Computational Aging

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

The life expectancy for a woman living in Japan is ~88 years, while the average American has life expectancy of ~79 [1]. Further, for a Japanese woman who does the known best practices for longevity and health (exercise, diet, no smoking, etc), life expectancy is likely easily over 90.

Thus, we have a science-translation gap of at least 11 years of lifespan for the average American. Healthier habits typically healthier aging, less disease and later onset of disease. It can also lead to lower rates of depression, greater wellbeing and greater productivity. Across 400 million Americans, that's 4.4 billion years of unnecessarily lost life. To me, this is a travesty and a huge opportunity for change. 

How do we close the gap? There are probably lots of ways to approach it. One idea is through a new company that does what Omada Health does for diabetes and hypertension, or what Octave Biosciences does for multiple sclerosis. As I understand it, these companies provide helpful interventions, often with a coach or advisor, to generate behavior change. For longevity and aging, simply increasing exercise and improving diet for Americans would be enough to close a lot of that gap. Healthcare payers, companies and our federal and state governments would benefit greatly if we did this. Maybe Omada will have more of a longevity focus over time? After all, alleviating diabetes and hypertension are closely related to slowing aging (diet, exercise, etc). Still, we would reach a much larger population if the focus was on extending lifespan vs. treating diabetes, pre-diabetes or hypertension. Both Omada and Octave are VC-backed. Might there be room for a similar new company focused on longevity?

Sources:

[1] Max Roser, Esteban Ortiz-Ospina and Hannah Ritchie (2013) - "Life Expectancy". Published online at OurWorldInData.org. Retrieved from: 'https://ourworldindata.org/life-expectancy' [Online Resource].

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