paul bunyan
Frostbite Falls, Minnesota
Hello Troops,
Time for some more amazing research information that may improve your brain function or increase you life span.
Yes, I know that Social Security and Our Current Constitution may go away soon
so why live longer? Well, I know there are a few positive thinkers out there that could use this data.
I am sure your Nematodes ( ie C. elegans ), round and flat worms, will appreciate the diet changes
even if your old bod does not.
PMC full text:
Ageing Res Rev. Author manuscript; available in PMC 2014 Jan 1.
Published in final edited form as:
Ageing Res Rev. 2013 Jan; 12(1): 445–458.
Published online 2012 Jul 6. doi: 10.1016/j.arr.2012.06.006
The edited text of the article follows, and the full article is over 150,000 characters so it will not fit and I am a computer tard
.
The bottom line is truly that.
A summary of all the compounds, drugs, herbs, chocolate and other tasty treats that are good for you and your worms is located at the bottom of the article as an attachment.
Feel free to jump down to the bottom and skip the chemical/ medical jargon!
As always,
YMMV
PB
Here you go:
Ageing Res Rev. Author manuscript; available in PMC 2014 Jan 1.
Published in final edited form as:
Published online 2012 Jul 6. doi: 10.1016/j.arr.2012.06.006
PMCID: PMC3552093
NIHMSID: NIHMS401906
Ageing Res Rev. 2013 Jan; 12(1): 445–458.
Pharmacological Lifespan Extension of Invertebrates
Mark Lucanic, Gordon J. Lithgow, and Silvestre Alavez
Author information ► Copyright and License information ►
The publisher's final edited version of this article is available at Ageing Res Rev
See other articles in PMC that cite the published article.
Abstract
There is considerable interest in identifying small, drug-like compounds that slow aging in multiple species, particularly in mammals. Such compounds may prove to be useful in treating and retarding age-related disease in humans. Just as invertebrate models have been essential in helping us understand the genetic pathways that control aging, these model organisms are also proving valuable in discovering chemical compounds that influence longevity. The nematode Caenorhabditis elegans (C. elegans) has numerous advantages for such studies including its short lifespan and has been exploited by a number of investigators to find compounds that impact aging. Here, we summarize the progress being made in identifying compounds that extend the lifespan of invertebrates, and introduce the challenges we face in translating this research into human therapies.
Keywords: Aging, chemical screening, drug discovery, lifespan, C. elegans, Drosophila
1. Introduction
Aging is the single largest risk factor for chronic disease in developed countries and is consequently responsible for an enormous social and economic burden. The development of therapies or preventive measures aimed at reducing or delaying age-related disease must be a priority for the biomedical community. However, the traditional models of drug discovery are failing when it comes to the major chronic diseases of the elderly. The disappointing outcomes of dozens of phase III clinical trials in Alzheimer’s disease and Parkinson’s disease, among others, suggest a general failure in our understanding of the mechanisms at play (Sperling et al., 2011). This has led some commentators to ask whether targeting aging mechanisms might lead to better outcomes.
Novel compounds that slow aging are highly sought after due to their potential for treating age related diseases. Here, we argue that recent growth of a new subfield, the chemical biology of aging, will lead to the identification of candidate compounds and mechanistic insights that will ultimately propel forward treatments of age related diseases. While identifying compounds that slow the aging of mammals is undoubtedly more relevant for human drug development, the prohibitive cost of mouse aging studies, make it extremely unlikely that large scale chemical screens will be carried out in mice.
Basic research in more cost effective model systems is therefore a critical starting point for identifying such compounds and elucidating their mechanism(s) of action. Cell culture and invertebrate model organisms provide opportunities to screen hundreds of thousands of chemical compounds in an efficient manner. Moreover, once candidate compounds are identified, the strengths of these model systems in molecular genetics, allows for rapid elucidation of the genetic pathways being targeted by these compounds.
In this review, we summarize the contribution of invertebrate models to our understanding of the pharmacology of aging, and speculate on the directions the field is headed in the imminent future. We will almost exclusively focus on C. elegans research, since most of the chemical biology of aging studies to date, have been conducted in the nematode. However, we will also discuss a limited number of pharmacological aging studies undertaken in the fruit fly Drosophila melanogaster (D. melanogaster).
