A Visual Introduction to SENS Rejuvenation Research
The SENS Research Foundation has assembled a set of narrated cellular biochemistry animations that serve as an introduction to the various distinct projects that make up the field of rejuvenation biotechnology. The videos outline the forms of cell and tissue damage that are the root cause of aging and age-related disease, as well as the classes of therapy that could, once constructed, either repair that damage or bypass it entirely. Since aging is exactly an accumulation of damage and the consequences of that damage, repair of the damage is the basis for rejuvenation, the reversal and prevention of degenerative aging and all age-related disease. The goal for the near future is to align ever more of the research community and its funding institutions with this goal, and make real progress towards bringing an end to the pain, suffering, and disease of aging.
Introducing SENS - Metabolism, Damage, Pathology
Many things go wrong with aging bodies, but at the root of them all is the burden of decades of unrepaired damage to the cellular and molecular structures that make up the functional units of our tissues. As each essential microscopic structure fails, tissue function becomes progressively compromised - imperceptibly at first, but ending in the slide into the diseases and disabilities of aging. SENS Research Foundation's strategy to prevent and reverse age-related ill-health is to apply the principles of regenerative medicine to repair the damage of aging at the level where it occurs. We are developing a new kind of medicine: regenerative therapies that remove, repair, replace, or render harmless the cellular and molecular damage that has accumulated in our tissues with time. By reconstructing the structured order of the living machinery of our tissues, these rejuvenation biotechnologies will restore the normal functioning of the body's cells and essential biomolecules, returning aging tissues to health and bringing back the body's youthful vigor.
ApoptoSENS - Clearing Senescent Cells
Senescent cells began their existence skin cells, or as related cells that normally play supporting roles in other organs, but were forced into an abnormal state where they lost the ability to divide and reproduce themselves as a protective response to some danger. In addition to halting growth, senescent cells secrete abnormally large amounts of proteins that inflame the immune system and degrade the normal supporting tissue architecture. The relatively small number of such cells in a youthful tissue is so small as to be harmless, but after decades of accumulation, the number becomes large enough that their abnormal metabolic state begins to pose a threat to surrounding, healthy tissues. Larger numbers of senescent cells in a tissue make it more vulnerable to the spread of cancer, contribute to inflammation, and skew the local activity of the immune system.
The most straightforward approach to dealing with these cells is to destroy them. There are two main approaches that could be used to achieve this: (1) develop a drug that is toxic to the unwanted cells, or that makes them commit suicide, but that doesn't harm healthy, normal cells; or (2) stimulate the immune system to selectively seek out and kill the target cells. The most likely way to selectively target these abnormal cells would be to make use of the distinctive molecules that occur on their surfaces. Luckily, different cell types tend to have different things on their surfaces, which play particular parts in their specialized roles in the tissue, so it is a matter of identifying and targeting cell-surface markers that are specific to these abnormal cell types.
AmyloSENS - Dissolving the Plaques
The most well-known form of extracellular junk is beta-amyloid: the stifling, web-like material that forms plaques in the brains of patients with Alzheimer's disease, and also (more slowly) in everyone else's, and impairs cognitive function. There are also a variety of similar aggregates that form in other tissues during aging and contribute to age-related diseases, including islet amyloid in type 2 diabetes and senile cardiac amyloidosis, which is a major contributor to heart failure. In fact, there is some evidence that senile cardiac amyloidosis may be the main cause of death in people who survive beyond age 110.
Extracellular aggregates can be removed from the brain and other areas of the body by specialized antibodies that hone in specifically on them and remove them from the tissue. There two main ways to introduce these antibodies into a person: "active" and "passive" vaccines. "Active" vaccines introduce a small fragment of the amyloid to stimulate the cells of the immune system to target the amyloid and remove it. "Passive" vaccines involve making the antibodies outside of the body, and introducing them directly via injection. More recently, a third and extremely promising variation on this approach has been developed. Researchers have discovered that a subset of human antibodies have catalytic activity against a particular antigen, breaking it down into smaller and less harmful fragments instead of trapping it for removal or destruction by other immune cells.
