Anti-Aging Drug

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Anti-Ageing Drugs

Background

Medicaments could one day slow down and reverse the ageing process in humans. Among the most ignored medical findings are that the biological ageing process is the greatest risk factor for life-threatening diseases such as atherosclerosis, cancer, dementia, and diabetes [Perez-Jimenez+Al:2005]. Logically it follows that we should interfere with the ageing process, instead of trying to treat one disease after the other. Anti-ageing strategies can therefore be viewed as an extension of medicine.

A review of recent research results indicate the following: Firstly, defined genetic mutations can prolong the lifespan and delay age-related disease [Mari:2011]. These genes could be targeted by therapeutics. A change in the receptors for growth factor hormone can for instance increase the lifespan of mice and inhibit tumourigenesis in humans [Coschigano+Al:2000] [Bonkowski+Al:2006] [Arum+Al:2009] [List+Al:2011] [Coschigano+Al:2003] [Zhou+Al:1997] [Kinney+Al:2001] [Guevara-Aguirre+Al:2011]. Secondly, in humans who are older than 100 - a feature that is partly inheritable - age-related diseases occur in later years [Deluty+Al:2015]. Thirdly, a significant reduction in caloric intake extends the lifespan and delays the incidence of chronic diseases in a range of animal species [Tocchetti+Al:2010]. Fourthly, compounds such as metformin [Martin-Montalvo+Al:2013], acarbose [Harrison+Al:2014], and rapamycin [Anisimov+Al:2011a] among others extend the lifespan and delay the occurrence of cancer and dementia in mice. From these observations it is possible to draw the conclusion that age-related diseases can be treated all at once, by modifying the basic ageing process using a therapeutic approach.

There are several major research programs to experimentally test compounds to determine their effect on ageing.The US National Institute of "Aging's Intervention Testing Program" (ITP) is a multi-institutional study on investigating treatments with the potential to extend lifespan and delay age-related disease and dysfunction by utilising lifespan experiments in mice [Nadon+Al:2016]. Secondly, a more recent international effort known as the Major Mouse Testing Program (MMTP) has been initiated from crowd funding campaigns [MMPT:2016].

Drugs that counteract ageing are often referred to as anti-ageing drugs or geroprotectors. Geroprotectors are therapeutics that aim to affect the root cause of ageing and thus treat age-related diseases all together, and therefore prolong the lifespan of organisms including humans [Fedichev+Al:2011].

Modification of the genome is very risky and extremely difficult to perform with prevision. Compounds that interfere with gene activity and metabolism are a more adequate approach.

Drug Discovery

A number of bioactive agents have been identified to have promising "anti-ageing" (geroprotective) effects. Usually a substance is considered to have ageing-modulating activity if its efficiency can be confirmed in vitro or in vivo.

A compound, or an intervention more generally, can be found to slow down the progression of a certain age-related change or reverse the change by reducing the quantity of this change / these changes. However, genuine anti-ageing drugs need to fulfil the criteria of being capable of extending the lifespan of an organism and especially prolonging the maximum lifespan.

Anti-ageing drugs can be identified in a variety of ways. One way is via molecular interactions with the protein products of ageing-related genes. Another approach is utilising gene expression data that is based on the effect of the compounds on gene expression that might either mimic the effect of dietary restriction, long-lived mutants, germ line expression (which is said to be immortal or have rejuvenating effect) or reverse age-related, progeroid or senescent cell gene expression. Another method may be based on a higher level of abstraction where those compounds would have shown previously to reverse a specific age-related change (i.e. not only on the gene expression level).

As anti-ageing drugs interfere with the ageing process they are often effective against numerous age-related diseases. Further, the ageing process seems to be a very ancient and evolutionarily conserved process. Drugs that are shown to be effective in slowing down or reversing ageing in multiple model organisms, including rodents, might also be effective in humans. Lifespan experiments in humans are feasible, but not practical. Therefore biomarkers of ageing are necessary that can serve as proxy indicators of the rate of ageing. Thus drugs can be tested for their efficiency in reversing certain age-related changes or effectiveness in alleviating age-related diseases. Aged individuals are suitable for any such clinical trials in order to test whether those compounds are capable of reversing the ageing process for these individuals as those individuals have already experienced the effects of ageing. To acquire evidence that the rate of ageing can be slowed would require young individuals being given such drugs. Also the possibility to affect premature ageing diseases or cellular senescence would be a good indication. Although premature ageing may be a special condition not indicative of ageing in the general population.

Classes of Anti-Ageing Drugs

With regard to the mechanism of action, anti-ageing drugs might be classified into defined groups broadly based on the type of anti-ageing strategy. This is primarily attributed to their assumed mode of action.

