What are the currently available methods to impede the accumulation of modified long-lived extracellular matrix proteins?
My recent short piece about the extracellular matrix, although it identified the current problems and priorities of aging research, it did not answer the main question — What are the currently available methods and processes to impede these processes without the need to wait for specific abzymes, spiroligomers (also known as bis-peptides), and nanobots for the matrix restoration to be created?
I would like to remind the readers that the accumulation of modified long-lived extracellular matrix proteins leads to pathological changes in the mechanical properties of the extracellular environment. The changes, first of all, in the structure and stiffness of the microenvironment of cells, which occur due to the formation of cross-links between collagen fibrils, which initiate a vicious cycle of a gradual increasing damage and limit the use of senolytics, stem cells, and other methods of ‘anti-aging’ therapies.
Here I wish to thank Alexander Fedintsev for providing the idea and additions to the original version of my note.
So, proteins, as well as lipids and nucleic acids, having undergone glycation (non-enzymatic glycosylation), that is, reactions between carbohydrates (glucose, fructose, and so on) and free amino groups, form so-called advanced glycosylation endproducts (AGEs).
The role of AGEs in the formation of intro- and intermolecular cross-links of proteins is well studied and is not in doubt.
Besides glycation, there is an equally important process that proceeds under both pathological and normal conditions — lipid peroxidation (LP).
Both processes, lipid peroxidation, and nonenzymatic glycosylation involve a network of various reactions that produce a very complex mixture of compounds.
Numerous studies indicate a relationship of the lipid composition of the membranes and the maximum lifespan of various animal species. Species with a predominant content of saturated fatty acids in the composition of cell membranes have a longer life expectancy, even compared with phylogenetically close species.
Moreover, this difference in the composition of the membranes allows for the explanation of the paradox of birds: birds have a very fast metabolism, but live an order of magnitude longer than mammals with a similar basal metabolic rate. It has been found that the peroxidation index of cell membranes within birds is much lower (see works by Hulbert et al., which can be found in the list of references at the end of the note).
Also, the lipid composition of the membranes makes it possible to explain the difference between the lifespan of worker bees and queens without involving the built-in program of aging.
Saturated and monounsaturated fatty acids are more stable and less susceptible to peroxidation, compared with polyunsaturated fatty acids (PUFAs). This is because PUFAs have protons in a vulnerable bis-allylic position. Such a proton is easily detached (abstracted) from the fatty acid molecule, and this is the first step in the chain of lipid peroxidation reactions.
The common perception that PUFAs are indisputably beneficial should be criticized. It is possible, nonetheless, that polyunsaturated fatty acids are indeed beneficial in that they create moderate oxidative stress, contributing to the hormetic stress response.
Some studies indicate a quantitative relationship between the process of lipid peroxidation and the formation of cross-linkage of matrix proteins. For example, one of the products of lipid peroxidation, malondialdehyde (which is a product of PUFAs degradation), forms the same amount of cross-links with proteins as glucose in vitro settings.
This is suggestive of that long-lived species not only suffer from the LP to a lesser extent, but also a process of altering the proteins of the extracellular matrix is slower in them, due to a decrease in the reactivity of fatty acids.
More than a decade ago, a Russian scientist Mikhail S. Shchepinov Ph.D. proposed using fatty acids, in which hydrogen is replaced by deuterium (an isotope with greater atomic weight and stronger bond to a carbon atom), to treat a number of diseases caused by excessive synthesis of free radicals. Altered fatty acids (dPUFA) are more resistant to oxidation and prevent the destruction of the cell membrane.
Retrotrope, a Shchepilov’s company, is currently awaiting FDA approval for the last stage of clinical trials of an experimental drug RT001. It is possible that this medication will not only help patients with hereditary neurodegeneration but also be capable of slowing down the aging of the extracellular matrix.
In the meantime, products with a predominance of monounsaturated fatty acids that do not contain protons in vulnerable bis-allylic positions and are therefore less prone to oxidation should be preferred.
The list of publications follows that show the link between the maximum species lifespan and the lipid composition of cell membranes:
Abbott, S. K., P. L. Else, T. A. Atkins and A. J. Hulbert (2012). “Fatty acid composition of membrane bilayers: importance of diet polyunsaturated fat balance.” Biochim Biophys Acta 1818(5): 1309–1317.
Ayala, A., M. F. Munoz and S. Arguelles (2014). “Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal.” Oxid Med Cell Longev 2014: 360438.
