Rejuvenation Biotechnology Update for January 2017

The Methuselah Foundation and SENS Research Foundation have sent around the latest edition of the Rejuvenation Biotechnology Update, highlighting and explaining a few of the more interesting research results of recent months. It is a quarterly newsletter for members of the Methuselah 300, a more than decade-old group of advocates and supporters who each pledge to donate $25,000 over 25 years to help fund the development of therapies to treat aging. The first of the 300 helped to launch the Methuselah Foundation, and their continued support drew in the funding needed to eventually spin off the SENS Research Foundation as its own venture. While it was just thirteen years ago that the 300 was first mentioned, a lot has happened since then. Tempus fugit.

Only thirteen years, yes, but for me that seems like a long time past. Back then advocates for longevity science were few in number, working so very hard to raise a few thousand dollars here and a few thousand dollars there, while being roundly mocked for declaring that aging should and could be treated as a medical condition when people did deign to pay attention. How far we've come since then! The entire environment has changed, the attitudes of the scientific establishment are remade, the concept of medicine to address aging is discussed in the media on a regular basis, available funding is greatly multiplied, and the first SENS rejuvenation therapies are moving towards the clinic. There is a still a long way to go yet towards the goal of defeating aging and all age-related disease, but the beginning has been written and done: we have now entered into the next phase.

Rejuvenation Biotechnology Update, January 2017 (PDF)

Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice.

This study provides evidence that adding senescent cells to a healthy joint can create a constellation of symptoms that resemble osteoarthritis. It is an important step in linking cellular senescence and osteoarthritic joint damage. However, the "smoking gun" that would really implicate senescent cells as a clinically-relevant target for osteoarthritis treatment would be to demonstrate that using senolytic drugs or genetic approaches to remove senescent cells from the joint of an animal with osteoarthritis leads to an improvement in osteoarthritis symptoms and the restoration of joint structure and function. Furthermore, the authors acknowledge that senescent cells may be one cause or a contributor to osteoarthritis, but osteoarthritis may also have other causes or contributing factors (such as chronic inflammation from other causes, mitochondrial dysfunction, and loss of glycosaminoglycans). So, we remain vigilant about the potentially-significant role of senescent cells is in the development of osteoarthritis.

Given that it is becoming increasingly clear that senescent cells significantly contribute to an overall phenotype of age-associated disease and dysfunction, these results are a promising step in the direction of implicating senescent cells as a therapeutic target for osteoarthritis. These findings no doubt hearten our colleagues at UNITY Biotechnology, who have identified osteoarthritis as their first target for senolytic drug therapy. Research on clearance of senescent cells as a strategy to correct aging damage is a high priority to SENS Research Foundation and Methuselah Foundation. Fortunately, this field seems to be advancing significantly and rapidly in the last few years. The company Oisín Biotechnologies (partially funded by SENS Research Foundation and Methuselah Foundation) is pursuing a "transient" (non-integrating) genetic approach to target and remove senescent cells from human bodies.

A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood.

This study represents an important advancement in technology to study blood-borne factors associated with youth and aging. It also contributes important findings that isolate the effect of blood-borne factors on tissue functions and injury repair in the context of aging. The authors anticipated that when the effects of blood alone were isolated, the findings would more relevant to human clinical applications. Some key findings from this study were that, at least when it came to neurogenesis, old blood seemed to inhibit neurogenesis more in young mice than young blood rejuvenated the brains of old mice. This would seem to implicate a greater increase in pro-aging factors, compared to the decrease in anti-aging factors, with age. This finding of old blood inhibiting neurogenesis in the hippocampus may be linked with the observed increase in β-2 microglobulin in young mice who received old blood, which occurred in the brain and muscle. However, the exact mechanism by which β-2 microglobulin levels came to be elevated in young mice who received old blood is still not clear. If it could be clarified, perhaps a potential therapeutic target or targets could be identified to lower β-2 microglobulin and other pro-aging factor levels in aged individuals.

