Collagen Protein & the ExtraCellular Matrix During Aging | Dr. Collin Ewald

Live Longer World Podcast #10

Live Longer World Podcast Episode #10 has been released!

My guest today is Dr. Collin Ewald who is a professor at the Health Sciences department at ETH Zurich. His lab focuses on understanding the extracellular matrix (ECM) and how it changes with age. Collin explains the role of the ECM in tissue repair, muscle strength, and overall longevity. In fact, Collin’s lab is also working on establishing the ECM as a biomarker for health and disease risk. So, studying the ECM can indeed tell us a lot about the aging process and ways to intervene.

Think of the ECM as the environment that surrounds the cell or the proteins secreted from the cell. It holds our organs and tissues in place. You’ve probably heard of collagen protein - it is largely found in the ECM.

Why is the ECM relevant for longevity research? Turns out, the ECM changes with age. In fact, each cell has a unique ECM and cancer cells can be detected by their ECM composition type! There is also a connection between the ECM and the muscle, and damage to collagen with age results in weakening of our muscles.

We discuss changes in collagen with age, how sugar impacts collagen, cancer cells & ECM, the overexpression of certain collagens with age, changes in collagen causing muscle impairment with age, and longevity interventions his lab is studying to repair the impairment damage.

(This podcast can be a little technical, especially in the beginning, so I’d recommend referring to the show notes for better understanding. The video version of the podcast also contains some explanations on the video slide itself).

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Time Stamps:

00:00 Live Longer World Intro

00:35 Collin Ewald Intro & ECM changes with age

1:46 ECM & It’s functions in the body

3:15 Each cell has a unique ECM; Cancer & ECM

7:11 What is a young ECM & ECM degradation with age

11:53 ECM & Muscle Connection; bi-directional link between cell & ECM

14:21 Parabiosis & ECM link?

15:42 Caloric restriction & rapamycin change the ECM

22:46 ECM type as a biomarker of health

24:23 Using ECM to predict longevity drugs

30:50 Chondoitin Sulfate as longevity drug

34:00 Supplementing with collagen

36:29 Centenarians & Collagen expression

39:26 Collagen Expression & Circadian Rhythm

41:18 Longevity Interventions temporarily scale healthspan in C. Elegans

47:33 Richard Dawkins Selfish Gene; Evolutionary perspective of aging

49:00 IGF-1 + Auxin: Increasing lifespan at old age

58:15 Summary of ECM points discussed

1:01:20 Support, share, and follow Live Longer World

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Extensive Show Notes & Transcript:

Your research is focused on understanding the Extracellular matrix to understand aging and longevity interventions. We will dive into that. Just to set the context for people first, can you explain what is the extracellular matrix and what functions does it serve?

• ECM is comprised of all the proteins that are secreted out of a cell and they form a network

  • These are collagens, glycoproteins

  • Then there are other proteins that associated with the ECM or re-model the ECM

  • In the human body, it’s found at the base of the membrane. It’s a sheet-like structure that holds the organs in place

  • There is also interstitial matrix or connective tissue that is found between cells

• Each cell produces its own ECM, so fat cells has its own ECM as compared to skin cells or muscle cells

• They are different because of different requirements. For example, the outside of the cell can either cushion the cell from pressure or stress and also helps in communication / signaling of cells

• There are ECM that are produced when you’re born, for example in cornea and stay with you throughout and over time you accumulate damage to it

• However, there are other collagens that are produced and turned-over very rapidly. For example, in your Achilles heel. When you go running or weightlifting, these collagens in the muscle get turned over rapidly in 72 hours

  • So you have a full spectrum of dynamics

  • You have some collagens that once make and stay and are forever there, and with age accumulate damage, and cross linking and fragmentation

  • But there are other ones, that when the ECM is close to the cell, they are turned over

  • The ones that are turned over, and close to the cell, the ECM matrix itself is held together by receptors

  • So the cells pull on the ECM and the ECM gives resistance back. So the cell senses how sensitive or stiff the environment is. So there are strong signals between the cell and the ECM environment

  • During development, this turnover of the ECM and the attachment is rapidly happening. But after everything is set, it is less so

  • So when a cell is in homeostasis (steady state), there is little turnover of the ECM

  • However, if a cell changes to a diseased state, the ECM is completely changed

    • For example, cancer cells change the ECM, they make a more rigid ECM, cells become reprogrammed to produce special ECM

    • So you can read out the changes happening in the ECM and refer to it’s cellular state

    • Collin’s lab looks at the composition of the ECM to really figure out what is the health status of cell

• Collin’s lab coined the term matreotype: just a snapshot of the composition of the ECM

  • The Matrisome During Aging & Longevity: https://www.karger.com/Article/FullText/504295

So you said that when we are younger there is collagen turnover. Sounds like, there might be specific collagens (like the Achilles heel) that turnover within 72 hours. But as we start aging, there is degradation and cross-link. You published some of this in your 2020 paper: Matrisome during Aging & Longevity, and there you tried to study the question, “What is a young ECM and what are the proteins that comprise it?” such that we can figure out why there is degradation with age. Can you discuss this paper? What were some of the proteins you find in the young ECM and why is there a degradation with age?

• It’s not just that there are changes in ECM composition with age. It also has a functional consequence. For example, if you have cells that stop dividing and become senescent, these senescent cells, if you pick them and put them in a young ECM, they rejuvenate and become young again! They start dividing again. You can do the same with old stem cells that have stopped dividing - put them in a young ECM and you rejuvenate them

  • Same thing is happening at the tissue level. Take a muscle from an old rat and put it into young rat, the old muscle functions like a young muscle again

  • Meaning that you take something old and put it into young environment and it has rejuvenation capacity

• So we started asking, what changes in ECM composition are happening with age? What changes are associated with healthy longevity? And how does the young ECM composition look like? With the idea that if we could change the ECM composition, we could reprogram cells back again to youthful state

• What is happening to the ECM with aging?

  • If cells are not close to it and the matrix is just there by itself, the collagens become damaged and fragmented

  • If you have a lot of glucose and sugar in your system, the sugar likes to bind to lysines (amino acid) and with aging they are called advanced glycation end products. If these accumulate with aging, they cross-link each other

    • Advanced glycation products are proteins that get attached to a sugar covalent bond due to exposure to excess sugars. They are a biomarker implicated in aging and are responsible for the worsening of many degenerative diseases like diabetes, Alzheimer’s, and artherosclerosis.

  • This makes the tissue much stiffer

  • During aging, the ECM is becoming mechanically weaker, but also stiffer because they are cross-linked and this has functional consequences

  • The cell reads out the physics of the matrix and changes gene expression, which is called mechano-transduction

    • Mechanotransduction is the process by which cells convert mechanical stimulus to electrochemical activity. It is responsible for senses like touch, balance, and hearing

• There is a 2020 paper that discusses the stiffening of the extracellular matrix with age that causes impairment in muscle regeneration in older folks. There is cross-linking of the collagen, which leads to stiffening of the ECM, and thereby weakens the muscle

• Extracellular Matrix Remodeling Following Injury is Impaired in Aged Muscle: https://www.fightaging.org/archives/2020/07/extracellular-matrix-remodeling-following-injury-is-impaired-in-aged-muscle/

There are a few points I want to highlight there - it sounds like there are 2 things that could be happening to the ECM with age: One is that the ECM and its proteins like collagen could start degrading with age and that could sometimes lead the cell to detach from the ECM. Two is that it could also be the cell itself that undergoes senescence and gets detached from the ECM. Sounds like there is a bi-directional relationship there. Is that correct?