An open science study of ageing in companion dogs.

The Dog Aging Project is a long-term longitudinal study of ageing in tens of thousands of companion dogs. The domestic dog is among the most variable mammal species in terms of morphology, behaviour, risk of age-related disease and life expectancy. Given that dogs share the human environment and have a sophisticated healthcare system but are much shorter-lived than people, they offer a unique opportunity to identify the genetic, environmental and lifestyle factors associated with healthy lifespan. To take advantage of this opportunity, the Dog Aging Project will collect extensive survey data, environmental information, electronic veterinary medical records, genome-wide sequence information, clinicopathology and molecular phenotypes derived from blood cells, plasma and faecal samples. Here, we describe the specific goals and design of the Dog Aging Project and discuss the potential for this open-data, community science study to greatly enhance understanding of ageing in a genetically variable, socially relevant species living in a complex environment.

From discoveries in ageing research to therapeutics for healthy ageing.

For several decades, understanding ageing and the processes that limit lifespan have challenged biologists. Thirty years ago, the biology of ageing gained unprecedented scientific credibility through the identification of gene variants that extend the lifespan of multicellular model organisms. Here we summarize the milestones that mark this scientific triumph, discuss different ageing pathways and processes, and suggest that ageing research is entering a new era that has unique medical, commercial and societal implications. We argue that this era marks an inflection point, not only in ageing research but also for all biological research that affects the human healthspan.

Neuroprotective Metabolites of Hericium erinaceus Promote Neuro-Healthy Aging.

Frailty is a geriatric syndrome associated with both locomotor and cognitive decline, typically linked to chronic systemic inflammation, i.e., inflammaging. In the current study, we investigated the effect of a two-month oral supplementation with standardized extracts of H. erinaceus, containing a known amount of Erinacine A, Hericenone C, Hericenone D, and L-ergothioneine, on locomotor frailty and cerebellum of aged mice. Locomotor performances were monitored comparing healthy aging and frail mice. Cerebellar volume and cytoarchitecture, together with inflammatory and oxidative stress pathways, were assessed focusing on senescent frail animals. H. erinaceus partially recovered the aged-related decline of locomotor performances. Histopathological analyses paralleled by immunocytochemical evaluation of specific molecules strengthened the neuroprotective role of H. erinaceus able to ameliorate cerebellar alterations, i.e., milder volume reduction, slighter molecular layer thickness decrease and minor percentage of shrunken Purkinje neurons, also diminishing inflammation and oxidative stress in frail mice while increasing a key longevity regulator and a neuroprotective molecule. Thus, our present findings demonstrated the efficacy of a non-pharmacological approach, based on the dietary supplementation using H. erinaceus extract, which represent a promising adjuvant therapy to be associated with conventional geriatric treatments.

Repurposed FDA-approved drugs targeting genes influencing aging can extend lifespan and healthspan in rotifers.

Pharmaceutical interventions can slow aging in animals, and have advantages because their dose can be tightly regulated and the timing of the intervention can be closely controlled. They also may complement environmental interventions like caloric restriction by acting additively. A fertile source for therapies slowing aging is FDA approved drugs whose safety has been investigated. Because drugs bind to several protein targets, they cause multiple effects, many of which have not been characterized. It is possible that some of the side effects of drugs prescribed for one therapy may have benefits in retarding aging. We used computationally guided drug screening for prioritizing drug targets to produce a short list of candidate compounds for in vivo testing. We applied the virtual ligand screening approach FINDSITEcomb for screening potential anti-aging protein targets against FDA approved drugs listed in DrugBank. A short list of 31 promising compounds was screened using a multi-tiered approach with rotifers as an animal model of aging. Primary and secondary survival screens and cohort life table experiments identified four drugs capable of extending rotifer lifespan by 8-42%. Exposures to 1 µM erythromycin, 5 µM carglumic acid, 3 µM capecitabine, and 1 µM ivermectin, extended rotifer lifespan without significant effect on reproduction. Some drugs also extended healthspan, as estimated by mitochondria activity and mobility (swimming speed). Our most promising result is that rotifer lifespan was extended by 7-8.9% even when treatment was started in middle age.