Possible geroprotectors include resveratrol, sirolimus (i.e. rapamycin; and its derivatives), metformin, spermidine, aspirin (including membrane penetrating aspirin), NAD, lipoic acid, ibuprofen, and carnosine, among many others. Many of those compounds can be classified to be belonging to multiple of those classes (not an exhaustive list):

  • Antioxidant
  • AGE-inhibitor/breaker
  • Pharmacoperone
  • Hormetin
  • Senolytic
  • DR-mimetic
  • Telomerase-Activating Component
  • Sirtuin-Activating Compound (STAC)
  • Histone Deacetylase Inhibitor (HDACi)

Most of those have been shown to extend the lifespan in at least one of multiple model organisms. For instance, Drosophila fed a biotin diet exhibit a 30% increase in lifespan [Smith+Al:2007]. Also for example long-term treatment with epithalamin in humans decelerates ageing of the cardiovascular system, prevents age-associated impairment of physical endurance, normalizes circadian rhythm of melatonin production and carbohydrate as well as lipid metabolism. Epithalamin significantly lowers mortality in coronary patients, which indicates that it has a geroprotective effect [Korkushko+Al:2011].

Antioxidants scavenge free radicals. Supplementation with some specific antioxidants failed to extend the lifespan, but certain antioxidants that were specifically targeted to the mitochondria were found to moderately extend lifespan in specific strains of mice [Anisimov+Al:2011b].

Yet other kinds of compounds were discovered based on their ability to reduce/eliminate specific types of accumulations of harmful aggregates. Glucose and other reducing sugars tend to react non-enzymatically with proteins leading to the generation of advanced glycosylation endproducts (AGEs) and induce AGE-derived protein cross-linking. AGEs build up slowly and accumulate with ageing which contribute to various pathological events and age-related disease (including nephropathy, retinopathy, vasculopathy and neuropathy). AGE-inhibitors and breakers are components that inhibit the formation of AGEs or disrupt the pre-formed AGE-protein cross-links, respectively. AGE-breakers in particular are a class of drugs that break the bonds of advanced glycation end-products. The AGE-inhibitor pimagedine and the cross-link breaker ALT-711 have been shown in animal models and preliminary clinical trials to reduce the severity of pathologies of advanced glycosylation [Vasan+Al:2001].

Pharmacoperones are small pharmacological chaperones that enter cells and serve as a molecular scaffolding in order to fold and route misfolded proteins. For instance, the amyloid-binding dye Thioflavin T can profoundly extend the median (60%) and maximal lifespan (43–78%) lifespan of Caenorhabditis elegans and therefore slow down ageing [Alavez+Al:2011].

Many compounds have been identified by a reductionist approach of being able to stimulate or inhibit a certain class of gene/protein product that itself exhibits anti-ageing or ageing-promoting effect. Resveratrol was identified based on its ability to stimulate sirtuins (hence the term Sirtuin-Activating Compound; STACS) [Bonkowski+Sinclair:2016]. Metformin activates AMP-activated protein kinase α (AMPK) [Onken+Driscoll:2010]. TA-65 (a.k.a. cycloastragenol) was specifically developed to activate telomerase [Bernardes_de_Jesus+Al:2011] Salvador+Al:2016]_. Sirolimus (rapamycine) was found to inhibit the target of rapamycin (TOR) [Anisimov+Al:2011a]. Sodium butyrate is a histone deacetylase inhibitor [Vaiserman+Al:2012].

Other compounds were found to induce certain kind of processes that are known to have rejuvenating/repairing activities. For example, spermidine was found for its ability to stimulate autophagy [Eisenberg+Al:2009].

Senolytic drugs (senolytics), like dasatinib and quercetin, are drugs that selectively induce death of senescent cells. Dasatinib eliminates senescent human cell progenitors. Quercetin eliminates senescent human endothelial cells and mouse bone marrow stem cells [Quick:2015].

Anti-cancer drugs selectively kill cancer cells. Some natural compounds, such as curcumin, exhibit cancer-killing properties.

Another class of drugs are those that mimic the effect of dietary restriction (so called dietary restriction or caloric/calorie restriction mimetics) such as alpha-lipoic acid which can mimic or even block the effect of dietary restriction. alpha-lipoic acid is also an inhibitor of histone deacetylases leading to hyperacetylated state of a range of proteins as does the classical dietary restriction feeding regimen [Merry+Al:2008].

Mixtures of components are found to be effective in lifespan extension even when the active ingredient is unknown. For instance, cranberry extract [Guha+Al:2013] [Guha+Al:2014] promotes healthspan and increases the lifespan by 8.2-80.9% and in C. elegans. Similar different Ilex paraguariensis extracts robustly extend average lifespan to varying degrees [Lima+Al:2014].

