Matrix Reloaded

In the 18^th century, before cells were identified as the basic unit of life, scientists believed we were made out of self-organising and self-replicating fibers. At the start of the 19^th century Virchow’s ideas of cellular primacy became accepted, and fibers receded into the background. Today, the apparent dichotomy between cells and fibers is re-categorised as a deep mutual inter-dependency, which occurs on and around the extra-cellular matrix.

The extra-cellular matrix, our ‘soft skeleton’, is an anomaly.

Initially recognised as a tissue back in the ‘70’s, the extra-cellular matrix (ECM) was promoted to quasi-organ status around the turn of the century. It is not exactly a living tissue (or organ) because it is acellular; but the micro-fiber network is produced and dynamically maintained by living cells such as fibroblasts, myofibroblasts and glia which are attached to the network, and it is essential for their health and function. 

If not quite alive, therefore, the ECM is as close to the border between life and non-life as we get. Closer, one might say, than the nano-crystals of calcium and magnesium salts that form the inorganic matrix of bone, and which is built upon a sub-set of the ECM known as osteoid.

The interstitium, which may also be an organ, describes the spaces between cells and the fluid in those spaces. It is the inverse of, and is defined by, the ECM.

It gets more complicated. Although some would deny the ECM organ status, it includes the most recently designated (by others) organ, the extended interstitium¹. The extended interstitium (EI) describes a series of larger fluid-filled compartments formed within the ECM that act as shock absorbers and transport channels. 

The extended interstitium provides essential physical buffering, but it can also be hijacked by pathogens and cancer cells spreading within the body¹. The interstitium itself is directly involved in disease states including edema, fibroses and amyloidoses in certain types of cardiac², renal³ and pulmonary⁴ disease, and could well become an important therapeutic target in those conditions. It may also present opportunities to enhance muscular performance⁵. 

My focus here, however, is on the interactions between the ECM and its makers, how these can go wrong, and the emerging role of nutrition in maintaining healthy as opposed to pathogenic interactions.

To begin with, the ECM is amazingly complex. It is not just collagen and elastin, and it is not just about elasticity, tensile strength and hydration; more than 300 molecular components of the ECM have been identified, each with unique biological functions. These include the modulation of multiple local cellular behaviours ranging from differentiation and proliferation to apoptosis^6-7. From this perspective, the ECM can be regarded as a spatially organised reservoir of growth factors. 

The ECM is also highly dynamic. It is continuously renewed and remodeled as needed by coordinated actions between the ECM-producing cells, ECM-degrading enzymes and their specific inhibitors, with equally continuous mechanical, biochemical and probably electrical cross-talk between the fibers and the cells around them. And all of these conversations must be conducted within defined ranges if tissue and organ function, and health, is to be maintained⁸.

Because of these multiple inter-dependencies, chronic dietary and lifestyle errors which chronically degrade the ECM impact negatively on the symptomology of ageing. Conversely, using diet and specific nutrients to reduce ageing of the ECM should manifest in slower and more successful ageing.

As the years pass, the composition of the ECM shows a predictable set of changes. They include loss of elastin, increased collagen deposition and cross-linking^9-13, and changes in the proportions of different collagen sub-types¹⁰.

These shifts lead to reduced elasticity and increased stiffness of the ECM^9,13, which contributes to three of the most characteristic signs of aging; wrinkled skin, stiffening arteries, and an increasing risk of cancer¹⁴. 

As these biochemical and structural changes accumulate the ECM progresses towards fibrosis, causing progressive and irreversible tissue dysfunction¹⁵. Advanced age is associated with an increased incidence of pathological fibrosis in many human organs¹⁶. This degradation of the SCM also creates an extra-cellular environment that actively encourages cells to become not only cancerous^{14, 17} but also senescent^{18, 19}, constituting a second profoundly pro-ageing mechanism. 

Remarkably, the last two papers^{18, 19} indicate that cellular senescence can be reversed when affected cells are given access to new and younger ECM. This strongly suggests that if ECM ageing can be slowed or reversed, some and perhaps many other signs of ageing can also be held back – or reversed. 

As chronic inflammation degrades the ECM, the foundation for any ECM maintenance program is an anti-inflammatory dietary regime. There are a number of other things that can be done to preserve ECM, but they are not instant fixes – they require long-term lifestyle changes. Fortunately, to help compliance, the impact of these changes on the ECM can be monitored via proxies such as arterial compliance.

The two dominant fibers in the ECM, collagen and elastin, have long half-lives in the body. This leaves them vulnerable to post-translational modifications such as glycation, carbamylation (see below) and fragmentation, all of which alter their structure and therefore degrade their functionality. 