Novel Natural Products for Healthy Ageing from the Mediterranean Diet and Food Plants of Other Global Sources-The MediHealth Project.

There is a rapid increase in the percentage of elderly people in Europe. Consequently, the prevalence of age-related diseases will also significantly increase. Therefore, the main goal of MediHealth, an international research project, is to introduce a novel approach for the discovery of active agents of food plants from the Mediterranean diet and other global sources that promote healthy ageing. To achieve this goal, a series of plants from the Mediterranean diet and food plants from other origins are carefully selected and subjected to in silico, cell-based, in vivo (fly and mouse models), and metabolism analyses. Advanced analytical techniques complement the bio-evaluation process for the efficient isolation and identification of the bioactive plant constituents. Furthermore, pharmacological profiling of bioactive natural products, as well as the identification and synthesis of their metabolites, is carried out. Finally, optimization studies are performed in order to proceed to the development of innovative nutraceuticals, dietary supplements or herbal medicinal products. The project is based on an exchange of researchers between nine universities and four companies from European and non-European countries, exploiting the existing complementary multidisciplinary expertise. Herein, the unique and novel approach of this interdisciplinary project is presented.

Ergothioneine promotes longevity and healthy aging in male mice.

Healthy aging has emerged as a crucial issue with the increase in the geriatric population worldwide. Food-derived sulfur-containing amino acid ergothioneine (ERGO) is a potential dietary supplement, which exhibits various beneficial effects in experimental animals although the preventive effects of ERGO on aging and/or age-related impairments such as frailty and cognitive impairment are unclear. We investigated the effects of daily oral supplementation of ERGO dissolved in drinking water on lifespan, frailty, and cognitive impairment in male mice from 7 weeks of age to the end of their lives. Ingestion of 4 ~ 5 mg/kg/day of ERGO remarkably extended the lifespan of male mice. The longevity effect of ERGO was further supported by increase in life and non-frailty spans of Caenorhabditis elegans in the presence of ERGO. Compared with the control group, the ERGO group showed significantly lower age-related declines in weight, fat mass, and average and maximum movement velocities at 88 weeks of age. This was compatible with dramatical suppression by ERGO of the age-related increments in plasma biomarkers (BMs) such as the chemokine ligand 9, creatinine, symmetric dimethylarginine, urea, asymmetric dimethylarginine, quinolinic acid, and kynurenine. The oral intake of ERGO also rescued age-related impairments in learning and memory ability, which might be associated with suppression of the age-related decline in hippocampal neurogenesis and TDP43 protein aggregation and promotion of microglial shift to the M2 phenotype by ERGO ingestion. Ingestion of ERGO may promote longevity and healthy aging in male mice, possibly through multiple biological mechanisms.

Cannabinoids and healthy ageing: the potential for extending healthspan and lifespan in preclinical models with an emphasis on Caenorhabditis elegans.

There is a significant global upsurge in the number and proportion of older persons in the population. With this comes an increasing prevalence of age-related conditions which pose a major challenge to healthcare systems. The development of anti-ageing treatments may help meet this challenge by targeting the ageing process which is a common denominator to many health problems. Cannabis-like compounds (cannabinoids) are reported to improve quality of life and general well-being in human trials, and there is increasing preclinical research highlighting that they have anti-ageing activity. Moreover, preclinical evidence suggests that endogenous cannabinoids regulate ageing processes. Here, we review the anti-ageing effects of the cannabinoids in various model systems, including the most extensively studied nematode model, Caenorhabditis elegans. These studies highlight that the cannabinoids lengthen healthspan and lifespan, with emerging evidence that they may also hinder the development of cellular senescence. The non-psychoactive cannabinoid cannabidiol (CBD) shows particular promise, with mechanistic studies demonstrating it may work through autophagy induction and activation of antioxidative systems. Furthermore, CBD improves healthspan parameters such as diminishing age-related behavioural dysfunction in models of both healthy and accelerated ageing. Translation into mammalian systems provides an important next step. Moreover, looking beyond CBD, future studies could probe the multitude of other cannabis constituents for their anti-ageing activity.

