Assessing the Causes of Aortic Stiffening in Aged Mice
Aortic stiffness occurs with age, and produces raised blood pressure, hypertension, by sabotaging the usual feedback mechanisms that control blood pressure. Hypertension in turn results in structural damage to delicate tissues throughout the body, as well as producing further biochemical changes that encourage ventricular hypertrophy, among other forms of dysfunction. It causes enough harm that control of blood pressure can meaningfully reduce mortality even without addressing underlying causes of degenerative aging.
Why do arteries stiffen with age? As today's open access paper discusses, this is in part a complex set of changes in the extracellular matrix of blood vessel walls, and in part dysfunction of the smooth muscle cells responsible for constriction and dilation of blood vessels. In the absence of ways to fully reverse one or other of these issues, it remains unclear as to how much of the problem is caused by each of these two contributions, but we can hope that this will change in the near future, given greater investment in research into the mechanisms of aging.
The structure and composition of the extracellular matrix defines the physical properties of a tissue, such as elasticity. With age, elastin laid down in youth becomes damaged and disordered, while other macromolecules that should slide past one another become cross-linked together by persistent advanced glycation end-products such as glucosepane. Meanwhile, inflammatory signaling and other forms of age-related biochemical dysfunction cause impairment in vascular smooth muscle, a failure to respond appropriately to signals to contract or dilate blood vessels.
As human life expectancy continues to grow, the incidence of age-related cardiovascular diseases (CVD) rises. CVD has long since become the leading cause of death, resulting in an estimated 17.9 million deaths each year (i.e., 30% of global death). Arterial stiffening - defined as the impaired capacity of the large elastic arteries to smoothen pulsatile blood flow - results in increased cardiac afterload, reduced coronary perfusion pressure, and pulsatile strain on the microcirculation. As such, arterial stiffness has gained much recognition as a hallmark and independent predictor of CVD.
Elastic arteries display a distinctly non-linear stiffness-pressure relation, with a limited increase in stiffness in the physiological pressure range but exponential increase at high distending pressure. Interestingly, despite pronounced variation in structural properties and vessel size across species, elastic modulus at mean physiological pressure is highly conserved across all vertebrate and invertebrate species with a closed circulatory system, suggesting strong evolutionary pressure.
In the present study, a longitudinal cardiovascular characterization of spontaneously (i.e., age-dependent) ageing C57Bl/6 mice is presented to establish the temporal relation of aortic stiffness to associated CVD, i.e., cardiac hypertrophy and peripheral hypertension. Furthermore, an in-depth physiological and biomechanical investigation of the isolated ex vivo thoracic aorta was employed to identify the key mechanisms of spontaneous arterial stiffening. We demonstrated that aortic stiffening precedes peripheral blood pressure alterations and left ventricular hypertrophy in spontaneously ageing C57Bl/6 mice, underlining the importance of implementing arterial stiffness measurement as an early marker of cardiovascular ageing in standard cardiovascular care.
Contraction-independent stiffening (due to extracellular matrix changes) is pressure-dependent. Contraction-dependent aortic stiffening develops through heightened α1-adrenergic contractility, aberrant voltage-gated calcium channel function, and altered vascular smooth muscle cell calcium handling. Endothelial dysfunction is limited to a modest decrease in sensitivity to acetylcholine-induced relaxation with age. Our findings demonstrate that progressive arterial stiffening in C57Bl/6 mice precedes associated cardiovascular disease. Aortic aging is due to changes in extracellular matrix and vascular smooth muscle cell signalling, and not to altered endothelial function.
Thank you Reason! This sort of focus on arteriosclerosis is very important.
Surprising the greater aging community does not put more effort into an arteriosclerosis treatment, as if everything they do works out, it likely still wont act to clear out the muck that has already accumulated inside our arterial system.
It seems to me the best way to exercise those vascular smooth muscles would be through occasional HIIT training and large muscle group lifts, squats, deadlifts, bench press.
The core approach - for cvs diseaese -should be to slow down or prevent the onset of AGE products in the ecm by long term dietary change ie increased vegetables, lightly cooked- in steam. That said, I do appreciate the occasional steak for dinner
and a fry-up for breakfast.
