Since the discovery that rapamycin, a small molecule inhibitor of the protein kinase mTOR (mechanistic target of rapamycin), can extend the lifespan of model organisms including mice, interest in ...understanding the physiological role and molecular targets of this pathway has surged. While mTOR was already well known as a regulator of growth and protein translation, it is now clear that mTOR functions as a central coordinator of organismal metabolism in response to both environmental and hormonal signals. This review discusses recent developments in our understanding of how mTOR signaling is regulated by nutrients and the role of the mTOR signaling pathway in key metabolic tissues. Finally, we discuss the molecular basis for the negative metabolic side effects associated with rapamycin treatment, which may serve as barriers to the adoption of rapamycin or similar compounds for the treatment of diseases of aging and metabolism.
In this Review Article, Kennedy and Lamming highlight recent findings regarding the central role of the mechanistic target of rapamycin (mTOR), a protein kinase regulated by many growth factors and environmental cues, in the regulation of organismal metabolism and aging.
Mutations in nuclear lamins or other proteins of the nuclear envelope are the root cause of a group of phenotypically diverse genetic disorders known as laminopathies, which have symptoms that range ...from muscular dystrophy to neuropathy to premature aging syndromes. Although precise disease mechanisms remain unclear, there has been substantial progress in our understanding of not only laminopathies, but also the biological roles of nuclear structure. Nuclear envelope dysfunction is associated with altered nuclear activity, impaired structural dynamics, and aberrant cell signaling. Building on these findings, small molecules are being discovered that may become effective therapeutic agents.
For centuries, people believed that bats possessed sinister powers. Bats are thought to be ancestral hosts to many deadly viruses affecting humans including Ebola, rabies, and most recently ...SARS-CoV-2 coronavirus. However, bats themselves tolerate these viruses without ill effects. The second power that bats have is their longevity. Bats live much longer than similar-sized land mammals. Here we review how bats’ ability to control inflammation may be contributing to their longevity. The underlying mechanisms may hold clues to developing new treatments for age-related diseases. Now may be the time to use science to exploit the secret powers of bats for human benefit.
Bats host and tolerate a wide range of viruses and live considerably longer than similar-sized land mammals. Here, Gorbunova et al. review mechanisms shaping the exceptional longevity and virus resistance of bats. The authors discuss how the bat’s ability to downregulate inflammation may ameliorate age-related diseases, and they propose anti-aging interventions for humans based upon the evolutionary adaptations of bats.
Display omitted
The quest to slow ageing through drug discovery Partridge, Linda; Fuentealba, Matias; Kennedy, Brian K
Nature reviews. Drug discover/Nature reviews. Drug discovery,
08/2020, Letnik:
19, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Although death is inevitable, individuals have long sought to alter the course of the ageing process. Indeed, ageing has proved to be modifiable; by intervening in biological systems, such as ...nutrient sensing, cellular senescence, the systemic environment and the gut microbiome, phenotypes of ageing can be slowed sufficiently to mitigate age-related functional decline. These interventions can also delay the onset of many disabling, chronic diseases, including cancer, cardiovascular disease and neurodegeneration, in animal models. Here, we examine the most promising interventions to slow ageing and group them into two tiers based on the robustness of the preclinical, and some clinical, results, in which the top tier includes rapamycin, senolytics, metformin, acarbose, spermidine, NAD
enhancers and lithium. We then focus on the potential of the interventions and the feasibility of conducting clinical trials with these agents, with the overall aim of maintaining health for longer before the end of life.
The continental margin off the northeastern United States (NEUS) contains numerous, topographically complex features that increase habitat heterogeneity across the region. However, the majority of ...these rugged features have never been surveyed, particularly using direct observations. During summer 2013, 31 Remotely-Operated Vehicle (ROV) dives were conducted from 494 to 3271 m depth across a variety of seafloor features to document communities and to infer geological processes that produced such features. The ROV surveyed six broad-scale habitat features, consisting of shelf-breaching canyons, slope-sourced canyons, inter-canyon areas, open-slope/landslide-scar areas, hydrocarbon seeps, and Mytilus Seamount. Four previously unknown chemosynthetic communities dominated by Bathymodiolus mussels were documented. Seafloor methane hydrate was observed at two seep sites. Multivariate analyses indicated that depth and broad-scale habitat significantly influenced megafaunal coral (58 taxa), demersal fish (69 taxa), and decapod crustacean (34 taxa) assemblages. Species richness of fishes and crustaceans significantly declined with depth, while there was no relationship between coral richness and depth. Turnover in assemblage structure occurred on the middle to lower slope at the approximate boundaries of water masses found previously in the region. Coral species richness was also an important variable explaining variation in fish and crustacean assemblages. Coral diversity may serve as an indicator of habitat suitability and variation in available niche diversity for these taxonomic groups. Our surveys added 24 putative coral species and three fishes to the known regional fauna, including the black coral Telopathes magna, the octocoral Metallogorgia melanotrichos and the fishes Gaidropsarus argentatus, Guttigadus latifrons, and Lepidion guentheri. Marine litter was observed on 81% of the dives, with at least 12 coral colonies entangled in debris. While initial exploration revealed the NEUS region to be both geologically dynamic and biologically diverse, further research into the abiotic conditions and the biotic interactions that influence species abundance and distribution is needed.
