Aging Networks & Biomarkers, Alpha-Ketoglutarate & Longevity of Bats | Dr. Brian Kennedy
Live Longer World Podcast #11
Live Longer World Podcast Episode #11 has been released!
My guest today is Dr. Brian Kennedy who is the Director for the Center of Healthy Aging at the National University of Singapore. He is also the former President and CEO of the Buck Institute of Research on Aging. Dr. Kennedy is well-known in the field of longevity & beyond and has been involved in critical aging research.
Dr. Kennedy's lab is working on different small molecules and natural products that could boost longevity. In today's discussion, we spoke about the network concept of the hallmarks of aging, the longevity effects of natural products like Alpha-Ketoglutarate (AKG), Spermidine and Urolithin A, and why combining some of these supplements might not be prudent. We also spoke about comparing the different biomarkers of aging, what we can learn from the longevity of bats, and why basic science is important.
I hope you enjoy my extensive discussion with Dr. Brian Kennedy on all things longevity!
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00:00 Live Longer World
00:35 Brian Kennedy Intro
1:24 Differences in lifespan vs healthspan in his grandmothers
3:37 Network concept of the hallmarks of Aging
7:17 Open questions on hallmarks of aging; combining interventions
13:08 Comparing biomarkers of aging
16:11 Alpha-Ketoglutarate (AKG) and Longevity
23:55 Aging across different ethnicities
26:00 Socioeconomic & housing differences contributing to aging
29:40 Spermidine & Autophagy
31:59 Different longevity supplements may cancel each other out
35:18 AKG in extended release form
36:24 AKG & Red Blood Cells + Glutathione production
38:43 Mechanisms by which AKG works; AKG & Microbiome
40:07 Urolithin A, Mitochondria & Longevity
41:55 Longevity of Bats!
47:57 Yeast as model organisms for aging research
50:24 Advocating for Basic Science Research (Feynman: The Pleasure of Finding Things Out)
57:34 Support, share, and follow Live Longer World
Extensive Show Notes & Transcript:
One of the reasons you got interested in aging is because both your grandmothers lived past 100. If you recall, do you know how they lived their lives differently or were they blessed with centenarian genetics?
One of them lived to 99 and one to 101, so the average was a 100!
I use my 2 grandmothers to illustrate the difference between lifespan and healthspan
One was healthy throughout her life and lived alone till 6 months before her death. She was driving and bowling around
My other grandmother got sick at about 60. She went to the doctor and the doctor said, you're probably not going to live five more years because you already have all these things wrong with you.
But she had one thing going for, which is stubbornness. Nobody was going to tell her she was going to die. And so she outlived two or three of those doctors. She was never a particularly healthy, but she was always mentally acute up until maybe the last four or five years.
One of them had long lifespan and healthspan and that’s what we want - compress morbidity and long life
You’ve spoken about the network concept of the hallmarks of aging - the fact that the hallmarks of aging are interconnected - can you speak to this?
It's not something that just came conceptually to me. It came from looking at the interventions that extended lifespan
And so we didn't know what they were doing. And then we set about trying to figure out the mechanism of action of many of these drugs. And what we found out is I think the idea was that we'll figure out which hallmark or pillar of aging that each of these drugs hit. And then once we know that we can combine them and get even bigger results. And the problem was, if you take something like rapamycin or Metformin or NAD they tend to improve all the hallmarks of aging
And so then you have to ask the question, why are they doing all these different things related to aging? And that led me to think of the idea that really, you know, these hallmarks are just readouts on a system that is in your body to try to keep you healthy. It's not there to make you live forever. It's there to keep you healthy as long as possible, especially during your reproductive years
And so things are happening even from birth to your body
But the aging network can compensate for that when younger and keep you healthy
But when enough things happen including DNA damage or environmental factors, the network starts to break down and you become susceptible to disease
But as long as that network's functioning, I think you're pretty much resistant to most of those chronic diseases
What I think these interventions are doing are really hitting nodes in this network. For example, mTOR signals nutrients and then it has lots of readouts like autophagy, protein synthesis, cell cycle, mitochondrial function.
A lot of the interventions hit the same nodes or have secondary effects on the nodes and end up being interconnected. However, there could be a hierarchy to the hallmarks of aging
It’s going to be easier to treat the chronic diseases before they happen, because then you tweak this aging network and make it function better
Whereas if you look at a chronic disease, like Alzheimer's, a lot of things have gone wrong by the time those people are symptomatic. And then you're trying to take everything from disorganization back to organization. And that's, I think a much more difficult
What are some other open questions you have on the hallmarks of aging or that are being studied? Hierarchy is one that you mentioned.
We're trying to think about this right now. The pillars of aging helped move the field forward and gave targets to the private sector.
The other big thing was the invention of the biomarkers of aging. But how do we go from here?
We need to understand how this system has put together a little bit better, because what we'd like to do is figure out how to combine different things, to have even bigger effects.
For example, you could take rapamycin and alpha-ketoglutarate but right now we can't predict what these combinations do. And, you know, I've got a lot of mouse data that we added a compound day and compound B. Got nothing or a compound B canceled out the effects of compound day.
Not sure why that’s happening. We are in a world of early-adopters who are taking different supplements out there and I can’t predict what 2 things do in a mouse, much less humans
So we need to understand the network concept better. What is it composed of? How does it help certain tissues and what’s happening to other ones?
It’s also important to understand because we need to figure out how to personalize interventions since people age differently
There are longevity clinics out there trying to do it, but they are mostly assessing disease risk and not really interpreting your aging pathway in a personalized manner. That’s fine, but we just need to be open about that
This brings me to the question of biomarkers, which I believe is also what some of these longevity clinics are trying to assess. You have a 2020 review where you wrote about these biomarkers: From aging functional tests to multi-omics approaches. Can you speak to that? How do you think of biomarkers in the field? What are some other open questions and how do some of these compare to each other?
I’m excited about them and using them in our clinical studies looking at potential longevity interventions in people
We’ve chose a number of different biomarkers because one question is how do the biomarkers compare with each other, is there a correlation, can you integrate all of these and get a true biological age of the person or do you need separate biomarkers?
For example, methylation clocks may not pick up senescence which is one theory
Really like the work being done by Morgan Levine to deconstruct the Epigenetic clocks and understand systems-specific aging