Advocating Arterial Destiffening to Treat Cardiovascular Disease

It is always good to see more scientists come around to the SENS viewpoint of damage repair as the best treatment for age-related disease. Addressing root causes is a much better approach than the current prevalent paradigm of trying to adapt failing biological systems to work less poorly when damaged, while failing to make a dent in the damage itself. Tackling the root causes should be much more cost-effective and simply much more effective overall, and in many cases the root causes for specific age-related conditions are known rather than merely surmised.

Cardiovascular risk factors (CVRFs) have been shown to induce end organ damage. Until now, the main approach to reduce CVRF-induced end organ damage was by normalization of CVRFs; this approach was found effective to reduce damage and cardiovascular (CV) events. However, a residual risk always remained even when CVRFs were optimally balanced. An additional risk factor which has an immense effect on the progression of end organ damage is aging. Aging is accompanied by gradual stiffening of the arteries which finally leads to CV events. Until recently, the process of arterial aging was considered as unmodifiable, but this has changed.

Arterial stiffening caused by the aging process is similar to the changes seen as a result of CVRF-induced arterial damage. Actually, the presence of CVRFs causes faster arterial stiffening, and the extent of damage is proportional to the severity of the CVRF, the length of its existence, the patient's genetic factors, etc. Conventional treatments of osteoporosis and of hormonal decline at menopause are potential additional approaches to positively affect progression of arterial stiffening.

The new approach to further decrease progression of arteriosclerosis, thus preventing events, is the prevention of age-associated arterial structural changes. This approach should further decrease age-associated arterial stiffening. A totally new promising approach is to study the possibility of affecting collagen, elastin, and other components of connective tissue that participate in the process of arterial stiffening. Reduction of pulse pressure by intervention in arterial stiffening process by novel methods as breaking collagen cross-links or preventing their formation is an example of future directions in treatment. This field is of enormous potential that might be revolutionary in inducing further significant reduction of cardiovascular events.



@Reason,speaking of SENS approaches to cardiovascular disease,are there any updates on the RB conference? We got one a few days ago at its start but nothing since. Any exciting alliances forming between researchers or Big Pharma? Any other interesting developments?

Posted by: Morpheus at August 27th, 2014 9:17 PM

Glucosepane could turn out to be much more difficult than anyone anticipates. I think it is very easy to conceptually describe the concept "Just find some drug, antibody, or enzyme that breaks these bonds". It could turn out to be easy, but then you could say that all we have to do to solve cancer is "to remove the bad cells".

I wonder how animals that are longer lived than humans avoid glucosepane crosslinking? Higher collagen turnover?

Posted by: Jim at August 28th, 2014 6:04 AM

@Jim: re: difficulty: of course. The only way to find out is to try :) .

Re: divergence in species rate: there are no studies on this, and indeed performing such studies would heretofore have been extremely difficult: it's an expensive and laborious process to even isolate the stuff from tissue, there has been no way to label it in situ, and to even track the rate of accumulation (let alone the more challenging matter of determining the rates of formation or degradation and the differential mechanisms thereof), you'd have to have either a long series of longitudinal samples in an animal with a longer lifespan than a human, or at the very least a cross-sectional series with multiple members of what will in many cases be rare animals (Bowhead whales, most obviously -- and see this embarrassing case).

I suspect that some cases are just boring: lobsters probably just dilute the stuff away through lifelong growth, and Quahogs are cold-blooded and live at the bottom of the sea, which passively slows down all nonenzymatic reactions. It's also not inconceivable that in some cases glucosepane builds up in these organisms as fast as it does in humans, but there hasn't been any selective pressure against it because eg. they don't develop atherosclerosis and are thus at lower risk of stroke for other reasons.

As I've said before, I think that questing after clues from extremely long-lived animals is an extremely inefficient path to developing therapies against the degenerative aging process. For biomedical research, it doesn't matter why one organism suffers some particular form of aging damage slower than another: what matters is to develop therapies that remove it, replace it, repair it, or render it harmless.

Posted by: Michael at August 28th, 2014 12:10 PM

I should also add that both of those enterprises — looking for glucosepane in the tissues of "normally" aging animals of whatever species, and developing glucosepane crosslink-breakers — will be made a heck of a lot easier thanks to the recent success of Dr. David Spiegel's team at Yale, who I can now report have (with SENS Research Foundation funding) successfully completed the first-ever synthesis of glucosepane, and are going on to work on its biologically-significant isomers (as well as pentosinane, another AGE crosslink that may have been mistakenly neglected). This will in turn enable the development of synthetic glucosepane-crosslinked peptides that can be used to developed antibodies against glucosepane in tissue, which will make it orders of magnitude faster and cheaper to look for it in biological tissues, and to test potential glucosepane-cleaving agents in vitro using high-throughput screening, and later in vivo by administering the compounds to animals and evaluating the effects on glucosepane burden in the animals' tissues (something that was not ever possible for the α-diketone crosslinks that were thought to be the targets of alagebrium).

(Don't press me for details yet, please! Our 2014 Annual Report, released at Rejuvenation Biotechnology 2014 (RB2014) and available "soonish," essentially repeats what I just said; a more detailed elucidation will be available in our 2014 Research Report, due out this Fall; and Dr. Spiegel and his team are working on a formal scientific publication of their breakthrough as we "speak").

Posted by: Michael at August 28th, 2014 12:43 PM

@Morpheus: RB2014 was an exciting event, as the SENS series have always been, with much shared vision, commiserated frustration, and breakthrough science; it was great to see industry, regulators, scientists, and advocates in so much harmony, and also collegial and enlightening discussion of disagreement. More in the next SENS Research Foundation newsletter, and eventually videos of most or all of the presentations and panels.

And keep your sister away from me — she's bad news ;) .

Posted by: Michael at August 28th, 2014 12:51 PM

That's very good news on glucosepane, thanks for sharing that tidbit with us.

Dr Spiegel's work on antibody recruiting molecules (ARMs) looks very interesting too. Although I imagine it could upset a few applecarts if it turns out to be a cheap alternative to some on patent biologics.

Posted by: Jim at August 29th, 2014 3:56 AM

"It's also not inconceivable that in some cases glucosepane builds up in these organisms as fast as it does in humans, but there hasn't been any selective pressure against it because eg. they don't develop atherosclerosis and are thus at lower risk of stroke for other reasons."- Michael

"Dr. Ornish's research offers strong scientific evidence that lifestyle changes alone can actually reverse the progression of atherosclerotic plaques in coronary arteries. These lifestyle changes can begin to reverse even severe coronary artery disease after only one year, without the use of cholesterol-lowering drugs."-- Claude Lenfant, M.D., director, National Heart, Lung, and Blood Institute, National Institutes of Health

It has been claimed that atherosclerotic buildup can be reversed in humans. Either that's wrong or the body does have a means of clearing it up.

Posted by: darian s at August 31st, 2014 8:12 PM

Oh the body is doing it already? Pens down then, I say.

Posted by: Michael-2 at September 2nd, 2014 5:35 AM

As well as Ornish, Caldwell B Esselstyn has demonstrated the ability of nutritional approaches to halt and reverse heart disease. The latest update to his long-runnning study was published in the Journal of Family Practice earlier this year:

I hesitate to write this, given the widespread prejudice against these drugs, but statin use has also demonstrated reversal of arterial plaque eg

Posted by: Tom G at September 3rd, 2014 7:24 PM

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