Category Archives: nutrition

Pascalian Longevity: Why not?

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Scott Alexander of SlateStarCodex / AstralCodexTen recently wrote Pascalian Medicine, in which he looks at various substances purported to improve covid outcomes, but which have relatively low amounts of evidence in their favor, likening administration of all of them to patients to a Pascal’s wager-type argument: if there is a small probability of a potential treatment helping with covid, and if it’s also very unlikely that this treatment is harmful, should we just give it to the patient regardless of if the quality of evidence is low and uncertain, as it would clearly have a positive expected outcome regardless?

The naive answer to this could simply be to attempt to calculate an expected value (note: I use the term expected value often here, but in some cases the terms hazard ratio, relative risk, or odds ratio would be more appropriate) for each treatment, and administer it if it’s positive. But there could be some unintended consequences of using this methodology over the entire set of potential treatments: we could end up suggesting treatments of 10 or 100+ pills for conditions, and apart from something just feeling off about this, it could magnify potential drug interactions, some treatments could oppose others directly, the financial cost could start to become prohibitive, and it could decrease patient confidence and have many other undesirable second-order effects.

Pascalian Longevity

There are many counter-arguments presented to the above concept which become less salient when the goal is changed from ‘find drug treatments to prescribe to all covid patients’ to ‘find personal health interventions that increase your own lifespan/longevity’.

I am fortunate enough that I am able to evaluate potential longevity interventions myself, pay for them myself, administer them myself, and review their potential effects on me myself. I might not do a perfect job of this – research is difficult, time-consuming, and lacking in rigor and quantity, and finding appropriate longevity biomarkers to quantitatively asses the effects of interventions is also difficult. But uncertainty is a given here, and that is why we incorporate it into our frameworks when deciding if something is worth doing or not by calculating an expected value. Furthermore, any harm that I may accidentally incur will only be done to myself, reducing the ethical qualms of this framework to near-zero (I would strongly oppose arguments that I should not have the right to take drugs which I think may significantly improve my own health, although some may disagree here).

My modus operandi with respect to longevity may have many uncertainties in its output, but still operates with a very strong (in my opinion) positive expected value: If a substance significantly and consistently increases the lifespan of organisms similar to humans (ideally in humans), and is also very safe in humans, then it is something that I want to take

This is how I operate personally with longevity, and it does result in me taking quite a few things (currently I’m at around 15). I do still try to minimize what I take as a meta-principle (for example, setting a minimum threshold of expected value that a substance must provide to warrant inclusion, rather than simply accepting any positive expected value) for a few reasons: firstly, to reduce potential drug interactions (which we do attempt to asses on a per-substance basis, rather than account for as an unknown, but unknowns are unfortunately a very large component of messing with biology regardless). Secondly, to keep my costs relatively sane, although I am not too worried about this as there are few ways to spend money more effectively than on trying to improve your health. Thirdly, to reduce the occurrence of interventions that may have the same or opposing mechanisms of action (taking two things with the same mechanism of action may be okay, but sometimes dose-response curves are less favorable, and taking >~2x of something will result in diminished or even negative returns). Lastly, to minimize potential secondary side-effects that could be cumulative over large classes of substances (for example, effects on the liver).

I don’t intend to promote any specific substances or interventions here as I don’t give medical advice, nor do I want anything specific to be the focus of this post, but I do want to remind us that just as we can calculate expected values in a utilitarian fashion and get effective altruism as a result, we can do the same for longevity interventions and get a very strong chance at notably increasing our lifespan/healthspan as a result. I do have a list of some of what I take here, but it is definitely not intended to promote anything specific to others.

Why Not?: Potential counter-arguments

Algernon’s Law

Algernon’s Law is sometimes brought up, suggesting that evolution has already put a lot of effort into optimizing our body, and thus we are unlikely to find improvements easily. But, as Gwern notes in the above link, there’s at least three potential ways around this reasoning: interventions may be complex (and/or too far away in the evolutionary plane) and could not have easily been found, they may be minor or only work in some individuals, or they may have a large trade-off involved and cause harm to reproductive fitness.

