The Impact of DNA Damage & Lifestyle on Aging & Longevity Medicine with Dr. Morten Scheibye-Knudsen

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In this episode of Longevity by Design, host Dr. Gil Blander is joined by Dr. Morten Scheibye-Knudsen, a leading figure in aging research. The goal of Dr. Scheibye-Knudsen's work is "to discover interventions leading to healthier, happier, and more productive lives. In this episode, he discusses his groundbreaking research on the role of DNA damage in the aging process and its implications for chronic diseases, aging research, and the importance of longevity medicine.

Dr. Scheibye-Knudsen's work is on understanding normal and premature aging, with a focus on the pivotal role of DNA damage in the aging process and interventions for healthier aging. By combining computational methods with laboratory experiments, his team explores innovative strategies to target DNA and counteract aging processes. This conversation illuminates the intricate relationship between DNA damage, aging, and chronic diseases. 

Dr. Scheibye-Knudsen also discusses the impact of lifestyle (diet, exercise, sleep, social factors) on aging. He goes on to describe his work using data-driven approaches to understand aging better and develop interventions for healthier aging. Additionally, he explains what longevity medicine is and the importance of educating clinicians and policymakers on this topic to translate research on aging into healthcare and improve people’s healthspan and lifespan. Dr. Scheibye-Knudsen's dedication to unraveling the mysteries of aging is advancing scientific knowledge, which has tangible benefits for global health and longevity. This episode is a must-listen for anyone interested in aging and health.

Episode highlights

• Introduction: 00:00-03:04
• What led Dr. Morten Scheibye-Knudsen to become a scientist?: 03:05-04:35
• An overview of the research Dr. Scheibye-Knudsen is doing?: 04:36-05:52
• What is DNA damage? What causes DNA damage?: 05:53-07:52
• What do we know about the influence of DNA damage on aging and age-related diseases?: 07:53-09:39
• Can DNA damage be repaired? 09:40-14:12
• What questions are Dr. Scheibye-Knudsen’s research group asking to better understand DNA damage and repair and their effects on aging?: 14:13-16:20
• What is NAD? Why is it the impact of NAD on aging and age-related diseases?: 16:21-19:54
• What are the benefits and risks of NR and NMN supplements in humans?: 19:55-24:48
• What is a ketogenic diet? What are the effects of a ketogenic diet or ketones on DNA damage or repair and aging?24:49-31:06
• What is the effect of a ketogenic diet on cancer?: 31:07-32:27
• What is the Aging Research and Drug Discovery (ARDD) conference and its mission?: 32:28-40:41
• What are the most prevalent features of aging?: 40:42-47:52
• Are there differences in aging between females and males?: 47:53-50:19
• Are there differences in tissue aging trajectories?: 50:20-53:59
• Identifying compounds that target aging: 54:00-56:14
• Can nuclear morphology predict cellular senescence and cancer?: 56:15-01:04:02
• What is longevity medicine? Why is longevity medicine important for physicians?: 01:04:03-01:07:23
• What pharmaceutical drugs are the most promising for targeting aging and extending human healthspan and lifespan?: 01:07:24-01:11:58
• How important are lifestyle factors such as nutrition, physical activity/exercise, sleep, and social engagement and connections for healthspan and lifespan?: 01:11:59-01:16:37
• Dr. Morten Scheibye-Knudsen’s top tip for improving health: 01:16:38-01:18:20

About Dr. Morten Scheibye-Knudsen

Dr. Morten Scheibye-Knudsen is an Associate Professor at the University of Copenhagen researching aging, with a focus on DNA damage and developing interventions to combat age-related diseases and extend healthspan. His fascination with aging research stems from witnessing his loved ones grow older and frailer, driving him to find ways to maintain health for longer periods. The mission of his work is "to discover interventions leading to healthier, happier, and more productive lives."

