The Extracellular Matrix in the Age-Related Impairment of Angiogenesis

The density of capillary networks declines with aging, the result of a progressive impairment of the complex process of angiogenesis responsible for growing new vessels. This loss of the smallest components of the circulatory system is likely important in the progression of aging, in that it affects blood pressure and deprives energy-hungry tissues such as muscle and brain of the oxygen and nutrients needed for correct function.

Researchers here view this aspect of vascular aging through the lens of the extracellular matrix, a tissue feature that also changes with age in ways known to be detrimental. Are these changes an important contributing cause of impaired angiogenesis? For any manifestation of aging, it is a challenge to determine which of the potential contributing causes are more or less important, given the inability to intervene in a very selective, pinpoint way. It is most likely faster and better to try to fix every potential issue, finding out along the way that some are not in fact all that important, than to first try to understand which processes should be targeted.

Angiogenesis is the process by which new capillaries form by sprouting from pre-existing ones. Each step in angiogenesis is regulated by the extracellular matrix (ECM). This process involves the migration, proliferation, and differentiation of endothelial cells (ECs) and pericytes and results in elongation of the initial tip, followed by anastomosis with other blood vessels to form perfused vascular branches. Accumulating evidence indicates that angiogenesis is impaired in older adults, contributing to cardiovascular and cerebrovascular disease and delayed wound healing, reducing the quality of life and causing a significant burden for healthcare systems.

Evidence indicates that ageing-related changes in the ECM driven by cellular senescence lead to a reduction in neovascularisation, reduced microvascular density, and an increased risk of tissue ischaemic injury. Elucidating interactions between the ECM and cells during angiogenesis in the context of ageing is necessary to clarify the mechanisms underlying reduced angiogenesis in older adults. In this review, we summarize ageing-related changes in the composition, structure, and function of the ECM and their relevance for angiogenesis. Then, we explore in detail the mechanisms of interaction between the aged ECM and cells during impaired angiogenesis in the older population for the first time, discussing diseases caused by restricted angiogenesis.

We also outline several novel pro-angiogenic therapeutic strategies targeting the ECM that can provide new insights into the choice of appropriate treatments for a variety of age-related diseases. Based on the knowledge gathered from recent reports and journal articles, we provide a better understanding of the mechanisms underlying impaired angiogenesis with age and contribute to the development of effective treatments that will enhance quality of life.



can the extracellular matrix truly be repaired once damaged? Is there a process within our genetics that can do this?

Posted by: Matt at July 27th, 2023 8:06 AM


The extracellular matrix (ECM) cannot be fully repaired once damaged in the same way that some tissues and organs can regenerate. The ECM is a complex network of proteins and carbohydrates that provides structural support to cells and tissues, and it plays a crucial role in various biological processes.

When the ECM is damaged, the body's response typically involves attempts to repair and remodel the affected area. Cells can produce new ECM components to try to restore the structure, and some degree of repair is possible in certain situations. However, the repair process might not fully restore the original ECM architecture, and significant damage to the ECM can lead to chronic conditions and impaired tissue function.

While there are ongoing research and developments in tissue engineering and regenerative medicine, the ability to fully repair the ECM remains a challenging task. It involves not only replacing damaged ECM components but also ensuring proper integration and functionality with surrounding tissues.

Regarding genetics, while certain genes may play a role in ECM synthesis and remodeling, our genetic makeup does not provide a straightforward mechanism for comprehensive ECM repair. Genetic factors can influence the production and organization of ECM components, but the complexity of ECM repair involves interactions with numerous cell types, signaling pathways, and tissue-specific factors.

Posted by: Jones at July 27th, 2023 12:44 PM

Could the theory of ECM degradation being the main driver of aging be correct ?

Posted by: Alberto at July 27th, 2023 1:33 PM

Hi Alberto! Just a 2 cents.

