Computational Aging

This figure (Buffenstein, 2008) shows maximum lifespan as a function of body mass of rodents. The naked mole rat maximum lifespan lies more than two standard deviations away from the trend line, according to the author. Naked mole rats also exhibit "negligible senescence" where the likelihood of death does not increase with age, while most other organisms including humans have exponentially increasing mortality rates.

I heard the author, Shelley Buffenstein, speak today at UW Nathan Shock Center 2022 Annual Geroscience Symposium. I almost skipped the talk (meh title). She was terrific. She is a world expert on the biology of naked mole rats. She recently published a book summarizing much of her research, The Extraordinary Biology of Naked Mole Rats. She spent the last 7 years at Calico (why did she leave?), and now is at University of Chicago. She has been publishing on the naked mole rat since at least 1991.

She shared this figure in her talk. It describes her view on how naked mole rats are able to achieve slower aging, including a more stable genome, transcriptome and proteome.

(Buffenstein, 2022)

Two parts were especially interesting. The first is the more stable cell cycle to avoid cancer. The second is the more stable proteome. The more stable proteome includes less protein synthesis, higher translational accuracy, upregulated HSP70 and HSP27, increased autophagy, increased proteosome activity and upregulated NRF2 and antioxidants. She shared data that the prevalence of misfolded proteins is much lower than in mice generally and in response to stress. I imagine the proteome of a naked mole rat to a city with new buildings, no traffic and no trash on the street, while the proteome of a mouse (and human) a crowded, messy city in disrepair.

How can humans get a more orderly proteome? We hear that diet, exercise and other aging-related compounds can help with things like autophagy. But how do we supercharge these pathways that seem to slow disorder and disease?

Evolution is smarter than we are. Evolution has figured out longevity pathways in naked mole rats, as well as other organisms. For example, Shelley described that when bears hibernate and don't move for six months, they don't lose bone mass, while humans do. As another example, elephants have double copies of the p53 gene, which reduces cancer risk.

How can we bring evolution's brilliant longevity discoveries into humans?

References:

Buffenstein, R. Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. J Comp Physiol B 178, 439–445 (2008). https://doi.org/10.1007/s00360-007-0237-5

Aging as a complex system that loses homeostasis

Is aging the result of a very complex machine falling out of homeostasis? This is a compelling high-level paradigm for aging.

Why do different organisms have different rates of aging and different lifespans? Evolution shaped each species to survive. The fly’s lifespan worked for it given all its other constraints. Human lifespans are relatively long and they have worked for us so far. Certain other organisms like Greenland sharks and bristlecone pines have even longer lifespans. The variation is orders of magnitude.

It is very likely that we can reprogram flies to live 100x longer. I also think it is very likely that we can reprogram people to live 10x longer. It is at least conceivable. Rejuvenation of the critical parts of our complex bodies should in theory fight the loss of homeostasis. Epigenetic reprogramming is starting to provide a proof of concept.

Given the complexity of all living things, and especially humans, I think we need to first prove 10x lifespan extension in smaller organisms. Maybe flies, maybe worms, maybe yeast. If we can’t do it for those organisms, it seems very difficult to do it for humans. Maybe some brilliant researchers will bypass this step and solve it for humans? I'm not sure how they will.

We have the opportunity to create accurate models of aging. Right now aging is too complex and we only have overly simplistic models. With the twin innovations of big data / ‘omics and deep learning, we are poised for data-driven discovery of the complex, high-dimensional, combinatorial interactions driving aging. First things first: let’s get this working in simple organisms.

A recent paper tied the Black Plague in the 1400s rapid evolution in the human immune system. I believe we are again on the cusp of rapid evolution. We will begin to edit our genes and rejuvenate our bodies. Buckle up.

Here are some of the very biggest questions in aging science as I see it:

1. What is aging? How do you measure aging on shorter timescales than death?
2. What drives aging? How? Is the epigenome the primary driver?
3. What slows aging? How? Which of the various possible interventions work? What combinations of these interventions is optimal?
4. What reverses aging? How? Does cellular reprogramming reverse aging?
5. What should humans do to live longer and healthier? How personalized do interventions need to be? How do I know if I'm doing the right things for my aging?
6. How can we develop a simpler model of aging to answer the above questions? While the particulars are different, almost every organism ages. Mammals are so large and complex, and we still don't understand many fundamentals. Could we start with C. elegans with ~1,000 somatic cells vs. ~37 trillion cells for humans?

What data could illuminate our understanding of these fundamental questions?

Here is a data pipeline that would be very interesting:

• Start with a tiny, well-understood organism like C. elegans.
• Do whole organism epigenomics, spatial transcriptomics, genomics and imaging across the full lifespan. Maybe 10-100 unique time points so you can see changes over time? This is a tremendous amount of data.
• Identify spatio-temporal aging patterns.
• Create a "biological clock" based on all this data.
• Pick candidates for "drivers" of aging, e.g. epigenomic remodeling, and then intervene/perturb to return towards "youthful" state.
• Elucidate drivers of aging and methods for slowing and reversing aging.
• Once this works, expand to larger and larger organisms.

I'm sure others have considered this kind of approach. Why aren't we doing it today?