Quantum dots (QDs) are used for imaging and transport of therapeutics. Here we demonstrate rapid absorption across the small intestine and targeted delivery of QDs with bound materials to the liver ...sinusoidal endothelial cells (LSECs) or hepatocytes in vitro and in vivo following oral administration. QDs were radiolabeled with 3H-oleic acid, with a fluorescent tag or 14C-metformin placed within a drug binding site. Three different biopolymer shell coatings were compared (formaldehyde-treated serum albumin (FSA), gelatin, heparin). Passage across the small intestine into mesenteric veins is mediated by clathrin endocytosis and micropinocytosis. 60% of an oral dose of QDs was rapidly distributed to the liver within 30 min, and this increased to 85% with FSA biopolymer coating. Uptake into LSECs also increased 3-fold with FSA coating, while uptake into hepatocytes was increased from 40% to 85% with gelatin biopolymer coating. Localization of QDs to LSECs was confirmed with immunofluorescence and transmission electron microscopy. 85% of QDs were cleared within 24 h of administration. The bioavailability of 14C-metformin 2 h post-ingestion was increased 5-fold by conjugation with QD-FSA, while uptake of metformin into LSECs was improved 50-fold by using these QDs. Endocytosis of QDs by SK-Hep1 cells (an LSEC immortal cell line) was via clathrin- and caveolae-mediated pathways with QDs taken up into lysosomes. In conclusion, we have shown high specificity targeting of the LSEC or hepatocytes after oral administration of QDs coated with a biopolymer layer of FSA or gelatin, which improved the bioavailability and delivery of metformin to LSECs.
Abstract
Many common chronic diseases and syndromes are ageing-related. This raises the prospect that therapeutic agents that target the biological changes of ageing will prevent or delay multiple ...diseases with a single therapy. Gerotherapeutic drugs are those that target pathways involved in ageing, with the aims of reducing the burden of ageing-related diseases and increasing lifespan and healthspan. The approach to discovering gerotherapeutic drugs is similar to that used to discover drugs for diseases. This includes screening for novel compounds that act on receptors or pathways that influence ageing or repurposing of drugs currently available for other indications. A novel approach involves studying populations with exceptional longevity, in order to identify genes variants linked with longer lifespan and could be targeted by drugs. Metformin, rapamycin and precursors of nicotinamide adenine dinucleotide are amongst the frontrunners of gerotherapeutics that are moving into human clinical trials to evaluate their effects on ageing. There are also increasing numbers of potential gerotherapeutic drugs in the pipeline or being studied in animal models. A key hurdle is designing clinical trials that are both feasible and can provide sufficient clinical evidence to support licencing and marketing of gerotherapeutic drugs.
There are no established or standardized definitions of aging-related disease. Data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 were used to model the relationship ...between age and incidence of diseases. Clustering analysis identified 4 groups of noncommunicable diseases: Group A diseases with an exponential increase in incidence with age; Group B diseases with an exponential increase in incidence that usually peaked in late life which then declined or plateaued at the oldest ages; and Groups C and D diseases with an onset in earlier life and where incidence was stable or decreased in old age. From an epidemiological perspective, Group A diseases are "aging-related diseases" because there is an exponential association between age and incidence, and the slope of the incidence curves remains positive throughout old age. These included the major noncommunicable diseases dementia, stroke, and ischemic heart disease. Whether any of the other diseases are aging-related is uncertain because their incidence either does not change or more often decreases in old age. Only biological studies can determine how the aging process contributes to any of these diseases and this may lead to a reclassification of disease on the basis of whether they are directly caused by or are in continuity with the biological changes of aging. In the absence of this mechanistic data, we propose the term "aging-related disease" should be used with precision based on epidemiological evidence.
The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional ...modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake. These consequences are associated with hepatic mammalian target of rapamycin (mTOR) activation and mitochondrial function and, in turn, related to circulating branched-chain amino acids and glucose. Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. The results suggest that longevity can be extended in ad libitum-fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation.
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•Food intake is regulated primarily by dietary protein and carbohydrate•Low-protein, high-carbohydrate diets are associated with the longest lifespans•Energy reduction from high-protein diets or dietary dilution does not extend life•Diet influences hepatic mTOR via branched-chain amino acids and glucose
Solon-Biet et al. look at whether health and aging are influenced by macronutrient balance or calorie intake in mice by investigating the effects of diets differing in protein, carbohydrate, and fat content. Diets low in protein and high in carbohydrates increase lifespan, while calorie restriction through high-protein diets does not extend life.
•Branched chain amino acids influence aging, sarcopenia and cardiometabolic disease.•Branched chain amino acids regulate food intake, protein synthesis and insulin release.•Therapeutic effects of ...branched chain amino acids depend upon background diet.
