Understanding Aging to Extend Healthspan and Longevity with Dr. Gordon Lithgow

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In this episode of Longevity by Design, hosts Ashley Reaver, MS, RD, CSSD, and Dr. Gil Blander sit down with Dr. Gordon Lithgow, a Professor and Vice President for Academic Affairs at the Buck Institute for Research on Aging. Dr. Lithgow's research focuses on understanding the mechanisms of aging and identifying genes and small molecules that can prolong lifespan. With a background in genetics from the University of Glasgow and extensive experience in biotechnology and aging research, Dr. Lithgow shares his journey from growing up in Scotland to leading a lab at the Buck Institute.

Dr. Lithgow discusses the compelling nature of aging as a profound biological mystery, which drew him into the field. He highlights his lab's approach of following curiosity-driven research, often using the nematode worm C. elegans as a model organism due to its short lifespan and genetic similarities to humans. This unbiased method has led to significant discoveries, including genetic mutations and drug-like molecules that extend lifespan. The conversation also covers the concept of geroscience, which Dr. Lithgow helped coin, emphasizing the link between aging and chronic diseases.

A major focus of Dr. Lithgow’s work is studying protein homeostasis, which declines with age. Protein misfolding is implicated in many age-related diseases; that discovery moved the lab’s focus from lifespan extension to efforts to understand drivers of healthspan and the causes of age-related chronic diseases, in particular Alzheimer’s and Parkinson’s. His work also includes the influence of environmental factors, such as mild heat stress, and dietary iron, vitamin D, and alpha-ketoglutarate (AKG) on aging. Dr. Lithgow's interdisciplinary collaborations aim to uncover new interventions to extend healthspan and longevity.

Episode highlights

• Introduction: 00:00-02:42
• What led Dr. Gordon Lithgow to become a scientist and research the biology of aging?: 02:43-06:20
• Why are worms (C.-elegans) a good model for studying aging?: 06:21-07:55
• Why did Dr. Gordon Lithgow transition from research investigating ways for extending lifespan to extending healthspan?: 07:56-09:24
• What specific diseases is Dr. Gordon Lithgow researching?: 09:25-12:01
• What does protein shape mean for aging?: 12:02-13:12
• How does mild heat stress impact health and aging?: 13:13-16:35
• How does vitamin D and alpha-ketoglutarate (AKG) impact aging, healthspan, and lifespan?: 16:36-25:26
• How does dietary iron impact aging, healthspan, and lifespan?: 25:27-29:57
• Are there more genes and proteins to be discovered that influence aging, or have they all been discovered?: 29:58-34:12
• What compound does Dr. Gordon Lithgow think has the most potential for extending healthspan and lifespan?: 34:13-35:54
• What is the impact of calorie restriction and exercise on healthspan and lifespan in humans?: 35:55-38:51
• What is the importance of clinical trials for aging research?: 38:52-42:09
• What are the future directions of Dr. Gordon Lithgow’s research?: 42:10-43:38
• Dr. Gordon Lithgow’s top tip for living better longer?: 43:39-48:

About Dr. Gordon Lithgow

Gordon Lithgow is a Professor and Vice President for Academic Affairs at the Buck Institute for Research on Aging in Novato, California. He received his PhD in Genetics from the University of Glasgow, Scotland, and briefly worked in biotechnology in Switzerland before becoming intrigued with the biology of aging. In 1991 he became a post-doctoral research fellow in the laboratory of Tom Johnson at the University of Colorado, Boulder. Johnson was the first scientist to discover a mutation in a gene Aage1) that increased the lifespan of the tiny nematode worm C. elegans.

In 1995 Lithgow moved to England to start his own lab and became a Senior Lecturer in Molecular Gerontology at the University of Manchester. In 2001 he and Buck faculty member Simon Melov published a groundbreaking paper in Science, which detailed the first use of a drug-like molecule to extend lifespan in a living animal. He moved his lab to the Buck Institute shortly thereafter.

At the Buck, Lithgow became a chief advocate for capitalizing on the Institute’s commitment to interdisciplinary research. In 2007, he spearheaded and became the Principal Investigator for a $28 million grant from the federal government, which established the Interdisciplinary Research Consortium on Geroscience. He is credited with coining the term “Geroscience,” which is now used worldwide to describe research focused on the connection between aging and chronic disease.

The Lithgow lab utilizes molecular genetics and biochemistry to define aging processes, and through extensive collaborations, they apply a range of leading-edge technologies to study protein homeostasis, which declines with age. Protein misfolding is implicated in many age-related diseases; that discovery moved the lab’s focus from lifespan extension to efforts to understand drivers of healthspan and the causes of age-related pathology and chronic disease, in particular Alzheimer’s and Parkinson’s diseases. The lab has taken compounds discovered to extend lifespan and healthspan in the nematode C. elegans and translated them into mouse studies with a high frequency of success. Related studies have been published in high-impact journals, including Science and Nature.