ECM degradation is, mostly, only, a manifestation/by-product of metabolistic aging; like AGEs (Advanced Glycation End products), they can be toxic on their own, but are not the (main) Cause, they are more a Correlation - to aging; it is the same thing with ECM degradation; it's an 'end result'; correlative; but not, 'driver' of aging (as you said). Or, let'say, a (rather) weak driver.
Losing ECM structure, collagen, etc, outside the cell matters of course; and, it's clear, if you can't rebuild ECM (enough), it will cause 'mechanical' (at macro-level) problems -- organs can't work correctly/dysfunction; but, it is not, necessarily, a (main) driver/cause of aging. Thus, it is downstream (in the chain/cascade of events - leading, to this (end result) degradation).

It is at the cellular level/inside it, that it is more Upstream; not extra-cellularly/outside the cell.
And, even more so (inside the cell), is in its mitochondia (mtROS, mito copy number, mtDNA, quadrillions of mitos in total - means big impact on aging), and its nucleus (nDNA, telomeric DNA/telomeres, DNA strand breaks, chromosomes, histones, genes, epigenetic clock/methylome); specifically.

We tried telomerase, repairing chromosomes, reversing epigenetic clock/epireprogramming...
but, there are always limits and as such, I'm not sure that nuclear tinkering will end up so the end. Because, it gets damaged -- by mitos, 'next door'. So, it is rather futile;
it's why, mitochondria are really the heart of it all; because they are the 'seat' of 'respiration/cell energy creation/oxygenation-to-ATP-energy/oxidation process(mtROS)' (constant every second you breathe); thus, are the (upstream) oxidant/oxidation seat, that triggers whole cascade downstream. Quadrillions of mitos produce mtROS, everysecond you live/breath/inhale/exhale;
this is 'mort à petit feu' ('death by slow burning' // 'death by a thousand cuts / a 1000 needle stings'). It's, actually, quadrillions - of quadrillions - of quadrillions .....(exponential) 'death cuts'...
these 'nano-cuts' are from the mitochondrial respirating process in ETC (electron transport chain; causing electron/ETC energy leakage (needed to produce ATP cell energy), and mtROS 'steal electron')/caused by mtROS (reactive oxygen species) formation; which then starts whole cascade, lipoperoxidation, carbonyls, 'long-chain effect'/one chain effect-after another-after another-after another...'chain..ECM degradation is 'far(ther) down the chain/stream'

We could talk about telomeres, DNA, DNA repair, DNA DSBs/double-strand breaks, methylome, proteasome, etc..but, so far, studies have not been able to change much about them; and if they do; it will likely be underwhelming -- because; they are not the main 'driver' of this aging -- the main driver 'damages/oxidizes' -- and that's the mitos -- the rest is the 'recipient' of this 'attacking/oxidation process'. And, also, because you must 'attack all these at the same time'; the further you are are 'downstream'...the more - you have to attack simultaneously -- to get 'any' effect on aging. Otherwise, there will be little to not effect; because, it is just 'one piece of the puzzle', downstream of the chain. There are thousands of 'downstream end results'...mostly; correlative, some are causative...but, they are under; not above; in terms of 'driving' the aging process. Because, they are outside the cells; mostly. The cells, are one, if not, the only, deepest level we can get at; you can't go much, further/deeper/smaller....deeper, is in the cell itself ( a a microcosm; smaller and smaller and smaller..).