2. General Consideration When Conducting Experiments to Identify Lifespan Extending Compounds
2.1 High-throughput chemical screens vs. candidate based approaches
In screening compounds for biological activity, investigators are often drawn to the idea of examining a wide range of chemical structures using high-throughput screens. Due to the prohibitive cost, labor and (for aging studies) the relatively long lifespan of the current vertebrate models, they are impractical for large scale chemical screens, particularly mice.
2.2 Choosing an appropriate model to identify lifespan extending compounds
2.2.1 In vitro based assays vs. whole organisms
In vitro biochemical or cell based assays have been the mainstay for decades of chemical screening. Such research has led to the identification candidate compounds that are of great interest to the aging community (Howitz et al., 2003) and will certainly continue to be an effective method of chemical screening.
2.2.2 Using C. elegans in chemical screens
Due to its ease of culture and short lifespan C. elegans is rapidly becoming the invertebrate model of choice for chemical tests on aging and age-related phenotypes. Indeed, C. elegans not only represents a model for assessing the biological effects of a large number of compounds, but the great number of genetic tools available in the nematode also make it a powerful system for determining the mechanism of action of known pharmacological treatments (Fitzgerald et al., 2006).
The organism’s relative simplicity and the wealth of knowledge of its biology, along with the large number of genetic tools available, make it an attractive organism for pharmacological research. The nematode has proved useful to assay both the compound’s bioactivity and for determining its mechanism of action. Additionally, its rapid growth and high fecundity make C. elegans well suited for high-throughput chemical screens.
2.2.3 Using Drosophila ( Fruit Fly ) in chemical screens
Screening large numbers of compounds in D. melanogaster, is more difficult than in C. elegans, but the existence of complex behavioral phenotypes and several good models of human age-related diseases in Drosophila, make such challenging endeavors worthwhile.
3. Summary of Aging Pathways That Can Serve as Targets for Lifespan Extending Compounds
Many compounds have now been identified that extend the lifespan of model organisms. Some of these have been discovered by conducting chemical screens in C. elegans, and Drosophila as mentioned above. For some of these compounds we merely know that they are capable of extending lifespan, for others we understand the biological mechanisms and longevity pathways involved. Before introducing the myriad of compounds capable of influencing lifespan, we first summarize the biological pathways implicated in mediating the lifespan extension effects of these compounds.
3.1 Regulation of oxidative stress and its effect on lifespan
Macromolecular oxidative damage is a feature of aging and is clearly a major component of age-related disease (Beckman et al., 1997). It has long been suggested as a cause of aging and a major determinate of lifespan. However, genetic manipulation of antioxidant functions has not provided a clear case for causality particularly in mammals (Bokov et al., 2004; Perez et al., 2009).
3.2 Role of protein homeostasis in promoting longevity
The formation of molecular aggregates is a long-studied phenomenon, shared among diverse human diseases. It is especially well studied in neurodegenerative conditions; here aberrant forms of proteins such as α-synuclein (in Parkinson’s), β-amyloid (in Alzheimer’s) and huntingtin (in Huntington’s) may contribute to disease progression (Selkoe, 2003). Aggregate formation is also observed in non-neurological systemic diseases like type II diabetes and several myopathies.
Indeed it has become clear over the last few decades that protein aggregate formation is a phenotypic hallmark of ageing. As organisms age their protein homoestasis networks degrade; the decrease in its fidelity with age has now been reported in many systems and is likely a major component of the aging of organisms.
3.3 Dietary Restriction and its effect on lifespan
Dietary restriction (DR) is a robust means of extending the lifespan of model organisms. In invertebrates the beneficial effects of DR are not merely restricted to lifespan extension, but also alleviate many of the age-related declines in motor function, stress resistance and protein homeostasis (Cohen et al., 2006; Kastman et al., 2010; Steinkraus et al., 2008; Valdez et al., 2010). The benefits derived from reduced food intake are the result of the modulation of several complex and only partially understood pathways.
3.4 Insulin/IGF like signaling and its effects on lifespan
Insulin/IGF like signaling (IIS) has been shown to be important for modulating lifespan. In fact, C. elegans genes in this pathway were the first to be shown to dramatically influence metazoan lifespan (Johnson and Wood, 1982; Kenyon et al., 1993; Kimura et al., 1997; Klass, 1983).
