Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice

AbstractThe decline in early life mortality since the 1950s has resulted in dramatic demographic shift towards aged population. Aging manifests as a decline in health, multiple organ dysfunction and increased vulnerability to diseases, which degrades quality of life. A verity of genetic and pharmacological interventions, mostly from non-vertebrate models, have been identified that can enhance lifespan. Whether these interventions extend healthspan, the disease free and functional period of life, has only sometimes been tested and is often a matter of debate. Human aging indices have been developed to assess elements of functional decline with aging (e.g. sarcopenia, cognitive function). However, corresponding comprehensive indices in mice are seldom applied to aging studies. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically-relevant healthspan measurements. Metabolism and aging are tightly connected and specific perturbations of nutrient-sensing pathways can enhance longevity in laboratory animals. Here we show that alpha-ketoglutarate (delivered in the form of a Calcium salt, CaAKG), a key metabolite in tricarboxylic (TCA) cycle that is reported to extend lifespan in worms, can significantly extend lifespan and healthspan in mice. AKG is involved in various fundamental processes including collagen synthesis and epigenetic changes. Due to its broad roles in multiple biological processes, AKG has been a subject of interest for researchers in various fields. AKG also influences several age-related processes, including stem cell proliferation and osteoporosis. To determine its role in mammalian aging, we administered CaAKG in 18 months old mice and determined its effect on the onset of frailty and survival, discovering that the metabolite promotes longer, healthier life associated with a decrease in levels of inflammatory factors. Interestingly the reduction in frailty was more dramatic than the increase in lifespan, leading us to propose that CaAKG compresses morbidity.

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Association Between Elevated suPAR, a New Biomarker of Inflammation, and Accelerated Aging

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa178 ◽

2020 ◽

Author(s):

Line Jee Hartmann Rasmussen ◽

Avshalom Caspi ◽

Antony Ambler ◽

Andrea Danese ◽

Maxwell Elliott ◽

...

Keyword(s):

Chronic Inflammation ◽

Functional Decline ◽

Accelerated Aging ◽

Multiple Organ ◽

Biological Aging ◽

Blood Levels ◽

Urokinase Plasminogen Activator Receptor ◽

Reactive Protein ◽

Age Related ◽

Organ Systems

Abstract Background To understand and measure the association between chronic inflammation, aging, and age-related diseases, broadly applicable standard biomarkers of systemic chronic inflammation are needed. We tested whether elevated blood levels of the emerging chronic inflammation marker soluble urokinase plasminogen activator receptor (suPAR) were associated with accelerated aging, lower functional capacity, and cognitive decline. Methods We used data from the Dunedin Study, a population-representative 1972–1973 New Zealand birth cohort (n = 1037) that has observed participants to age 45 years. Plasma suPAR levels were analyzed at ages 38 and 45 years. We performed regression analyses adjusted for sex, smoking, C-reactive protein, and current health conditions. Results Of 997 still-living participants, 875 (88%) had plasma suPAR measured at age 45. Elevated suPAR was associated with accelerated pace of biological aging across multiple organ systems, older facial appearance, and with structural signs of older brain age. Moreover, participants with higher suPAR levels had greater decline in physical function and cognitive function from childhood to adulthood compared to those with lower suPAR levels. Finally, improvements in health habits between ages 38 and 45 (smoking cessation or increased physical activity) were associated with less steep increases in suPAR levels over those years. Conclusions Our findings provide initial support for the utility of suPAR in studying the role of chronic inflammation in accelerated aging and functional decline.

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A biomimetic natural sciences approach to understanding the mechanisms of ageing in burden of lifestyle diseases

Clinical Science ◽

10.1042/cs20201452 ◽

2021 ◽

Vol 135 (10) ◽

pp. 1251-1272

Author(s):

Lu Dai ◽

Leon Schurgers ◽

Paul G. Shiels ◽

Peter Stenvinkel

Keyword(s):

