Advances in Genetics

 
 
Academic Press Inc
  • 1. Auflage
  • |
  • erschienen am 1. September 2015
  • |
  • 220 Seiten
 
E-Book | ePUB mit Adobe DRM | Systemvoraussetzungen
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978-0-12-803695-2 (ISBN)
 
The field of genetics is rapidly evolving, and new medical breakthroughs are occurring as a result of advances in our knowledge of genetics. Advances in Genetics continually publishes important reviews of the broadest interest to geneticists and their colleagues in affiliated disciplines.



- Critically analyzes future directions
- Written and edited by recognized leaders in the field
0065-2660
  • Englisch
  • USA
Elsevier Science & Technology (Digital)
  • Für Beruf und Forschung
  • Höhe: 229 mm
  • |
  • Breite: 152 mm
  • 8,82 MB
978-0-12-803695-2 (9780128036952)
0128036958 (0128036958)
weitere Ausgaben werden ermittelt
- Genetics and Pharmacology of Longevity: the Road to Therapeutics for Healthy Aging
Jorge Iván Castillo-Quan, Kerri J. Kinghorn and Ivana Bjedov
- MicroRNAs: Tools of Mechanistic Insights and Biological Therapeutics Discovery for the Rare Neurogenetic Syndrome Lesch-Nyhan Disease (LND)
Ghiabe-Henri Guibinga
- Small RNAs in Bacteria and Archaea: Who They Are, What They Do, and How They Do It
E. Gerhart H. Wagner and Pascale Romby

3. Pharmacology of Aging


3.1. Searching for a DR Mimetic


The widespread health benefits of DR have encouraged the search for drugs that can mimic the effects of DR, i.e. DR mimetics (Passtoors et al., 2013). The concept of a DR mimetic was put forward by Lane, Ingram, and Roth when trying to identify pharmacological agents capable of reproducing the beneficial life span-extending effects of DR, without reducing food intake (Lane et al., 1998). In pharmacology, a drug mimetic (from the Greek for imitative) is an agent capable of eliciting or inhibiting a process without the need of its natural activator or inhibitor. In cardiovascular medicine, sympathomimetic drugs are those that elicit similar effects as the catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline). These drugs can act either by directly stimulating a- or ß-adrenergic receptors, and an example of a direct ß2-adrenergic receptor agonist would be salbutamol or albuterol used for asthma control. Sympathomimetic drugs would also include those that indirectly act by increasing the availability of endogenous catecholamines at the site of action, for example, by inhibiting its transport (hence clearance) from the extracellular space back into the cell (e.g. amphetamines and cocaine). In the case of a DR mimetic, the molecular target would be less clear given the pleiotropic effects of DR. However, a DR mimetic agent should be able to extend life span and resemble some of the beneficial health effects of food restriction. Though not usually considered, a DR mimetic could also be a drug that mimics the action of food restriction, and could probably be achieved with the use of antiobesity drugs, which affect metabolism and induce weight loss (Bray & Ryan, 2014; Rodgers, Tschöp, & Wilding, 2012). However, it should be noted that such agents have not been tested for life span extension in humans or model organisms. The search for DR mimetics can be performed using model organisms like worms and flies, where screens for drugs reducing food intake can easily be performed. Moreover, the use of these organisms can help determine whether such compounds reduce food intake by mechanisms localized in the gut, brain, and/or other metabolic tissues (Gasque, Conway, Huang, Rao, & Vosshall, 2013). However, the classical interpretation of a DR mimetic is the ability to confer all or some of the effects of DR (life span and healthspan) without reducing food intake. Although some populations like the Okinawas in Japan are thought to be a natural DR population (Gavrilova & Gavrilov, 2012; Willcox, Willcox, Todoriki, & Suzuki, 2009), others (particularly members of the Caloric Restriction Society) self-restrict their food consumption based on the assumption, following the findings in animal studies, that reducing their food intake will protect them against the diseases of old age and the aging process itself (Holloszy & Fontana, 2007). This dietary interventional behavior is unlikely to be adopted by the majority of the population, even with the promise of a healthy life span, as a result of the widespread accepted difficulty in restricting calories. Dietary interventions have been at the core of many first-line treatments for a variety of chronic degenerative diseases, and have been proven to be effective in reducing symptoms and improving quality of life. However, the compliance is usually short-lived in comparison to drug interventions (Delamater, 2006; Kwan et al., 2013). We consider that the most important property of a DR mimetic should be its inability to extend life span beyond conditions maximized for DR (Figure 3). In model organisms, multiple protocols to extend life span have been developed, making it ever more challenging to perform epistatic experiments between potential DR mimetics and DR. We consider that these experiments should be performed with the protocol capable of extending life span the most, as this DR intervention is likely to recapitulate the ceiling effect for life span extension under food restriction.

