The Conundrum of Applying Research to Longevity Medicine

Integrating research findings into longevity medicine can be more challenging than first meets the eye. Why would this be?

First let's start with one of the main postulates of longevity medicine: that delaying the onset of disease will give a person more years are spent in good health AND extend their lifespan. The main killers of humans in this day and age are Cardiovascular Disease, Cancer, Dementia, and sequela from Insulin Resistance. Notably, each of these disease processes take many decades to progress.

Here are a couple pictures to help capture that concept.

The first figure is looking at diabetes:

Lipoprotein abnormalities occur before changes in fasting glucose and insulin. Credit to Tom Dayspring.

This graphic displays the sequential physiological abnormalities that one incurs as they go from lipid abnormalities to insulin resistance to diagnosed diabetes to cardiovascular disease.

Note that while the figure does not have specific time denoted on the x-axis, the time to go from a rise in fasting insulin to a rise in fasting glucose is often on the scale of 10 to 15 years. Extrapolating that out, this figure is showing that the entire process of going from a metabolically healthy individual to heart disease spans about 40 to 50 years.

And this figure here also shows the extended timeline of the progression of plaque formation in the artery:

ASCVD and Plaque Progression Over Time. Credit to Wikipedia.

Again, the process takes decades.

We can also see this in dementia:

Trajectories of cognitive and motor decline. Oveisgharan et al.

With global cognitive decline and physical manifestation showing up decades before the gradual fall into MCI and Dementia.

And again we can see it in cancer progression:

The long timeline from initiation to progression to disease of cancer. Ruggiero et al.

So if these leading killers take decades to initiate, progress, and ultimately kill us then it stands to reason that the treatment and prevention of them should also be viewed on the timescale of decades.

However, while some prospective cohorts are able to look at longer timescales, our gold standard form of testing hypothesis in the medical field, the double blind placebo-controlled randomized controlled trials, often range on a scale from 3 to 5 years, and very rarely go beyond 7 years in length.

While data and conclusions from these studies are helpful, they don't actually answer the question we are asking: "Does this treatment prevent disease and death over the span of many decades?"

This is also why you will often get underwhelming absolute risk reduction and number needed to treat stats from these studies. For example, if you run a 2 year study you may get a 0.5% absolute risk reduction in heart attack events or a number needed to treat in the 200-400 range. While initially underwhelming, those numbers might be incredibly meaningful. Why? Because in a study so short intervening on a disease process so long, to get any change in outcomes is unbelievable. Now you have to extrapolate out the potential disease mitigating effects of that treatment over another 2 or 3 decades to see its true potential.

So, for those interested in practicing a preventative style of longevity medicine, we need to take insights from the data available and practice evidence-informed medicine. This integrates the clinical studies, with what we know about the pathophysiology of the disease, with the risks and benefits of the interventions, with the specific risks and preferences of the patients in front of us, and allows us to make our best effort.

The key is keeping the long game in mind. We need to actively and aggressively prevent these diseases while at the same time accepting an extremely low risk profile from any intervention we take on.

Dementia Paper PDF

The time course of motor and cognitive decline in older adults and their associations with brain pathologies: a multicohort study Oveisgharan, Shahram et al. The Lancet Healthy Longevity, Volume 5, Issue 5, e336 - e345

Ruggiero, Luca & Sogno, Ilaria & Focaccetti, Chiara & Bartolini, Desirée & Magnani, Elena & Principi, Elisa & Noonan, Douglas & Albini, Adriana. (2012). Effects of Diet-Derived Molecules on the Tumor Microenvironment. Current Angiogenesis. Volume 1. 206 - 214. 10.2174/2211552811201030206.