Waving the pirate flag: The future of science publishing is black?

Preface: I feel like I am too scatter-brained to blog as regularly as I would like to. When I have an idea it is often easier to put it on Twitter (@Aging_Scientist) instead of writing a post. The problem with blogging is once I get obsessed with an idea, I turn into a perfectionist and start writing these long and rambling posts. But they are never "good enough" or "quite finished". Not sure how often I will blog from now one.

The era of sci-hub

Evidently it is desirable to access the scientific literature efficiently and cheaply ("open access"), because papers are written to be shared. As researchers we want to benefit the public and make our voice heard. Three types of open access (OA) schemes are well established by now (ref. 5). Green, is the publication of manuscripts in archives. Gold, is the placement of publications in journals that guarantee free access. Despite high expectations, neither approach has managed to overtake regular pay-per-view and institutional subscription based models ("paywall"). Black, can describe a service called sci-hub which copies and saves almost all biomedical papers that are being published. This “black” approach is set to revolutionize publishing, but why?

The need for a heroic effort?

If there is one thing I am particularly proud of, it is providing insights into HOW to carry out research. Whether my suggestions are useful or not, you can be the judge. Overall, this topic is related to the problem of Eroom's law in drug discovery. The latter claims that the research pace in the drug industry has slowed down, or research is becoming more and more expensive. The authors go on to speculate that the regulatory climate is one of several reasons. I will go on to suggest that the regulatory framework is even more inadequate to deal with the science of biogerontology.

Methods to accelerate research progress in biogerontology - a recap from my blog
1. We need to take Tauber's paradox and preclinical data seriously when designing human studies if we want to help our aging population. On the one hand, there is a political reason to play it slow, because any failure may lead to bad publicity and public backlash. However, from a purely intellectual point of view there is every reason to be aggressive about aging research because the risk benefit/ratio is so much better for aging interventions than any other drug. Our conservative approach has led to large studies using an inferior anti-aging agent, Metformin, and almost no useful human research on Rapamycin and derivatives (1). This fear of side-effects has also ruined human calorie-restriction research because "classic harm" and "biogerontologic benefit" were weighed incorrectly (2).

2. We have to re-consider how we carry out animal research. Regulatory bodies could leverage pre-clinical testing as a shortcut to mass screening of potential anti-aging compounds (3).

Study dump: food groups, vitamin K, sleep, nuts, B12 and phosphate

In the best case we should use epidemiology and nutrition science to guide public health policy through flexible incentives and taxes. Let's be prepared when the time comes and we can make that change real. One day, maybe by sheer luck, some politician will listen to good science. Study dump based on interesting abstracts:

Food group centric view. The author Schwingshackl works or used to work at our Viennese nutrition department. This study is a thing of beauty for everyone interested in epidemiology and our dear friends who suffer from orthorexia and will outlive us all.
A 56% reduction in relative risk for mortality with optimal intakes? Interestingly we should (or could?) see a 75% reduction by very naive multiplication (RR estimated at nadir in Figure 2). At a quick glance I do not see if the authors truly prove diminishing returns or not, though.:

With increasing intake (for each daily serving) of whole grains (RR: 0.92; 95% CI: 0.89, 0.95), vegetables (RR: 0.96; 95% CI: 0.95, 0.98), fruits (RR: 0.94; 95% CI: 0.92, 0.97), nuts (RR: 0.76; 95% CI: 0.69, 0.84), and fish (RR: 0.93; 95% CI: 0.88, 0.98), the risk of all-cause mortality decreased; higher intake of red meat (RR: 1.10; 95% CI: 1.04, 1.18) and processed meat (RR: 1.23; 95% CI: 1.12, 1.36) was associated with an increased risk of all-cause mortality in a linear dose-response meta-analysis. A clear indication of nonlinearity was seen for the relations between vegetables, fruits, nuts, and dairy and all-cause mortality. Optimal consumption of risk-decreasing foods results in [ONLY] 56% reduction of all-cause mortality, whereas consumption of risk-increasing foods is associated with a 2-fold increased risk of all-cause mortality.

Optimal consumption (the smallest serving with significant results and no further substantial change in risk or no further data for larger amounts) of risk-decreasing foods [3 servings whole grains/d (RR = 0.79), 3 servings vegetables/d (RR = 0.89), 3 servings fruit/d (RR = 0.90), 1 serving nuts/d (RR = 0.85), 1 serving legumes/d (RR = 0.90), and 2 servings fish/d (RR = 0.90)] results in a 56% reduction 

Could be a problem:  "We rated the quality of meta-evidence for the 12 food groups. The NutriGrade meta-evidence rating was “very low” for eggs; “low” for refined grains, vegetables, fruits, and SSBs; “moderate” for nuts, legumes, dairy, fish, red meat, and processed meat; and “high” for whole grains"

Schwingshackl, Lukas, et al. "Food groups and risk of all-cause mortality: a systematic review and meta-analysis of prospective studies." The American Journal of Clinical Nutrition 105.6 (2017): 1462-1473.

In defense of being underweight

It is common wisdom to claim that underweight people are at increased risk of death and disease. Epidemiologists, doctors and nutritionists would tend to favour this position but certainly not biogerontologists (1) because weight-loss is very similar to calorie restriction (CR), which is one of the most robust life-extending interventions known. Now the question is which science best informs health policy in an aging, obese world and were do these differences in opinion come from? This review published in 2014 by Luigi Fontana, an expert in human CR, and the distinguished epidemiologist Frank Hu is worth a read as primer (1).