Dr. Scheibye-Knudsen received his MD degree from the University of Copenhagen. After that, he started his research track as a postdoctoral fellow at the National Institute on Aging, NIH, in Baltimore. There, he worked for close to a decade on developing interventions for rare genetic diseases characterized by premature aging.  He returned to Copenhagen in 2016 and is now an Associate Professor running a lab where he applies machine learning algorithms to define aging phenotypes and develop interventions for aging. He combines computational approaches with wet-lab exploration to understand normal and premature aging, with a focus on DNA damage and interventions leading to healthy aging. 

Beyond these scientific contributions, he is the Chief Scientific Officer at the Healthy Longevity Clinic, the organizer of the yearly Aging Research and Drug Discovery conference, serves as a chief editor at Frontiers in Aging, and is the founder and president of the Nordic Aging Society.  

What is DNA damage, and how does it impact health? Can DNA damage be repaired?

Dr. Scheibye-Knudsen explains that our DNA acts as a cellular blueprint, like a manual for a car. It contains the biological instructions that make each species and person unique and is pivotal to our growth, reproduction, and health. Over time, our DNA accumulates damage from various sources like oxidative stress, radiation, and environmental exposures. While our cells have over 400 enzymes dedicated to repairing this damage, a breakdown in these repair mechanisms accelerates aging and increases the risk of developing age-related diseases such as dementia, Alzheimer’s, cancer, cardiovascular disease, and diabetes. "If the manual gets damaged, you can't repair the car," explains Dr. Scheibye-Knudsen. 

Dr. Scheibye-Knudsen's work involves studying premature aging diseases caused by mutations in DNA repair genes, such as Cockayne syndrome and Werner syndrome. "These children have mutations in single genes, and those genes are typically involved in repairing DNA," he says. His research aims to understand why certain types of persistent DNA damage cannot be repaired, potentially leading to inflammation, tissue degeneration, and an increased risk for age-related diseases. 

His research also involves developing drugs or engineered enzymes that can target and repair these persistent DNA damage sites. He has discovered that DNA damage leads to changes in certain metabolites and that replenishment of these molecules may alter the rate of aging. These findings suggest that normal aging and age-associated diseases may be malleable to similar interventions that could extend healthspan and lifespan.

What is the role of NAD and ketogenic diets in DNA damage and aging?

Another area of focus for Dr. Scheibye-Knudsen is the role of NAD (nicotinamide adenine dinucleotide), a central molecule involved in numerous cellular processes. His work has shown that NAD levels decline with age, potentially driven by the DNA damage response enzyme PARP, which consumes NAD. 

To counteract this, his lab has investigated the effects of NAD precursors like NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide) in clinical trials. "In our trial, we found that NR did reduce inflammation in the lungs of COPD patients," says Dr. Scheibye-Knudsen. However, he cautions that these are still experimental drugs/supplements with unknown long-term effects and advises against widespread supplementation until more data is available. 

Ketogenic diets, which promote the production of ketones as an alternative energy source, are another avenue Dr. Scheibye-Knudsen’s lab is exploring. His team has observed that ketones can extend lifespan in animal models, though the mechanisms are not fully understood. "Ketones kind of circumvent this loss of NAD and can be used as an energy substrate," he explains.

Dr. Scheibye-Knudsen hypothesizes that ketones may circumvent the metabolic dysfunction associated with DNA damage and aging, potentially impacting the epigenetic landscape and reducing inflammation.

Aging research and data-driven approaches for healthier aging

One of the key approaches in Dr. Scheibye-Knudsen's lab is the use of computational methods and machine learning algorithms to analyze aging phenotypes. By leveraging large Danish healthcare registry datasets, his team has identified aging signatures based on pathological descriptions and text analysis of over 30 million pathology reports. "We looked for patterns of aging at a very broad level," he explains. 