All this in the context of a low sucrose diet. HFCS absolutely out.
We await the advent of molecules targeted directly at glucosepane.
how much of lipofuscin is glucosepane and other AGEs?
Hi Matt! Just a 2 cents.
I agree, I think people need to understand that arteriosclerosis (and atherosclerosis) don't just magically reverse even after lots of efforts/exercice etc...even switching diet..they are 'upcoming' diseases (I mean 'happening as speaking') or 'in the making' (silently), arteriosclerosis is the loss of arterial function; and as this study showed, it's not (just) endothelial dysfunction, there is clearly a loss of 'elasticity' and '(vaso)contraction/(vaso)dilation' with age...and as they said, it's mainly the ECM (Extra-Cellular Matrix) loss/disorganisation/crosslinked and the loss of smooth muscle cells/ function. It's very finnicky..this is why people (any) (any one) is at risk for that...because we all age...and thus, we all lose arterial function with age. Because, it is normal ECM loss process (with aging and epiclock advancing). Centenarians and Supercentenarians avoid CVDs (cardiovascular diseases); in fact, the largest cause of death (besides cancer, diabetes and alzheimer's) is heart attack/failure/CVDs/vasculardiseases...it is Unconditional to living to a 100+..you must have a great heart and great vasculature; otehrwise won't reach it.. it means they maintain Younger and Sufficient Pumping/Flowing and Elasticity...this is also the elastin, and the collagen scaffolds in ECM; younger people have more collagen, which gives the 'pulpous/plump-y/botox-y' look (subsurface dermal scattering/SSS) (the right one; collagen Type I), with age with accumulate other types of collagens (in excess) which cause fibrosis, or even psoriasis/excess skin (epi-dermal layers) vs shedding etc,, and disorganisation of the matrix; this can't work; it will stiffen the arteries...high blood pressure (like trying to 'siphon-through' an ocean of water....in a tiny/shrinking pinhole; extreme pressure inside it) and lowered blood throughput (O2 loss is evident with age, especially by loss of red blood cells/erythocytes - less O2 carried around; but, also, by 'skrinking diameter' of the arteries/veins...); it's the biggest thig in atherosclerosis where LDL pockets/fibrous plaques shrink the arteries until blood can't pass anyone and then the plaque ruptures/blood clot -> jams huge artery/no more blood flow -> embolism/ischemia -> heart will pump more (trying to overcome the blockage) until it will let go/tachycardia/arythmia/fail or be heart attack...and the artery itself will be lacking oxygen, so both the artery and the heart will suffer ischemic damage, necrosis and cyanosis will appear on their tissues; then death. All this can happen in (a few) minute(s) or less. I lived it.
Autopsy of centenarians/super ones...showed that they had a 'younger brain'..than regular population and retarded the 'brain pruning' with age..same, for thymus, 'thymic involution' 'thymus pruning'..and same thing for heart/arteries..they have a (epi/biologically) younger body and younger vasculature - than their chronological age. On average was 8 years epiclock younger; but I think some parts of their body was closer to up to 15-20...or maybe 25 years younger...so that is why they can reach 100+; maintenance of youth (size/proportion/body..etc) in old age (neoteny; or, bioneoteny/epineoteny/epibioneoteny). If you look young(er), you have more chances (then if you look old-er 'visually').
Even the ECM/skin derman/collagenous content was collerated (by SSS) to the age...meaning, that this youth appearance (in skin) was a good basis of 'overall' how it's going inside...with that said, you can still die of whatever disease despite a 'nice exterior'...but, overall..yes, people that live long lives have glowing skin and glowing youth appearance (and that is related to SSS/ECM) which can be measure by the skin depth (ECM/layers/elastin/collagen...). Fibroblast will produce less fibre/collagen with age as they die and age..thus, it's a good marker overall.
Just a 2 cents.
Hi JohnD! Just a 2 cents.
