A Chapter Excerpt from the Forthcoming Longevity Cookbook

You might recall that last year longevity science advocate Maria Konovalenko raised more than $50,000 via crowdfunding to create the Longevity Cookbook, an examination of the state of research and development for aging and longevity. My impression from the materials at the time was that this will be something analogous to Kurzweil and Grossman's Fantastic Voyage, in which a mix of the irrelevant and the interesting are presented. In that work, diet, supplements, and existing pharmaceuticals, all of which are near completely irrelevant to the future of human life extension, are given a lot of space, and discussed alongside some of the latest lines of research that might in the future be relevant once developed into clinical therapies, such as the SENS research programs. The public fixates on diet and supplements, encouraged by relentless "anti-aging" industry propaganda, and much of the aging research community focuses on slow and expensive pharmaceutical development aimed at metabolic adjustment that might, one day, slightly slow the pace of aging. None of that will add a decade of additional healthy years to human life any time soon, but it certainly sucks up all of the oxygen in the room when it comes to talking about human longevity.

The only path ahead that can produce radical life extension in the near future, an addition of decades or more, is the path of damage repair: SENS-like therapies capable of fixing the fundamental forms of cell and tissue damage that cause aging. Senescent cell clearance, removal of metabolic wastes, and so forth. The work needed to produce these therapies has far less support and funding, and receives far less attention than slow and expensive efforts to slightly slow down the pace of aging via metabolic tinkering, however. Nonetheless, SENS rejuvenation therapies are the future, because they are the only way to succeed in this game. Sooner or later all of the other approaches and hobbies will fall by the wayside because they cannot extend life. They will be discarded in favor of the SENS approaches that work, on an ongoing basis as the data is produced.

Work on the Longevity Cookbook is proceeding apace, and I see that an excepted chapter is now available to read online. It is focused on pharmacology, one of the areas where I think that the current mainstream research focus is of little relevance to the end goal of greatly enhanced human longevity. Obviously small molecule and enzyme development has tremendous promise for rejuvenation based on clearance of specific forms of metabolic waste, such as amyloids, cross-links, and lipofuscin constituents, but that isn't what is taking place in the industry. Similarly, outside of cancer research, there isn't a great deal of effort put towards pharmacology for destruction of other types of unwanted or harmful cells, such as senescent cells or errant immune cells. Most pharmacological work related to aging and longevity involves scanning existing drug catalogs for things that might do a little good by altering metabolism into a state more like that of the calorie restriction response: researchers would be pretty excited to obtain a two year statistical gain in life span in humans via this strategy. Not a useful approach to my eyes, since it has a high cost and poor expected outcomes even if wildly successful. That doesn't stop it from being interesting, but bear in mind the low expectation value given the past decade of work on dead ends like sirtuins.

Longevity Cookbook: Pharmacological Extension of Lifespan

Can we impact lifespan with pharmaceuticals? The average lifespan of humans has increased unevenly throughout history, but since the beginning of the industrial revolution it has taken rapid and steady strides upward. Much of this increase has been due to better sanitation, nutrition and living standards. Improvements in medicine, such as vaccines and antibiotics, have been very successful in combating infectious disease. This used to be the main cause of death for humanity but we have been so successful in combating them (world wide) that the main causes of death are now chronic age-related disease and cancer. These are what we hope to tackle now.

We will not cover all of the compounds that have been studied to extend lifespan, but those that I find most promising or most interesting. We will also discuss compounds that possibly work through different mechanisms. This could mean that we are neglecting some potentially important compounds, so we will try to explain what we think constitutes good evidence for a compound being promising. Extending lifespan in a model organism is certainly an important factor.

Combinatorial interventions are used for treating different diseases in the clinic. In cancer therapies, combinatorial treatments are used with success. The cancer can be attacked from different angles with multiple targeted therapies and cytotoxic agents. So what is the difference between testing one compound and testing a combination of compounds? At some level a single compound may act as a combination of compounds. Single compounds can bind to many targets. But aren't those off-target effects just creating negative side effects? Often that may be true, but some compounds might work well, precisely because they have multiple targets.

If two compounds can extend lifespan separately, together they must be even better, right? Well, it might not be that simple. The only published combination of compounds that has successfully extended lifespan to my knowledge is valproic acid and trimethadione in C. elegans. On their own, valproic acid extended the mean lifespan by 35% and trimethadione extended it by 45% at optimal dose. Together they extended the mean lifespan by 61%. This same study from the Kornfeld lab also shows that combining two compounds that on their own extend lifespan, can produce toxic effects. This was the case when mixing ethosuximide with trimethadione. So why is this? One explanation can be that they are both acting on the same pathway. Too much of a good thing is not always good.

So how do we know which compounds will work well together? The truth is we don't really know. We can try to make educated guesses though. Perhaps targeting different pathways is the way to go. However, sometimes targeting the same pathway can yield very potent effects with genetics. The insulin/IGF1 signaling pathway can be targeted from different angles in C. elegans yielding very long lived worms. There is also the possibility that two compounds targeting the same pathway can maximize the beneficial outcome while minimizing the side effects. Targeting different pathways can also work very well. In C. elegans the TOR and insulin signaling pathway were targeted genetically to produce a worm with nearly 5 times its normal lifespan.

Rapamycin and metformin are two drugs that could potentially work well together to extend longevity. A side effect of rapamycin is insulin resistance but metformin improves this condition. A combination of rapamycin and metformin treatment was started by the NIA Interventions Testing Program in 2011. No results are yet published, but rumor has it, it's working. One combination of compounds that was reported to be working in mice to combat one aspect of aging is quercetin and dasatinib. The combination is for killing senescent cells. They were each effective in killing senescent cells in different tissues but worked better together. No lifespan was measured, but health was improved. The mice were able to run farther on a treadmill.

Testing different compounds in combination is certainly a daunting task. How many compounds do you want in your longevity cocktail? Lets say we want to test 100 promising geroprotectors in combination. Perhaps we are assaying lifespan of C. elegans in a 96-well format. If we are just doing pairwise combinations it is almost manageable. 10,000 combinations performed in triplicate make 30,000 wells to be assayed. Only very large effects will be noticed in these types of screens if we are to eliminate false positives. If we are combining 3 or 4 compounds together in our screen we need to assess 3,000,000 or 300,000,000 wells respectively. In this setup, we are only using one concentration per compound. We have seen that sometimes concentrations of drugs need to be lowered when used together with another drug. A way to get around some of the problem is to first do a pairwise screen and use your best combination as the base for the next screen. This way you can keep adding compounds to your cocktail with a manageable amount of screening. This will of course miss some combinations that would be in the massive 300,000,000 well screen but some compromises always have to be made.

One of the main problems with research in general is the reliability of the data. Many times a finding is not repeatable when tried by another lab. This is usually not due to fraud or anything as nefarious as that. It is mainly that research is hard and there are many ways to fool yourself. One way to easily fool yourself is to use too small a sample size. This is quite common. Using a small sample size when looking at lifespan increases the chance that a long-lived or short-lived population was picked by chance. Generally around 100 animals should give around 80% chance of detecting a 10% difference in lifespan. By detecting I mean the difference being statistically significant (if they indeed are). But not only large sample sizes and statistical significance are important. Large effects are generally more reproducible than small effects. What I like to see is a large effect with a large sample size with a good statistically significant result. It is always nice to see if can be replicated by other groups. However, many small badly designed studies do not equal one large well-designed study.

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