Although some areas of future longevity treatments may fall under exception one and be complex enough that evolution could not have found them, I would suggest that the majority of today’s potential treatments fall under exception three: evolution optimizes for reproductive fitness, not for longevity, and for this reason there are many interventions which will improve our longevity that it has not given to us already (this is part of why I am more optimistic about longevity interventions than I am about intelligence interventions/nootropics).

For an extreme example of this, it has been noted that castrated males often live longer, and that this is obviously something evolution would not be very interested in exploring. Although this has been found with median lifespan in male mice (maybe in females too?), there is also purported historical data on Korean eunuchs suggesting that they may have lived a full 14-19 years longer (there are definitely potential confounding variables and/or bad data here, but we don’t have RCTs on this in humans for obvious reasons..), and a more recent study in sheep that is also highly relevant: Castration delays epigenetic aging and feminizes DNA methylation at androgen-regulated loci, where epigenetic aging clocks that look at DNA methylation are used in castrated sheep. There are other traits that seem to improve longevity as well, for example decreased height. It seems quite plausible that there are a lot of trade-offs that optimize for strong reproductive fitness early in the lifespan of organisms, which end up costing the organism dearly in terms of longevity. These trade-offs may be involved in many areas such as testosterone, estrogen, growth hormone, IGF-1, caloric restriction, mtor activation, and many others.

Large error in estimating unknown risks

One other counter-argument here is often along the lines of “you are messing with things you don’t understand, and you could be hurting yourself but be unaware of this; the damage may also be difficult to notice, or perhaps only become noticeable at a much later time”

It is true that our understanding of biology is lacking, and therefore also that we are operating in highly uncertain environments. I would be open to evidence that suggests reasoning for why we may be systemically underestimating the unknown risks of longevity interventions, but given how strong the potential upside is, these would have to be some pretty terrible mistakes that are being made. It is often noted how curing cancer may only extend human lifespan by a few years, whereas a longevity improvement of 5% for everyone would provide much more value (and is also much easier to find in my opinion). One could make an argument here that even if I was doing something that notably increased my risk of e.g. cancer, if the expected lifespan increase of this intervention was as much as 1-5%, this could still be a huge net positive for my health! I don’t take approaches that are this extreme regardless, and I try to keep the risk side of my risk/reward ratio low independently of the level of potential reward in attempt to account for this uncertainty. I am also not aware of many interventions that seem to have very high numbers in both the numerator and denominator here, although I am pretty certain that they do exist; I don’t currently take anything that I think has notably detrimental side-effects for the time being.

Is it fair to call this approach Pascallian?

The original nature of Pascal’s wager is that of extreme probabilities resulting in positive expected values, but the numbers that we are operating with are nowhere near as extreme as they could be. It is probably not a good idea to take 10,000 supplements, each of which have a 0.1% chance of extending your lifespan by a year for many reasons (similarly, if 10,000 people that claimed to be God all offered me immortality for a small fee, I would hope to decline all of their offers unless sufficient evidence was provided by one).

As I’m not arguing in favor of taking hundreds or thousands of supplements in the hopes that I strike gold with a few of them, it may be worth noting that ‘Pascallian Longevity’ would be a poor label for my strategy. Regardless, taking just 5-10 longevity interventions with a strong upside potential seems to be significantly more than almost everyone is doing already, so I still stand by my claim that there are many free lunches (free banquets, if you ask me) in this area, and I am very optimistic about the types of longevity interventions we’ll find in the coming decades.

Open to any corrections/comments on Twitter or any medium on my about page

Allulose: The Best Sugar Substitute

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Allulose (sometimes D-psicose) is by-far one of the best ways to add sweetness to home-cooked meals in a healthy and low-calorie way. As an epimer of fructose, it has been steadily gaining popularity within the last few years, and not without good reason! Allulose is not only nearly calorie-free, but also decreases blood glucose levels with meals, and seems to have a wide range of potentially beneficial effects.This post is a short summary of why allulose is so appealing over sugar and other sugar substitutes.