Glycation and subsequent cross-linking between fibres occurs slowly in ‘normal’ ageing²⁰, and is accelerated by advanced glycemic end-products (AGE’s). These are either formed in the body due to loss of glycemic control²¹ or ingested in certain foods, particularly ultra-processed ones²².

The increase in ECM stiffness over time manifests inter alia as increased arterial stiffness, which can be measured as vascular compliance via pulse wave analysis. This is a little tricky because there are two components to arterial stiffness. There is a functional component which is short-term, reversible and caused by (inflammatory) endothelial dysfunction, which can occur after ingesting certain foods; and a longer-term and supposedly irreversible component which is due to physical degradation of the ECM.

The fibers in the ECM turn over very slowly, as mentioned above, and if the slowly incoming new fibers can be continuously protected against glycation, carbamylation and cross-linkage then over time the arterial walls will become populated with a less damaged and therefore more elastic mesh of microfibers. In short, the ECM will be refreshed and rejuvenated. 

Life-style and specifically dietary factors play a role here.

Increasing arterial stiffness is a risk factor for developing essential hypertension²³, and the gradual rise in blood pressure associated with ageing in industrial societies is closely linked to increasing arterial stiffness. In vestigials, however, essential hypertension does not occur with ageing^{24, 25}, and one can reasonably assume that their arteries do not get stiffer as they age.

There must be something in our water, or food. And maybe some things that are no longer there.

In a study in mice, seven months of a ‘Western diet’ caused gut dysbiosis, endothelial dysfunction and increased arterial stiffness and endothelial dysfunction²⁵. Interestingly, there was clear evidence of microbiotal involvement in the arterial changes; reduced numbers of probiotic Bifidus species²⁶ played an important role, and restoring them lead to vascular improvement.

This suggests that an increased intake of prebiotic fibers will, over the long term, be vaso- and probably ECM-protective. The polyphenols appear here too.

Not only are many polyphenols excellent anti-inflammatory agents, they have also been shown in numerous studies to reduce oxidative / nitrosative / glycative stress^{27, 28}, and alleviate endothelial dysfunction²⁹. If taken over longer periods of time, they protect against the accumulation of cross-links in collagen^{30, 31} and at the same time they promote the regeneration of the other main fiber, elastin³². These are both appropriate anti-ECM ageing mechanisms.

When it comes to choosing which polyphenol to use, you could opt for rosemarinic acid. Lemon balm seems to be the most effective food for stopping glycation reactions³³, and its main polyphenol component, rosmarinic acid, is an even more potent anti-glycosylant than the reference compound aminoguanidine³⁴.

I would advise against ingesting significantly supra-dietary levels of polyphenols like rosmarinic acid over long periods of time. You do not want to stop all cross-link formation, as a certain level of cross-linkage is required for the mechanical stability of tissues such as the aorta³⁵.

Questions remain about the polyphenols’ modes of action. They target the ECM in many ways, both direct and indirect. They clearly exert part of their ECM-protective effects via the microbiome³⁶, and it would make sense, based on what is already known, to combine them with the prebiotic fibers.

You should also consider hydration.

Carbamylation of proteins is another age-associated marker, and may be even more important than glycation in driving ageing of the ECM³⁷. This involves the non-enzymatic reaction of proteins such as collagen and elastin with isocyanic acid, and it would therefore make sense to reduce exposure to this protein-denaturing agent. One source of isocyanic acid is tobacco³⁸, so here is another argument against smoking.

A probably more important source of isocyanic acid is urea. This becomes a serious problem in chronic kidney disease where hyperuremia, which amplifies carbamylation, significantly increases the risk of cardiovascular events and all-cause mortality^{39, 40}. High levels of carbamylated plasma proteins are a significant risk factor for cardiovascular events and mortality in hemodialysis patients^{40, 44}.

This suggests that you should take care of your kidneys by avoiding (or at least treating) hypertension and diabetes, the two most common causes of chronic kidney disease. If your kidneys are not already devilled, maintain low blood urea levels by staying well hydrated⁴² – which happens to be, as I discussed last week, an established way of staying healthier for longer⁴³. 

If you protect your ECM the knock-on effects will likely include improved function of muscle cells⁴⁴, neurons⁴⁵, hair follicles⁴⁶ and fibroblasts themselves^{44, 47, 48}, thereby making up a virtuous cycle.

Protecting the ECM will also likely reduce your risk of dementia. The brain is over 20% ECM by volume⁴⁹, making it particularly matrix-dependent. Chronic (neuro)inflammatory stress is known to damage and destroy neurons, but it will simultaneously degrade the ECM, causing tissue disorganization and then dysfunction.

