Rapamycin, Caloric Restriction, and Inflammaging with Dr. Arlan Richardson - The VitaDAO Aging Science Podcast

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In the current episode of The VitaDAO Aging Science Podcast, we dive into the intricate world of rapamycin, caloric restriction, and inflammaging with the distinguished Dr. Arlan Richardson. Dr. Richardson, a pioneer in aging research with a career spanning over five decades, shares his extensive knowledge and groundbreaking insights. We discuss his pioneering work on rapamycin, the complexities of caloric restriction, and the role of chronic inflammation in aging. This episode also touches on the significance of necroptosis, the intriguing connections between senescence and inflammation, and the future of aging interventions. Join us as we explore these vital topics and their implications for human longevity, shedding light on the critical role of preclinical studies in advancing our understanding of aging.

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Brief Bio – Dr. Arlan Richardson

Arlan Richardson, earned his Ph.D. in biochemistry from Oklahoma State University in 1968, and for the past 50 years has devoted his career to aging research at Illinois State University, the University of Texas Health Science Center at San Antonio (where he directed the Barshop Institute on Longevity and Aging Studies), and the University of Oklahoma Health Sciences Center.

Dr. Richardson's research has focused on various aspects of aging: (i) the effects of aging and dietary restriction on gene expression in rats and mice, (ii) testing the oxidative stress theory of aging by measuring the effect of alterations in the antioxidant defense system on the lifespan and pathology of transgenic and knockout mice, and (iii) studying the effect of rapamycin on aging and age-related diseases. He is currently studying the mechanism responsible for genotype differences in response to dietary restriction and the role of chronic inflammation in aging.

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Aging, rapamycin and the clinic

Arlan expressed disappointment in the hesitancy to test rapamycin in healthy individuals. In the 70s when he started it seemed it would difficult to change the lifespan of any organism at all, but then in 2008 with rapamycin came a big breakthrough; and a time of confusion and disappointment for us basic scientists:

"I am sitting here thinking, oh now, those of us in the basic sciences got you something that will potentially slow aging in humans and now I thought everybody, all the clinical people, will be running to us and saying  we want to test it and we are sitting back about fifteen years and there is hardly [any progress]..." (Arlan Richardson)

We both agreed that hope for faster clinical translation of rapamycin.

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On being a generalist and working in science

"My whole career has been in aging...I am basically led by where the experiments go.. I go where I think the models will allow me to.” (Arlan Richardson)

Arlan has never stuck with one subject area. He studied caloric restriction and small molecules like rapamycin or necrostatin with the only unifying theme being his focus on preclinical work in rodents. As long as he can get something to work in mice or rats, he is interested and, during the podcast, we discuss how “getting things to work” is not always trivial.

In fact, earlier during his career studied rats but then everyone else moved to mice because they are easier to keep and more amenable to genetic manipulation. Nevertheless he wants to study rats once again over mice due to their closer resemblance to humans in terms of disease pathology and their higher genetic diversity. Given this, Arlan decided to develop a hybrid cross, akin to the HET3 mouse, just in rats. He emphasizes that these rats also have higher mitochondrial genetic diversity than HET mice, making them a great model to study future longevity interventions. Unsurprisingly Arlan was one of the co-authors of a recent review with the memorable name “Bring back the rat!”.

Finally, Arlan highlighted that many breakthroughs in biogerontology were made by junior people, e.g. Clive McCay (mice) or Tom Johnson (worms). Perhaps younger people are less biased, he adds.

Necroptosis, senescence, inflammation and aging

If you have never heard the word “necroptosis” before you are not alone. Arlan joked that he too did not know about this pathway when an immunologist first suggested he should look into this pathway in one of his mouse models.

Necroptosis, a form of programmed cell death distinct from apoptosis, is highly inflammatory and may contribute to the aging pathology in the brain, liver and adipose tissue. It is characterized by the release of damage-associated molecular patterns (DAMPs), which exacerbate inflammation—a key feature of aging known as inflammaging. Interestingly necroptosis can lead to the release of inflammatory TNFa which itself can promote necroptosis, in a vicious cycle.