70% as sweet; 100% as white and crystalline

Overview of Allulose

Allulose is found naturally in wheat, figs, raisins, maple syrup, and molasses, although in relatively trace amounts. It has around 10% the calories of traditional sucrose and can be manufactured from fructose. It’s around 70% as sweet as sucrose (regular sugar), but has a similar taste and feel, which is a large factor behind why it makes a great substitute (or partial substitute) for baking or dissolving into things. The taste of Allulose has a more natural and relaxing quality than some other sugar-replacement options such as xylitol and erythritol, which are both sugar alcohols, but generally have a ‘cooling effect’ (often likened to the aftertaste of consuming mint, which allulose conveniently lacks).

Allulose is also an actual sugar (not a sugar alcohol or other compound), and has similar browning properties to sucrose via the Maillard reaction. One downside to mention is that it does seem challenging to keep some styles of baked goods crunchy with allulose as the only sugar; while it definitely seems to be one of the best options for sweetening drinks, yogurts, ice creams, cakes, and so on, it may not be the best option for super-crunchy cookies (although can make great softer ones!). This seems to be due to allulose not crystallizing when it cools, its ability to hold more moisture, and that it is more soluble in liquids than sucrose; hence it being a great fit for drinks, sauces, and spongy baked goods.

Allulose was designated as GRAS by the FDA in 2019, so is still relatively new to the market compared to many other sugar substitutes, although has been gaining significant popularity for the short period that it has been available for general usage in foods. I’m sometimes now able to find allulose for sale in a supermarket or included in a sweet good (and it is also now being used in products such as Soylent), although its usage is still a small fraction to that of sugar and corn syrups. It can easily be purchased on Amazon for around $10 per lb (regular sugar is generally closer to $1-2 per lb, so it is quite a bit more expensive if you happen to use very large amounts of sugar).

What Sets Allulose Apart

Why might we want alternative sources of sweetness from sucrose to begin with? Although much has been said about the ways sugars are (in some cases) potentially harmful, it seems reasonable to posit that there are two qualities of a diet with high sugar content (remember, this means any typical western diet!) that are undesirable: firstly, the high caloric content of sugar, which makes over-eating significantly easier and therefore contributes to obesity, and secondly, the effects of sucrose on blood glucose levels and thus insulin resistance, which contributes to diabetes and metabolic syndrome.

As we would hope from an alternative to sucrose, allulose doesn’t cause an increase in blood sugar. The reason for this is that it is not absorbed and digested by the gastrointestinal tract, but rather processed by intestinal bacteria. For the most part this is a good thing, and is what enables allulose to both be low-calorie and to not be converted to glucose in the blood stream. The downside of this is that for some people, especially if consumed in large enough quantities, it can cause mildly discomforting side effects such as flatulence, subpar digestion, and abdominal discomfort. This is much more likely to occur if you, for example, eat an entire batch of allulose cookies by yourself (who would do such a thing..!?), rather than simply use it to sweeten a drink or a snack. While I haven’t experienced anything negative myself, everyone is certainly very different when it comes to food.

But, it gets much better than this! Allulose not only doesn’t increase your blood sugar, but actually decreases it! It does this by inhibiting alpha-glucosidase (along with several other similar enzymes), which is an enzyme that breaks down starches and disaccharides into glucose (i.e. causes carbohydrates to lead to blood glucose spikes). Other well-known inhibitors of alpha-glucosidase include acarbose, a popular and simple diabetic drug which significantly extends lifespan in mice and has the exact same potential side effect profile as large allulose doses (and in my opinion is probably very good for most people to be taking, perhaps extending human lifespan via the same mechanism of action as in mice), and sweet potatoes (source, another source). Thus, adding allulose to meals that contain carbohydrates will result in less of a blood glucose spike than if allulose had been excluded.