Nutrient Sensing ◽

Laboratory Animals ◽

Comparative Approach ◽

Public Healthcare ◽

Ageing Population ◽

Related Disease ◽

Age Related ◽

Oxidative Protein Damage ◽

In The Wild ◽

Cell Matrix Interactions

Abstract The worldwide landscape of an ageing population and age-related disease brings with it huge socio-economic and public healthcare concerns across nations. Correspondingly, monumental human and financial resources have been invested in biomedical research, with a mission to decode the mechanisms of ageing and how these contribute to age-related disease. Multiple hallmarks of ageing have been identified that are common across taxa, highlighting their fundamental importance. These include dysregulated mitochondrial metabolism and telomeres biology, epigenetic modifications, cell–matrix interactions, proteostasis, dysregulated nutrient sensing, stem cell exhaustion, inflammageing and immuno-senescence. While our understanding of the molecular basis of ageing is improving, it remains a complex and multifactorial process that remains to be fully understood. A key aspect of the shortfall in our understanding of the ageing process lies in translating data from standard animal models to humans. Consequently, we suggest that a ‘biomimetic’ and comparative approach, integrating knowledge from species in the wild, as opposed to inbred genetically homogenous laboratory animals, can provide powerful insights into human ageing processes. Here we discuss some particularities and comparative patterns among several species from the animal kingdom, endowed with longevity or short lifespans and unique metabolic profiles that could be potentially exploited to the understanding of ageing and age-related diseases. Based upon lessons from nature, we also highlight several avenues for renewed focus in the pathophysiology of ageing and age-related disease (i.e. diet-microbiome-health axis, oxidative protein damage, adaptive homoeostasis and planetary health). We propose that a biomimetic alliance with collaborative research from different disciplines can improve our understanding of ageing and age-related diseases with long-term sustainable utility.

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Altered Glycosylation in the Aging Heart

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.673044 ◽

2021 ◽

Vol 8 ◽

Author(s):

Patricia Franzka ◽

Lynn Krüger ◽

Mona K. Schurig ◽

Maja Olecka ◽

Steve Hoffmann ◽

...

Keyword(s):

Cardiovascular Disease ◽

Molecular Mechanisms ◽

Causes Of Death ◽

Population Aging ◽

Functional Decline ◽

Developed Countries ◽

Biological Properties ◽

Quantitative Mass Spectrometry ◽

Age Related ◽

Old Mice

Cardiovascular disease is one of the leading causes of death in developed countries. Because the incidence increases exponentially in the aging population, aging is a major risk factor for cardiovascular disease. Cardiac hypertrophy, fibrosis and inflammation are typical hallmarks of the aged heart. The molecular mechanisms, however, are poorly understood. Because glycosylation is one of the most common post-translational protein modifications and can affect biological properties and functions of proteins, we here provide the first analysis of the cardiac glycoproteome of mice at different ages. Western blot as well as MALDI-TOF based glycome analysis suggest that high-mannose N-glycans increase with age. In agreement, we found an age-related regulation of GMPPB, the enzyme, which facilitates the supply of the sugar-donor GDP-mannose. Glycoprotein pull-downs from heart lysates of young, middle-aged and old mice in combination with quantitative mass spectrometry bolster widespread alterations of the cardiac glycoproteome. Major hits are glycoproteins related to the extracellular matrix and Ca2+-binding proteins of the endoplasmic reticulum. We propose that changes in the heart glycoproteome likely contribute to the age-related functional decline of the cardiovascular system.

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Associations Between a New Biomarker of Elevated Chronic Inflammation and Accelerated Aging

Innovation in Aging ◽

10.1093/geroni/igaa057.464 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 141-142

Author(s):

Line Rasmussen ◽

Avshalom Caspi ◽

Terrie Moffitt

Keyword(s):

