Computational Aging

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

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].