Let's start with the big goal that humanity should work to achieve significant lifespan and healthspan extension by 2063. That gives us 41 years, with no time to spare. How can we make sure we're on the right track? How do we know we're working on the right things?
Here are some questions that could help guide a long-term aging research program:
1. What are examples of research programs that made major progress on an intractable disease, e.g. multiple sclerosis? Why did it work? What hasn't worked? What can we recreate for aging science?
2. What does a multi-decade research program look like to significantly extend human lifespan and healthspan? What are some examples of this done well in aging? Done poorly?
3. What is the right "paradigm" for aging science? Thomas Kuhn's The Structure of Scientific Revolutions argues that identifying the right "paradigm" or high-level lens for a problem is critical. Until you get the right high-level paradigm for a problem, researchers can be focused on the wrong things. For aging, there is not consensus on what causes it. We have 9 "hallmarks" of aging, but what are the drivers?
One tantalizing theory is the "information theory of aging." It goes something like this:
- DNA damage => epigenetic unwinding
- Epigenetic unwinding => loss of transcriptional control
- Loss of transcriptional control => protein noise
- Protein noise => cellular dysfunction
- Cellular dysfunction => tissue dysfunction
- Tissue dysfunction => increased risk of disease and death
Is this right, or at least close enough? What would be true if this theory were right? For example, do organisms with slower aging have slower DNA damage and less epigenetic unwinding? Does each item in the chain hold, e.g. if you reduce DNA damage, do you get less epigenetic unwinding, etc.
If we can settle on a good paradigm, we could focus our efforts.
4. How would we know we're on track? Can you even predict what the benchmarks might be? Science can feel like you're wandering in the woods, and it's hard to know if you're making real progress or not.
5. Pre-mortem: How might we fail? In other words, what are things that could have gone wrong such that we don't make major progress in aging science over the next 40 years? One interesting example of this is the case of Alzheimer's disease research. Karl Herrup's How Not To Study a Disease: The Story of Alzheimer's argues that an excessive focus on the amyloid beta hypothesis came at the expense of other inquiry and led to a herd mentality among funders and researchers. Are there other similar examples?
6. How do we answer questions 1-5? I expect it will take a while to form a good perspective. I'll start by reading a lot of scientific histories. There are good books written about many of the major scientific discoveries (E.g. James Watson's The Double Helix). I'm working down a list, but please share any recommendations you might have. Reading the seminal papers on each field (e.g. aging, Alzheimer's, Parkinsons, spatial transcriptomics, deep learning, etc) help give clues to how intellectual progress happens. I'm also asking these questions of people who might know. UCSF and the SF Bay Area is a great place for this, and I've learned a lot from the coffee chats and lunches with top researchers.
Maybe science doesn't proceed in this systematic of a manner? Still, if we answer these questions I believe we will find better approaches to aging science.