Comparison of blood glucose area under curve for small quantities of fructose vs allulose (source: figure 1)

There’s now quite a few studies showing this in humans (and dogs and mice!), with allulose consistently attenuating the postprandial glucose levels both in diabetic and regular adults (effect sizes are often larger in pre-diabetic and diabetic individuals, as is often the case here).

Allulose blood glucose and insulin areas under the curve in comparisons with other sugars (source: figure 2)

But wait, there’s more!

Several studies also appear to show lower plasma triglyceride levels and improved lipid profiles (perhaps via the lowering of hepatic lipogenic enzyme activity, maybe involving SCARB1, but probably many others as well), decreased feeding (perhaps via agonizing glucagon-like peptide-1), enhanced fat oxidation, and a reduction in inflammation related to adipokine and cytokine plasma levels (one paper claims this is partially due to down-regulating gm12250 in mice, but if this applies to humans it may be a side-effect of more upstream metabolic changes more so than specific agonism/antagonism, although as is the case with most foods, things get absurdly complicated very quickly with the amount of pathways involved).

Allulose resulting in reduced feeding in high-fat diet obese and diabetic mice (source: figure 3)

It’s worth noting that several of the above studies (particularly ones that attempt to hone in on specific mechanisms of action) are in mice, and in fact, we could go much further if we want to look at mice; it’s trivial to find many more potentially favorable results such as “Not only metformin, but also D-allulose, alleviates metabolic disturbance and cognitive decline in prediabetic rats” or “D-allulose provides cardioprotective effect by attenuating cardiac mitochondrial dysfunction in obesity-induced insulin-resistant rats“. Although there is less (and sometimes conflicting) evidence for e.g. improved lipid profiles in humans, there is certainly more than sufficient evidence of allulose’s effect on reducing blood glucose levels and overall calories consumed, from which we would naturally expect many other beneficial effects to follow. Searching for allulose on pubmed results in a wonderful selection of studies showing very consistent outcomes in this area, and it thus seems plausible that, at the very least, we would see significant reductions in diabetes and obesity if allulose were to be more widely adopted in consumer food products.

Conclusion

In general it seems like replacing sugar with allulose will result in fewer calories consumed, a lower risk of obesity, lower blood glucose (average and area under the curve, sometimes peak) levels and thus improved insulin resistance and a lower risk of diabetes and metabolic syndrome, and potentially some other beneficial effects (which may or may not apply in humans, but if allulose improves your diet and lowers your food intake, I would not be surprised to see improved lipid profiles and a reduction in inflammation, even if entirely for indirect reasons, e.g. cooking at home with allulose instead of purchasing processed foods from the store. It’s also worth noting that while some of these benefits are a direct result of allulose consumption, many are also partially from a reduced intake of sugar and calories – similar to how cutting down on your sugar intake would offer many benefits).

It’s quite possible that if a notable fraction of other sugars in our diet were to be replaced with allulose, the amount we would gain both in QALYs and dollars saved via the resulting reduced healthcare burden would be extremely favorable. Allulose is still relatively new to the market, and as it is also much more expensive than sugar or corn syrups, its future market penetration may be relatively limited by consumer preferences. Regardless of its presence in our broader food ecosystem, you can start experimenting with it yourself today! (Amazon search results page link, in case this saves you 10 seconds)

I usually use allulose to sweeten drinks, greek yogurt, and sometimes add it to sauces or baked goods in small quantities. I’m also pretty interested in glycine and think it may be something that most of us should be having a lot more of as well (some notes on this in the glycine section on my supplements page), but consider it outside the scope of this article for now. Lastly, if the idea of significantly reducing the glycemic index of your meals is appealing, I strongly suggest looking into acarbose – it is a much stronger inhibitor of alpha-glucosidase, well-tolerated, and also relatively cheap.

If you enjoyed this article you might also enjoy my supplements page which discusses many other ingredients and drugs that I find interesting with respect to longevity. Feel free to reach out with any comments or corrections via any communication method on my about page, thanks for reading!