Taurine linked with healthy aging.

Reversing age-associated taurine loss improves mouse longevity and monkey health.

Melatonin and healthy aging.

Preservation of a robust circadian rhythmicity (particulsarly of the sleep/wake cycle), a proper nutrition and adequate physical exercise are key elements for healthy aging. Aging comes along with circadian alteration, e.g. a disrupted sleep and inflammation, that leads to metabolic disorders. In turn, sleep cycle disturbances cause numerous pathophysiological changes that accelerates the aging process. In the central nervous system, sleep disruption impairs several functions, among them, the clearance of waste molecules. The decrease of plasma melatonin, a molecule of unusual phylogenetic conservation present in all known aerobic organisms, plays a particular role as far as the endocrine sequels of aging. Every day, the late afternoon/nocturnal increase of melatonin synchronizes both the central circadian pacemaker located in the hypothalamic suprachiasmatic nuclei as well as myriads of peripheral cellular circadian clocks. This is called the "chronobiotic effect" of melatonin, the methoxyindole being the prototype of the endogenous family of chronobiotic agents. In addition, melatonin exerts a significant cytoprotective action by buffering free radicals and reversing inflammation via down regulation of proinflammatory cytokines, suppression of low degree inflammation and prevention of insulin resistance. Because of these properties melatonin has been advocated to be a potential therapeutic tool in COVID 19 pandemic. Melatonin administration to aged animals counteracts a significant number of senescence-related changes. In humans, melatonin is effective both as a chronobiotic and a cytoprotective agent to maintain a healthy aging. Circulating melatonin levels are consistently reduced in the metabolic syndrome, ischemic and non-ischemic cardiovascular diseases and neurodegenerative disorders like the Alzheimer's and Parkinson's diseases. The potential therapeutic value of melatonin has been suggested by a limited number of clinical trials generally employing melatonin in the 2-10mg/day range. However, from animal studies the cytoprotective effects of melatonin need higher doses to become apparent (i.e. in the 100mg/day range). Hence, controlled studies employing melatonin doses in this range are urgently needed.

Lithium can mildly increase health during ageing but not lifespan in mice.

Lithium is a nutritional trace element, used clinically as an anti-depressant. Preclinically, lithium has neuroprotective effects in invertebrates and mice, and it can also extend lifespan in fission yeast, C. elegans and Drosophila. An inverse correlation of human mortality with the concentration of lithium in tap water suggests a possible, evolutionarily conserved mechanism mediating longevity. Here, we assessed the effects of lithium treatment on lifespan and ageing parameters in mice. Lithium has a narrow therapeutic dose range, and overdosing can severely affect organ health. Within the tolerable dosing range, we saw some mildly positive effects of lithium on health span but not on lifespan.

A 12-Week Randomized Double-Blind Placebo-Controlled Clinical Trial, Evaluating the Effect of Supplementation with a Spinach Extract on Skeletal Muscle Fitness in Adults Older Than 50 Years of Age.

The aim of a 12-week randomized double-blind placebo-controlled study was to assess the effect of daily supplementation with a natural extract of Spinacia oleracea L. (4 × 500 mg capsules/day; total 2 g per day) combined with a moderate-intensity training program (1 h session/3 times a week) on skeletal muscle fitness in adults over 50 years of age. Muscle strength assessed by isokinetic and isometric dynamometry improved significantly in the experimental (n = 23) and the placebo (n = 22) groups, but the magnitude of improvement was higher in the experimental group, with between-group differences in almost all variables, including isokinetic at 60° s-1 in knee extension, peak torque (p < 0.007); total work per repetition maximum (p < 0.009); isokinetic at 180°s-1 in knee extension, peak torque (p < 0.002); total work (p < 0.007); total work per repetition maximum (p < 0.005); average power (p < 0.027); isometric in knee extension, peak torque (p < 0.005); and average peak torque (p < 0.002). Similar findings were observed for muscle quality. Changes in quality of life (SF-36) were not found, except for improvements in the role physical (p < 0.023) and role emotional (p < 0.001) domains, likely as a result of the physical training sessions. A nutritional survey did not revealed changes in dietary habits. No adverse events were recorded. In subjects over 50 years of age, moderate-intensity strength training combined with daily supplementation for 12 weeks with a natural extract of Spinacia oleracea L. improved muscle-related variables and muscle quality. Maintaining muscle health is a key component of healthy aging.