Interestingly, their analysis revealed six specific patterns of aging, with differences observed between men and women. "We observed that for women, aging seems to maybe start a little bit earlier than for men, but then it goes much slower. Whereas for men, it starts a little bit later, maybe around 40 years of age, and then it goes more rapidly downhill," explains Dr. Scheibye-Knudsen.

Additionally, their analysis revealed tissue-specific aging trajectories, with some tissues, like the brain aging slower initially before accelerating later in life. "We still don't really understand tissue-specific aging," says Dr. Scheibye-Knudsen, suggesting varying mechanisms may be at play in different organs.

Dr. Scheibye-Knudsen's team has also developed a novel technique for detecting cellular senescence based on nuclear morphology. Using neural networks, they can classify senescent cells in tissue samples like skin and breast biopsies based on their distinct nuclear shapes. This high-throughput approach has shown promise in predicting cancer risk and could potentially be used for risk stratification in clinical settings.

The Aging Research & Drug Discovery (ARDD) Conference

As a co-founder of the Aging Research & Drug Discovery (ARDD) conference, Dr. Scheibye-Knudsen has played a pivotal role in bringing together key stakeholders in the aging research and drug discovery ecosystem. The conference aims to foster collaborations between pharma companies, researchers, investors, clinicians, and policymakers, all working toward developing interventions for healthy aging.

"The reason that we have ARDD is really an attempt to bring together all the players that can influence how we treat aging in the future, basically," says Dr. Scheibye-Knudsen. The conference has expanded over the years to include not just pharma and academia but also venture capitalists, clinicians, and even policymakers like the Danish Minister of Senior Citizens.

An exciting development is the integration of the XPRIZE Healthspan Challenge at this year's ARDD event in Copenhagen. This $100 million competition seeks to incentivize the development of interventions that can extend human healthspan by at least 10 years by 2030.

Longevity medicine and lifestyle factors

Dr. Scheibye-Knudsen strongly advocates for the importance of longevity medicine, which focuses on preventative approaches to maintain health for longer periods. However, he acknowledges that aging is often overlooked by the current medical system, which is focused on treating conditions after they have occurred rather than prevention. He emphasizes that while behavioral factors like smoking and poor diet increase cancer risk by around 75%, the risk increase associated with aging itself is a staggering 3,500%.

"If we can somehow target processes of aging with behavioral interventions or other types of interventions, then there is a huge potential to impact people's health," he states.

On the pharmaceutical front, Dr. Scheibye-Knudsen is optimistic about the potential of GLP-1 receptor agonists, which have been shown to be effective in losing weight and reducing obesity. “You lose weight, and then you reduce your risk of developing cardiovascular disease, dementia, and diabetes,” he explains. He also highlights metformin, rapamycin, NR, and senolytics as promising candidates for targeting aging processes and extending healthspan, with over 130 clinical trials currently underway.

However, he also stresses the significance of lifestyle factors like exercise, fasting, good sleep, and a balanced diet rich in vegetables, fish oils, dark chocolate, and moderate amounts of coffee. "If you look at what determines a human's lifespan, genetics has a role, but it's actually tiny. It's 10 to 20 percent of your lifespan is determined by your genes, which means the rest is really all behavior," explains Dr. Scheibye-Knudsen.

Dr. Morten Scheibye-Knudsen’s top tip for health

Dr. Scheibye-Knudsen emphasizes some form of fasting combined with exercise to maintain muscle mass as we age. "Skipping breakfasts is in our hands…people simply start fasting, and then you reduce your risk of many adverse events with age…but it can be probably detrimental when you're very old...and you have to exercise at the same time to maintain muscle mass,” says Dr. Scheibye-Knudsen.

Similar Longevity By Design episodes we think you would love: 

• XPRIZE Healthspan: Revolutionizing Human Aging & Healthspan with Dr. Jamie Justice 
• Dr. Emma Teeling—DNA Repair Mechanisms and Aging: Lessons From Bats
• Do NAD Analogs and Resveratrol Boost Cellular Health and Longevity With Dr. Joe Baur

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