Dr. Arlan Richardson, Promises in Modulating the Aging Process

Author(s): Scott Douglas Jacobsen

Publication (Outlet/Website): The Good Men Project

Publication Date (yyyy/mm/dd): 2025/02/03

Dr. Arlan Richardson is a Professor of Geriatric Medicine and the Donald W. Reynolds Endowed Chair of Aging Research at the University of Oklahoma Health Sciences Center. With over 40 years of experience, he has authored over 300 peer-reviewed publications and mentored over 50 scientists. His pioneering work includes research on dietary restriction and gene expression, oxidative stress, and rapamycin’s effects on aging. Dr. Richardson has received numerous accolades, including the Nathan Shock Award and the Irving Wright Award of Distinction. His current focus is on oxidative stress, necroptosis, inflammation, and dietary restriction in aging using genetic mouse models. Richardson discussed the evolution of aging research over the past 50 years. Key findings include the benefits of dietary restriction and rapamycin in animal models. However, translating these to humans remains a challenge. Richardson emphasized the importance of addressing aging itself rather than focusing solely on curing individual diseases like cancer or heart disease, as these yield limited lifespan increases. He highlighted the societal challenge of obesity and stressed that combining caloric restriction with exercise could improve healthspan. Moving forward, advancing human trials and reliable anti-aging interventions are essential goals.

Scott Douglas Jacobsen: Today, we are here with Dr. Arlan G. Richardson, a distinguished American biochemist renowned for his extensive research on aging. He is a professor in the Department of Biochemistry and Molecular Biology and holds the Donald W. Reynolds Endowed Chair of Aging Research.

Anyway, in your decades of research in the field of aging, what developments have become more factual and moved away from being considered science fiction? Conversely, what areas still appear as intractable as they were when you began your career?

Richardson: That is an excellent question. When I started in the field in the 1970s—over 50 years ago—while I was very excited about studying aging, I seriously doubted whether we would ever discover a way to manipulate the aging process. It didn’t matter whether it was a model; it wasn’t even a human model.

When people ask me when we would find something to slow aging, I would always say, “Probably in 10 years.” Even though I didn’t believe it would happen even within my life time, I figured that in 10 years, nobody would remember what I had said.  S

At that time, dietary restriction was the only known way to manipulate lifespan. I conducted many studies on this topic. We believed that if we could understand what dietary restriction was doing, we could target drugs to replicate its effects.

One of our significant findings was that dietary restriction almost reversed many problems associated with aging, such as disrupted biological pathways and the onset of age-related diseases. Dietary restriction delayed these issues. Animals subjected to dietary restriction lived longer and remained biologically younger. However, applying dietary restrictions to humans was a significant challenge because we all know that maintaining a strict diet for more than a year or two is extremely difficult for most people.

About 90% of people fail to sustain weight loss through dieting. I am an example of this myself. Given these limitations, I did not believe that, within my career, we would develop a drug capable of increasing lifespan and slowing aging.

What surprised me was the discovery in 2009 that rapamycin—a drug used in organ transplant rejection and some cancers—was shown to slow down aging in animal models. That was a significant milestone in the field of aging research.

Jacobsen: What areas should people be aware of regarding cautionary notes? Because, as with anything, there can be extraordinary promises that are technically grounded in the laws of physics or biology without necessarily negating their possibility. In finance, banking, or wellness, there’s always the potential for scams, fraud, or extraordinary claims that exceed the evidence.

As an expert, what are the main things people should be wary of—things known to be scams or frauds or that simply do not work?

Richardson: From a scientific standpoint, when discussing the ability of certain manipulations to work—whether in laboratory animals or life in general—the big question is whether these results will translate to humans. This is a significant issue because most of the manipulations that show promise in preventing conditions like cancer or Alzheimer’s disease in animal studies often fail to work in humans.

One consistent problem I see involves claims made about various supplements. These are often marketed as having effects on humans, even though there’s no solid foundation to support these claims, especially in animal studies. That doesn’t mean they won’t work in humans, but if something doesn’t show efficacy in animal studies, the likelihood of it working in humans is significantly reduced. On the other hand, just because a treatment works in animal models doesn’t guarantee it will work in humans. Does that make sense to you?

Jacobsen: Yes, it does. Please continue.

Richardson: Our studies are typically performed under what we call pristine conditions. The animals used are not exposed to infectious diseases or other external factors humans face daily. This raises the question of whether the results from these studies will translate to humans.

The most reliable advice remains the same: eat less and exercise more. This has been known for a long time, and everyone understands it. Yet, people often seek shortcuts—concoctions of drugs or supplements that claim to increase lifespan. If there’s no robust scientific evidence to back these claims—and in most cases, there isn’t—you must approach them cautiously.