4. Identification of Compounds Capable of Extending Lifespan
4.1 Compounds that extend lifespan via regulation of oxidative stress
There are many published and unpublished accounts concerning the effects of antioxidant treatment on lifespan. One of the first carefully conducted demonstrations of lifespan extensions as a consequence of compound treatment was provided in D. melanogaster (Brack et al., 1997) where it was shown that dietary uptake of the antioxidant and glutathione precursor N-acetylcysteine (NAC) results in a dose-dependent increase in median and maximum life span of up to 27%.
4.2 Compounds that modulate protein homeostasis
Aggregation models, particularly those generated in C. elegans, have recently been used to assay the effects of pro-longevity compounds. Interestingly, many of the compounds that extend lifespan also cause a decrease in protein aggregation. For instance, celecoxib, which increases lifespan in worms through modulation of IIS, also decreases polyglutamine accumulation and improves the paralysis associated with aggregation of this peptide (Ching et al., 2011).
4.3 Compounds that effect DR pathways and mediate lifespan extension
Reports of lifespan extension in multiple model organisms by the TOR pathway inhibitor rapamycin, has provided motivation to identify more such pharmacological modulators of DR pathways (Harrison et al., 2009).
4.4 Compounds that effect IIS pathways and mediate lifespan extension
Many of the chemicals shown to modulate lifespan through IIS are known drugs or natural compounds that have been used in traditional healing practices and supplements associated with alternative medicine. Natural products represent an untapped reservoir filled with great therapeutic potential. Natural compounds may hold particular promise because they are likely to have been subject to evolutionary pressure to sustain biological activity, and therefore have a high probability of influencing animal physiology. Several such compounds have been found to affect the lifespan of C. elegans in an IIS dependent manner.
Flavonoids are a class of plant derived polyphenols that share a common sub-structure, and have been widely reported to affect mammalian physiology; among these are quercetin and catechin, both of which seem to impact the IIS signaling pathway. Quercetin is widely distributed in edible fruits, vegetables and plants and may increase C. elegans lifespan by increasing the worms’ resistance to several kinds of cellular stresses (Kampkotter et al., 2008; Pietsch et al., 2009).
4.5 Compounds that affect lifespan extension by as yet undetermined means
Many other natural products have recently been tested for their ability to modulate C. elegans’ lifespan. While several of these have been reported to require IIS pathways, some of these compounds appear to work in an IIS independent manner. A series of experiments in Drosophila have shown that extracts from the Damask rose, Rosa damascena have lifespan extending effects in Drosophila with no obvious detriment on quality of life measures (Jafari et al., 2008; Schriner et al., 2011). Blueberry extracts which contain complex mixtures of polyphenols have also been shown to extend the lifespan of both C. elegans, in a DAF-16 independent manner, and D. melanogaster (Peng et al., 2012; Wilson et al., 2006).
5 Translating Chemical Biology of Aging Studies from Invertebrates to Humans
5.1 General Challenges That Impede the Discovery of Drugs Capable of Extending Human Lifespan
If the motivation for discovering compounds capable of extending the lifespan of invertebrates is ultimately to improve human health, then we must address how the basic experiments described here are to be translated into clinical research. Many investigators choose to study natural products, possibly because they wish to understand the mechanistic action of these products, but also perhaps due to the fact that FDA approval of edible natural product is considerably less complex and costly than approval of synthetic compounds. Others often begin even one step closer, by studying already approved human drugs, and examining whether they have an effect on invertebrate lifespan. Still, one of the biggest obstacles to stand between pharmacological research in invertebrates and ultimate human drug development is the intermediary step of testing compounds in mammalian models. Testing the ability of drugs to extend the lifespan of mice is expensive, especially when one considers its relatively long lifespan. This points to the need to choose compounds to be tested in mammals in a directed manner, so that a limited number of promising candidates can be tested in a cost effective manner, and further highlights the importance of invertebrate models in meeting such challenges.
6 Ways to Circumvent Challenges
6.1 Working Backwards: Testing Human Drugs for Lifespan Extension in Invertebrates
One way to expedite the discovery of drugs capable of extending the lifespan of humans is to begin by examining existing human drugs for their ability to extend the lifespan of invertebrates. Once these drugs have been verified to extend invertebrate lifespan, and the mechanism(s) by which they extend lifespan is determined, the likelihood that they might extend mammalian lifespan can be assessed.