Finally there is exercise, which among other things disseminates biomechanical stress and therefore information throughout the ECM.

The exercise mimetic Metformin is acknowledged to be a gerosuppressant, and recently its ability to activate the ‘metabolic master switch’ AMPK was shown to prevent abnormal ECM remodelling and fibrosis⁴⁸. If you prefer old-fashioned exercise to an exercise mimetic there is a likely additional causative association between improved cardiorespiratory fitness and survival⁵⁰, probably mediated via metabolic improvement.

So you can either take regular strength or power exercise^{51, 52}, or use an alternative exercise mimetic such as ActivAMP, berberine or dihydroberberine.

To summarise, maintaining your matrix seems to be a potent way of extending your health expectancy⁵³. You could opt for a low GI diet combined with an anti-oxidative / -inflammatory / -glycative regime, good hydration, and exercise or an exercise mimetic. Or you could ignore all of this well-meaning advice.

Choice. The problem is choice.

Next week: Metallica. Nothing else matters.

References

1. Benias PC, Wells RG, Sackey-Aboagye B, Klavan H, Reidy J, Buonocore D, Miranda M, Kornacki S, Wayne M, Carr-Locke DL, Theise ND. Structure and Distribution of an Unrecognized Interstitium in Human Tissues. Sci Rep. 2018 Mar 27;8(1):4947.
2. Schelbert EB, Butler J, Diez J. Why Clinicians Should Care About the Cardiac Interstitium. JACC Cardiovasc Imaging. 2019 Nov;12(11 Pt 2):2305-2318.
3. Wiig H, Luft FC, Titze JM. The interstitium conducts extrarenal storage of sodium and represents a third compartment essential for extracellular volume and blood pressure homeostasis. Acta Physiol (Oxf). 2018 Mar;222(3).
4. Salisbury ML, Han MK, Dickson RP, Molyneaux PL. Microbiome in interstitial lung disease: from pathogenesis to treatment target. Curr Opin Pulm Med. 2017 Sep;23(5):404-410.
5. Tanaka Y, Poole DC, Kano Y. pH Homeostasis in Contracting and Recovering Skeletal Muscle: Integrated Function of the Microcirculation with the Interstitium and Intramyocyte Milieu. Curr Top Med Chem. 2016;16(24):2656-63.
6. Hynes RO. Extracellular matrix: not just pretty fibrils. Science. (2009) 326: 1216–9.
7. Manon-Jensen T, Itoh Y, Couchman JR. Proteoglycans in health and disease: the multiple roles of syndecan shedding. FEBS J. (2010) 277:3876–89.
8. Romani P, Valcarcel-Jimenez L, Frezza C, Dupont S. Crosstalk between mechanotransduction and metabolism. Nat Rev Mol Cell Biol. (2021) 22:22–38.
9. Mays PK, McAnulty RJ, Campa JS, Laurent GJ. Age-related changes in collagen synthesis and degradation in rat tissues. Importance of degradation of newly synthesized collagen in regulating collagen production. Biochem J. 1991;276(Pt 2):307–313.
10. Stephens EH, Grande-Allen KJ. Age-related changes in collagen synthesis and turnover in porcine heart valves. J Heart Valve Dis. 2007;16:672–682.
11. Gazoti Debessa CR, Mesiano Maifrino LB, Rodrigues de Souza R. Age related changes of the collagen network of the human heart. Mech Ageing Dev. 2001;122:1049–1058.
12. Snedeker JG, Gautieri A. The role of collagen crosslinks in ageing and diabetes – the good, the bad, and the ugly. Muscles Ligaments Tendons J. 2014;4:303–308.
13. Schnellmann, R., Gerecht, S. Reconstructing the ageing extracellular matrix. Nat Rev Bioeng (2023). https://doi.org/10.1038/s44222-023-00049-1
14. Chaudhuri O, Koshy ST, Branco da Cunha C, Shin JW, Verbeke CS, Allison KH, Mooney DJ. Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium. Nat Mater. 2014 Oct;13(10):970-8.
15. Phillip JM, Aifuwa I, Walston J, Wirtz D. The Mechanobiology of Aging. Annu Rev Biomed Eng. 2015;17:113–141.
16. Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174:810–816.