'occasional' or moderate/sustained is the word...you can do more 'intense' training...but it should relatively not long and thus, overal quick-enough; moderate sustained 'harder/mild-to-hard' training exercise...but never overdo it. I would wager excess exercise/training etc...is very deleterious - even on those smooth muscle cells; muscle creation is increased by contraction of muscle (exercises)...by (type II) myofiber formation (myocytes cells)...but, too much a good thing is just as bad as too little --- some people died while 'over exercising' and 'not listening' to your body..trying to 'push it' to the limit..can die on the spot..when everything seems going perfectly well (the last day before). It's why when I see trained athletes..they are trained and can do that..so they can push it higher...but some of them died precipitously; and exercise can precipitate problems when (very) sick; this is when you have to slow down and gauge...your body. Excess -> too much stress on the body...(over)exercises ends up that...and it was shown that only mild-stress is benefitial (hormesis). Also, some athletes develop 'enlarged hearts' and that is deadly. Moderation was also the word; centenarians...it was always that, never excess (of pretty much anything...maybe except eating veggies...). (and being 'born lucky with the genetic luck of the draw')
Just a 2 cents.
Hi JLH! Just a 2 cents.
Yes, that'S a good approach...lowering AGEs, ALEs ---especially.. will be helpful. If you look at some vegetarians (for their whole life - since basically birth)...though they may have lacking in vitamins or proteins (unless they go get them); they are very oftenly is great condition and have glowing skin/look quite younger --in effect...it's basically CR (calorie restriction) pretty much..
since we don't expose ourselves to excess glucosepane, furosine, and glycoxidation/glycation products...that makes a difference; but the Biggest one is the ALEs (Advanced Lipoxidation End products)..this one is very toxic...more so almost then being exposed to excess fructose, lactose or sucrose..TBARs (thiobarbiturates), MDA (malon-dy-aldehyde), and lipid peroxidation products. Another very toxic one is 4-HNE (4-hydroxynonenal) and Acrolein...these Cause serious havoc. Plus, of course, Oxizied PUFAs (poly-unsaturates fatty acids); that cause cataclysmic-chains of lipoperoxidation. That need quenchin/scavenging (ROS)...but, still, all this contribues to health loss and diseases..but it's much more the loss of DNA stability/count/function (breaks/DNA frags)..and the (epi)clock. Because DNA is the Gene 'Content'...if you destroy it...you cause the clock to advance, which means one step closer to death ''of natural 'healthy' aging''.
Hi SilverSeeker! Just a 2 cents.
Lipofuscin is majorily composed of oxidized PUFAs (as said previously); they are the biggest stuff..there is also dead effette/giant deadmitos, ceroid/drusen...a mishmash...crap'cocktail'...
but largely..the destruction of mitochondrial membrane lipids/fatty acids (namely, the long-chain ones - PUFAs; like DHA or EPA; those Omega - 3s you take for your brain to keep it sharp..except..they peroxidize... and in the brain have great antioxidative protection -against that); but in mitos; it's not always well protected/quenched; as such; it makes tons of Peroxide formation 'peroxidation (O-O)'; that (per)oxidizes the innermembrane); thiscauses 'stiffening'/'viscosity' and loss of 'fluidity/aqua/hydroflow' of the mitochondira itself -> reduciton of ATP cell energy production. It'S what happen when eat too much Saturated Fats (as I did..and nearly died of it); especially, the longer-chain ones; some Very Small chain saturated fats may have protectvie effects; most don't; mainly the Palm Saturated Fats and Stearic Saturated Fat (in coco butter/chocolate...) IT's funny/ironic (but not really) it that the person that lived the longest..consumed a Ton of dark chocolate and lived 122 years; binge-eating Stearic Acid -> lived Cholesterol formation...atherosclerosis (as it hapepned to me; I consumed Plentty of dark chocolate..and nearly died of it); thus biggest point, is that there is such a thing as 'too much fat'...and in my case there was never Too much fat (i was thin / below 150 lbs...always at 120-130..5'10'' tall..thin. yet, still got this dreaded disease). You can accumulate fat in your arteries - no matter if thin or obeses...no difference; and die of it - thin or fat. The fat may accumulate 'aroudn your organs'...visceral fat that 'chokes' the organ (irrespective of your 'outside weight'); it's Inside that it happens...I want to warn people (of doing like Mrs. Calment or 'greek people') binging on chocolate and foie gras and extra-virgin olive oil...did all that...I don't anymore (and it's why I'm alive). Jsut a 2 cents.