GlycoSENS - Breaking Extracellular Crosslinks
Many of the major structural features of the body are built out of proteins that are laid down early in our life, and then more or less have to last for a lifetime. The healthy functioning of these tissues relies on these constituent proteins maintaining their proper structure. Such proteins are responsible for the elasticity of the artery wall, the transparency of the lens of the eye, and the high tensile strength of the ligaments, for example. But occasionally, blood sugar (and other molecules in the fluids in which these tissues are bathed) will react with these proteins, creating chemical bonds called crosslinks. Crosslinks act like molecular "handcuffs," taking two neighboring proteins that were previously able to move independently of one another and binding them together.. In the case of the artery wall, for instance, the crosslinking of strands of the protein collagen prevents them from spreading apart from one another to accommodate the surge of the pulse being driven forward by the pumping action of the heart. As more and more strands of collagen become crosslinked together over time, the blood vessels to become ever more rigid, leading to a gradual rise in systolic blood pressure with age. With the loss of the cushioning effect provided by free-moving collagen in the blood vessels, the force of the surge of blood that is driven into the arteries by the pumping action of the heart is carried directly to organs like the kidneys and the brain, damaging to the structures that filter our blood and that connect the functional regions of our brain, and putting us at risk of a stroke.
Fortunately, the crosslinks that occur as chemical accidents in our structural tissues have very unusual chemical structures, which are not found in proteins or other molecules that the body makes on purpose. This should make it possible to identify or design drugs that can react with the crosslinks and sever them, without breaking apart any essential structural bystanders. So the search is on now to develop new and more human-specific crosslink breakers. It's now known that the single greatest contributor to total unintentional collagen crosslinking in humans is a very complex molecule called glucosepane; therefore, drugs that cleave this molecule are likely to have the strongest rejuvenative effect on tissue elasticity.
RepleniSENS - Replacing Lost Tissues
Every day, our cells are damaged by both tiny molecular-level insults and by obvious trauma. Some of these damaged cells are repaired, but others are either destroyed, or forced into a dysfunctional 'senescent' state where they can no longer divide, or commit 'cellular suicide' (apoptosis) for the greater good of the body. Some of the lost cells are replaced by the pools of specialized, tissue-specific stem cells, but the degenerative aging process makes these stem cell pools less effective at repair over time. The net result is that over the course of many decades, long-lived tissues like your brain, heart, and skeletal muscles begin to progressively lose cells, and their function becomes increasingly compromised.
The solution to this problem involves the rejuvenation biotechnologies with which most people are most familiar: cell therapy and tissue engineering, the science of growing organs for transplant in an artificial, biodegradable scaffold outside the body. The foundations of this form of medicine lie in the transplantation of organs and tissues that we already use to replace the blood of chemotherapy patients or the kidneys of dialysis patients. In addition to replacing lost, dying, or dysfunctional cells, the ability to engineer new cells and tissues gives us an opportunity to use them as delivery systems for other rejuvenation biotechnologies.
LysoSENS - Reversing Heart Disease
The proteins and other constituents of our cells are all eventually damaged as the result of biochemical accidents that occur during normal metabolism, or simply outlive their usefulness. Cells have a variety of systems for breaking down and recycling such unwanted materials, allowing them to clear garbage out of the way and reuse the raw materials. One such system is the lysosome, a kind of cellular "incinerator" that contains the most powerful enzymes in the cell for breaking mangled molecules down into manageable pieces. However, sometimes these constituents are so badly fused together that not even the lysosome is able to tear them apart. And if something can't be broken down in the lysosome, there's nowhere else for it to go: it just stays there until either the lysosome disastrously ruptures, or the cell itself is destroyed.
Since the root of the problem is that the lysosome is unable to break down all of these stubborn waste products, the most direct solution is to supply them with new enzymes that can degrade those wastes. And fortunately, we know that enzymes capable of breaking down these materials exist - specifically, in the soil bacteria and fungi that help to decompose dead bodies. If such enzymes didn't exist, then the planet would be ankle-deep in the undegraded lysosomal wastes left over from the cells of 600 million years of animal life on this planet. So the idea would be to identify the enzymes these organisms use to digest lysosomal wastes, modify them a bit to help them work in the slightly different environment of the human lysosome, and then deliver them to where they need to go in our cells.
OncoSENS - Stopping Cancer at the Starting Line
Two types of damage accumulate in our genes as we age: mutations and epimutations. Mutations are damage to the DNA sequence itself, whereas epimutations are damage to the "scaffolding" of that DNA, which controls how and when genes get turned on in the cell. For practical purposes, both mutations and epimutations ultimately harm us in the same way: by causing abnormal gene expression. So what kind of harm can the changes in gene expression resulting from (epi)mutations cause? The one that most people know about is cancer, which is the result of a series of (epi)mutations that happen in sequence in the cell, leading to its uncontrolled growth.