6.2 Anticonvulsants
In 2005, Kerry Kornfeld and colleagues described a small chemical screen of drugs with known influence on human physiology for effects on C. elegans lifespan (Evason et al., 2005). The authors found that the anticonvulsant ethosuximide had a potent effect on the lifespan of worms.
6.3 Anti-depressants
In search of small molecules that extend the lifespan of C. elegans, Petrascheck and colleagues discovered a lifespan extending compound that bears structural similarity to known antidepressants of the serotonin receptor antagonist type (Petrascheck et al., 2007). They found that several of these known human drugs, also extend lifespan.
6.4 Anti-inflammatories
Celecoxib is a non-steroidal anti-inflammatory (NSAID), originally developed as a cyclooxygenase 2 inhibitor. However, it was suspected of having additional targets including PDK-1, a known component of IIS (Hsu et al., 2000; Zhu et al., 2004).
6.5 Anti-diabetics
The anti-diabetic drug metformin, a chemical of the biguanide class, has been found to extend the lifespan of C. elegans through a DR type mechanism (Onken and Driscoll, 2010).
6.6 Start out in Mice: Identification of Compounds that Extend the Lifespan of Mice
The current excitement surrounding the development of drugs that target aging processes, is partly attributable to the realization that mammalian lifespan can be extended with small molecules. For example, male, but not female lifespan can be increased by feeding mice nordihydroguaiaretic acid and aspirin (2-acetoxybenzoic acid) (Strong et al., 2008). In addition, the immunosuppressant rapamycin inhibits mTOR signaling and is able to increase lifespan in both male and female mice when administered late in life (Harrison et al., 2009; Miller et al., 2011).
6.7 Choosing Lifespan Extending Candidates from Invertebrate Models to be Tested in Mammalian Systems
While initially testing compounds in mice means that any discoveries are more likely to be relevant for drug development in humans, the prohibitive cost of mouse aging studies make it extremely impractical to carryout large scale chemical screens in mice. It is difficult to select candidates a priori based on their perceived likely hood of success. However, several criteria can be described that, if completely fulfilled, should immediately promote an effective invertebrate treatment into testing on mammals. First of all, the mechanism should be defined and found to be non-idiosyncratic for the model. That is, the chemical treatment should have a known mechanism that targets a conserved pathway important for aging in multiple models. Additionally, the response should be robust, should show a dose response and should be effective at multiple points during the lifespan.
7 The Challenge of Translation
If one of the goals of pharmacological lifespan extension in invertebrates is to improve human health then we must address how the basic experiments described here are to be translated into clinical research or healthy dietary choices. It is clear that many investigators choose to study natural products. This in part may come from the need to develop a mechanistic understanding of the action of natural products but also may be because the regulatory path to human use is considerably less complex and costly.
One of the biggest hurdles is the testing of compounds in mammalian models. The cost to individual investigators of a mouse aging study makes it unlikely that large numbers of compounds will be tested in the near future. It is difficult to select the best high value candidate compounds, which highlights the need for an ever more detailed understanding of the mechanisms at play. The invertebrate models can provide this information. Most critical, is the issue of whether the mechanism of action is likely to be conserved between invertebrates and mammals. By determining the mechanisms at play and uncovering which factors (intracellular signaling pathways, transcription factors, etc.) are required for compound action, research in the invertebrates could provide high value compounds for mammalian studies.
One area of small molecule research in invertebrate aging has received little attention; the role of metabolism in compound action. Future studies should take standard pharmacokinetics into account and consider the role of modifications to compounds on the observed biological action. Classical pharmacokinetics is difficult in invertebrates mainly because of the lack of circulatory systems and the difficultly in dissecting individual tissues; animals usually have to be pulled to provide enough material for analysis. However, this should not be an insurmountable barrier to basic metabolic studies.
The need to develop therapies and preventions for age-related disease is great. Recent demonstration of lifespan extension with rapamycin in the mouse (Harrison et al., 2009), as well as the demonstration that resveratrol induces metabolic changes in obese humans that mimic the beneficial effect of DR (Timmers et al., 2011) provide some very encouraging examples of how discoveries in invertebrates can be translated into pre-clinical and clinical research. There is a bright future for this approach and a clear role to be played by the invertebrate models.