One especially encouraging finding from this study was, as the authors put it, "the plasticity of age" - the observation that changes in tissues took place rapidly and old tissues were restored to a more youthful state within days of when blood exchange took place. And, unlike parabiosis experiments, a therapeutic approach based on blood exchange or blood filtration would be feasible in humans. Exchange transfusion is already an established treatment for several human autoimmune diseases where diluting auto-antibodies out of the circulation is beneficial, and exchange transfusion devices are currently available and FDA-approved for treatment of these diseases. Similarly, hemodialysis is a well-established procedure, and a more selective device that would scrub old blood of excessive "pro-aging" factors could extend this paradigm. The investigators in this study are looking to develop their findings into a clinical application for human patients soon: a startup company founded by a colleague is now preparing a clinical trial to adapt existing medical equipment test this very possibility in aging humans.

Vestibular Perceptual Thresholds Increase above the Age of 40.

The vestibular system in humans senses body motion and positioning of the body in space. The vestibular apparatus in the inner ear consists of a fluid-filled organ lined with sensing cells. The study found that after age 40, in both males and females, vestibular function steadily declined: vestibular perceptual thresholds increased; that is, the older a person gets, the more movement it takes for them to detect a change in position. According to the CDC, 1 out of 4 older Americans falls each year. In older individuals, falling is strongly associated with serious injuries and death. In fact, falls are the leading cause of injury and death from injury in Americans over age 65. The major factors for avoiding falls are functional balance and leg strength. The vestibular system plays a critical role in balance. So, understanding age-related declines in vestibular function may reveal critical insights into how to maintain balance and prevent falls.

Unfortunately, the major thing missing from this study was the identification of a mechanism for the decline in vestibular function after approximately age 40, and evidence supporting the identification of this mechanism. Several other studies have measured the number of vestibular hair cells (sensory cells) at various ages and showed a steady decline every year since birth. At first glance, this data does not seem to fit with the observation that vestibular function only starts to decline after age 40, this may be a case of a common phenomenon in aging that Dr. Aubrey de Grey has referred to as the "threshold of pathology." That is, humans may have enough vestibular hair cells so as to be redundant before age 40. Beyond that age, they may have lost enough cells that vestibular function starts to be affected as more cells die off. The authors speculate that free radical damage may be responsible for the death of vestibular hair cells with age, and further that vestibular function may serve as a reliable marker for the level of aging damage an individual has incurred, which can be measured noninvasively by simply testing vestibular function as they did in the current study.

Although the authors do not have experimental evidence that free radical damage is responsible for declining vestibular function with age, there is a range of evidence supporting the involvement of mutations in mitochondrial DNA and of mitochondrial free radical generation in vestibular damage from other causes. Vestibular damage is a major side-effect of the antibiotic gentamycin and others in its class, and free radicals are thought to be one of the mechanisms. Moreover, people with specific mutations in mitochondrial genes that code for the organelles that assemble proteins that are components of the mitochondrial energy production machinery are unusually vulnerable to this toxicity. Mice with a mutation that prevents the building of one of the complexes of the mitochondrial energy-production line develop vestibular damage, and human patients with the mitochondrial mutation disease Kearns-Sayre syndrome frequently have vestibular dysfunction as one of the many effects of the disease.

One way to address the rise in free radical damage with age is to prevent it at the source. This is the strategy behind SENS Research Foundation's "MitoSENS" program. Briefly: mitochondria in a subset of cells acquire large deletions in their DNA as individuals age, and the abnormal metabolic activity that cells harboring such mitochondria undertake results in a rise in oxidative stress in the body. To fix this problem, mitochondrial genes should be stably expressed in the cell nucleus instead of in the mitochondria, where these genes are more easily damaged. The strategy of MitoSENS is to fix the source of the damage: the inability of these dysfunctional mitochondria to generate the proteins they need to carry out normal metabolism with lower free radical production. If vestibular function is indeed connected to the rise of cells that have been taken over by mitochondria bearing such deletions and creating additional free radicals, this would enhance the value of the goals of the MitoSENS project, which could provide the benefit of preserving vestibular function and prevent the common, dangerous, and deadly scourge of falls.