The role of curcumin in aging and senescence: Molecular mechanisms.

Healthy aging and human longevity are intricate phenotypes affected by environmental factors such as physical exercise, diet, health habits, and psychosocial situations as well as genetic factors. Diet and caloric restriction have a crucial role in healthy aging. Curcumin, a polyphenolic compound isolated from the Curcuma longa, has been shown to exert anti-aging characteristics. Recently, investigations on curcumin with regard to aging and age-associated disease in model organisms has described that curcumin and its metabolites, prolong the mean lifespan of some aging model organisms such as C. elegans, D. melanogaster, yeast, and mouse. It has been proposed to have several biological activities, such as antioxidative, anti-inflammatory, anticancer, chemopreventive, and anti-neurodegenerative characteristics. In several studies on various model organisms it has been shown that the lifespan extension via curcumin treatment was connected with enhanced superoxide dismutase (SOD) activity, and also declined malondialdehyde (MDA) and lipofuscin levels. As well as the pivotal role of curcumin on the modulating of major signaling pathways that influence longevity of organisms like IIS, mTOR, PKA, and FOXO signaling pathways. This review defines the use of curcumin in traditional and modern medicine, its biochemistry and biological functions, such as curcumin's anti-aging, anti-cancer, anti-microbial, anti-inflammatory, and anti-oxidant characteristics. Also, the review further describes the role of curcumin in a pharmacological context and new insights on its therapeutic capacity and restrictions. Particularly, the review emphasizes in-depth on the efficiency of curcumin and its mechanism of action as an anti-aging compound and also treating age-related disease.

Key Signaling Pathways in Aging and Potential Interventions for Healthy Aging.

Aging is a fundamental biological process accompanied by a general decline in tissue function. Indeed, as the lifespan increases, age-related dysfunction, such as cognitive impairment or dementia, will become a growing public health issue. Aging is also a great risk factor for many age-related diseases. Nowadays, people want not only to live longer but also healthier. Therefore, there is a critical need in understanding the underlying cellular and molecular mechanisms regulating aging that will allow us to modify the aging process for healthy aging and alleviate age-related disease. Here, we reviewed the recent breakthroughs in the mechanistic understanding of biological aging, focusing on the adenosine monophosphate-activated kinase (AMPK), Sirtuin 1 (SIRT1) and mammalian target of rapamycin (mTOR) pathways, which are currently considered critical for aging. We also discussed how these proteins and pathways may potentially interact with each other to regulate aging. We further described how the knowledge of these pathways may lead to new interventions for antiaging and against age-related disease.

Treatment with Bacterial Biologics Promotes Healthy Aging and Traumatic Brain Injury Responses in Adult Drosophila, Modeling the Gut-Brain Axis and Inflammation Responses.

Drosophila are widely used to study neural development, immunity, and inflammatory pathways and processes associated with the gut-brain axis. Here, we examine the response of adult Drosophila given an inactive bacteriologic (IAB; proprietary lysate preparation of Lactobacillus bulgaricus, ReseT®) and a probiotic (Lactobacillus rhamnosus, LGG). In vitro, the IAB activates a subset of conserved Toll-like receptor (TLR) and nucleotide-binding, oligomerization domain-containing protein (NOD) receptors in human cells, and oral administration slowed the age-related decline of adult Drosophila locomotor behaviors. On average, IAB-treated flies lived significantly longer (+23%) and had lower neural aggregate profiles. Different IAB dosages also improved locomotor function and longevity profiles after traumatic brain injury (TBI) exposure. Mechanistically, short-term IAB and LGG treatment altered baseline nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κß) signaling profiles in neural and abdominal tissues. Overall, at select dosages, IAB and LGG exposure has a positive impact on Drosophila longevity, neural aging, and mild traumatic brain injury (TBI)-related responses, with IAB showing greater benefit. This includes severe TBI (sTBI) responses, where IAB treatment was protective and LGG increased acute mortality profiles. This work shows that Drosophila are an effective model for testing bacterial-based biologics, that IAB and probiotic treatments promote neuronal health and influence inflammatory pathways in neural and immune tissues. Therefore, targeted IAB treatments are a novel strategy to promote the appropriate function of the gut-brain axis.