Time for some more amazing research information that may improve your brain function or increase you life span.
Yes, I know that Social Security and Our Current Constitution may go away soon
so why live longer? Well, I know there are a few positive thinkers out there that could use this data.I am sure your Nematodes ( ie C. elegans ), round and flat worms, will appreciate the diet changes
even if your old bod does not.PMC full text:
Ageing Res Rev. Author manuscript; available in PMC 2014 Jan 1.
Published in final edited form as:
Ageing Res Rev. 2013 Jan; 12(1): 445–458.
Published online 2012 Jul 6. doi: 10.1016/j.arr.2012.06.006
The edited text of the article follows, and the full article is over 150,000 characters so it will not fit and I am a computer tard
.The bottom line is truly that.
A summary of all the compounds, drugs, herbs, chocolate and other tasty treats that are good for you and your worms is located at the bottom of the article as an attachment.
Feel free to jump down to the bottom and skip the chemical/ medical jargon!
As always,
YMMV
PB
Here you go:
Ageing Res Rev. Author manuscript; available in PMC 2014 Jan 1.
Published in final edited form as:
Published online 2012 Jul 6. doi: 10.1016/j.arr.2012.06.006
PMCID: PMC3552093
NIHMSID: NIHMS401906
Ageing Res Rev. 2013 Jan; 12(1): 445–458.
Pharmacological Lifespan Extension of Invertebrates
Mark Lucanic, Gordon J. Lithgow, and Silvestre Alavez
Author information ► Copyright and License information ►
The publisher's final edited version of this article is available at Ageing Res Rev
See other articles in PMC that cite the published article.
Abstract
There is considerable interest in identifying small, drug-like compounds that slow aging in multiple species, particularly in mammals. Such compounds may prove to be useful in treating and retarding age-related disease in humans. Just as invertebrate models have been essential in helping us understand the genetic pathways that control aging, these model organisms are also proving valuable in discovering chemical compounds that influence longevity. The nematode Caenorhabditis elegans (C. elegans) has numerous advantages for such studies including its short lifespan and has been exploited by a number of investigators to find compounds that impact aging. Here, we summarize the progress being made in identifying compounds that extend the lifespan of invertebrates, and introduce the challenges we face in translating this research into human therapies.
Keywords: Aging, chemical screening, drug discovery, lifespan, C. elegans, Drosophila
1. Introduction
Aging is the single largest risk factor for chronic disease in developed countries and is consequently responsible for an enormous social and economic burden. The development of therapies or preventive measures aimed at reducing or delaying age-related disease must be a priority for the biomedical community. However, the traditional models of drug discovery are failing when it comes to the major chronic diseases of the elderly. The disappointing outcomes of dozens of phase III clinical trials in Alzheimer’s disease and Parkinson’s disease, among others, suggest a general failure in our understanding of the mechanisms at play (Sperling et al., 2011). This has led some commentators to ask whether targeting aging mechanisms might lead to better outcomes.
Novel compounds that slow aging are highly sought after due to their potential for treating age related diseases. Here, we argue that recent growth of a new subfield, the chemical biology of aging, will lead to the identification of candidate compounds and mechanistic insights that will ultimately propel forward treatments of age related diseases. While identifying compounds that slow the aging of mammals is undoubtedly more relevant for human drug development, the prohibitive cost of mouse aging studies, make it extremely unlikely that large scale chemical screens will be carried out in mice.
Basic research in more cost effective model systems is therefore a critical starting point for identifying such compounds and elucidating their mechanism(s) of action. Cell culture and invertebrate model organisms provide opportunities to screen hundreds of thousands of chemical compounds in an efficient manner. Moreover, once candidate compounds are identified, the strengths of these model systems in molecular genetics, allows for rapid elucidation of the genetic pathways being targeted by these compounds.
In this review, we summarize the contribution of invertebrate models to our understanding of the pharmacology of aging, and speculate on the directions the field is headed in the imminent future. We will almost exclusively focus on C. elegans research, since most of the chemical biology of aging studies to date, have been conducted in the nematode. However, we will also discuss a limited number of pharmacological aging studies undertaken in the fruit fly Drosophila melanogaster (D. melanogaster).