Thus, to have to most impact, one would strike 'at the root/cause/heart' of the situation. People see stuff happening in the body and think it's all 'happening haphazardyl..and sort of a 'sort of order/chronology/rank/importance'...but, not really; it's 'all over the place'' it's why it's difficult to untangling the important/consequential, from the less - if we wish to defeat aging. And, that means, knowing what is (in order) upstream, and, downstream; and there is - such a thing. People think (even I thought it), that it is disorder/random stuff happening - and 'giving some random result'. Which, there is some truth to. But, it's more 'Orderly' 'Pattern'ed' 'Motifs-ed' 'Pre-Designed' 'Pre-Thought'- than that. It is not 100% Disorder (I mean, it becomes disorder...but, for a while, it was Quite 'orderly' -- function = order; dysfunction = disorder). So when things get messy, it's understandable that function would be lost; because 'chaos';
chaos = imbalance/disorder/dysfunction;
no chaos = balance/order/function.
Chaos can be construed many ways..but, overall, it means loss of Order (of things, happening, in a disorderly fashion)...because, even, 'randomness' (entropy) has a 'certain' order behind it.
Think like an army...if there is chaos in the army...well, there is no more army. Like, for example, mutinization, not following orders, rampant disobeying, the army - fighting itself, cannibalization of will disband as a 'non-functioning' (dis)entity; caused by disorganization,
Loss of Structure. Loss of Rank(ing)/Positioning. Loss of Trust. Loss of Leadership.
Loss of Order.
Our body is like a microcosmic army...which, despite seemingly a total chaos, has some, Order.
It's why 'we grow the we do -- and look - the way we do'...there is Definitely some 'order' there; about why we are all humans, looking alike, bipeds, 2 eyes. 2 arms, 2 legs etc - pattern design/design pattern -- it 'just works' for us/our blueprint.....(that's Nature Selection/Evolution/Genetic selection/pressure/adaptation (for specie survival)).
I used to think that nuclear/cell nucleus tinkering would on its enough...but, now, I realize it won't be -- and that's because it's quasi impossible to repair damage/nDNA lesions/strand breaks -- caused by quadrillions upon quadrillions of damagers - next door

(namely, mitos).

If we can repair them, then yes, it could save us; this, is aking, to telomeric DNA/telomere increase via telomerase far, it was not enough...we accumulate somatic mutations (something found after epigenetic reprogramming, that does nothing on them; so partial reprogramming is 'limited' in effect; very limited, actually, because, it only increases 'compression of morbidity'/as in, you can live longer -- to your maximum; but you will die, at maximum (120 or less). Thus, the interventions, it seems, are 'plateauing' in effect/potential (and having redundance/same pathways used, makes them less powerful because they are Already being used/100% optimal, as it is); thus, can't go further..can't 'benefit further'..of, something you already benefit of, maximally. It becomes 'pushing things to the very limit''s why, I say, that we have to get back 'at the core', downstream...down down down...until we arrive to the 'core/kernel' (in cell mitos); like, Earth's firey smoldering core/kernel (that is made of the 'lava/magma' that shoots out of volcanoes; a straight connection between a volcanoe -- down -- to the core..)

in the deep center of Earth below crusts/kernmantel/tectonic plaques/caves/karsts/ocean/ water/abysses/rock layers/minerals and everything else above...; below, all that, that's where the 'doing' is happeing (i.e. driving, aging). I would wager, probably 70-80% of therapies in the future, if they cannot reverse telomere attrition, stop replicative senescence, stop chromosomal decompaction/epigenetic aging or fix DNA nuclear defects...they will not do almost anything
'for aging'..they will remain healthy aging therapies/Average lifespan boost -- increase 'morbidity compression' allowing you to live longer healthier..but, will die, at 120-140 years or so, as maximum as human specie/that you can reach (like right now, is (still) the case/same).If you want to increase life above maximum, that's the mito and nucleus domain; because, upstream.
They may be the most 'down/deep' you can find (via microscope)..but they are the most Up(stream)/At Highest Ranking/Importance/Impact/Weight/ terms of aging/weight of aging process.

Just a 2 cents.

PS: Not one single study, (besides immortal cancer cells hijacking telomerase, ALT-telomere lenghtening, not accumulating lipofuscin, not being affected by epigenetic age; or, actually, targeting the cause, mitos), was capable of making substantial increase of lifespan, so far -- in fact, there is not one single therapy/study that shows that you could surpass the maximum human lifespan -- doing whatever they say we should do; because, they don't target the 'damager'; hence, the damage piles in and then, you see lackluster results; if we can't repair DNA damage, can't reverse telomer shrinking, can't stop replicative senescence - then we have to go at cause/source of cascading damage (& that lies in mitodomain where 'respiration' happens, & oxidation is the major driver, as you breathe,& rust/oxidize daily).

Posted by: CANanonymity at July 28th, 2023 12:25 AM

@ CANanonymity thank you very much for your explanation as I am a beginner in longevity …

Posted by: Alberto at July 28th, 2023 12:00 PM
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