Importance of Dietary Phosphorus for Bone Metabolism and Healthy Aging.

Inorganic phosphate (Pi) plays a critical function in many tissues of the body: for example, as part of the hydroxyapatite in the skeleton and as a substrate for ATP synthesis. Pi is the main source of dietary phosphorus. Reduced bioavailability of Pi or excessive losses in the urine causes rickets and osteomalacia. While critical for health in normal amounts, dietary phosphorus is plentiful in the Western diet and is often added to foods as a preservative. This abundance of phosphorus may reduce longevity due to metabolic changes and tissue calcifications. In this review, we examine how dietary phosphorus is absorbed in the gut, current knowledge about Pi sensing, and endocrine regulation of Pi levels. Moreover, we also examine the roles of Pi in different tissues, the consequences of low and high dietary phosphorus in these tissues, and the implications for healthy aging.

[Aging: a global, multidimensional and preventive approach]. / Vieillissement - Une approche globale, multidimensionnelle et préventive.

Aging is physiological and begins very early. It can be accelerated by our lifestyle and by chronic diseases. There are over 300 "theories" of aging and many animal models have been developed ranging from yeast to more complex organisms. Civil age is not a reflection of an individual's physiological age. Starting from the age of 30 a decrease in organ function can be observed. The aging of an individual leads him to 3 states: vigourous, polypathological and dependent or frail. The state of fragility is reversible. We have to be an actor in our aging and no longer suffer it. The centenarians of the blue zones have achieved, culturally, active aging which has led them to successful aging.

TITLE: Vieillissement - Une approche globale, multidimensionnelle et préventive. ABSTRACT: Le vieillissement est un événement physiologique qui commence très tôt dans la vie. L'âge civil, qui nous est donné, ne reflète cependant pas notre âge physiologique. Le vieillissement peut s'accélérer selon nos habitudes de vie. C'est à partir de l'âge de 30 ans que l'on constate une diminution du fonctionnement de nos organes. Le vieillissement conduit ainsi vers 3 états : robuste, polypathologique et dépendant, ou fragile. L'état de fragilité est réversible. Afin de « bien vieillir ¼, il est donc nécessaire d'être acteur de son vieillissement et non plus de le subir. Les centenaires des « zones bleues ¼ qui, culturellement, ont réalisé un vieillissement actif, sont un exemple de vieillissement réussi et donc du « bien vieillir.

From mitochondria to healthy aging: The role of branched-chain amino acids treatment: MATeR a randomized study.

RATIONALE: Malnutrition often affects elderly patients and significantly contributes to the reduction in healthy life expectancy, causing high morbidity and mortality. In particular, protein malnutrition is one of the determinants of frailty and sarcopenia in elderly people. METHODS: To investigate the role of amino acid supplementation in senior patients we performed an open-label randomized trial and administered a particular branched-chain amino acid enriched mixture (BCAAem) or provided diet advice in 155 elderly malnourished patients. They were followed for 2 months, assessing cognitive performance by Mini Mental State Examination (MMSE), muscle mass measured by anthropometry, strength measure by hand grip and performance measured by the Timed Up and Go (TUG) test, the 30 s Chair Sit to Stand (30-s CST) test and the 4 m gait speed test. Moreover we measured oxidative stress in plasma and mitochondrial production of ATP and electron flux in peripheral blood mononuclear cells. RESULTS: Both groups improved in nutritional status, general health and muscle mass, strength and performance; treatment with BCAAem supplementation was more effective than simple diet advice in increasing MMSE (1.2 increase versus 0.2, p = 0.0171), ATP production (0.43 increase versus -0.1, p = 0.0001), electron flux (0.50 increase versus 0.01, p < 0.0001) and in maintaining low oxidative stress. The amelioration of clinical parameters as MMSE, balance, four meter walking test were associated to increased mitochondrial function. CONCLUSIONS: Overall, our findings show that sustaining nutritional support might be clinically relevant in increasing physical performance in elderly malnourished patients and that the use of specific BCAAem might ameliorate also cognitive performance thanks to an amelioration of mitochondria bioenergetics.

