Thank you for the insightful question! It allows me to emphasize the important distinction between ketosis and atherosclerosis. Foam cell formation, which is a key event in the development of atherosclerotic plaques, is not limited to individuals with risk factors for heart disease. There’s evidence showing that plaque precursors, including foam cells, can be found even in healthy adolescents. This suggests that the initial stages of atherosclerosis might occur as part of natural biological processes, but the progression to harmful plaque formation depends on various factors, including lifestyle, genetics, and environmental triggers.

As for ketosis, the metabolic state is designed to utilize fat as a primary energy source. In individuals with excess body fat or those who have unfavorable lipid profiles, entering ketosis allows them to metabolize their more abundant fat stores, often resulting in improved lipid biomarkers and overall metabolic health. However, in individuals with a leaner, “healthy” phenotype and lower fat reserves, the situation is different.

When these individuals enter ketosis, if their body fat is below a certain threshold, their body may need to either mobilize fat from existing stores or synthesize new fats to provide substrates for ketone production. This process can lead to a temporary or sustained worsening of lipid biomarkers as the body shifts its fat metabolism pathways. This difference in how ketosis is utilized likely explains the variation in biomarkers you mentioned between individuals with different body compositions.

Delish! Thanks for the Qs

“Aren’t the shorter-lived strains functioning under genetic pressures in order to be short-lived?” They weren’t intentionally bred to be short-lived. It’s more of an unintended consequence. The goal was to create a docile, general-purpose lab mouse, and in the process of enriching for these traits, genetic diversity decreased. This reduction in diversity inadvertently shortened the lifespan in certain strains.

“From a research perspective, this makes sense as conducting studies through end-of-life would be more exhaustive if longer-lived strains were used.” I see your point but the actual difference in lifespan is only about 0.5 to 1 year—so not as big a difference as it might seem when considering the added effort for end-of-life studies or even just dealing with the mice that have several more months of health/life. To take your numbers, it would only be 110 days which is less than half a year.

“Outside of longevity, it would be better to use short-lived models.” Not necessarily. For example, heart disease is heart disease, and you don’t need to artificially impose unrelated lifespan limits to study it effectively. Long-lived models can still provide meaningful data on a variety of conditions without the confounding factor of an “unnaturally” short lifespan.

“Any intervention would undoubtedly help a short-lived strain…” That depends. For instance, if a strain is highly susceptible to cancer, interventions targeting cancer might extend its lifespan. However, if the strain tends to die of kidney disease, cancer therapeutics won’t affect longevity. The effectiveness of an intervention varies depending on the underlying/predominant cause of death in these strains.

“It would essentially be undoing years of genetic constraints that caused them to be short-lived in the first place.” Exactly—this is what I was getting at. In the study we’re discussing, the intervention not only had to counteract these added genetic or environmental stresses but also extend lifespan beyond the norm for long-lived strains. That’s what makes the result more meaningful in a way.

“There seems to be an invisible, yet squishy ceiling on lifespan up to a certain age with interventions…” The point I was trying to make was that the gene therapy in this case surpassed both the softer and harder limits you are referring to, suggesting that the therapy had a significant impact not just on addressing the deficits these animals had but also pushed these shorter lived animals past the hard ceiling for longevity set by the (theoretical) long-lived controls.

TIL what a true phantom is. Neat!

I am not terribly adjacent to radiology but do find this niche product fascinating, Thank you!

I’d like to add something to this discussion, but first, I want to acknowledge that all of these points are correct, important, and well taken. That said, a subpar control doesn’t necessarily equate to a subpar study or suggest that an intervention isn’t worth getting excited about. What the “900-day rule” indicates is what the expected median lifespan of a healthy control group should be. Control groups that fall short of this 900 day benchmark are facing an additional stressor (genetic or otherwise) that is negatively affecting their longevity. When comparing the experimental arm to these controls, the conclusion must include that the intervention is at least partially increasing their lifespans by counteracting these added stressors.

So, a simple way around throwing the entire study out would be to compare the experimental arm to a theoretical 900-day cohort. If the intervention group has a median lifespan of around 37 months, that translates to 1,125 days—about a 25% increase over the theoretical, normal, healthy 900-day control group. Yes, 25% is less dramatic than 41%, and it may not be as robust as some rapamycin results, but it is still a significant increase in longevity compared to both a healthy control group and the in-study control that shows evidence of stressors affecting all mice.

I argue that the utility of the “900-day rule” isn’t to dismiss studies that don’t meet this benchmark, but rather to provide another metric to aid in our interpretation of the data.

Great post!

Yes, that is exactly why! The safety concerns around using spectrometry for anthrax primarily stem from how the samples are handled and prepared. Nuance incoming!

The dogma in our lab is that mass spectrometry, especially MALDI-TOF, involves creating an aerosol or vapor from the sample, which could potentially release live spores or other dangerous particles into the environment. In the case of anthrax, because it’s a highly infectious pathogen, this aerosolization could pose serious biohazard risks if the spores aren’t completely neutralized.

In reality, it’s much more likely that the true concern lies in the upstream processing. In fact, many labs have the capacity to, and ultimately do, run anthrax samples on the MALDI. This is because the samples are chemically deactivated with reagents like trifluoroacetic acid and α-cyano-4-hydroxycinnamic acid, which also aid in the production of adduct ions that are ultimately detected by the machine.

A key difference between most hospital microbiology labs is the biosafety classification. At my location, for example, the only part of the lab that is rated Biosafety Level (BSL) 2 is the mycology suite. To handle anthrax safely, you would want manipulations performed in a BSL-3 lab within a class 2 safety cabinet, which is what the reference labs would do. Then, once the sample is inactivated, they proceed to MALDI. In hospital labs, we usually limit our manipulations of possible anthrax and therefore use quick assays to rule it out. If we can’t, we send it to other labs… through the mail… there may be a dark joke somewhere in there.

Fun fact: most of Robert Koch’s (a, if not the, father of germ theory) early work was actually with the anthrax bacillus, long before our BSL equipment existed!