Fortunately, a strategy to achieve extremely strong protection against cancer does exist, although its implementation is extremely challenging. This strategy is based on the one inescapable vulnerability that all cancer cells share in common: their absolute need to renew their telomeres. Because cancer cells reproduce at a furious pace, they quickly reach the ends of their telomeric "ropes," and need to find a way to lengthen them again in order to keep going. Successful cancer cells are the ones that have evolved mutations that exploit one of the cell's two systems for renewing telomeres: either a primary system called telomerase, or in a few cases an "alternative" system appropriately called Alternative Lengthening of Telomeres (ALT). If a nascent cancer can't find a way to seize hold of the telomerase-lengthening machinery, their telomeres will run down, their chromosomes will fray, and the cell will be destroyed before it can kill us. So despite their diversity, all cancer cells share one critical thing in common: they are absolutely dependent for their survival on their ability to hijack telomerase (or, less frequently, ALT). This fact has led the search for drugs that inhibit telomerase activity in cancer cells to become one of the hottest areas of cancer research today.
MitoSENS - Preventing Mitochondrial Aging
Mitochondria are the living machines within cells that act as their "power plants," converting the energy-rich nutrients in our food into ATP that directly powers biochemical reactions in the cell. Unlike any other part of the cell, mitochondria have their own DNA (mtDNA), separate from the DNA in the cell's nucleus, where all the rest of our genes are kept. Just like real power plants, mitochondria generate toxic waste products in the process of "burning" food energy as fuel - in this case, spewing out highly-reactive molecules called free radicals, which can damage cellular structures. And the mtDNA is especially vulnerable to these free radicals, because it is located so close to the center of its production. At worst, a free radical "hit" to the mtDNA can cause major deletions in its genetic code, eliminating the mitochondria's ability to use the instructions to make proteins that are critical components of their energy-generating system. Lacking the components needed to produce cellular energy the normal way, these mutant mitochondria enter into an abnormal metabolic state to keep going - a state that produces little energy, while generating large amounts of waste that the cell is not equipped to metabolize. Perversely, the cell tends to hang onto these defective, mutant mitochondria, while sending normal ones to the recycling center, so if just one mitochondrion suffers a deletion, its progeny quickly take over the entire cell.
It would be ideal if we could prevent mitochondrial deletions from happening, or fix them after they've occurred before they can do harm; unfortunately, the state of the science is nowhere near the point where this would be a realistic goal. Instead, the MitoSENS strategy is to accept that mitochondrial mutations will occasionally happen, but engineer a system to prevent the harm they cause to the cell. We can do this by putting "backup copies" of the mitochondrial genes into the nucleus, where they cannot be damaged by free radicals generated in the mitochondria. That way, even if the original genes in the mitochondrial are deleted, the backup copies will be able to supply the proteins needed to keep normal energy production going, allowing the cellular power plants to continue humming along normally and preventing them from entering into the toxic, mutant metabolic state.
Cool videos. I like that they approach this in a more subdued professional-clean but not arrogant 'me too' or 'sales pitch cold selling' fashion (closet 'behind closet door' company doing some medical business but 'Reaching Out') with great CGI animation that is Demonstrative to understand better, rather than all balls to the wall 'We Give You Immortality Tomorrow or Your Money $$$ Back! Guaranteed. or we die (maybe not since we will use SENS on us)'
more sensationalistic 'outlandish claim' tone (though with a name like S.E.N.S., it would make SENSE, that it would be SENSATIONAL ;). I guess it does make sense, we can play on this acronym a lot, it never gets old. Hah (sorry..)
They want to be more 'sensical' about it (ok I had to...:D...last one), as in not make ridiculous claims and then fall flat/lose face when people realize
they are another Pipe Dream - Pie in the Sky. And we don't want that big pie from above to fall back down in our face, that would be catastrophic.
I looked each video (very well made) and also realize they use broader simpler but still concise enough terminology, that'S really great to increase reach and be more 'approachable' because sometimes
regular everyday people on the street don't know all or have heard the mumbo jumbo jargon in biogerontology (they will think you are a pompous alien nerd - stuck up who thinks he knows more because
he was like a lab rat in his lab books studying aging; on top of that they will more Resentful towards you for Daring to Question their Life beliefs
on Life and Death by your '2-cents worth knowledge (couldn't give a f...)' on aging).
