Rejuvenation Biotechnology Update for April 2016

The latest edition of the Rejuvenation Biotechnology Update arrived today. This newsletter series is a collaboration between the Methuselah Foundation and SENS Research Foundation, two of the most important organizations involved in advocacy and research to speed the defeat of aging and age-related disease. The newsletter goes out to members of the Methuselah 300, a long-standing group largely made up of ordinary philanthropists of modest means. Over the years these donors have collectively helped to fund many of the important projects carried out at the Methuselah Foundation: the Mprize for longevity science; the initial set of SENS rejuvenation research programs; seed funding tissue engineering startup Organovo and senescent cell clearance startup Oisin Biotechnologies; the establishment of the New Organ prize series; and much more.

If you want to see how everyday people with entirely ordinary incomes can band together to make a real difference to progress in the sciences, look no further than the Methuselah Foundation and the Methuselah 300. This is how it is done: persuade the core supporters, build a network of connections in the research community, and make smart, targeted investments in research and advocacy. On the back of this simple formula, and with the help of hundreds of supporters, the Methuselah Foundation has played a strong role in the significant, pivotal change that has taken place in the aging research community in the past fifteen years. Over the lifetime of the Methuselah Foundation the environment has gone from one in which talking about life extension through medical science was to risk your career to one in which the leaders of the field - and pretty much everyone else - openly advocate for greater human longevity. That didn't happened by chance, and it wasn't inevitable: it took a lot of hard work, both openly and behind the scenes, to bring about this important cultural change.

One of the great secrets of our time is that early stage medical research has become very cheap over the past few decades. The pace of progress in tools and knowledge is staggering. Any number of important, small, discrete projects at the cutting edge of the medical life sciences can be accomplished for a few tens of thousands of dollars, given an established lab to work with and smart young researchers to carry out the work. For a few hundred thousand dollars, a biotechnology company can be established, complete their prototype therapy, and carry out animal studies needed to attract greater investment. This is an age of communication, and research funding is in the process of becoming extremely transparent and collaborative: we can choose the projects to learn about and support, and we can see exactly what the organizations we trust to do this for us, such as the Methuselah Foundation and SENS Research Foundation, are doing with our donations. Every twist and turn of the race is there to be cheered on - and make no mistake, it is very much a race. Scientific progress and funding on the one hand, and aging on the other. We'll all win together in the best of worlds, in which rejuvenation therapies are developed soon enough, but lot of work remains in order to get to that goal. So consider joining the Methuselah 300 or donating to support SENS research programs. It is the smart thing to do.

Rejuvenation Biotechnology Update for April 2016 (PDF)

Because it doesn't take a scientist to understand the vital importance of investing in healthy life extension, these newsletters strive to report three significant studies from the past 3-6 months accessibly and approachably, describing how each one fits into the broader landscape of rejuvenation biotechnology research.

Announcing the $500,000 Vascular Tissue Challenge Under Development at NASA and Methuselah Foundation

The deadline for comments is only a few weeks away. The Vascular Tissue Challenge is a $500,000 prize purse to be divided among the first three teams who can successfully create thick, human vascularized organ tissue in an in vitro environment while maintaining metabolic functionality similar to their in vivo native cells throughout a 30-day survival period. NASA's Centennial Challenges Program is sponsoring this prize to help advance research on human physiology, fundamental space biology, and medicine, taking place both on the Earth and the International Space Station National Laboratory. The Vascular Tissue Challenge rules are currently open for public comment. If interested in this challenge, please provide your feedback. We encourage readers to attempt to submit comments even if they received this newsletter after April 15th.

Naturally occurring p16Ink4a-positive cells shorten healthy lifespan

Senescent cells have accumulated DNA damage or other abnormalities, have lost the ability to divide, and may create cancer-prone environments locally to where they reside in tissues through the secretion of growth factors, as well as may inflame the immune system through the secretion of cytokines. These cells also appear to have detrimental effects on tissues in which they reside. Senescent cells accumulate in all tissues with age and are a concern to longevity researchers; it is hypothesized that these cells contribute to aging and that removing them from an aged person could have rejuvenation effects. In this study, researchers chose a protein marker of senescent cells, and used a genetic system to induce programmed cell death in their mice when a drug was administered, but only in cells that express the marker at high enough levels to be considered senescent cells. They found that elimination of the senescent cells ameliorated the dysfunction that typically occurs with age in multiple organs and tissues, including fat, cardiomyocytes (heart), and the glomeruli of the kidney (which are involved in filtering the blood). Furthermore, the removal of senescent cells reduced early deaths in the mice and decreased the incidence of cancers, leading to an increase in median life expectancy.