2. General Consideration When Conducting Experiments to Identify Lifespan Extending Compounds
2.1 High-throughput chemical screens vs. candidate based approaches
In screening compounds for biological activity, investigators are often drawn to the idea of examining a wide range of chemical structures using high-throughput screens. Due to the prohibitive cost, labor and (for aging studies) the relatively long lifespan of the current vertebrate models, they are impractical for large scale chemical screens, particularly mice.
2.2 Choosing an appropriate model to identify lifespan extending compounds
2.2.1 In vitro based assays vs. whole organisms
In vitro biochemical or cell based assays have been the mainstay for decades of chemical screening. Such research has led to the identification candidate compounds that are of great interest to the aging community (Howitz et al., 2003) and will certainly continue to be an effective method of chemical screening.
2.2.2 Using C. elegans in chemical screens
Due to its ease of culture and short lifespan C. elegans is rapidly becoming the invertebrate model of choice for chemical tests on aging and age-related phenotypes. Indeed, C. elegans not only represents a model for assessing the biological effects of a large number of compounds, but the great number of genetic tools available in the nematode also make it a powerful system for determining the mechanism of action of known pharmacological treatments (Fitzgerald et al., 2006).
The organism’s relative simplicity and the wealth of knowledge of its biology, along with the large number of genetic tools available, make it an attractive organism for pharmacological research. The nematode has proved useful to assay both the compound’s bioactivity and for determining its mechanism of action. Additionally, its rapid growth and high fecundity make C. elegans well suited for high-throughput chemical screens.
2.2.3 Using Drosophila ( Fruit Fly ) in chemical screens
Screening large numbers of compounds in D. melanogaster, is more difficult than in C. elegans, but the existence of complex behavioral phenotypes and several good models of human age-related diseases in Drosophila, make such challenging endeavors worthwhile.
3. Summary of Aging Pathways That Can Serve as Targets for Lifespan Extending Compounds
Many compounds have now been identified that extend the lifespan of model organisms. Some of these have been discovered by conducting chemical screens in C. elegans, and Drosophila as mentioned above. For some of these compounds we merely know that they are capable of extending lifespan, for others we understand the biological mechanisms and longevity pathways involved. Before introducing the myriad of compounds capable of influencing lifespan, we first summarize the biological pathways implicated in mediating the lifespan extension effects of these compounds.
3.1 Regulation of oxidative stress and its effect on lifespan
Macromolecular oxidative damage is a feature of aging and is clearly a major component of age-related disease (Beckman et al., 1997). It has long been suggested as a cause of aging and a major determinate of lifespan. However, genetic manipulation of antioxidant functions has not provided a clear case for causality particularly in mammals (Bokov et al., 2004; Perez et al., 2009).
3.2 Role of protein homeostasis in promoting longevity
The formation of molecular aggregates is a long-studied phenomenon, shared among diverse human diseases. It is especially well studied in neurodegenerative conditions; here aberrant forms of proteins such as α-synuclein (in Parkinson’s), β-amyloid (in Alzheimer’s) and huntingtin (in Huntington’s) may contribute to disease progression (Selkoe, 2003). Aggregate formation is also observed in non-neurological systemic diseases like type II diabetes and several myopathies.
Indeed it has become clear over the last few decades that protein aggregate formation is a phenotypic hallmark of ageing. As organisms age their protein homoestasis networks degrade; the decrease in its fidelity with age has now been reported in many systems and is likely a major component of the aging of organisms.
3.3 Dietary Restriction and its effect on lifespan
Dietary restriction (DR) is a robust means of extending the lifespan of model organisms. In invertebrates the beneficial effects of DR are not merely restricted to lifespan extension, but also alleviate many of the age-related declines in motor function, stress resistance and protein homeostasis (Cohen et al., 2006; Kastman et al., 2010; Steinkraus et al., 2008; Valdez et al., 2010). The benefits derived from reduced food intake are the result of the modulation of several complex and only partially understood pathways.
3.4 Insulin/IGF like signaling and its effects on lifespan
Insulin/IGF like signaling (IIS) has been shown to be important for modulating lifespan. In fact, C. elegans genes in this pathway were the first to be shown to dramatically influence metazoan lifespan (Johnson and Wood, 1982; Kenyon et al., 1993; Kimura et al., 1997; Klass, 1983).
