Remarkably, the optimum content and ratio of dietary protein to carbohydrates for ageing in experimental animals are almost identical to those in the traditional diets of the long-lived people on the island of Okinawa., (© The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions., (Published by Elsevier Inc.)

Objective: To investigate in women older than 60 whether aortic stiffness or pulse pressure (PP) is associated with selected procoagulant or anticoagulant factors and to examine whether pulsatile stretch influences these factors in human vascular smooth muscle cells (VSMCs) in vitro., Methods and Results: Aortic pulse wave velocity (PWV) and carotid PP were studied in 123 apparently healthy postmenopausal women. PWV, PP, von Willebrand factor, and free tissue factor pathway inhibitor (TFPI), but not mean arterial pressure, increased with age. Free TFPI and PWV were positively correlated, even after adjustment for age and PP and other confounding parameters. In vitro, 5% or 10% pulsatile stretch (at 1 Hz) enhanced TFPI synthesis and secretion by VSMCs in a time-independent manner (1 to 48 hours) without changes in protein level of smooth muscle myosin heavy chain. Application of 5% static stretch had no effect., Conclusions: In postmenopausal women, free TFPI increases as vascular wall function deteriorates and PP increases. These findings are supported by the increase in TFPI synthesized by VSMCs in response to cyclic stress in vitro. They suggest that VSMCs require pulsatility to interfere with the coagulation process and highlight the relevance of plasma free TFPI levels to cardiovascular diseases.

Objectives: Since few studies have investigated Health related Quality of Life (HRQoL) in older patients with atrial fibrillation, the aim of this cross-sectional study was to compare HRQoL in AF elderly inpatients of 65 and more with that of age-matched controlled subjects., Design: HRQoL was assessed with two generic HRQoL instruments: the MOS-SF 36, a largely recognized instrument, and the Duke Health Profile., Setting and Patients: Nancy University Hospital patients presenting with atrial fibrillation and three controls per patient free of cardiac arrhythmias, matched by age, sex and hospital department to atrial fibrillation patients., Results: Forty one atrial fibrillation patients and 123 controls were included. Both groups were comparable for associated disorders, other than coronary artery disease and chronic respiratory failure. After adjustment, scores among atrial fibrillation patients were lower than among controls in 8 of 10 Duke and 6 of 8 SF-36 subscales. In terms of Quality of Life, meaningful differences (>or= 5 points) were recorded in the Duke: Mental, Depression, Anxiety, General Score; and in the SF-36: Physical functioning, Role emotional, Social functioning and Vitality. Nevertheless statistically significant differences were only observed for the Duke Mental (p=0.01), Depression (p=0.003) and Anxiety (p=0.03) scores., Conclusions: In our study HRQoL measured in elderly inpatients with atrial fibrillation as compared with matched controlled was mainly altered in the "psychological" domains of the Duke Health Profile. From the patient's point of view, atrial fibrillation appears to have more mental than physical consequences. This study pointed out the utility to assess HRQoL in the management and treatment of elderly hospitalised atrial fibrillation patients.