Chronic Inflammation ◽

Functional Capacity ◽

Functional Decline ◽

Accelerated Aging ◽

Multiple Organ ◽

Biological Aging ◽

Blood Levels ◽

Urokinase Plasminogen Activator Receptor ◽

Age Related ◽

Organ Systems

Abstract To further understand and measure the association between chronic inflammation, aging, and age-related diseases, broadly applicable standard biomarkers of systemic chronic inflammation are needed. We tested whether elevated blood levels of the emerging chronic inflammation marker soluble urokinase plasminogen activator receptor (suPAR) were associated with accelerated aging, lower functional capacity, and cognitive decline. We used data from the population-representative longitudinal Dunedin Study (N=875). Plasma suPAR levels were analyzed at ages 38 and 45 years. We performed regression analyses adjusted for sex, smoking, and C-reactive protein. suPAR levels increased from 2.39 ng/mL (SD 0.89) at age 38 to 3.01 (SD 1.03) at age 45 years. Elevated suPAR was associated with accelerated pace of biological aging across multiple organ systems (β 0.28, 95% CI 0.21–0.35), older facial appearance (β 0.16, 95% CI 0.10–0.22), and with structural signs of older brain age (β 0.06, 95% CI -0.00–0.13). Moreover, participants with higher suPAR levels had lower functional capacity (more physical limitations [β 0.24, 95% CI 0.18–0.30]; slower gait speed [β -0.14, 95% CI -0.20; -0.08]) and greater decline in cognitive function (β -0.07, 95% CI -0.13; -0.01) from childhood to adulthood compared to those with lower suPAR levels. Finally, improvements in health habits between age 38 and 45 (smoking cessation or increased physical activity) were associated with less steep increases in suPAR levels over those years. Our findings provide initial support for the utility of suPAR in studying the role of chronic inflammation in accelerated aging and functional decline.

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Spontaneous Eye Blinks Predict Executive Functioning in Seniors

Journal of Cognitive Enhancement ◽

10.1007/s41465-021-00217-4 ◽

2021 ◽

Author(s):

Jessika I. V. Buitenweg ◽

Jaap M. J. Murre ◽

K. Richard Ridderinkhof

Keyword(s):

Older Adults ◽

Working Memory ◽

Executive Functioning ◽

Cognitive Training ◽

Functional Decline ◽

Future Research ◽

Blink Rate ◽

Memory Updating ◽

Age Related ◽

Working Memory Updating

AbstractAs the world’s population is aging rapidly, cognitive training is an extensively used approach to attempt improvement of age-related cognitive functioning. With increasing numbers of older adults required to remain in the workforce, it is important to be able to reliably predict future functional decline, as well as the individual advantages of cognitive training. Given the correlation between age-related decline and striatal dopaminergic function, we investigated whether eye blink rate (EBR), a non-invasive, indirect indicator of dopaminergic activity, could predict executive functioning (response inhibition, switching and working memory updating) as well as trainability of executive functioning in older adults. EBR was collected before and after a cognitive flexibility training, cognitive training without flexibility, or a mock training. EBR predicted working memory updating performance on two measures of updating, as well as trainability of working memory updating, whereas performance and trainability in inhibition and switching tasks could not be predicted by EBR. Our findings tentatively indicate that EBR permits prediction of working memory performance in older adults. To fully interpret the relationship with executive functioning, we suggest future research should assess both EBR and dopamine receptor availability among seniors.

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Targeting impaired nutrient sensing with repurposed therapeutics to prevent or treat age-related cognitive decline and dementia: A systematic review

Ageing Research Reviews ◽

10.1016/j.arr.2021.101302 ◽

2021 ◽

Vol 67 ◽

pp. 101302

Author(s):

Benjamin Kioussis ◽

Camilla S.L. Tuttle ◽

Daniel S. Heard ◽

Brian K. Kennedy ◽

Nicola T. Lautenschlager ◽

...

Keyword(s):

Systematic Review ◽

Cognitive Decline ◽

Nutrient Sensing ◽

Age Related ◽

Age Related Cognitive Decline

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Blood Pressure Profiles and Cognitive Function from Adulthood to Old Age: Chasing a Golden Middle Way?

Journal of Clinical Medicine ◽

10.3390/jcm10153243 ◽

2021 ◽

Vol 10 (15) ◽

pp. 3243

Author(s):

Rita Del Pinto ◽

Davide Grassi ◽

Raffaella Bocale ◽

Francesco Carubbi ◽

Claudio Ferri ◽

...

Keyword(s):

Cognitive Impairment ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Demographic Shift ◽

Antihypertensive Medications ◽

Microvascular Damage ◽

Middle Way ◽

Alzheimer Type Dementia ◽

Age Related ◽

Pressure Profiles

With the demographic shift toward advanced ages, it is imperative to understand the biological mechanisms behind common, disabling age-related diseases such as cognitive impairment in its mild form to overt dementia. Hypertension, a major cardiovascular risk factor, is epidemiologically linked to vascular and Alzheimer-type dementia, with possible mechanisms being atherosclerotic macro- and microvascular damage leading to neuronal cell death, as well as proinflammatory events responsible for neurodegeneration. Nevertheless, there is currently a knowledge gap as to which population to target, what the diagnostics test, and how to manage early pathogenic events in order to prevent such a dramatic and disabling condition. While clinical trials data support the benefit of active BP control with antihypertensive medications on the risk of future cognitive impairment, hypotension appears to be related to accelerated cognitive decline in both the fit and the cognitively frail elderly. Dedicated, technologically advanced studies assessing the relation of BP with dementia are needed to clarify the pathophysiological mechanisms in the association before a tailored preventive, diagnostic, and therapeutic approach to one of the most widespread modern medical challenges becomes a reality.