PS: She lived a long life, because there was benefits to that..but in Unhealthy situation these can very bad to you; they are only good in moderation and Only if you are healthy Already; because, there may be 'complications' from their consumption (as happened to me). Again,...moderation, listen to your body and just be careful..and adapt accordingly (as you age).
PPS: My apology...I did not meant to write 'greek people' (in brackets) or mean anything bad..by that.....I meant Greek, persons ..that consume lots of Their Histoerical Mediterannean diet..a Great one..but just be careful...'s all I'm saying (it may not be best for you or not work so well or even complicate things; (at least, at the start)). I think people need to be careful of simply equating; veggies = saved..or 'whatever diet' = saved...it's more nuanced and may not go the way you planned/hoped (and it'S why many people try 'various' diets...and have difficulty Despite so..); we do our best...it's pretty much 'the best' you can do..(in moderation) because there are so many factors...but yes CR or an Haliki-diet Greek Mediterranean (diet) is great (just...have some control and see how you respond (to it)). Am pratically vegetarian since 6 years now, it sure changed things (and haven't eaten a steak since neither; no carnivorus dino anymore).
Thanks CAN. Calment is much less of an outlier if you believe, as I do, that her daughter assumed her identity when she died at the age of 59 in order to game a life estate contract
Re JohnD Thank your for that. That's a solid rebuttal point; I do agree, even with her, it's not 100%-100%-100% solid irrefutable proof of the longest lived person; and as you said, her story with her daughter impersonating her after...mixes it all up and could be all fake/bunk..it's why it is important to debunk claims of Hypercentenarians...like people that say I have reached 147...it's pretty much never true and as not been shown the case/1 single person to have lived so (that we can confirm beyond All Doubts that she/he is telling the truth about her extreme age; they said, oftenly, it's centenarian people that forgot how many years they lived (it's normal at that age to have memory blanks/suffer memory holes/or be pre-alzheimer's; the brain has been pruning, albeit slower than majority people..as such, they may 'agrandize' a bit their age..''I think??...I remember that..I am I think about or 128..'' which is not very accurate (and some because they know are Rare..for reaching that noble age..they try to slightly 'increase it' and gain some fame (I am the oldest person alive); which is impressive/commendable, it's just that sometimes they wish to be in guiness book or records or get fame (money); and I don't have a problem with that - Good For Them, they reached extreme age..it's just that it needs to Be Fair to Other Centenarians who are just as old...); it'S why authorities have to check passport/historical document of the person - and compare - to other ones..and then sort of piece it all and see if 'it gels'...or makes no sense; plus, one of the Easiest way or Best way I wouls say - is measuring their clocks/epigenetic clocks - Then - we will have 100% Truth about how old they are; because it can tell us more about their Real biological age - but we can't know their Chronological Age; but we may infer more data and piece it to know their chronological age vs biological age;- and then, we could say ''nope..you're not 128 or 147...or any other -- says so right in your DNA''.).
Still, if you look at her photos...clearly..she was very 'young looking' glowing skin and everything..she aged slowly...and the photos Seem true...now could be not true..as in she Only reached say..105 or 110, 115...and not 122.. Still, she did (I think) reach At the very last 100.
But now other centenarians may well beat her and children born today..have much more chances of reaching 120 (IF, they don't fall in the 'western diet' pit...because western diet..she did not consume..she consumed much more closely to a Mediterannean diet - hence had benefit; but not just that, her genetics; but it's incredible that her daughter lived only 59 (like the age of my mother/died of cancer (57)..but my grand-ma lived 92 (and my dad is alive (75) has diabetes)...so it gives me 'some' hope..I am scared that I won't go above my mother's age...having had/still ahve atherosclesis; it'S why we must do all we can - while we are still young..too late..is generally, too late)).