Active ageing, emotional care and the threat of stigma: Identity management in older adults using sleeping medication long-term.

Amid fears about the medicalisation of old age, the high prevalence of sleeping medication use in older cohorts is a significant public health concern. Long-term use is associated with a plethora of negative effects, such as cognitive impairment and risk of addiction. However, little is known about the lived experience of older adults using sleeping medication longer term. Episodic interviews lasting approximately 90 minutes were conducted with 15 independently living adults, aged 65-88 years, who were using sedative-hypnotic or tricyclic sleeping medication for more than 11 years on average. Thematic analysis shows that participants divided their rationale for use into two temporal periods: (1) to ensure physical ability in the daytime and (2) to ensure emotional stability at night. Long-term sleeping medication was thus characterised as a form of 'emotional self-management' of the negative emotions associated with later life, blotting out feelings of loss and loneliness by inducing sleep. Participants feared loss of access to their medication 'supply', employing strategies to ensure its continuity, while expressing shame about their dependence. However, identity management, in the form of explanations, minimisations and social comparisons, functioned to downplay their addiction. Through this, long-term sleeping medication users were able to elude the spoiled identities and multiple stigmas of both the 'out of control' addict and the unsuccessful older adult by asserting a positive identity; that of the 'new' older adult, actively medicating for success both day and night.

Acarbose improves health and lifespan in aging HET3 mice.

To follow-up on our previous report that acarbose (ACA), a drug that blocks postprandial glucose spikes, increases mouse lifespan, we studied ACA at three doses: 400, 1,000 (the original dose), and 2,500 ppm, using genetically heterogeneous mice at three sites. Each dose led to a significant change (by log-rank test) in both sexes, with larger effects in males, consistent with the original report. There were no significant differences among the three doses. The two higher doses produced 16% or 17% increases in median longevity of males, but only 4% or 5% increases in females. Age at the 90th percentile was increased significantly (8%-11%) in males at each dose, but was significantly increased (3%) in females only at 1,000 ppm. The sex effect on longevity is not explained simply by weight or fat mass, which were reduced by ACA more in females than in males. ACA at 1,000 ppm reduced lung tumors in males, diminished liver degeneration in both sexes and glomerulosclerosis in females, reduced blood glucose responses to refeeding in males, and improved rotarod performance in aging females, but not males. Three other interventions were also tested: ursolic acid, 2-(2-hydroxyphenyl) benzothiazole (HBX), and INT-767; none of these affected lifespan at the doses tested. The acarbose results confirm and extend our original report, prompt further attention to the effects of transient periods of high blood glucose on aging and the diseases of aging, including cancer, and should motivate studies of acarbose and other glucose-control drugs in humans.

Comparison survey of EVOO polyphenols and exploration of healthy aging-promoting properties of oleocanthal and oleacein.

Olive oil is widely accepted as a superior edible oil. Great attention has been given lately to olive oil polyphenols which are linked to significant health beneficial effects. Towards a survey of Greek olive oil focusing on polyphenols, representative extra virgin olive oils (EVOOs) from the main producing areas of the country and the same harvesting period have been collected and analyzed. Significant differences and interesting correlations have been identified connecting certain polyphenols namely hydroxytyrosol, tyrosol, oleacein and oleocanthal with specific parameters e.g. geographical origin, production procedure and cultivation practice. Selected EVOOs polyphenol extracts, with different oleacein and oleocanthal levels, as well as isolated oleacein and oleocanthal were bio-evaluated in mammalian cells and as a dietary supplement in the Drosophila in vivo model. We found that oleocanthal and oleacein activated healthy aging-promoting cytoprotective pathways and suppressed oxidative stress in both mammalian cells and in flies.