Aiming to Develop Monoclonal Antibodies for Glucosepane

Funded by the SENS Research Foundation and allied philanthropists, the researchers at the Spiegel Lab are working on the tools needed to build the means to remove glucosepane cross-links from aged tissue. Like clearance of senescent cells, this is one of the more promising near-term approaches to rejuvenation therapies because it is just the single, narrow problem, rather an enormous range of compounds and mechanisms grouped into a category, as is the case for amyloids, lipofusin, and other forms of damaging metabolic waste. It should be possible to develop and deploy working approaches to glucosepane cross-link breaking in a much shorter period of time, once the initial hurdles are overcome.

Persistent sugary cross-links form in the extracellular matrix as a side-effect of the normal operation of cellular metabolism. In humans the vast majority of lasting, problematic cross-links involve glucospane. These cross-links alter and corrode the structural properties of tissue, making bone and cartilage fragile, and producing loss of elasticity in skin and blood vessels. While all of these are bad, the loss of blood vessel elasticity is probably the most important of these consequences, as increased vascular stiffness with advancing age drives the progression of hypertension, cardiac hypertrophy, and fatal cardiovascular disease. The sooner the research community makes the leap to far greater funding and interest in cross-link breaking, the better. This requires better tools, such as those planned in this new research project.

SENS Research Foundation (SRF) has launched a new research program focused on developing monoclonal antibodies against glucosepane. David A. Spiegel will be running the project in his laboratory, which focuses on developing new methods and molecules that will facilitate our understanding and treatment of human disease.

Glucosepane is the most prevalent crosslink found in collagen in people over 65 years of age, and its presence has been correlated to age-related tissue damage through various mechanisms. Understanding of glucosepane has been hampered by the molecule's complex and sensitive chemical structure; it can only be isolated from human samples in minute quantities and in an impure form. To enable these advances in both basic and therapeutic science, the Spiegel laboratory has recently accomplished the first total synthesis of glucosepane.

The lab is now utilizing its novel synthetic glucosepane derivatives to generate the first monoclonal anti-glucosepane antibodies. Access to these antibodies would profoundly accelerate the goal of developing the first discrete, specific reagents for labeling, studying, and perhaps also cleaving glucosepane in vivo. Such tools have tremendous potential to help illuminate, and reverse, age-related damage as it occurs in human tissues.

This research has been made possible through the generous support of Michael Antonov and the Forever Healthy Foundation and its founder Michael Greve. The Forever Healthy Foundation is a private nonprofit initiative whose mission is to enable people to vastly extend their healthy lifespans and be part of the first generation to cure aging. In order to accelerate the development of therapies to bring aging under full medical control, the Forever Healthy Foundation directly supports cutting-edge research aimed at the molecular and cellular repair of damage caused by the aging process.



Nice to see another richman funding SENS. Welcome aboard, Mr. Antonov!

Posted by: Antonio at September 19th, 2017 8:22 AM

Is that Michael Antonio of Occulus Rift?

Posted by: Jim at September 19th, 2017 9:55 AM


Posted by: Jim at September 19th, 2017 9:56 AM

This is excellent news. Although we have been anticipating this with baited breath, its always good to finally see it coming together.

Just think... Draino for your vascular system...

Not just yes, but HELL YES!

Hmmm.. Antonov works for Oculous...He talks to Zuckerberg on a regular basis... Hmmm...

Posted by: Mark Borbely at September 19th, 2017 10:00 AM

I would to see some proof of concept for this, that reducing crosslinks actually significantly increases lifespan. Perhaps the opposite proof would be easier to achieve, that intentionally increasingly glucospane cross links results in reduced lifespan

Posted by: JohnD at September 19th, 2017 11:46 AM

@Jim: Yes. He appears in some earlier SRF publicity materials as well.

Posted by: Reason at September 19th, 2017 1:36 PM

@JohnD: you wouldn't expect that cleaving glucosepane would significantly increase lifespan, or indeed that removing, replacing, or repairing any single form of aging damage would do so, because of the "weakest link in the chain" problem: to move the needle on maximum lifespan, you have to push back on all of the cellular and molecular damage of aging, not just one form. See further on this in a previous FightAging! discussion about glucoepane cleavage.

Additionally, you might expect lesser benefit from cleaving crosslinks in normally-aging mice than normally-aging people, because wild-type mice don't develop atherosclerotic cardiovascular disease, to which hypertension (and thus crosslinking) is both a long-term contributor and also the trigger to its acute insults (heart attack and stroke).

On the other hand, it's not really informative to show that damaging an animal in some way shortens its lifespan: as Michael Rose once said, "A lot of people can kill things off sooner, by screwing around with various mechanisms, but to me that's like killing mice with hammers -- it doesn't show that hammers are related to aging." This is part of the reason why "accelerated aging" models are such a problematic construct.

Posted by: Michael at September 19th, 2017 5:02 PM

Given that maximum lifespan is 120 and a one in a billion chance anyway, at the moment most people would be quite pleased with an increase in median lifespan. Even an increase to 100, which many scientists believe already possible since senescent cell clearing, for example, has beneficial effects on multiple systems, would give many the chance to benefit from the more sophisticated and complete therapies that will emerge in a few decades.

There is a 30-40 years difference between median and maximum lifespan - which is a whopping 35-50% of current life expectancy - and while I agree that the ultimate goal should be to affect the latter, presently a significant extension of the former is both more technically feasible and psychologically acceptable.

Posted by: Barbara T. at September 20th, 2017 3:27 PM

Barbara: I'm 43 and, assuming current trends in life expectancy increase in my country (say, in the last half century), my life expectancy is around 90, so increasing it further to 100 is not that much.

Posted by: Antonio at September 20th, 2017 5:20 PM

Antonio: according to trends in my country I am expected to live to 94.... I was talking about increasing it for people in late middle age now, so 15-20 extra years for a 65 year old as opposed to the less than 3 additional years that someone that age would get if we consider a period life expectancy of 80 (I am using the US as reference) and a remaining life expectancy at 65 of 1.5 years. If we are talking about cohorts, a newborn in San Marino would reach 100 just by extrapolating from current trends.

Twenty years is a lot for someone who doesn't have all that much left, and if you tell a 60 year old that they will be able to enjoy the same health, strength, mental acuity and - why not - looks at 80 that they do now, and then that they will hang around for another two decades in decent health with a shot at benefiting from further rejuvenation treatments, I am pretty sure that few people would decline the offer.

Problem is, the community either talks about numbers that most people can't wrap their head around (150, 1000, indefinite) or dismisses the possibility of any significant  - and a jump of 15-20 years in a decade or so is definitely significant - increase in life expectancy with treatments currently in the pipeline. I believe it's the difficulty of reconciling this dichotomy that leads people to dismiss what is a goal that can be attained quickly and would benefit many. When a scientist says that you can live to 1000, which by the way is a very scary perspective for most, and another rubbishes the idea by pushing instead some metformin-type pill that will perhaps increase "healthspan", you are quite rightly going to dismiss the first expectation as outlandish, and the second as stupendously uninspiring.

This affects crowdfunding, since most 43 year olds with a remaining life expectancy of half a century may not feel the urgency to contribute, and a 70 year old may prefer spending his cash on stuff that he can enjoy now-now rather than funding studies to increase his odds to die at 85 instead of 82. I think the messaging is in dire need of some fine tuning.

Posted by: Barbara T. at September 20th, 2017 8:19 PM

@ Barbara T, your last paragraph is the most important having to do with funding. Steve Hill should probably address this as his group is doing public outreach.

Posted by: Morpheus at September 21st, 2017 8:30 PM
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