A Tour of Pharmaceuticals that Extend Life in Nematodes

Most threads of aging research start in studies of very short-lived species, most commonly the nematode worm C. elegans. These animals are cheap to maintain over the course of a study, live for only a few weeks, and are probably better understood at the cellular and genetic level than any other species. A mature and continually improving infrastructure of automation and provision exists to serve scientists running nematode studies. Despite the vast gulf between humans and nematodes many of the fundamental cellular mechanisms of metabolism are similar. Both degenerative aging and the basic structure of animal cells arrived early on in the evolution of multicellular life. Thus most of the better known phenomena of aging, such as the slowing of aging induced by calorie restriction, are preserved across near all species, whether nematodes or mammals. Researchers have learned a great deal about the fundamentals of aging by studying nematodes, and it makes good sense to pursue uncertain ideas with an unknown likelihood of success in a low-cost environment before moving to much more expensive mammalian studies.

Over the past twenty years researchers have developed scores of ways to slow aging and extend life in nematodes, some of which have translated to some degree into mice. There are outright genetic alterations and drugs that tweak some of the same levers of metabolism: genes produce protein that serve as machinery and signals, and a drug can be tailored to produce a similar effect to that of a genetic alteration upon the circulating levels of a specific protein. In many cases the goal isn't to find ways to extend life but rather to gain insight into portions of metabolism that would otherwise remain opaque, and it happens that slowing aging can be very useful for that purpose. Nematodes may be perhaps the most cataloged and understood form of life on the planet, but it remains that case that the present model of the operation of metabolism is woefully incomplete. There is a long way to go yet towards the grail of a complete, enormously complicated catalog of every last detail of the metabolism of a complete individual and how it changes over the course of aging.

Fortunately we don't need that catalog in order to build effective means to treat degenerative aging. Researchers just need the list of fundamental differences, forms of damage, that distinguish old tissues from young tissues. That list is much less complicated and essentially complete today. All that needs to be done is build therapies that can repair the damage: still a huge project, but well within the budget of the medical research community, something that might be completed in a decade or two were researchers to start in earnest today. If we want to safely slow down aging by altering the operation of metabolism, however, then the research community really would need to establish much more of the vast and incomplete catalog of metabolic processes. No-one has the knowledge today to produce a good plan for recreating even calorie restriction, the most studied altered state of metabolic operation. No-one has the knowledge to even estimate how long it would take to produce such a plan, or what it would look like. Scientists are a long, long way away from being able to safely alter metabolism to slow aging in a deliberate and planned way.

What researchers do have is a panoply of drugs that happen to alter some of the same mechanisms involved in the calorie restriction response, or produce other related changes in the biochemistry of nematode worms. All have side-effects, and none are resulting in exactly the same changes as are produced actual calorie restriction. When you mine the natural world for compounds that happen to do more good than harm, you take what you get. Again, you should probably look upon all this work as an investigation of metabolism that helps to build the grand catalog, not efforts aimed at producing treatments to extend life. Life extension is not a primary goal for most researchers in the field.

Pharmacological classes that extend lifespan of Caenorhabditis elegans

As a consequence of the seminal discoveries demonstrating that lifespan can be modulated by genes, it became clear that lifespan might also be extended using chemicals. This concept has certainly been demonstrated, and today many compounds have been identified that extend lifespan in model organisms such as worms, flies and even mice. Among all of these model organisms, Caenorhabditis elegans stands out because of the large variety of compounds known to extend lifespan. It is now possible to group these compounds into pharmacological classes, and use these groupings as starting points to search for additional lifespan extending compounds. For many of these compounds, mammalian pharmacology is known, and for some the actual targets have been experimentally identified.

There are two fundamentally different approaches to identify compounds that have a desired biological effect. These two approaches are often referred to as forward and reverse pharmacology, analogous to forward and reverse genetics. Forward pharmacology approaches, also called phenotypic screens, screen for compounds that elicit a desired phenotype, like the extension of lifespan. While forward pharmacology is intuitively appealing, as it searches for the desired effect, it has a number of drawbacks. The first is that screens must generally be conducted in vivo. In vivo screens are more complex, generally longer, and have higher costs associated than in vitro screens. Even if these disadvantages are overcome, elucidating the mechanisms by which a hit-compound achieves the desired effect is difficult. Elucidating drug mechanisms generally requires the identification of the drug target, which even today represents a major challenge (i.e., the binding target of the compound).