Bozek, K., E. E. Khrameeva, J. Reznick, D. Omerbasic, N. C. Bennett, G. R. Lewin, J. Azpurua, V. Gorbunova, A. Seluanov, P. Regnard, F. Wanert, J. Marchal, F. Pifferi, F. Aujard, Z. Liu, P. Shi, S. Paabo, F. Schroeder, L. Willmitzer, P. Giavalisco and P. Khaitovich (2017). “Lipidome determinants of maximal lifespan in mammals.” Sci Rep 7(1): 5.
Bustos, V. and L. Partridge (2017). “Good Ol’ Fat: Links between Lipid Signaling and Longevity.” Trends Biochem Sci 42(10): 812–823.
Duffy, J., A. S. Mutlu and M. C. Wang (2017). Lipid Metabolism, Lipid Signalling and Longevity. Ageing: Lessons from C. elegans: 307–329.
Furness LJ and Speakman JR (2008). Energetics and longevity in birds. Age 30: pp. 75–87.
Gonzalez-Covarrubias, V., M. Beekman, H. W. Uh, A. Dane, J. Troost, I. Paliukhovich, F. M. van der Kloet, J. Houwing-Duistermaat, R. J. Vreeken, T. Hankemeier and E. P. Slagboom (2013). “Lipidomics of familial longevity.” Aging Cell 12(3): 426–434.
Haddad, L. S., L. Kelbert and A. J. Hulbert (2007). “Extended longevity of queen honey bees compared to workers is associated with peroxidation-resistant membranes.” Exp Gerontol 42(7): 601–609.
Hulbert, A. J. (2007). “Membrane fatty acids as pacemakers of animal metabolism.” Lipids 42(9): 811–819.
Hulbert, A. J. (2008). “Explaining longevity of different animals: is membrane fatty acid composition the missing link?” Age (Dordr) 30(2–3): 89–97.
Hulbert, A. J., S. C. Faulks, J. M. Harper, R. A. Miller and R. Buffenstein (2006). “Extended longevity of wild-derived mice is associated with peroxidation-resistant membranes.” Mech Ageing Dev 127(8): 653–657.
Hulbert, A. J., R. Pamplona, R. Buffenstein and W. A. Buttemer (2007). “Life and death: metabolic rate, membrane composition, and life span of animals.” Physiol Rev 87(4): 1175–1213.
Kniazeva, M. and M. Han (2013). “Fat chance for longevity.” Genes Dev 27(4): 351–354.
Ma, S. and V. N. Gladyshev (2017). “Molecular signatures of longevity: Insights from cross-species comparative studies.” Semin Cell Dev Biol 70: 190–203.
Miura, Y., N. Hashii, Y. Ohta, Y. Itakura, H. Tsumoto, J. Suzuki, D. Takakura, Y. Abe, Y. Arai, M. Toyoda, N. Kawasaki, N. Hirose and T. Endo (2018). “Characteristic glycopeptides associated with extreme human longevity identified through plasma glycoproteomics.” Biochim Biophys Acta Gen Subj 1862(6): 1462–1471.
Naudi, A., M. Jove, V. Ayala, M. Portero-Otin, G. Barja and R. Pamplona (2013). “Membrane lipid unsaturation as physiological adaptation to animal longevity.” Front Physiol 4: 372.
Papsdorf, K. & Brunet, A. Linking Lipid Metabolism to Chromatin Regulation in Aging. Trends in Cell Biology (2018). doi:10.1016/j.tcb.2018.09.004
Ristow, M. and S. Schmeisser (2011). “Extending life span by increasing oxidative stress.” Free Radic Biol Med 51(2): 327–336.
Saitou, M., D. Y. Lizardo, R. O. Taskent, A. Millner, O. Gokcumen and G. E. Atilla-Gokcumen (2018). “An evolutionary transcriptomics approach links CD36 to membrane remodeling in replicative senescence.” Mol Omics 14(4): 237–246.
Sajithlal, G. and G. Chandrakasan (1999). Role of lipid peroxidation products in the formation of advanced glycation end products: Anin vitro study on collagen. Proceedings of the Indian Academy of Sciences-Chemical Sciences, Springer.
Schroeder, E. A. and A. Brunet (2015). “Lipid Profiles and Signals for Long Life.” Trends Endocrinol Metab 26(11): 589–592.
Spindler, S. R., P. L. Mote and J. M. Flegal (2014). “Dietary supplementation with Lovaza and krill oil shortens the life span of long-lived F1 mice.” Age (Dordr) 36(3): 9659.
Valencak, T. G. and T. Ruf (2007). “N-3 polyunsaturated fatty acids impair lifespan but have no role for metabolism.” Aging Cell 6(1): 15–25.