Also, they are careful to say, now, that intend to improve ill-health but as we know from epigenetic aging, these concepts can untangled and uncoupled;
and thus, remaining healthy would theoretically allow eternal life; but that is something epigenetic aging has answers that are more muddled and
less hopeful. I am fearing this part (epigenetic aging) is omething SENS should add as 8th therapy, very important.
''SENS Research Foundation's strategy to prevent and reverse age-related ill-health is to apply the principles of regenerative medicine to repair the damage of aging at the level where it occurs''
The damage that it will repair is the one that is causal in senenscence of DNA pathway (such x-ray radiation causing senescence) and
oncogenic activated senescence; but not of the type of replicative senescence (that's the domain of telomeres/telomerase/sub-telomeres and epigenetics)
and cellular replication/proliferation.
It may be that, most likely, 5 of the therapies will impact health to nullify many disease but will not change the 'aging' process (the one that is disconnected from telomeres but related with epigenetics) and 2 last therapies will be of intrinsic aging, of which one could end up not doing anything but remain a mitochondrial improvement manifesting as removal of mitopathies (such as MELAS) but would not alter the course of aging (such as the seperate epigenetic aging going on). I don'T want to put it down, it is already a major feat but we have to be Real.
I am bit scared by this truthfully, I had hoped it would be higher/more therapies but this is about what I had planned/guesses earlier (guessing is bad I know). But we have more than sufficient data
to see that the targets it aims have been mapped as to what they would do if they were removed/stopped.
Health improvement (allowing to post-pone/escape the diseases and thus live, healthier/disease-free longer, but not above human MLSP of around 122 years; thus these therapies do not affect epigenetic aging whatsoever, they are degenerative aging problems not regular healthy aging problem (except OncoSENS - only when you Already Have Cancer - which cancer increases epigenetic aging, but cancer removal thus does not change anything/makes no difference about what happens in the other cells/about what happens in the normal epigenetic 'aging' course in Normal non-cancerous healthy cells)
Although there is not such thing as 'healthy aging' all aging in 'unhealthy' (as seen from elders who are 'healthy enough' who show much damage), it's just 'tolerable/liveable' enough (in terms of damage accumulating) that it does not affect their quality of life (enough yet), that is 'healthy aging' :
ApoptoSENS - Clearing Senescent Cells (this will have great impact to reduce diseases, the largest one, since it's all inflammation fueled by the inflammation secretory phenotype (SASP) of these senescent cells)
AmyloSENS - Dissolving the Plaques (this will allow humans to evade Alzheimer's, Parkinsons and general brain degenerescence, allowing quite a boost; making people much more easily reach the big 100 - since the brain is causal to how long we live; keeping brain amyloid-free and keeping our memories/neuron sharp/means longer LongTerm Potentiation - means longer brain function means longer heavy brain mass (gray matter/white matter retention seen in 'sharp-witted' Centenarians who show are younger brain for their age), and both are correlated to MLSP). Also centenarian cardiac senyle amyloidosis (transthyretin) which kills supercentenarians from this plaque in their hearts, will be reduced by this therapy since it shares similar mechanism as amyloid and parkin(son).
GlycoSENS - Breaking Extracellular Crosslinks (this will allow also to slow aging quite a bit, not as much previously though, because crosslinks, though important (and others such AGEs who create them, Pentosidine, have strong correlation with aging; but it's most correlation not total causation; although to be honest they play a strong role. I would wager they play about 20-30% in impact (seen in diabetes AGEs and glucosepane formation; again this where this is very touching on the DNA damage role and seperating from the epigenetic role of aging; they can be uncoupled making these DNA damage elements muddled and less important than previously thought
(I'm only talking about healthy aging, not pathological aging (as in the diabetes, Diabetes will greatly improve by GlycoSENS. Healthy people will not feel the impact of effect as already diseased with diabetes people who are the major recipient of this health improvement gains since their health was bad already (and needed improvement)).