3.2. Drugs in Aging: The Role of Model Organisms


3.2.1. Rapamycin and Rapalogs

The hopes of identifying drugs with antiaging properties were boosted in 2009 when a report showed that the drug rapamycin was able to extend the life span of mice even when fed late in life (Harrison et al., 2009). Since then, others have replicated this result using different rapamycin protocols (Delamater, 2006; Kwan et al., 2013). Rapamycin is a drug approved for human consumption as an immunosuppressant and chemotherapeutic agent (Guertin & Sabatini, 2009). It has a specific pharmacological target: rapamycin inhibits mTORC1 (Wullschleger et al., 2006; Zoncu, Efeyan, & Sabatini, 2011). As discussed previously, mTORC1 controls protein translation and autophagy. When rapamycin is administered to cells, or multicellular organisms, it reduces translation and increases autophagy (Bjedov & Partridge, 2011). Although these mechanisms were not shown to be responsible for the life span extension in mice per se, inhibition (by lower phosphorylation) of the downstream effector p70-S6K was shown as proof of mTORC1 inhibition (Harrison et al., 2009). Moreover, research in Drosophila showed that rapamycin treatment reduced translation and increased autophagy in vivo (Bjedov et al., 2010). These processes were shown to be required for the life span-extending properties of rapamycin, as overexpression of a constitutively active form of p70-S6K, or inhibition of autophagy (by RNAi-mediated knockdown of atg5), were sufficient to block the life span extending effects of rapamycin (Bjedov et al., 2010). Rapamycin has also been shown to extend the life span of yeast and worms (Powers, Kaeberlein, Caldwell, Kennedy, & Fields, 2006; Rallis, Codlin, & Bähler, 2013; Robida-Stubbs et al., 2012). The fact that a drug approved for human consumption can extend the life span of evolutionary diverse organisms has sparked interest in the identification of other drugs, already labeled for disease treatment, with antiaging properties. In addition to extending life span across evolutionary distant organisms, rapamycin treatment conferred resistance to the redox cycler paraquat and to starvation (Bjedov et al., 2010). Whether resistance to oxidative stress requires the up-regulation of autophagy and/or reduction of translation is still unclear. Resistance to starvation by rapamycin treatment did not seem to require 4E-BP, S6K inhibition or autophagy up-regulation, suggesting that the starvation phenotype is likely to be mTORC1 independent, or alternatively the processes downstream of mTORC1 should be simultaneously blocked (Bjedov et al., 2010). The effects of rapamycin have also been shown to modulate disease progression. For example, rapamycin treatment is protective in fly and mouse models of neurodegenerative disorders like Alzheimer's and Parkinson's diseases (Majumder, Richardson, Strong, & Oddo, 2011; Malagelada, Jin, Jackson-Lewis, Przedborski, & Greene, 2010; Spilman et al., 2010; Tain et al., 2009). It also rescues the cardiac and skeletal muscle defects associated with lamin A/C deficiency in mice (Ramos et al., 2012), age-related macular degeneration in rats (Kolosova et al., 2012), some forms of cancer (Johnson et al., 2013), among other age-related diseases. However, in spite of extending life span and protecting against age-related pathologies, rapamycin is associated with some complex side effects. These include immunosuppression, edema, dermatological abnormalities, and metabolic changes like hypertriglyceridemia, glucose intolerance, and reduced insulin sensitivity (Lamming, Sabatini, & Baur, 2013). Indeed, rapamycin also leads to increased triglyceride levels in Drosophila (Bjedov et al., 2010), which probably accounts for the starvation resistance-effect associated with rapamycin (Bjedov et al., 2010; Emran, Yang, He, Zandveld, & Piper, 2014). A recent study using mice showed that the metabolic side effects of rapamycin are likely to be secondary to mTORC2 inhibition, particularly in the liver (Lamming et al., 2012). In spite of the side effects, the success of rapamycin for promoting healthy aging has generated interest in rapalogs, drugs with similar structure and/or function to rapamycin. Indeed more selective inhibitors of mTORC1 may provide even greater benefits in promoting true healthy aging (Blagosklonny, 2012; Lamming et al., 2013).

3.2.2. Metformin and the Microbiota: Opening a can of Worms

The antidiabetic drug metformin has been shown to extend life span in C. elegans and mice, but not in Drosophila (Slack, Foley, & Partridge, 2012). Metformin supplementation late in life in mice was shown to increase median and maximum life span. This occurred in association with reduced cholesterol levels (total cholesterol and LDL), improved glucose tolerance and locomotor ability, increased antioxidant defense, and reduced markers of inflammation. The life span extension afforded by metformin in mice was not associated with altered mitochondrial respiratory complex function, but with AMPK activation. Interestingly, the transcriptional profile of animals treated with metformin showed similarities to the transcriptomic response of animals under DR (Martin-Montalvo et al., 2013). The first study to show life span extension by metformin was performed in C....
Praise for previous volumes in the series: ""Outstanding both in variety and in the quality of its contributions."--Nature "Can be highly recommended to geneticists, and biologists in general...will prove to be of high importance for the development of the science of genetics."--Science"

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