Reverse pharmacology circumvents the problem of target identification by screening for compounds that bind to, or inhibit, the function of a specific protein target. Reverse pharmacology screens are largely done in vitro, and offer the ability to screen very large chemical libraries (+500,000). Targets are validated based on prior knowledge, such as genetic studies in model organisms or gene association studies in humans affected by the disease. However, target validation, or choosing the protein target against which to develop a drug, also poses considerable difficulties. As the process of aging is not easily replicated in vitro, most lifespan extending compounds have been identified by simply testing whether or not a given compound extends lifespan in a model organism (forward pharmacology). Thus far, most compounds that have been tested for their ability to extend lifespan had prior known pharmacology. Initially, these compounds were developed to inhibit a specific target, independent of their effect on aging. Only later were they tested for their ability to extend lifespan in C. elegans or other organisms. Thus, at its current state, the pharmacology of aging is a hybrid of forward and reverse pharmacology.

Antioxidants

Because of Harman's theory of oxidative stress, antioxidants were some of the first compounds to be tested for their ability to extend lifespan. Indeed, antioxidants that extend C. elegans lifespan have been identified. These findings initially lent support to the idea that oxidative stress causes aging. However, later experiments guided by the theory of hormesis have challenged this view of aging. While lifespan extending antioxidants were found based on candidate approaches, unbiased screens testing many pharmacological classes for their ability to extend C. elegans lifespan did not result in any lifespan extending antioxidants. This observation suggests that, as a pharmacological class, antioxidants may not be a particularly strong candidate for identification of lifespan extending compounds.

Metabolites

The first ever intervention found to verifiably extend lifespan was dietary restriction. Thus, dietary restriction immediately linked the process of aging to metabolism. In recent years, metabolites have received increased interest, due in part to technical advances in metabolomics and the identification of metabolic enzymes important in the determination of lifespan. Today, multiple metabolites are known that play a role in the determination of adult lifespan.

Kinase Inhibitors

The first cloned gene found to be important for lifespan determination was the class-I phosphatidylinositol 3-kinase age-1. In addition to age-1, numerous mutations in various kinases have been found to extend C. elegans lifespan, including the receptor tyrosine kinase daf-2, akt-1, TOR, and S6 kinase, to name a few. Mutations in kinases like age-1 and the insulin/IGF receptor daf-2 cause some of the most dramatic effects on lifespan. As mutations in kinases are also frequently found in cancers and other diseases many kinase inhibitors were found to extend C. elegans lifespan with the most promising being rapamycin. However, thus far none of the tested kinase inhibitors has been able to reproduce the spectacular longevity seen in age-1 or daf-2 mutants.

Nuclear Hormone Receptors

Nuclear hormone receptors are an important class of regulatory proteins that activate or repress gene expression patterns in response to cellular signals. The fact that these signals generally consist of small molecules, like steroid hormones, makes nuclear hormone receptors important drug targets. One problem with studying nuclear hormone receptors using C. elegans is its vastly expanded repertoire of 284 nuclear hormone receptors, compared to 49 in mammals making it difficult to translate C.elegans findings to mammals.

G Protein Coupled Receptor Ligands

Compounds affecting GPCR are among the most important pharmacological classes for drug discovery. In medium scale screens for compounds with known pharmacology that extend lifespan, 50% of all hit compounds targeted GPCRs. It appears that GPCRs exist that must be active during development in order to affect lifespan when blocked in adults, probably because their function is to modulate lifespan in response to environmental change.

Natural Compounds

What makes a natural compound approach attractive is that plant extracts are generally regarded as safe, and are often used as food supplements. However, natural compounds are hard to synthesize and modify, and thus target identification is particularly difficult for natural compounds. The ongoing dispute on the mechanism of action of resveratrol certainly gives testimony on such difficulties.

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