First of all, weight-loss, low bodyweight, low adiposity and CR are not one and the same. CR is, however, associated with initial weight-loss, low bodyweight and adiposity. Mice can be obese but still in a CR-state because they lost weight from their individual ad libitum set point. To define our working hypothesis I favour the idea that low body-weight in healthy people is suggestive of a CR-like state (i.e. mild CR). Being thin is a similar phenotype to CR and it seems like a plausible idea.

As is often the case reality is more complicated than our assumptions. Existing associations may be real but exaggerated or not as well supported as we thought, which is the case for cancer & obesity (4). We know that adiposity is harmful, but recently the controversial idea of an "obesity paradox" was suggested. Observational studies have found that being somewhat overweight could be healthy, but before making a final judgement we have to consider other study types that are in disagreement. What is more, new evidence suggests even the very observational studies are flawed.

The three strongest study designs informing our opinion on CR and leanness are epidemiology, biomarker studies and animal experiments*. One may wonder why I would mention human and animal studies in the same breath if everyone knows that human studies are superior. However, the point is that human studies are only superior if all else is equal. A well-designed, controlled mouse experiment measures healthspan across 100% of the animal's lifespan. If these experiments can be replicated in diverse non-human species the data cannot be ignored anymore. In contrast, observational studies follow human subjects only across 25% of their lifespan and usually much shorter. They are also uncontrolled which can lead to technically insurmountable biases (residual confounding, self-selection, etc).

*other type of circumstantial evidence exists e.g. the Okinawan population, see (1)

Just to drive this point home: One could claim that the CR studies and BMI epidemiology measure something completely different. A low BMI is healthy if you arrived at it per force (e.g. experimental imposition in animal experiments and elite dieters), but not if you were always thin, i.e. "self-selected" (what the observational studies measure). In reality I think there is an intersection between the two at a CR-like state. It is also important to address the BMI literature because for better or worse it is often trotted out as a counter-argument to do human CR.

Historically, animal and biomarker studies have favoured the biogerontologist's view (thinner is better, see [1]) while epidemiology did not. Therefore in this post I will mostly discuss how observational studies have recently shifted closer to the biogerontologist's view. In addition I will mention some studies not discussed in (1), including self-selected bodyweight in animals and the anorexia nervosa literature.

Aging across the tree of life?

Just read a beautiful paper and I am not disagreeing. Just criticizing their approach and conclusions to learn something for myself. So let's see. Aging is conserved in different species, right? The authors (2, 3) claim that there are big problems with this assumption and I will discuss the two articles together.

Here we contrast standardized patterns over age for 11 mammals, 12 other vertebrates, 10 invertebrates, 12 vascular plants and a green alga..Although it has been predicted that evolution should inevitably lead to increasing mortality and declining fertility with age after maturity, there is great variation among these species

 Furthermore:

More sophisticated analyses including both shape and pace have confirmed the importance of slow, negligible, and negative aging [44].One of the most striking findings in recent years is that demographic aging appears to be far from universal [3,39]
......
This finding is crucial and paradigm-shifting because it implies that there is no single, universal aging pathway. At most, there might be a pathway that is shared when aging is present but can be turned off. 

Current issues in GH/IGF1 research: adult-onset studies and mediators

CR, calorie restriction
IGF, insulin-like growth factor
GH, growth hormone
GHRKO, growth hormone receptor knock out
MLS, LS, (maximum) lifespan

In this post I would like to expound on an idea that allows us to make sense of the studies on adult-onset GH/IGF1 deficiency. As a disclaimer, let me emphasize that I am not working in this field, but I do try to keep up with the literature.

The search for independent pathways: why study these animals at all?
One unresolved question is linked with the evolvability and mutability of lifespans. Given that LS is quite flexible within and between species, we would expect the existence of lifespan assurance mechanisms, and most likely they should include signalling pathways and transcription networks, because these can change quickly over reasonable time frames. This is the optimistic view that many biogerontologists agree with. In contrast, the pessimistic view holds that CR-related pathways are a curiosity and normally changes in lifespan require thousands of independent mutations in wildly different pathways, precluding significant human lifespan extension using drugs or other interventions.

So far we know that there exist partly redundant longevity-assurance pathways that are all loosely linked to CR, anabolism and perhaps cellular "quality control" and multistress resistance. It will be very important to define the degree of overlap between these pathways to clarify whether the optimistic or pessimistic view is closer to reality. We need to know if there are pathways that are truly distinct from CR or that produce additive benefits with CR even if they are redundant.

In the end, we need to know how to combine interventions to achieve the best results, i.e. which genes are epistatic and hence in the same signalling cascade. We have to answer questions such as: How much of the effect of CR is due to GH and IGF1? Is protein and methionine restriction operating through the same mechanisms as CR? It seems, both of these overlap with CR but are distinct. What about mTOR? It seems linked to GH, IGF1 and CR but distinct (long-lived GH dwarfs have diminished mTOR signalling for example but mTOR inihibtion produces a different phenotype from dwarfism). What about the two novel players, c-myc and H2S?

Statins and mortality: fat benefits or slim pickings?

If 50% of people die from CVD, the rest from cancer, and statins halve CVD mortality. What will be the impact on all-cause mortality? What will be the impact on life expectancy? Probably less than expected.

This goes back to a very real issue with statins and all other drugs but there may be some additional confusion among lay people because statins have a bad reputation in some circles. Not that I am an expert on statins or epidemiology, but I want to offer an interesting take on this problem.