Computational Aging

“Restoring order to the whole system is surely the eventual future of medicine. Unraveling the systems biology of aging is going to take incomprehensible amounts of data, enormous computing power, and smart computational biologists, working in tandem with those in the lab. Replacing numerical with narrative representation has revolutionized whole fields of science in the past, and the data and computation revolution in biology has only just begun. Once we can model our biology in detail, we’ll be able to reprogram it. Human beings will finally be negligibly senescent, biologically immortal, and ageless… It should be our collective mission.” - Andrew Steele, Ageless, 2020

One of the surprising things about aging science is how little we still know. We know far more than we did 40 years ago, thanks to a generation of pioneering investigators. But it seems that we have some puzzle pieces without the picture of how they fit together.

Another surprising thing is how little we know about our own bodies and health. We have high-level markers, such as blood panels, w physiological measures, etc. And we mostly rely on how we feel. If we feel good, we typically don't worry about our health. If we don't feel good, then something might be wrong. I generally feel great, young, energetic and healthy. Still, I know that damage from aging is accumulating throughout my 37 trillion cells and the tens of millions of biomolecules in each cell. Rust, damage and waste are taking root.

We don't yet know where this damage is happening. I can see the sun damage on my skin. I can feel my creaky ankles. But how is my heart aging? How is my brain aging? Where are little cancers forming? Which tissues are increasingly damaged that don't yet have noticeable dysfunction? It's hard to manage what you can't measure.

To Steele's quote, I believe it is critical to measure and model our biology. We need to know what's going on and intervene before it's too late. This will be a foundation for slowing and reversing aging. It's a massive challenge and will require new methods, data and computational techniques. It's where I expect to spend the next 20+ years of my career.

Are we getting better at treating age-related disease? I wouldn't know how to answer this. It has been discouraging to see the average lifespan fall in the last few years in the United States.

Encouragingly, a recent study argues that the risk of dementia has significantly declined in Americans from 2000 to 2016 [1]. From the study: "The age-adjusted prevalence of dementia decreased from 12.2% in 2000 (95% CI, 11.7 to 12.7%) to 8.5% in 2016 (7.9 to 9.1%) in the 65+ population, a statistically significant decline of 3.7 percentage points or 30.1%."

It is not clear what is driving this decrease. Reason's most recent Fight Aging newsletter speculates authors speculate it may have to do with better maintenance of blood pressure and the use of statins [2]. Neurodegenerative diseases like dementia are critical for lifespan extension. If we don't have a healthy brain, is life worth living? This study suggests we are making progress.

[1] Hudomiet, Hurd and Rohwedder. Trends in inequalities in the prevalence of dementia in the United States. PNAS 2022, 119 (46) e2212205119. https://doi.org/10.1073/pnas.2212205119  

[2] Reason. "The risk of suffering dementia is declining." Fight Aging. Accessed on Nov 19, 2022. URL: https://www.fightaging.org/archives/2022/11/the-risk-of-suffering-dementia-is-declining/

Many have proposed using the 9 hallmarks of aging as a roadmap for extending healthspan and lifespan. Encouragingly, this is actually happening.

As a reminder, these are the 9 hallmarks [1]:

1. Genomic instability
2. Telomere attrition
3. Epigenetic alterations
4. Loss of proteostasis
5. Deregulated nutrient sensing
6. Mitochondrial dysfunction
7. Cellular senescence
8. Stem cell exhaustion
9. Altered intercellular communication

The hallmarks are believed to be molecular drivers of aging. Thus, these are compelling targets. The hallmarks have held up pretty well since publication nearly 10 years ago now in 2013. You might argue that several of these are more important than others (e.g. loss of proteostasis (#4) seems especially damaging). You can also argue that these are not mutually exclusive or collectively exhaustive. They are deeply interwined. For example, cellular senescence (#7) leads to the senescence-associated secretory phenotype (SASP) which alters intercellular communication (#9). You might also argue that any of genomic instability (#1), epigenetic alterations (#3) or loss of proteostasis (#4) is an upstream cause of senescence. Still, slowing or reversing these hallmarks are likely to slow aging.

Researchers are learning how to reverse these hallmarks, both individually and in combination. For example, we have developed senolytics that remove senescent cells and show extended lifespan in mice [2], and human trials are underway [3]. One exciting recent paper combined partial reprogramming with senolytics in Drosophila (fruit flies) [4]. Each therapy on its own led to increased lifespan. Combining the two led to even larger increased in lifespan and the survival curve. The combined therapies led to improved stem cell proliferation, addressing hallmark 7, as well as reducing cellular senescence, addressing hallmark 7.

Researchers are also developing biomarkers for these hallmarks. A 2020 paper proposes a specific biomarker for each of the hallmarks of aging [5]. If we can measure the molecular basis of aging as it progresses, we can more directly develop therapies for model organisms and humans. These kinds of measurements could become successful consumer products for the longevity nerds of the world, similar to how biological age measurements have had direct-to-consumer commercial success.

One of the reasons I write this blog is to explore how to guide a long-term research program for aging research. Targeting the hallmarks of aging is one reasonable path 

References:

[1] Carlos López-Otín, Maria A. Blasco, Linda Partridge, Manuel Serrano, Guido Kroemer. The Hallmarks of Aging. Cell,Volume 153, Issue 6, 2013, pp. 1194-1217, https://doi.org/10.1016/j.cell.2013.05.039

[2] Xu, M., Pirtskhalava, T., Farr, J.N. et al. Senolytics improve physical function and increase lifespan in old age. Nat Med 24, 1246–1256 (2018). https://doi.org/10.1038/s41591-018-0092-9

[3] Search for "senolytics" at ClinicalTrials.gov. U.S. National Library of Medicine. Accessed Nov 13, 2022. URL: https://clinicaltrials.gov/ct2/results?cond=&term=senolytics&cntry=&state=&city=&dist=

[4] Kaur P, Otgonbaatar A, Ramamoorthy A, Chua EHZ, Harmston N, Gruber J, Tolwinski NS. Combining stem cell rejuvenation and senescence targeting to synergistically extend lifespan. Aging (Albany NY). 2022 Oct 25; 14:8270-8291. https://doi.org/10.18632/aging.204347

[5] Guerville, F., De Souto Barreto, P., Ader, I. et al. Revisiting the Hallmarks of Aging to Identify Markers of Biological Age. J Prev Alzheimers Dis 7, 56–64 (2020). https://doi.org/10.14283/jpad.2019.50