17. Chandler C, Liu T, Buckanovich R, Coffman LG. The double edge sword of fibrosis in cancer. Transl Res. 2019 Jul;209:55-67.
18. Choi HR, Cho KA, Kang HT, Lee JB, Kaeberlein M, Suh Y, Chung IK, Park SC. Restoration of senescent human diploid fibroblasts by modulation of the extracellular matrix. Aging Cell. 2011;10:148–157.
19. Hecker L, Logsdon NJ, Kurundkar D, Kurundkar A, Bernard K, Hock T, Meldrum E, Sanders YY, Thannickal VJ. Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med. 2014;6:231ra247.
20. Snedeker JG, Gautieri A. The role of collagen crosslinks in ageing and diabetes – the good, the bad, and the ugly. Muscles Ligaments Tendons J. 2014;4:303–308.
21. Miyata T, Maeda K, Kurokawa K, van Ypersele de Strihou C. Oxidation conspires with glycation to generate noxious advanced glycation end products in renal failure. Nephrol Dial Transplant. 1997;12:255–258.
22. Gil A, Bengmark S. Advanced glycation and lipoxidation end products–amplifiers of inflammation: the role of food. Nutr Hosp. 2007 Nov-Dec;22(6):625-40.
23. Oh YS. Arterial stiffness and hypertension. Clin Hypertens 24, 17 (2018).),
24. Gurven M, Kaplan H, Winking J, Eid Rodriguez D, Vasunilashorn S, Kim JK, Finch C, Crimmins E. Inflammation and infection do not promote arterial aging and cardiovascular disease risk factors among lean horticulturalists. PLoS One. 2009 Aug 11; 4(8):e6590.
25. Gurven M, Blackwell AD, Rodríguez DE, Stieglitz J, Kaplan H. Does blood pressure inevitably rise with age?: longitudinal evidence among forager-horticulturalists. Hypertension. 2012 Jul;60(1):25-33.
26. Battson ML, Lee, DM, Jarrell DK, Hou S, Ecton KE, Weir TL, Gentile CL. Suppression of gut dysbiosis reverses Western diet-induced vascular dysfunction. Am. J. Physiol. Endocrinol. Metab. 2018, 314, E468–E477.
27. Sánchez-Rodríguez C, Martín-Sanz E, Cuadrado E, Granizo JJ, Sanz-Fernández R. Protective effect of polyphenols on presbycusis via oxidative/nitrosative stress suppression in rats. Exp Gerontol. 2016 Oct;83:31-6.
28. Justino AB, Pereira MN, Peixoto LG, Vilela DD, Caixeta DC, de Souza AV, Teixeira RR, Silva HCG, de Moura FBR, Moraes IB, Espindola FS. Hepatoprotective Properties of a Polyphenol-Enriched Fraction from Annona crassiflora Mart. Fruit Peel against Diabetes-Induced Oxidative and Nitrosative Stress. J Agric Food Chem. 2017 Jun 7;65(22):4428-4438.
29. Di Pietro N, Baldassarre MPA, Cichelli A, Pandolfi A, Formoso G, Pipino C. Role of Polyphenols and Carotenoids in Endothelial Dysfunction: An Overview from Classic to Innovative Biomarkers. Oxid Med Cell Longev. 2020 Oct 19;2020:6381380.
30. Sajithlal GB, Chithra P, Chandrakasan G. Effect of curcumin on the advanced glycation and cross-linking of collagen in diabetic rats. Biochem Pharmacol 1998; 56:1607-14.
31. Babu, P. V., Sabitha, K. E., & Shyamaladevi, C. S. (2006). Therapeutic effect of green tea extract on advanced glycation and cross-linking of collagen in the aorta of streptozotocin diabetic rats. Clin Exp Pharmacol Physiol, 33(4), 351-357.
32. Sinha A, Nosoudi N, Vyavahare N. Elasto-regenerative properties of polyphenols. Biochem Biophys Res Commun. 2014 Feb 7;444(2):205-11.
33. Xie, Y.X.; Chen, X.Q. Structures Required of Polyphenols for Inhibiting Advanced Glycation end Products Formation. Curr. Drug Metab. 2013, 14, 414–431.
34. Yui S, Fujiwara S, Harada K, Motoike-Hamura M, Sakai M, Matsubara S, Miyazaki K. Beneficial Effects of Lemon Balm Leaf Extract on In Vitro Glycation of Proteins, Arterial Stiffness, and Skin Elasticity in Healthy Adults. J. Nutr. Sci. Vitaminol. 2017, 63, 59–68.
35. Brüel A, Ortoft G, Oxlund H. Inhibition of cross-links in collagen is associated with reduced stiffness of the aorta in young rats. Atherosclerosis. 1998 Sep;140(1):135-45.
