#359 ‒ How metabolic and immune system dysfunction drive the aging process, the role of NAD, promising interventions, aging clocks, and more | Eric Verdin, M.D.

Eric’s scientific journey from virology to the field of geroscience [2:45]

Give folks a little bit of a sense of what attracted you to the field of geroscience and how your journey and background brought you to where you are today  

• It’s a bit of a serendipitous type of story 
• Eric is an MD by training from Belgium
• He did his last year of medical school at Harvard, and this just opened his eyes to a whole world
• He was the first person in his family to go to college

Eric explains, “Ending up at Harvard with some of the best teachers, some of the best students, was just mind-blowing. I went to medical school wanting to do research, never had that sort of a ‘doctor fiber,’ I call it, so I really wanted to research.” 

• He finished medical school and came back for a postdoc at the Charleston Clinic, working on diabetes and metabolism
• This is where the story gets circuitous
• He ended up becoming interested in the reason for the etiology of type 1 diabetes and worked on viruses and autoimmunity

This led him to mostly a career in virology, which confuses people 

• He spent many years working on a variety of viruses including HIV, and herpes viruses, and so on
• Through that work, he ended up cloning some of the first epigenetic regulators, a family of proteins called HDACs
• This family of epigenetic regulators ended up being important in aging, and starting in 1995, 1996, his lab shifted toward the study of aging
• Today, he has only one postdoc in the lab who is working on HIV

The whole lab is focused on epigenetics, immunology, and metabolism, so the interface between these variables 

Eric reflects, “In some way, it’s the beauty of an academic career, which I’ve just followed my interest, sometimes followed the money a little bit in terms of funding.” 

• Now, Eric has another additional responsibility, which is to lead the Buck Institute for Research on Aging
• He splits his time between the lab and some more leadership type of activities

How dysfunction in the immune system and central nervous system can drive aging throughout the body [5:00]

You mentioned two things there, metabolism and immunology ‒ talk a little bit more about how each of those individually contributes to aging 

• Immunology is central to aging in many respects

“There is data showing that there are two organs that are rate-limiting in terms of your aging. It’s the central nervous system and the immune system.”‒ Eric Verdin

• One could have predicted this based on the fact that both organs are distributed organs
  • If you think of your immune system, it’s located in pretty much throughout the whole organism, and so its activity can influence the wellbeing or the functioning of every single organ
  • The same goes for a central nervous system
• A recent study came out from the lab of Tony Wyss-Coray showing that those biomarkers that measure aging in those organs appears to be the most predictive of your lifespan
• There’s also incredible data showing that if you induce a specific lesion in the immune system, for example in mice model, if you knockout ERCC1 (DNA damage repair) only in the bone marrow so that the whole immune system is affected, you actually induce accelerated aging in the whole organism and senescence in every single organ
  • It’s been done with the ERCC1 mutation 
  • It’s also been done by knocking down the major TFAM (the major transcription factor for mitochondria)
  • If you induce mitochondrial dysfunction only in the immune system, you induce secondary senescence in the whole organism

Peter asks, “Do you think that would be true in humans?”

• It’s a million-dollar question
• It’s been shown in 2 different models in mice
  • Eric doesn’t remember the exact strain of the mouse, but there’s no reason why it should be different
• It points to the importance of the immune system
• The second wave for the immune system is through chronic inflammation, which is tied cause and effect in the whole aging process 

“I find it fascinating, the whole idea of chronic inflammation which is induced by the aging process, which itself actually further accelerates aging.”‒ Eric Verdin

• There’s really a lot of work that’s being conducted in this area
• The other one that you were asking is metabolism.

Peter finds it very interesting: 2 organ systems that are going to be rate-limiting in age are the central nervous system and the immune system (both of which are distributed throughout the body) 

Where would you put the endothelium in that list? 

• Peter notes that the endothelium is also quite distributed across the organism

Do you think that there’s an inevitability to basically endothelial damage as a process of aging, which, of course, results in the leading cause of death, the atherosclerotic diseases? 

• It’s not sort of defined as an organ by itself
• It’s a cell type
• Eric agrees about its incredible importance, especially as it affects the heart and the cardiovascular system and the brain
• But he thinks of it more as a principle that maintains barrier function
  • Not only in the endothelium but also in the skin, in the blood brain barrier
  • These are emerging as key areas to focus on if you want to maximize your longevity 

The role of metabolism and oxidative stress in aging, and why antioxidant strategies have failed to deliver clear benefits [8:45]

Metabolism is essential to life expectancy for a number of reasons 

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