Comments

Hi ! Very Nice.

I hope this greatly contributes to saving lives in the future; when the 7 therapies are completed.

I realllly think SENS must add More therapies as they will not be able make LEV or such a strong RMR/HMR (Robust Mouse Rejuvenation) as expected; or let's say it will help strongly healthwise but it won't make much difference on the longevity of the mouse or the human. Only LysoSENS or MitoSENS or AGEsSENS (glucosepane) have power to reverse aging the others don't, they cure pathologies but don't stop the actual damage accrual problem of aging.

They should other specific therapies that will reverse aging :
such as

- Redox tinkering (altering the Redox is a order of magnitude more powerful than trying to go at it on certain tiny-effect genes)

- Nuclear/Chromosomal tinkering (altering chromosomes/telomeres and, especially, Nuclear DNA (not mitochondrial DNA) will have dramatic effect on lifespan because chromosomes ditacte lifespan, uncondensed and decompacted loose chromosomes are a natural feature of aging, seen both in Senescence (Oncogene, Replicative and Spontaneous/stress-induced ones) and also, specially, in progeric disease (which is a form extreme premature aging by failure of chromosome arrangment (Lamina failure/progerin accumulation, and whaht's more regular healthy people display the same lamina failure assembly around histones (certain histones are lost from chromosomes, One study showed that chromosomal dysfunction is hallmark of healthy aging - and is the cause of all these damages happening : aging is the 'end' of the nuclear division and synthesis cycle; chromosomes erode as they rebuild themselves sustaining these damages each cycle until it 'can't work' anymore - that's the end/death. Seen in progeria (in accelerated) or slowly in healthy people who live a long life))).

- Epigenetic Transcription/gene Reprogramming and DNA methylation tinkering

Without these extra therapies LEV is impossible on the 7 ones. Or almost. But it will give the possibility of 20 or so years when combined together.
Still that is very Far from the LEV possibility; lipofuscin or AGEs removal are not enough; neither is mitochondrial protein replacement, these will greatly reduce mitopathologies but regular healthy aging will continue its course - because it relies on more than that (epigenetics, redox, chromosomes, telomeres (replicative senescence), and so forth)..

Posted by: CANanonymity at February 2nd, 2017 12:23 AM

What about giant mitochondria? They accumulate in aging postmitotic cells and I don't think their function can be restored by delivering backup copies of proteins. Their problem is that they are too large to become autophagocytosed and they do not take part in the fusion and fission cycle anymore. Why do they accumulate is not clear, but it seems they represent fused mitochondria which cannot part anymore. The proteins which mediate fusion and fission are coded in the nucleus and transported into the mitochondria. It might be that mutations in the nuclear DNA or epigenetic regulation of those proteins is responsible for that mechanism.

Posted by: K. at February 2nd, 2017 1:51 AM

Hi K,

Eaxctly as you said, they can't be autophagocytosed because of their giant size thus they accumulate; autophagy becomes defective from this excess of giant effete, this is very similar to lipofuscin accumulation in lysosomes creating lysosomal mass increase; in fact these is an amalgam of giant mitochondrias mixed with lipofuscin, drusen, ceroid, oxidized lipids/sugars (AGEs/MDA/TBARS/CML/carbonyls) and other oxidized DNA molecules. As you say some fuse and become a large mass of fused badly-working mitochondrias; but as a 'whole' it can be viable (seen in centenarians who have a large mass/hyperthrophy of fused ill-mitochondrias, the fusing protects the mitochondrias against eradication from autophagy; it's a strategy and it works, because centenarians have a change like that in their mitochondrais); it's the old '2 heads are better than one' and in this case : '2 heads are better than one - even if they are both old and dysfunctional'.