36. De Bruyne T, Steenput B, Roth L, De Meyer GRY, Santos CND, Valentová K, Dambrova M, Hermans N. Dietary Polyphenols Targeting Arterial Stiffness: Interplay of Contributing Mechanisms and Gut Microbiome-Related Metabolism. Nutrients. 2019 Mar 8;11(3):578.
37. Gorisse L, Pietrement C, Vuiblet V, Schmelzer CE, Köhler M, Duca L, Debelle L, Fornès P, Jaisson S, Gillery P. Protein carbamylation is a hallmark of aging. Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):1191-6.
38. Roberts JM, Veres PR, Cochran AK, Warneke C, Burling IR, Yokelson RJ, Lerner B, Gilman JB, Kuster WC, Fall R, de Gouw J. Isocyanic acid in the atmosphere and its possible link to smoke-related health effects. Proc Natl Acad Sci U S A. 2011 May 31;108(22):8966-71.
39. Berg AH, Drechsler C, Wenger J, Buccafusca R, Hod T, Kalim S, Ramma W, Parikh SM, Steen H, Friedman DJ, Danziger J, Wanner C, Thadhani R, Karumanchi SA. Carbamylation of serum albumin as a risk factor for mortality in patients with kidney failure. Sci Transl Med. 2013 Mar 6;5(175):175ra29.
40. Koeth RA, Kalantar-Zadeh K, Wang Z, Fu X, Tang WH, Hazen SL. Protein carbamylation predicts mortality in ESRD. J Am Soc Nephrol. 2013 Apr;24(5):853-61.
41. Kalim S, Tamez H, Wenger J, Ankers E, Trottier CA, Deferio JJ, Berg AH, Karumanchi SA, Thadhani RI. Carbamylation of serum albumin and erythropoietin resistance in end stage kidney disease. Clin J Am Soc Nephrol. 2013 Nov;8(11):1927-34.
42. Calomino F, Di Paolo N, Nicolai G, Miglio A. Mineral water administration may increase kidney elimination of urea, creatinine and folic acid in a concentration-dependent fashion. Int J Artif Organs. 2010 May;33(5):317-20.
43. Drpaulclayton.eu/dry-spell
44. Stearns-Reider KM, D’Amore A, Beezhold K, Rothrauff B, Cavalli L, Wagner WR, Vorp DA, Tsamis A, Shinde S, Zhang C, Barchowsky A, Rando TA, Tuan RS, Ambrosio F. Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion. Aging Cell. 2017;16:518–528.
45. Tewari BP, Chaunsali L, Prim CE, Sontheimer H. A glial perspective on the extracellular matrix and perineuronal net remodeling in the central nervous system. Front Cell Neurosci. 2022 Oct 20;16:1022754.
46. Xiao S, Deng Y, Mo X, Liu Z, Wang D, Deng C, Wei Z. Promotion of Hair Growth by Conditioned Medium from Extracellular Matrix/Stromal Vascular Fraction Gel in C57BL/6 Mice. Stem Cells Int. 2020 Jun 13;2020:9054514.
47. Tracy LE, Minasian RA, Caterson EJ. Extracellular Matrix and Dermal Fibroblast Function in the Healing Wound. Adv Wound Care (New Rochelle). 2016 Mar 1;5(3):119-136.
48. Luo T, Nocon A, Fry J, Sherban A, Rui X, Jiang B, Xu XJ, Han J, Yan Y, Yang Q, Li Q, Zang M. AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity. Diabetes. 2016 Aug;65(8):2295-310. doi: 10.2337/db15-1122.
49. Nicholson, C. & Sykova, E. Extracellular space structure revealed by diffusion analysis. Trends Neurosci 21, 207–215 (1998).
50. Kokkinos P, Faselis C, Samuel IBH, Lavie CJ, Zhang J, Vargas JD, Pittaras A, Doumas M, Karasik P, Moore H, Heimal M, Myers J. Changes in Cardiorespiratory Fitness and Survival in Patients With or Without Cardiovascular Disease. J Am Coll Cardiol. 2023 Mar 28;81(12):1137-1147.
51. Soendenbroe C, Heisterberg MF, Schjerling P, Kjaer M, Andersen JL, Mackey AL. Human skeletal muscle acetylcholine receptor gene expression in elderly males performing heavy resistance exercise. Am J Physiol Cell Physiol. 2022 Jul 1;323(1):C159-C169.
52. Fiatarone MA, Marks EC, Ryan ND, Meredith CN, Lipsitz LA, Evans WJ. High-intensity strength training in nonagenarians. Effects on skeletal muscle. JAMA. 1990 Jun 13;263(22):3029-34.
53. Iozzo RV, Gubbiotti MA. Extracellular matrix: The driving force of mammalian diseases. Matrix Biol. 2018 Oct;71-72:1-9.