This paper was met with a lot of excitement. The results are indeed impressive, showing that the normal function of several different organs - fat tissue, kidney, heart - can be restored, and healthy lifespan can be prolonged, without apparent side effects, simply by ablating a key subset of senescent cells. This study provides a clear and important piece of evidence to support the idea that senescent cells shorten lifespan, and conversely, that their elimination extends it. With this study, it became clear that, yes, eliminating senescent cells in otherwise healthy aged mice is a net benefit without any apparent downsides. Getting rid of senescent cells is one of the seven key rejuvenation biotechnologies of SENS.

Lanosterol reverses protein aggregation in cataracts.

Cataracts develop due to changes in the lens of the eye, which must be transparent and maintain its optical properties within narrow parameters for proper vision. The major protein which constitutes the lens of the eye is called crystallin, and disruptions to its structure on a molecular level can cause the normally clear lens to become opaque. Currently the only treatment option for cataracts involves surgery. The researchers in this group started by examining some families who had severe cataracts, and found that many of them carried rare gene mutations in the gene that codes for an enzyme called lanosterol synthase. This research group then found that the normal version of lanosterol synthase, but not the mutant versions, were able to prevent the mutant crystallin proteins from forming aggregates. Then they moved to an in vivo study in dogs with age-related cataracts. Cataract scores improved in the dogs treated with lanosterol eye drops.

This is a very interesting result, and of particular relevance is the in vivo portion of the study in dogs, showing that lens clarity could be improved in living organisms with real cataracts by treatment with eye drops alone, with no requirement for surgery. Lanosterol is a naturally occurring compound, which bodes well for its safety if it is effective at doses within the normal range for youthful people without cataracts, and it could potentially be very inexpensive to produce, although the actual price to consumers might be determined more by intellectual property claims and marketing factors rather than by manufacturing costs. Cataracts definitely qualify as an important disease of aging, especially when considering how much impaired vision can affect quality of life and independence.

The mechanism for how lanosterol may reverse cataracts is still uncertain. The authors suggest that the amphipathic (in-between water and oil soluble; like a detergent) nature of lanosterol could allow crystallin proteins which have undergone changes in folding/conformation to return to their normally folded state, which restores clarity of the lens on a macroscopic level. If there is a treatment that works for reversing aging damage, we don't necessarily need to know the mechanism of how it works to benefit from it. However, it might be important to link this new information about lanosterol and cataracts to what occurs in aging. Does lanosterol synthase activity decline with age? How long does lanosterol treatment keep lenses clear? More broadly, a very common theme in diseases of aging is the aggregation of proteins. Removal of crosslinked protein aggregates is one of the main planks of SENS Research Foundation's focus. Protein crosslinking and aggregation is apparently what occurs in cataracts, and according to this study may be at least partially reversible with lanosterol. Could lanosterol, or similar amphipathic molecules, be used to untangle other types of protein aggregates besides crystallin?


I am glad to see some progress made in different areas of medical research including challenge put forth NASA Methuselah . Sometimes Reason puts out blogs (and attached news articles) to give us some hope to hang in there.

But, I just finished reading the lengthy reply by Michael on the April 8 blog regarding AudreydeGray comments. Reading his comments today was rather disappointing but so was AdG section. I was really hoping that as time goes on and we have organs that can be replicated in the next decade or so, immunology fighting cancer, AI, and gene therapy, that we could extend the average life by an additional 10 year or longer in the 20's and/or 30's. But, maybe I am too optimistic, and biased:(

Posted by: Robert Church at April 15th, 2016 11:38 PM

Comment on the theme: "Lanosterol reverses protein aggregation in cataracts".
Lanosterol synthase overexpression may increase blood cholesterol that leads to atherosclerosis.
Preliminary studies in dogs and rabbits have shown that lanosterol can prevent and even reverse cataract formation. However, an attempt to replicate these results in age-related cataractous human lens nuclei removed during manual small incision cataract surgery by immersing them in lanosterol solution and incubating them for 6 days according to the method of Zhao et al., failed to reverse nuclear opacity. See: Shanmugam, P. M., Barigali, A., Kadaskar, J., Borgohain, S., Mishra, D. K. C., Ramanjulu, R., & Minija, C. K. (2015). Effect of lanosterol on human cataract nucleus. Indian journal of ophthalmology, 63(12), 888-890 doi:10.4103/0301-4738.176040
Obviously it is necessary to recheck results of treatment with lanosterol eye drops.

Posted by: Dmitry Dzhagarov at April 16th, 2016 1:44 PM

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