''The proteins which mediate fusion and fission are coded in the nucleus and transported into the mitochondria. It might be that mutations in the nuclear DNA or epigenetic regulation of those proteins is responsible for that mechanism.''

Yes, that's it. Nuclear damage is chromosomal damage and that is incompatible with life (up to a certain point); chromosomes can only take so much before it's game over. Nuclear DNA and chromatin control epigenetics; of course the minute you damage them, the rest down the line suffers; such as mitophagy, autophagy, lysophagy, mitochondrais themselves, etc. We always think mitochondrias are one notch up the ladder; but it's the inverse, nucleus is notch above and controls down the lower in the ladder mitochondrias. Mitochondrias are only power makers (ATP producers) as 'the heart' that's about it they are not the 'control tower/the brain' of the cell.

''The overall data indicate that longevity is characterized by a preserved bioenergetic function likely attained by a successful mitochondria remodeling that can compensate for functional defects through an increase in mass, i.e. a sort of mitochondrial "hypertrophy".''

Mitochondria hyperfusion and elevated autophagic activity are key mechanisms for cellular bioenergetic preservation in centenarians

1- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032796/

Posted by: CANanonymity at February 2nd, 2017 2:41 AM

thanks for the link CANanonymity. I will analyze the paper and its implications.

Posted by: K. at February 2nd, 2017 3:39 AM

Normally I would be excited about this blog but reading a comment from Michael earlier this week about people who are 50 and older missing out on rejuv, but can only hope for cryogenics leaves me disappointed as I am in my 50's. I had hoped that given the bio-tech, Crisper, the first wave of rejuv via the elimination of senscient cells, and coming AI, plus exponiential everything medical and tech, that anyone alive within 20 years would make it. But given Michael's knowledge of the field he is in, I have to assume he knows what he is talking about:(

Posted by: Robert at February 2nd, 2017 9:45 PM

@Robert: I'm assuming that you're referring to the comment posted in this thread:
https://www.fightaging.org/archives/2017/01/international-longevity-and-cryopreservation-summit-in-spain-may-2017/#comment-26270

by "Michael" on January 31st, 2017 3:06 PM . First, note that that commenter is not me, and I don't know what his expertise is. Second, note that the commenter did not say that people over 50 would miss out on rejuvenation therapies - only that you are on the cusp, with which I'd agree.

Posted by: Michael at February 2nd, 2017 10:51 PM

@ Robert : Aubrey (de Grey) is about the same age as you, and he doesn't seem overly pessimistic about his own outcome.

In fact, I recall he rated his own chances of making to LEV to about 50/50 upon certain conditions. Not that bad really ; if anything, it should incite you to fund SENS even more, as well as doing even more advocacy work.

Posted by: Spede at February 3rd, 2017 3:49 AM

Well if you are 50, and life expectancy is 80 (or 85 if you are from the right side of the wealth bell curve) then you've got 30 years for rejuvenation biotechnologies to come about in some reasonable form.

Posted by: Jim at February 3rd, 2017 2:59 PM

@Jim, thanks for your input. Unfortunately, I am in my mid 50's. I hope to push it out as much as possible since I exercise often, never been over weight, don't smoke, and never did like alot of foods, thus CR diet. Feeling hunger is a good thing, buffets are a bad thing:)

@Spede, thanks for the reminder of DeGray comment, I looked up his current age, he is about 53-54, so yea, not much different from my age.

@Michael, thanks for your clarification. Wow, it would be easy to confuse people who have identical names here.

But, it seems the odds improve for everyone as medical technology gets better. I dont know if medical tech is expontiential, but I would think the knowledge for the genome would be. It seems with CRISPR, and other medical tech, we will get closer to Ray K. idea of instead of getting a year older, we increase years, and that should be within 1 to 2 decades, I believe Rays timeline quote.

Posted by: Robert at February 4th, 2017 12:16 PM

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