RepleniSENS - Replacing Lost Tissues (that has me puzzled, replacing tissues is great kind of like being a cybord, replacing parts...I guess this could be a way out somehow. If you replace (continously) every part and organ in our body, it would be akin to was is happening in Hydras or other replasticizing animals. It would technically allow eternal life, should we have infinite 'replacement parts'; the challenge is making sure all these 'parts' work together and we have the 'least' amount of 'repairing' going on to try to minimize 'excessive invasion of the body with 'Replacements'' and end up 'messing' things up (like a failed surgery procedure after than 100th one...there is this risk)
OncoSENS - Stopping Cancer at the Starting Line (That is Extremely impressive, it will save so many lives, nothing more to add; and, perhaps one more thing, it will slow epigenetic aging of Already cancer patients giving them hope to at least post pone it should it fail at eradicating it. )
MitoSENS - Preventing Mitochondrial Aging (I put here because the ultimate result of allotopic expression of 13 genes back will mostly affect mitochondrial matters, such mitopathologies (MELAS for example). Mitochondria are definately involved in intrinsic aging as they produce the element that keeps the cell alive - but some cells don'T have any mitochondrias (such a Red Blood Cells (Erythrocytes)) although that is a moot point. In mammals, mitochondrias are highly relevant and important points of ROS production. Diabetes creates early nephropathy and that is through mitochondrial super oxide production; as such, this again makes the whole mitochondrial controls aging more moot but is strong correlator for disease progression/pathogenesis by ROS overproduction.
In healthy aging, it's less clear, although studies showed that mitochondrial lipid perodixation as strong correlation with MLSP (in mammals) but it's not necessarily 100% causal but more correlative (studies said that mitochondrial membrane peroxidation contributes about 30% in intrinsic aging weight; not 100% itself alone. This means that if it is controlled it can have a dramatic impact in lifespan. MitoSENS won't alter membrane lipids but it will allow for remodulation to a better (prior) lipid composition; I don'T know how much that will impact in terms of lifespan, I am thinking it will be neutral and improve health not alter the metabolism that much (since that is what the membrane does through the lipids in it, for example DHA/EPA accelerate membrane kinetics and this in turn increases the organism metabolism)
Intrinsic aging :
MitoSENS - I put it here too because if they are capable of making Complexes Reassemble in mitochondrais it would allow ATP production anew (in diseases) and even in intrinsic aging; what will be the 'extent' of that in healthy people is less clear but will be less than it mitopathy-diseased people.
LysoSENS - I always believe in sole one (might be to hopeful with bacterial enzyme-filled nanorobots clearing lipofuscin) Reversing Heart Disease, not just heart disease, reverting the major age pigment accumulation problem - lipofuscin in lysosomes that is a major
cause of aging (by blocking the proteasome, blocking autophagy and mitophagy process (critical for cell survival).
And done forget we are almost at 71k for OncoSENS and there is 1 more day if anyone wants to be part of this research effort.
Next week I'll participate in an audition for a TV quiz show. If I pass the audition, go to the show and win the big prize (as of now, €1.8M and growing) I'll donate most of it to SENS!
These will be good to show to skeptical friends and family whose eyes tend to glaze over as soon as they encounter an unfamiliar biology noun when I try to explain the potential of rejuventation biotechnology to them.
I think in the future someone (not necessarily SENSRF) could make some cartoons explaining the differences between the three types of aging research and answers to the common objects such as overpopulation, why isn't good research being funded etc.
I noticed Aubrey semi regularly publishes some comments on recent papers/technologies in Rejuvenation Research. Maybe someone could make short cartoons about how these discoveries and technologies are relevant?
@ Antonio : Fantastico ! But what would already help a lot is that you wear a SENS t-shirt during the show :)
@Spede: Good idea! Anyway, at the beginning of the show they always ask what would you do with the money if you win.
@Jim: Something like this? https://en.wikipedia.org/wiki/File:Aneurysms.webm
@Antonio: If you get on the show, make sure to upload the episode to YouTube and share it around the Internet. This is a really cool opportunity, and I'd really like to see it! By the way, what game show is it?
Sure! It's this: https://en.wikipedia.org/wiki/Pasapalabra
Today I passed the audition :D I'll go to the show some day between October and Mars, I don't know the date yet. I'll try to get a MitoSENS T-shirt.
Woohoo ! I think I have one such t-shirt laying around but I'm not sure where I've put it. Any chances are it'd be too small for you. Anyway, keep us updated and we'll see what we can do for the t-shirt.
Thanks :) Anyway, I'll contact SRF first. Maybe there is some way to buy one.
Cool. That makes me think that maybe the SRF could make special edition t-shirts / sweaters for people promoting the foundation in large scale events.
Like, those clothes wouldn't available for buying either directly or through crowdfunding campaigns. The only way to get them is for the would-be wearer to be visible in front hundreds or thousands of people.
It'd be a nice reward for a nice effort.
I already contacted them. They have some spare mito t-shirts they can sell.
That special edition t-shirt would be a great idea for a fun run or other activity for raising funds!