Dr. Gordon Lithgow is also the host of Buck Institute for Research on Aging's podcast, "We're not getting any younger... yet" on which he speaks with some of the brightest scientific stars on the planet to search for—and actually find answers to—questions on aging. The podcast can be found at https://www.buckinstitute.org/podcasts/ and on podcast apps.

How did Dr. Gordon Lithgow become interested in science and studying aging?

Dr. Lithgow's journey into the field of aging research began with a childhood fascination with biology, fueled by his love for birdwatching. However, it was a single pivotal discovery that truly ignited his curiosity about aging. In the late 1980s, researchers found that a mutation in a single gene could significantly extend the lifespan of the tiny nematode worm, C. elegans. This revelation shattered the notion that aging was an immutable process, prompting Dr. Lithgow to delve deeper into the biology of aging.

Why are worms (C. elegans) good model organisms to study and understand aging?

The simplicity and short lifespan of C. elegans worms make them an ideal model for aging research. These tiny nematodes live for only about 20 days, yet they undergo many of the same biological processes that occur in more complex organisms, including humans. Dr. Lithgow's lab has leveraged this model to identify hundreds of gene mutations and small molecules that can extend lifespan in worms.

One key advantage of using model organisms like C. elegans is the ability to conduct rapid and cost-effective experiments that would be impractical or unethical in humans. For example, Dr. Lithgow's team can screen thousands of compounds for their effects on lifespan in a matter of weeks, providing valuable leads for further investigation in mammalian models.

What is protein homeostasis (proteostasis), and how does it impact aging and chronic diseases?

One of the key areas of focus in Dr. Lithgow's research is the role of protein homeostasis (proteostasis) in aging. As organisms age, proteins can lose their proper shape and function—referred to as loss of proteostasis, which is one the key hallmarks of aging—leading to cellular dysfunction and disease. Dr. Lithgow's work has shown that maintaining the integrity of proteins through mechanisms like molecular chaperones can extend lifespan in worms. Interestingly, mild stresses like heat exposure can also activate these protective mechanisms, a phenomenon known as hormesis.

Dr. Lithgow's research has shed light on the intricate mechanisms that regulate protein homeostasis, or proteostasis. One particularly intriguing finding is the role of molecular chaperones, specialized proteins that assist in the proper folding and maintenance of other proteins. By upregulating the activity of these chaperones, either through genetic manipulations or small molecules, Dr. Lithgow and his team have been able to extend lifespan in worms and protect against age-related protein misfolding and aggregation.

Interventions that extend healthspan and lifespan

Through unbiased screening approaches, Dr. Lithgow's lab has identified several small molecules that can extend lifespan in worms and even in mice. Compounds like alpha-ketoglutarate (AKG), vitamin D, and appropriate concentrations of iron have shown promising results, not only increasing lifespan but also compressing the period of morbidity—delaying the onset and shortening duration of chronic illness, disease, or disability—towards the end of life. These findings highlight the potential for developing interventions that promote healthy aging and delay the onset of age-related diseases.

Why is aging so complex?

While the research on model organisms has yielded remarkable insights, Dr. Lithgow acknowledges the complexity of aging in human populations. Environmental exposures, nutrition, behavior, and individual genetics all play a role in shaping the aging trajectory. This complexity underscores the need for personalized approaches and careful consideration when designing clinical trials for aging interventions.

One of the key challenges in translating findings from model organisms to humans is accounting for the vast diversity in genetic backgrounds, environmental exposures, and lifestyles. Dr. Lithgow emphasizes the importance of personalized approaches, recognizing that a "one-size-fits-all" solution may not be effective for everyone. Additionally, the timing and duration of interventions may play a crucial role, as certain compounds or therapies, or combinations of compounds or therapies, may have different effects depending on the age and physiological state of the individual.

Future directions and the quest for new science to continue to improve our understanding of aging and extend healthspan and lifespan

Despite the significant progress made in understanding aging, Dr. Lithgow remains driven by a sense of curiosity and a desire to explore new avenues. He encourages his team and students to take an unbiased approach, studying different organisms and species and challenging existing paradigms. By drawing "new pictures" in aging research, Dr. Lithgow believes that groundbreaking discoveries may emerge, potentially leading to interventions that could revolutionize healthcare and redefine the aging experience.

Dr. Gordon Lithgow's top tip for health

When asked for his top tip for living a healthier, longer life, Dr. Lithgow emphasized the importance of maintaining a balanced perspective. While his research has uncovered promising interventions, he cautions against making broad recommendations without considering individual circumstances.
"I would love to make recommendations, but I can't because I am not an MD," Dr. Lithgow stated. "That's medicine and not science."

Dr. Lithgow's hesitation to prescribe specific interventions stems from his recognition of the inherent complexity and individuality of aging processes. Each person's genetic makeup, environmental exposures, and lifestyle factors can influence how they respond to various interventions. As such, he emphasizes the importance of seeking personalized guidance from healthcare professionals who can assess an individual's unique circumstances and provide tailored recommendations.

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