4. Identification of Compounds Capable of Extending Lifespan
4.1 Compounds that extend lifespan via regulation of oxidative stress
There are many published and unpublished accounts concerning the effects of antioxidant treatment on lifespan. One of the first carefully conducted demonstrations of lifespan extensions as a consequence of compound treatment was provided in D. melanogaster (Brack et al., 1997) where it was shown that dietary uptake of the antioxidant and glutathione precursor N-acetylcysteine (NAC) results in a dose-dependent increase in median and maximum life span of up to 27%.
4.2 Compounds that modulate protein homeostasis
Aggregation models, particularly those generated in C. elegans, have recently been used to assay the effects of pro-longevity compounds. Interestingly, many of the compounds that extend lifespan also cause a decrease in protein aggregation. For instance, celecoxib, which increases lifespan in worms through modulation of IIS, also decreases polyglutamine accumulation and improves the paralysis associated with aggregation of this peptide (Ching et al., 2011).
4.3 Compounds that effect DR pathways and mediate lifespan extension
Reports of lifespan extension in multiple model organisms by the TOR pathway inhibitor rapamycin, has provided motivation to identify more such pharmacological modulators of DR pathways (Harrison et al., 2009).
4.4 Compounds that effect IIS pathways and mediate lifespan extension
Many of the chemicals shown to modulate lifespan through IIS are known drugs or natural compounds that have been used in traditional healing practices and supplements associated with alternative medicine. Natural products represent an untapped reservoir filled with great therapeutic potential. Natural compounds may hold particular promise because they are likely to have been subject to evolutionary pressure to sustain biological activity, and therefore have a high probability of influencing animal physiology. Several such compounds have been found to affect the lifespan of C. elegans in an IIS dependent manner.
Flavonoids are a class of plant derived polyphenols that share a common sub-structure, and have been widely reported to affect mammalian physiology; among these are quercetin and catechin, both of which seem to impact the IIS signaling pathway. Quercetin is widely distributed in edible fruits, vegetables and plants and may increase C. elegans lifespan by increasing the worms’ resistance to several kinds of cellular stresses (Kampkotter et al., 2008; Pietsch et al., 2009).
4.5 Compounds that affect lifespan extension by as yet undetermined means
Many other natural products have recently been tested for their ability to modulate C. elegans’ lifespan. While several of these have been reported to require IIS pathways, some of these compounds appear to work in an IIS independent manner. A series of experiments in Drosophila have shown that extracts from the Damask rose, Rosa damascena have lifespan extending effects in Drosophila with no obvious detriment on quality of life measures (Jafari et al., 2008; Schriner et al., 2011). Blueberry extracts which contain complex mixtures of polyphenols have also been shown to extend the lifespan of both C. elegans, in a DAF-16 independent manner, and D. melanogaster (Peng et al., 2012; Wilson et al., 2006).
5 Translating Chemical Biology of Aging Studies from Invertebrates to Humans
5.1 General Challenges That Impede the Discovery of Drugs Capable of Extending Human Lifespan
If the motivation for discovering compounds capable of extending the lifespan of invertebrates is ultimately to improve human health, then we must address how the basic experiments described here are to be translated into clinical research. Many investigators choose to study natural products, possibly because they wish to understand the mechanistic action of these products, but also perhaps due to the fact that FDA approval of edible natural product is considerably less complex and costly than approval of synthetic compounds. Others often begin even one step closer, by studying already approved human drugs, and examining whether they have an effect on invertebrate lifespan. Still, one of the biggest obstacles to stand between pharmacological research in invertebrates and ultimate human drug development is the intermediary step of testing compounds in mammalian models. Testing the ability of drugs to extend the lifespan of mice is expensive, especially when one considers its relatively long lifespan. This points to the need to choose compounds to be tested in mammals in a directed manner, so that a limited number of promising candidates can be tested in a cost effective manner, and further highlights the importance of invertebrate models in meeting such challenges.
6 Ways to Circumvent Challenges
6.1 Working Backwards: Testing Human Drugs for Lifespan Extension in Invertebrates
One way to expedite the discovery of drugs capable of extending the lifespan of humans is to begin by examining existing human drugs for their ability to extend the lifespan of invertebrates. Once these drugs have been verified to extend invertebrate lifespan, and the mechanism(s) by which they extend lifespan is determined, the likelihood that they might extend mammalian lifespan can be assessed.