Jacobsen: What are some things where experts are still on the fence? For instance, areas with enough evidence to suggest a modest effect but not enough to recommend them as regular practices for everyday life?

Richardson: A variety of laboratories have documented the observation of rapamycin. If you look at animal models, the best intervention is dietary restriction, which I’ve already discussed. The other significant intervention is rapamycin. While rapamycin is not a dietary system, its effects mimic some aspects of dietary restriction.

We know that rapamycin increases lifespan in animal models. However, people often overlook the need for consistent and rigorous scientific replication. Multiple labs have repeated the observation of rapamycin’s effects. The challenge is translating these findings to humans. Rapamycin does have some adverse effects, which has led to a reluctance to conduct large-scale clinical trials in humans.

Another major issue is how to test potential anti-aging compounds in humans. For instance, Neil Barclay at Albert Einstein College of Medicine has been thinking about this challenge and has proposed some ideas. Still, human lifespan studies are impractical due to the extended timeframe required. Instead, we need to identify compounds that do not require lifelong administration but can be introduced later in life to slow aging, prevent diseases, and maintain physiological function.

One area of interest is the development of compounds that can reduce appetite without the negative effects associated with traditional dietary restrictions. These compounds could reduce adiposity and have anti-aging effects. Preliminary animal studies suggest significant potential, but we are just beginning to explore their limits regarding anti-aging effects in humans.

Jacobsen: Who would you consider the leaders in this field?

Richardson: Dr. Steven Barthelon at UAB and Tim Kirkland, previously at the University of Texas and now at Cedars-Sinai. Both have made significant contributions to anti-aging therapies. Another prominent figure is Dr. Sara Espinoza, a leading geriatrician at the University of Texas Health Science Center in San Antonio.

Jacobsen: On the whole, are supplements effective or ineffective?

Richardson: Based on studies with animal models, most vitamin supplements and related products are ineffective in extending lifespan or improving health outcomes.

Jacobsen: What about treatments that fall in between, such as over-the-counter options or medications typically prescribed for specific conditions? For example, you mentioned something like Ozempic, which has gained popularity. I recall working at a horse farm where some higher-income clients purchased and used it. They reported weight loss and some health improvements. Others have looked into metformin or anti-inflammatory treatments. Are these effective?

Richardson: Medications like Ozempic (semaglutide) and metformin have shown potential in specific contexts. Ozempic, for instance, was originally developed for managing diabetes but has demonstrated benefits for weight loss, which can indirectly improve overall health. Similarly, metformin has been studied for its potential anti-aging effects, but its efficacy is not yet definitive. Both require more robust clinical studies to determine their broader applicability for aging and longevity. Reducing chronic inflammation is another promising avenue, but the science is still evolving.

Metformin, in addition to its effects on diabetes, may also reduce the risk of cancer and other age-related conditions in humans. Interestingly, it did not significantly affect lifespan when studied in mice and rats. On the other hand, interventions like GLP-1 receptor agonists, such as Ozempic, which were originally developed for diabetes and are now used for weight loss, hold potential as anti-aging interventions. This is mainly because their mechanisms of action mimic some effects of caloric restriction.

We know caloric restriction has universal benefits in animal models, including vertebrates, dogs, and non-human primates. It consistently shows positive effects on lifespan. Even in human studies, such as a two-year caloric restriction trial, while lifespan effects weren’t measured, improvements were observed in insulin sensitivity, cardiac health, and other physiological markers.

Jacobsen: This raises questions about the impact of specific choices: whether to take Ozempic or metformin, exercise or not or follow a calorically restricted but nutritious diet. These are not just binary choices but matters of degree. How do increments of caloric restriction—say 10%, 20%, or 50%—impact health and longevity? Additionally, does the effect depend on the nutritional quality of the restricted diet?

Richardson: There’s been some debate, but reducing calories is key, regardless of the specific nutritional components. Exercise also plays a role, but it’s challenging to disentangle its effects from caloric reduction. The best approach is a combination of both.

In animal models, caloric restriction typically involves a 30–40% reduction, which is substantial. Some studies suggest benefits even with a 20% or as little as a 10% reduction. Based on this data, I believe a 15–20% reduction could be effective in humans. However, reductions exceeding 40% could lead to negative side effects.

You also asked about the duration of caloric restriction. In animal studies, many benefits have been observed over their lifespans. However, other studies, including ours, indicate that even applying caloric restriction during certain life stages—early or late—can yield benefits. My recommendation would be to focus on caloric restriction for overweight individuals. A more conservative approach would be appropriate for those at a normal weight.