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Cytokine profile in human olfactory cleft mucus and associated changes in olfactory function

10.1101/332395 ◽

2018 ◽

Cited By ~ 1

Author(s):

Hong Wang ◽

Cristina Jaen ◽

Keiichi Yoshikawa ◽

Mai Haneoka ◽

Naoko Saito ◽

...

Keyword(s):

Inflammatory Cytokines ◽

The Elderly ◽

Inflammatory Factors ◽

Olfactory Cleft ◽

Olfactory Loss ◽

Age Related ◽

Environmental Agents ◽

Human Olfactory Mucosa ◽

Molecular Aspects ◽

Physical Changes

AbstractMultiple factors, including physical changes of the nasal mucosa and epithelium and exposure to air-borne environmental agents, appear to contribute to age-related olfactory loss. However, the molecular aspects of aging-associated olfactory loss in humans are not well understood. Although inflammation can be a significant underlying cause for olfactory impairment, whether aging increases the levels of inflammatory cytokines in the human olfactory mucosa and whether any inflammatory markers are associated with age-related olfactory loss remain unclear. Using a noninvasive method for collecting human olfactory mucus, we characterized and compared inflammatory cytokines, chemokines, and some growth factors, in the mucus collected from the olfactory cleft or the anterior nasal cavity from 12 healthy, young (18-40 years old) and 12 elderly (60-85 years old) individuals. We also hoped to identify candidate molecular biomarkers associated with age-associated olfactory loss in humans. Olfactory thresholds were obtained for two odorants and individual mucus samples were analyzed using multiplex assays for the levels of 30 cytokines. Results indicated elevated levels of certain inflammatory cytokines (IL-12, MCP-1) in olfactory mucus of the elderly, and high levels of some inflammatory factors (MCP-1, IL-8, IL-13 and VEGF) were associated with reduced olfactory sensitivity, suggesting that inflammation may play a role in olfactory decline associated with aging.

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Potential Benefits of a Minimal Dose Eccentric Resistance Training Paradigm to Combat Sarcopenia and Age-Related Muscle and Physical Function Deficits in Older Adults

Frontiers in Physiology ◽

10.3389/fphys.2021.790034 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sara A. Harper ◽

Brennan J. Thompson

Keyword(s):

Older Adults ◽

Resistance Training ◽

Functional Performance ◽

Functional Decline ◽

Therapeutic Interventions ◽

Training Paradigm ◽

Exercise Participation ◽

Minimal Dose ◽

Age Related ◽

And Function

The ability of older adults to perform activities of daily living is often limited by the ability to generate high mechanical outputs. Therefore, assessing and developing maximal neuromuscular capacity is essential for determining age-related risk for functional decline as well as the effectiveness of therapeutic interventions. Interventions designed to enhance neuromuscular capacities underpinning maximal mechanical outputs could positively impact functional performance in daily life. Unfortunately, < 10% of older adults meet the current resistance training guidelines. It has recently been proposed that a more “minimal dose” RT model may help engage a greater proportion of older adults, so that they may realize the benefits of RT. Eccentric exercise offers some promising qualities for such an approach due to its efficiency in overloading contractions that can induce substantial neuromuscular adaptations. When used in a minimal dose RT paradigm, eccentric-based RT may be a particularly promising approach for older adults that can efficiently improve muscle mass, strength, and functional performance. One approach that may lead to improved neuromuscular function capacities and overall health is through heightened exercise tolerance which would favor greater exercise participation in older adult populations. Therefore, our perspective article will discuss the implications of using a minimal dose, submaximal (i.e., low intensity) multi-joint eccentric resistance training paradigm as a potentially effective, and yet currently underutilized, means to efficiently improve neuromuscular capacities and function for older adults.

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