6.2 Anticonvulsants
In 2005, Kerry Kornfeld and colleagues described a small chemical screen of drugs with known influence on human physiology for effects on C. elegans lifespan (Evason et al., 2005). The authors found that the anticonvulsant ethosuximide had a potent effect on the lifespan of worms.
6.3 Anti-depressants
In search of small molecules that extend the lifespan of C. elegans, Petrascheck and colleagues discovered a lifespan extending compound that bears structural similarity to known antidepressants of the serotonin receptor antagonist type (Petrascheck et al., 2007). They found that several of these known human drugs, also extend lifespan.
6.4 Anti-inflammatories
Celecoxib is a non-steroidal anti-inflammatory (NSAID), originally developed as a cyclooxygenase 2 inhibitor. However, it was suspected of having additional targets including PDK-1, a known component of IIS (Hsu et al., 2000; Zhu et al., 2004).
6.5 Anti-diabetics
The anti-diabetic drug metformin, a chemical of the biguanide class, has been found to extend the lifespan of C. elegans through a DR type mechanism (Onken and Driscoll, 2010).
6.6 Start out in Mice: Identification of Compounds that Extend the Lifespan of Mice
The current excitement surrounding the development of drugs that target aging processes, is partly attributable to the realization that mammalian lifespan can be extended with small molecules. For example, male, but not female lifespan can be increased by feeding mice nordihydroguaiaretic acid and aspirin (2-acetoxybenzoic acid) (Strong et al., 2008). In addition, the immunosuppressant rapamycin inhibits mTOR signaling and is able to increase lifespan in both male and female mice when administered late in life (Harrison et al., 2009; Miller et al., 2011).
6.7 Choosing Lifespan Extending Candidates from Invertebrate Models to be Tested in Mammalian Systems
While initially testing compounds in mice means that any discoveries are more likely to be relevant for drug development in humans, the prohibitive cost of mouse aging studies make it extremely impractical to carryout large scale chemical screens in mice. It is difficult to select candidates a priori based on their perceived likely hood of success. However, several criteria can be described that, if completely fulfilled, should immediately promote an effective invertebrate treatment into testing on mammals. First of all, the mechanism should be defined and found to be non-idiosyncratic for the model. That is, the chemical treatment should have a known mechanism that targets a conserved pathway important for aging in multiple models. Additionally, the response should be robust, should show a dose response and should be effective at multiple points during the lifespan.
7 The Challenge of Translation
If one of the goals of pharmacological lifespan extension in invertebrates is to improve human health then we must address how the basic experiments described here are to be translated into clinical research or healthy dietary choices. It is clear that many investigators choose to study natural products. This in part may come from the need to develop a mechanistic understanding of the action of natural products but also may be because the regulatory path to human use is considerably less complex and costly.
One of the biggest hurdles is the testing of compounds in mammalian models. The cost to individual investigators of a mouse aging study makes it unlikely that large numbers of compounds will be tested in the near future. It is difficult to select the best high value candidate compounds, which highlights the need for an ever more detailed understanding of the mechanisms at play. The invertebrate models can provide this information. Most critical, is the issue of whether the mechanism of action is likely to be conserved between invertebrates and mammals. By determining the mechanisms at play and uncovering which factors (intracellular signaling pathways, transcription factors, etc.) are required for compound action, research in the invertebrates could provide high value compounds for mammalian studies.
One area of small molecule research in invertebrate aging has received little attention; the role of metabolism in compound action. Future studies should take standard pharmacokinetics into account and consider the role of modifications to compounds on the observed biological action. Classical pharmacokinetics is difficult in invertebrates mainly because of the lack of circulatory systems and the difficultly in dissecting individual tissues; animals usually have to be pulled to provide enough material for analysis. However, this should not be an insurmountable barrier to basic metabolic studies.
The need to develop therapies and preventions for age-related disease is great. Recent demonstration of lifespan extension with rapamycin in the mouse (Harrison et al., 2009), as well as the demonstration that resveratrol induces metabolic changes in obese humans that mimic the beneficial effect of DR (Timmers et al., 2011) provide some very encouraging examples of how discoveries in invertebrates can be translated into pre-clinical and clinical research. There is a bright future for this approach and a clear role to be played by the invertebrate models.