Brute-Force Drug Discovery: Drug Screening

A way of identifying new anti-ageing drugs would be to screen small-molecule libraries via lifespan tests in lower model organisms. An issue would be the selection of the correct dose and the test species. Any drug can be toxic if applied at too high a dose, which would mask its anti-ageing effect. Similarly if too low doses are used no significant effect might be detected. It is advantageous to start screening with a model organism that has a short lifespan. One could start screening in one of the simplest eukaryotic organisms such as budding yeast. Assays can be conducted to increase its replicative or chronological lifespan. Such compounds identified could be screened in nematode species, which have a lifespan of about 30 days and also in the fruit fly which have a lifespan of 80 days. An important consideration is the amount of labour required to conduct life-time studies. Ideally robots can be used to conduct the lifespan assays in a high-throughput manner. Promising compounds so identified would then be required to be tested in a short-lived mammal, such as a number of mouse strains, to verify its effectiveness in retarding mammalian ageing. In order to get results in a quicker time frame it is suggested to start applying the drug in adult organisms and see to what extent they are able to modify the remaining lifespan. Biomarkers of ageing and health can be used even earlier to detect anti-ageing properties and reverse signs of ageing (i.e. rejuvenate). In humans starting with already old individuals and assessing ageing biomarkers seems to be the most practical way of testing the effect of anti-ageing drugs. Drugs can for instance quickly be tested for the ability to rejuvenate the immune system in already aged humans [Mannick+Al:2014].

Without performing lifespan assays drugs can be tested for the ability to reverse different classes of age-related changes. Gene expression profiling can be used to check whether those candidate drugs are able to reset gene expression patterns to that of a young organism when applied to old ones [Merry+Al:2008].

Targeted Drug Discovery

Targets for small-molecule interventions can be identified using bioinformatics. For instance proteins in pathways containing the greatest numbers of genes responsible for lifespan control are attractive targets (e.g. via guilt-by-association).

Modern structure-based drug discovery then enables the identification of novel compounds readily testable in in vitro models of age-related diseases in lifespan-measuring experiments in multiple organisms. An initial screen can be conducted via genetic means, such as with knockout/overexpression libraries or via gene silencing with whole organisms or just single cells (cell culture). The identified target genes can be used to test drugs that are known to specifically act on those or new drugs can be developed that are likely to enhance or inhibit those gene products.

Pitfalls

There are several pitfalls that need to be taken into account for developing effective anti-ageing drugs:

  • Interventions that target "private" mechanisms of ageing
  • Involuntary DR
  • Hormetic response
  • Dose
  • Drug-drug interactions

Some common pitfalls in drug discovery for anti-ageing are that the compound may only extend the lifespan in a single type of model organism as it affects a private mechanism of ageing only operating in this model organism type. Therefore validation in multiple organisms is good indication that it acts via a shared mechanism across phyla.

Some pharmaceutical interventions may provoke dietary restriction simply due to suppression of appetite or reduction of nutrient intake and therefore indirectly lead to lifespan extension but primarily via DR [Masoro:2007]. For this reason when testing for the lifespan effect of a compound it is useful to measure the food consumption and compare to controls in order to rule out lifespan extension by sole involuntary DR.

Another problem is hormesis. Even toxic substances might lead to lifespan extension by stimulating repair systems. Whether the hormetic response is additive is rather questionable. It may be so if different hormetins stimulate different repair systems.

A further and important issue is the one regarding the dose. Identification of the ideal dose of a drug requires the assessment of a dose response curve by testing different concentrations of the compound [Paracelsus:1965].

Lastly, the combination of many drugs might need to consider network effects as possible unwanted drug-drug interaction may occur and different drugs may cancel each other out. Ideally would be the identification of drugs that are synergistic with each other and do not cause any unwanted side effects when combined together. The transition from reductionism to a system-oriented perspective and utilization of systematic approaches in modern biogerontology may result in the development of ageing-modulating treatments [Vaiserman:2014].

Developing anti-ageing drugs is possible and harbours a huge potential. There are different ways of developing drugs against ageing. There are also different types of drugs that can be found to slow down and reverse certain classes of age-related changes. Defined pitfalls need to be paid attention to discover genuine powerful anti-ageing drugs. Testing in multiple model organisms and the assessment of biomarkers of ageing are recommended. Because of the huge search space (number of components and tests to perform) computational approaches are desirable to narrow down the number of potential candidates and needed experiments in order to speed up effective drug identification.

References

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