The broader context is also important. Obesity has become a significant societal issue. Historically, life expectancy has increased dramatically—from around 40 years in the late 1800s to nearly 80 years today. This improvement is due to advancements in healthcare, nutrition, and living conditions. However, the obesity epidemic poses a significant challenge, potentially reversing some of these gains by increasing the prevalence of diseases that compromise health and productivity.

Jacobsen: On a sociological and health note, as well as within media, there are debates about the portrayal of weight and health. Some individuals, including influencers, argue—rightly, in my opinion—that overweight individuals should not be shamed. I completely agree with that.

At the same time, another perspective suggests that we should not encourage unhealthy lifestyles in general culture. I also agree with that. These two views are not necessarily contradictory. However, there are cases where some influencers who are quite overweight have died young, which highlights the importance of not promoting unhealthy habits. So, while individuals should be happy with themselves, we must also be cautious about inadvertently normalizing unhealthy lifestyles. What are your thoughts?

Richardson: I completely understand where you’re coming from. I once weighed 260 pounds, and now I’m around 180. I’ve experienced firsthand the sensitivity surrounding weight issues, but I also understand that being obese is not healthy. Similarly, not exercising is also detrimental, as I’ve often discussed.

Ignoring the fact that obesity poses serious health risks is not the solution. That said, I completely agree that it’s unfair to assume that people who are overweight lack willpower. It’s like telling an alcoholic they need more willpower to stop drinking—it doesn’t work that way.

For example, I’ve taken certain medications that have significantly curbed my appetite. Now, I can sit with my wife, eat a satisfying meal, and stop there. Previously, I would eat multiple helpings, and within hours, I’d be back at the refrigerator.

From a compassionate perspective, we should acknowledge that many people who are overweight don’t want to be. Still, they often face significant biological and psychological barriers. Recognizing and addressing those challenges is key, in my opinion.

Jacobsen: What parts of aging will be the hardest to overcome with science and research? What areas will present the toughest challenges for reaching strong, evidence-based conclusions in the future?

Richardson: The toughest challenge will be determining whether an intervention truly has an anti-aging effect on humans. This is a complex issue, and experts like Dr. Nir Barzilai might offer differing opinions.

One of the most remarkable developments over the past 50 years is discovering multiple ways to slow aging, particularly in animal models like mice. Evolution has demonstrated the ability to manipulate lifespan across different organisms, so extending lifespan is no longer as surprising as we once thought.

The real challenge lies in translating these findings from animal studies to humans. Testing interventions for aging fundamentally differs from testing treatments for diseases like cancer. You can administer a cancer therapy and observe its effects over a few years. With aging, it’s much harder to measure the impact of an intervention in a relatively short timeframe.

Until we solve this problem—finding reliable, evidence-based ways to test anti-aging interventions in humans—the ability to translate findings from mice to humans will remain limited. We need solid evidence that a given intervention can improve healthspan by enhancing function, reducing disease progression, and slowing the effects of aging.

Jacobsen: Is there anything else I haven’t covered that you think we should discuss?

Richardson: One important thing to consider is that most of our current research is focused on curing specific diseases, like cancer or heart disease. This approach—treating one disease at a time—has been incredibly powerful in the past. For example, we’ve seen the success of vaccines in addressing diseases like Ebola.

That said, some people now spread misinformation about vaccines, but that’s another topic entirely. The point is, even if we cured cancer and heart disease today, the increase in life expectancy would only be around 8 to 10 years, according to predictions. However, curing those diseases doesn’t necessarily improve the quality of life in a significant way.

The reason is straightforward: if you don’t die of cancer or heart disease, another disease will eventually emerge, and these later-stage conditions often come with significant costs—both financial and emotional. For example, Alzheimer’s disease is a prime example. It’s extremely expensive to manage and takes a heavy toll on family members who provide care.

If we want to have a real impact on quality of life, we need to focus on slowing the aging process itself. Addressing aging would have a broader and more profound effect on quality of life than curing individual diseases. Animal models treated with caloric restriction show this clearly. Animals at the equivalent of 90 human years that have undergone caloric restriction look and behave much younger than their ad-lib-fed counterparts. Their fur is healthier, they move more, and they exhibit overall better vitality.

From these models, we know that slowing aging benefits health and lifespan. The real question is whether these findings can effectively be translated to humans. That’s where the next big breakthroughs need to happen.

Jacobsen: Excellent. Arlan, thank you for the opportunity and your time today. It’s been a pleasure.

Richardson: Thank you so much. You take care.

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