Computational Aging

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:

1. DNA damage => epigenetic unwinding
2. Epigenetic unwinding => loss of transcriptional control
3. Loss of transcriptional control => protein noise
4. Protein noise => cellular dysfunction
5. Cellular dysfunction => tissue dysfunction
6. 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.

While there are tailwinds for aging science, there are also many unanswered questions, barriers and headwinds.

Here are a few issues:

1. Lack of understanding of root cause of aging. We have 9+ hallmarks of aging, but what drives aging? Until we have a clear answer on the root causes, we will be shooting in the dark.
2. Decades of effort on aging science with no "life extension" drugs on the market. The Mediterranean diet might be the closest thing we have so far. 
3. Decades of effort on Alzheimer's with little to show for it. Alzheimer's is narrower than aging and therefore seems like it should be easier to make progress on. Yet, Alzheimer's patients have few options.
4. Slow progress in model organism life extension. There are examples, mostly of marginal life extension in lower organisms, but we aren't seeing mice live for 2x their typical lifespan. (Encouragingly, a June 2022 study in Nature Communications Biology showed Drosophila melanogaster living to >200 days, a 120% increase vs. average lifespan, with a combination of interventions [1].) 
   
5. Not a national/global priority. Only a tiny sliver of our population works on aging science.
6. How do you run clinical trials? Healthy humans live to be 80+. How do you prove an intervention significantly extends lifespan in a reasonable amount of time?
   

These issues raise concerns about our ability to make progress on aging science, especially if we want significant lifespan and healthspan extension in the next 40 years (which is my goal). Most importantly in my view, we need to get clear on the drivers of aging at the molecular, cellular, tissue and organism level. Once we know the drivers / root causes, it will make it easier to create therapies.

[1] Shaposhnikov, M.V., Guvatova, Z.G., Zemskaya, N.V. et al. Molecular mechanisms of exceptional lifespan increase of Drosophila melanogaster with different genotypes after combinations of pro-longevity interventions. Commun Biol 5, 566 (2022). https://doi.org/10.1038/s42003-022-03524-4

Aging science is incredibly hard and complex. However, I believe we are poised for stunning breakthroughs in the next 40 years, driven by three tailwinds for aging science.

First, consider the aging population globally, which will bring increasingly intense pressure, interest and resources to find solutions. The UN predicts that the over-65 population will more than double from 2019 to 2050, to 1.3 billion people [1]. The UN also predicts the over-80 population will nearly triple from 2019 to 2050, to 426 million. Aging people will push for progress against age-related disease. They will vote for more funding. They will donate their money and effort to help. This is already happening. Witness the rapid growth of new aging science centers and labs, and startups working on longevity. It's not hard to imagine 10x the number of people working on aging science in 2030 vs. a few decades ago.

Second, consider how much foundational work has been done in the last few decades to understand aging at the molecular, cellular, tissue and organismal levels. 1000s upon 1000s of studies to understand the hallmarks of aging, the mechanisms of age-related diseases and the success of countless interventions. This base of knowledge means we can stand on the shoulders of giants. For example, in the last 30 years, we now understand what senescent cells are, how they impact aging and how to remove them (via senolytics). These could be FDA-approved medicines in the next decade. As another example, we identified that "parabiosis" (blood-sharing) rejuvenates old mice with young mice blood, and that the mechanism is likely clearing out molecular "noise" [2]. These benefits appear to come from plasma exchange that doesn't even require any "young blood". Once again, this could be an FDA-approved therapy in the next decade. 

Third, consider a few fundamental breakthroughs, including genomics, cellular reprogramming, CRISPR and artificial intelligence. These are general purpose technologies that are creating revolutions in biological research and beyond. The progress in single-cell genomics is leading to exponential growth in data and insights into our cells. The ability to reprogram cells, originally via "Yamanaka Factors," is leading to a flurry of new research and heavily funded startups. For example, we can now program astrocytes into functional dopamine neurons, and even reverse a model of mouse Parkinson's [3]. CRISPR drastically simplifies gene editing, which is a boon for research and for new treatments. The progress in deep learning even in the last 5 years is night and day. These breakthroughs are being used together, and are building on each other. Labs and startups are using genomics, reprogramming and AI together to do things that would have been impossible 5 years ago.

Together, these tailwinds set the table for what I believe will be astounding progress in aging science in the next 40 years.

For example, let's do a quick thought experiment: imagine that going forward, we find just one new thing that extends lifespan/healthspan by 10 years in each decade. In four decades, your life expectancy could be 40 years longer than you thought.

[1] United Nations Department of Economic Social Affairs. World population prospects 2019: highlights. New York: United Nations Department of Economic Social Affairs; 2019.

[2] Kim, D., Kiprov, D.D., Luellen, C. et al. Old plasma dilution reduces human biological age: a clinical study. GeroScience (2022). https://doi.org/10.1007/s11357-022-00645-w

[3] Qian, H., Kang, X., Hu, J. et al. Reversing a model of Parkinson’s disease with in situ converted nigral neurons. Nature 582, 550–556 (2020). https://doi.org/10.1038/s41586-020-2388-4