The yeast replicative aging model He, Chong; Zhou, Chuankai; Kennedy, Brian K.
Biochimica et biophysica acta. Molecular basis of disease,
September 2018, 2018-09-00, 20180901, Letnik:
1864, Številka:
9
Journal Article
Recenzirano
Odprti dostop
It has been nearly three decades since the budding yeast Saccharomyces cerevisiae became a significant model organism for aging research and it has emerged as both simple and powerful. The ...replicative aging assay, which interrogates the number of times a “mother” cell can divide and produce “daughters”, has been a stalwart in these studies, and genetic approaches have led to the identification of hundreds of genes impacting lifespan. More recently, cell biological and biochemical approaches have been developed to determine how cellular processes become altered with age. Together, the tools are in place to develop a holistic view of aging in this single-celled organism. Here, we summarize the current state of understanding of yeast replicative aging with a focus on the recent studies that shed new light on how aging pathways interact to modulate lifespan in yeast.
•Yeast aging research over the last three decades has provided insights into human aging.•Genetic studies have identified hundreds of yeast aging genes.•Recent cell biological approaches have shed light on cellular changes in aging cells.•Yeast offers an ideal system to understand aging holistically.
Several lines of evidence suggest schizophrenia is a segmental progeria, that is, some but not all aspects of accelerated aging may be present. However, the evidence has not been consistent. Problems ...with matching and confounding may account for some of these discrepancies. Given the etiopathophysiological heterogeneity of schizophrenia, it is possible that only a specific pathophysiological group within schizophrenia is associated with progeroid features, while others are not, or that one group is associated with a particular segment of aging features, while other progeroid features are found in another pathophysiological subgroup. In the aging research field, significant progress has been made in identifying the molecular pathways that confer aging: epigenetic changes, inflammation, proteostasis, adult stem cell function, metabolic changes, and adaptation to stress, and macromolecular damage. In addition to replication and clarification of existing kinds of evidence, examining these aging pathways would improve our understanding of progeria in schizophrenia.
Once thought to be impossible, it is now clear that changing the activity of several conserved genetic pathways can lead to lifespan extension in experimental organisms. In humans, however, the goal ...is to extend healthspan, the functional and disease-free period of life. Are the current pathways to lifespan extension also improving healthspan?
Metabolism and aging are tightly connected. Alpha-ketoglutarate is a key metabolite in the tricarboxylic acid (TCA) cycle, and its levels change upon fasting, exercise, and aging. Here, we ...investigate the effect of alpha-ketoglutarate (delivered in the form of a calcium salt, CaAKG) on healthspan and lifespan in C57BL/6 mice. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically relevant measurements. We find that CaAKG promotes a longer, healthier life associated with a decrease in levels of systemic inflammatory cytokines. We propose that induction of IL-10 by dietary AKG suppresses chronic inflammation, leading to health benefits. By simultaneously reducing frailty and enhancing longevity, AKG, at least in the murine model, results in a compression of morbidity.
Display omitted
•A CaAKG-supplemented diet extends lifespan of middle-aged female mice•AKG supplementation extends healthspan of both female and male mice•AKG compresses morbidity. Reduction in frailty is more dramatic than lifespan extension•AKG reduces chronic inflammation and induces IL-10 in T cells of female mice
Asadi Shahmirzadi et al. report that an alpha-ketoglutarate-supplemented diet extends lifespan of middle-aged female mice and increases healthspan in both sexes. With simultaneous reduction in frailty and increase in longevity, the intervention compresses morbidity. AKG suppresses chronic inflammation and induces secretion of IL-10 in T cells of female mice.
DNA repair has been hypothesized to be a longevity determinant, but the evidence for it is based largely on accelerated aging phenotypes of DNA repair mutants. Here, using a panel of 18 rodent ...species with diverse lifespans, we show that more robust DNA double-strand break (DSB) repair, but not nucleotide excision repair (NER), coevolves with longevity. Evolution of NER, unlike DSB, is shaped primarily by sunlight exposure. We further show that the capacity of the SIRT6 protein to promote DSB repair accounts for a major part of the variation in DSB repair efficacy between short- and long-lived species. We dissected the molecular differences between a weak (mouse) and a strong (beaver) SIRT6 protein and identified five amino acid residues that are fully responsible for their differential activities. Our findings demonstrate that DSB repair and SIRT6 have been optimized during the evolution of longevity, which provides new targets for anti-aging interventions.
Display omitted
•DSB repair, but not NER, coevolves with maximum lifespan (MLS) in rodents•The activity of SIRT6 in stimulating DSB repair coevolves with MLS in rodent species•Five amino acids determine the differential activities of mouse and beaver SIRT6•Stronger SIRT6 leads to a longer lifespan
A comparative analysis of 18 rodent species identifies a role for SIRT6-dependent DNA double strand break repair as a major factor in organismal lifespan
PDF