Branched chain amino acids (BCAA: leucine, valine, isoleucine) have key physiological roles in the regulation of protein synthesis, metabolism, food intake and aging. Many studies report apparently inconsistent conclusions about the relationships between blood levels of BCAAs or dietary manipulation of BCAAs with age-related changes in body composition, sarcopenia, obesity, insulin and glucose metabolism, and aging biology itself. These divergent results can be resolved by consideration of the role of BCAAs as signalling molecules and the bidirectional mechanistic relationship between BCAAs and some aging phenotypes. The effects of BCAAs are also influenced by the background nutritional composition such as macronutrient ratios and imbalance with other amino acids. Understanding the interaction between BCAAs and other components of the diet may provide new opportunities for influencing age-related outcomes through manipulation of dietary BCAAs together with titration of macronutrient ratios and other amino acids.
Although the increased lifespan of our populations illustrates the success of modern medicine, the risk of developing many diseases increases exponentially with old age. Caloric restriction is known ...to retard ageing and delay functional decline as well as the onset of disease in most organisms. Studies have implicated the sirtuins (SIRT1-SIRT7) as mediators of key effects of caloric restriction during ageing. Two unrelated molecules that have been shown to increase SIRT1 activity in some settings, resveratrol and SRT1720, are excellent protectors against metabolic stress in mammals, making SIRT1 a potentially appealing target for therapeutic interventions. This Review covers the current status and controversies surrounding the potential of sirtuins as novel pharmacological targets, with a focus on SIRT1.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Significance A fundamental tenet of life-history theory is that reproduction and longevity trade off against one another. Experiments on invertebrates show that, rather than competing for limiting ...resources, reproduction and lifespan are optimized on different dietary macronutrient compositions. In mice, studies have yet to establish the relationship between macronutrient balance, reproduction, and lifespan. We evaluated the effects of macronutrients and energy on lifespan and reproductive function. Indicators of reproductive function (uterine mass, ovarian follicle number, testes mass, epididymal sperm counts) were optimized by high protein (P), low carbohydrate (C) diets whereas lifespan was greatest on low P:C diets. Corpora lutea and estrous cycling were higher in females on lower P:C diets. Macronutrient balance has profound and opposing effects on reproduction and longevity.
In invertebrates, reproductive output and lifespan are profoundly impacted by dietary macronutrient balance, with these traits achieving their maxima on different diet compositions, giving the appearance of a resource-based tradeoff between reproduction and longevity. For the first time in a mammal, to our knowledge, we evaluate the effects of dietary protein (P), carbohydrate (C), fat (F), and energy (E) on lifespan and reproductive function in aging male and female mice. We show that, as in invertebrates, the balance of macronutrients has marked and largely opposing effects on reproductive and longevity outcomes. Mice were provided ad libitum access to one of 25 diets differing in P, C, F, and E content, with reproductive outcomes assessed at 15 months. An optimal balance of macronutrients exists for reproductive function, which, for most measures, differs from the diets that optimize lifespan, and this response differs with sex. Maximal longevity was achieved on diets containing a P:C ratio of 1:13 in males and 1:11 for females. Diets that optimized testes mass and epididymal sperm counts (indicators of gamete production) contained a higher P:C ratio (1:1) than those that maximized lifespan. In females, uterine mass (an indicator of estrogenic activity) was also greatest on high P:C diets (1:1) whereas ovarian follicle number was greatest on P:C 3:1 associated with high-F intakes. By contrast, estrous cycling was more likely in mice on lower P:C (1:8), and the number of corpora lutea, indicative of recent ovulations, was greatest on P:C similar to those supporting greatest longevity (1:11).
Putting the Balance Back in Diet Simpson, Stephen J.; Le Couteur, David G.; Raubenheimer, David
Cell,
03/2015, Letnik:
161, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The notion of dietary balance is fundamental to health yet is not captured by focusing on the intake of energy or single nutrients. Advances in nutritional geometry have begun to unravel and ...integrate the interactive effects of multiple nutrients on health, lifespan, aging, and reproduction.
The notion of dietary balance is fundamental to health, yet is not captured by focusing on the intake of energy or single nutrients. Advances in nutritional geometry have begun to unravel and integrate the interactive effects of multiple nutrients on health, lifespan, aging, and reproduction.
Frailty, a multisystem ageing syndrome Thillainadesan, Janani; Scott, Ian A; Le Couteur, David G
Age and ageing,
08/2020, Letnik:
49, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Abstract
The management of frail older people is a key component of aged care. There has been a plethora of tools developed for the diagnosis and screening of frailty. Some of these tools are ...entering routine clinical practice at a time when the higher healthcare costs involved in caring for older people who are frail have become a potential target for cost-cutting. Yet there is still only limited evidence to support the widespread adoption of frailty tools, and foundational factors impact on their accuracy and validity. Despite the acceptance of frailty as a valid term in research and clinical practice, older people believe the term carries stigma. Such issues indicate that there may be a need to reconsider current approaches to frailty. Recent advances in the science of ageing biology can provide a new framework for reconfiguring how we screen, diagnose, treat and prevent frailty. Frailty can be considered to be a multisystem ageing syndrome of decreased physiological and functional reserve, where the biological changes of ageing are seen in most tissues and organs and are the pathogenic mechanism for frailty. Likewise age-related chronic disease and multimorbidity are syndromes where ageing changes occur in one or multiple systems, respectively. This model focusses diagnostic criteria for frailty onto the biomarkers of ageing and generates new targets for the prevention and treatment of frailty based on interventions that influence ageing biology.
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