Key proteins involved in this process include RIPK1, 3 and MLKL. Arlan found that necroptosis increases with aging and is counteracted by caloric restriction. Presently he studies animals transgenic for MLKL to gain a better understanding of necroptosis and he also studies the ncroptosis inhibitor necrostatin. He found necrostatin reduces age-related inflammation and, surprisingly also, senescence suggesting these two are connected.

Arlan believes that senolytics show some promise. In this regard he is more optimistic than Rich Miller, although he also highlights a lack of gold standard lifespan studies with senolysis. When I asked him about his top three interventions he mentions caloric restriction, dwarfism and rapamycin. These are the interventions supported by the strongest evidence so far, he argues.

The great ILSXISS caloric restriction controversy (somewhat technical)

During the podcast Arlan and I talked about the controversial ILSXISS publication and his effort to replicate and qualify the findings of the original papers (now published as Unnikrishnan et al. 2021). Let me give you my account of the story.

Briefly, the original study by Liao and Rikke et al. showed that when CR was tried in dozens of heterogenous – although still inbred – so called ILSXISS strains the intervention produced no benefit on average. This shocked some of us since it was counter to the consensus saying that CR is highly robust. Others dismissed this publication because of some methodological flaws. To his credit, Arlan took the findings seriously and sought to address some of the issues raised that weakened the conclusions from the original paper.

His decisions were partly driven by science and partly by funding constraints. As we mentioned multiple times during the podcast, there is so much to study and too little grant money. Given limited funding Arlan decided to re-test a well-defined subset of ILSXISS strains in a study with larger sample sizes, using graded CR and measuring potential explanatory variables. The choice of strains is crucial as I will explain in a moment.

When we started working on our manuscript to highlight the need for long-lived controls in mouse lifespan studies (Pabis et al. 2023) one of the areas I focused on was a re-analysis of the ILSXISS dataset. I was one of the people who wanted to find a flaw in the ILSXISS study because I truly wanted to believe in CR. Trust me, if anything, I was biased in favor of the CR hypothesis. After months of analysis, I came away none the wiser and more confused. Perhaps with a more nuanced opinion.

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Unnikrishnan is considered to weaken the conclusions of the original paper because the authors “focused … on those..[originally] lines reported to show a decrease in lifespan” and found that, on average, neither of them showed lifespan shortening in their new study. That is amazing, perhaps it means the whole dataset should be shifted upwards, so to say. This would imply that the other lines should show a much more pronounced benefit and CR would be beneficial on average. Unfortunately, these other lines could not be tested.

There is an alternative more pessimistic hypothesis. In our analysis we confirmed that while control lifespans in the diverse ILSXISS papers are somewhat consistent, the CR response is not. Whatever the reason for this, it means you cannot select non-responders because you are most likely just selecting based on noise. So if the strains reanalysed by Unnikrishnan are perfectly average in their CR response this would mean their result is entirely consistent with the whole body of ILSXISS data showing that the average mouse does not benefit from CR. The only way to distinguish the optimistic and pessimistic interpretation is by also retesting the top responders from the original paper. If the top responders show no benefit of CR in a re-test the pessimistic hypothesis is right, if the top responders show at least some benefit it suggests that the optimistic hypothesis might be right (1). 

On a positive note, recent data shows that CR does work in highly heterogenous diversity outbred (DO) mice (Di Francesco et al. 2023). There is a lot left to learn and the CR hypothesis remains alive!

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References and further reading

Mohammed, Sabira, et al. "Necroptosis contributes to chronic inflammation and fibrosis in aging liver." Aging cell 20.12 (2021): e13512.
https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13512

25 Years after age-1: Genes, Interventions and the Revolution in Aging Research
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686982/

Unnikrishnan, Archana, et al. "Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice." Aging Cell 20.11 (2021): e13500.

Pabis, Kamil Konrad, et al. "The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience." bioRxiv (2023): 2023-10.
https://www.biorxiv.org/content/10.1101/2023.10.08.561459v1.abstract

Di Francesco, Andrea, et al. "Regulators of health and lifespan extension in genetically diverse mice on dietary restriction." bioRxiv (2023): 2023-11.

Carter, Christy S., et al. "Bring back the rat!." The Journals of Gerontology: Series A 75.3 (2020): 405-415.

(1) And even that study design might be problematic since the best and worst responders from the original study with small group sizes are likely to regress towards the mean in a much larger study. Science is complicated!

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