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- Undoing Aging with Cellular Repair Therapies: an /r/futurology AMA with Aubrey de Grey on December 7th
- A High Level View of Progress in SENS Rejuvenation Research in Recent Years
- Does Blood Pressure Decrease in Late Life, and Why Would this Happen?
- mTOR and the Age-Related Decline in Stem Cell Activity
- Highlights from Yesterday's /r/futurology AMA with Aubrey de Grey
- George Church Discusses Gene Therapies as a Basis for Therapies to Control Aging
- Low Cost Biotechnologies can be Inconvenienced but not Halted by Regulators
- Another Study to Suggest that the Harms of Excess Fat Tissue are Understated
- Adrenomedullin is Involved in Age-Related Memory Loss
- Towards a Mass Production System for Liver Organoids
- ANGPTL2 Knockout Reduces Inflammation and Slows Muscle Loss in Mice
- Boosting Mitochondrial Function Reduces Plaque and Improves Cognitive Function in a Mouse Model of Alzheimer's Disease
- mTOR and Cellular Senescence
- Covalent Bioscience is One of the Current Crop of SENS Rejuvenation Biotechnology Startup Companies
- Increased Autophagy Improves Stem Cell Activity and Restores Bone Loss in Mice
Undoing Aging with Cellular Repair Therapies: an /r/futurology AMA with Aubrey de Grey on December 7th
Aubrey de Grey of the SENS Research Foundation will be answering your questions in the /r/futurology subreddit later this week, on Thursday December 7th 2017 at 2PM PST / 10PM GMT. There is a stickied post up now to collect questions in advance for the Ask Me Anything (AMA) post that will go up on Thursday, largely as a service for those who might not be able to be online at the time. For this audience, de Grey needs little introduction - he has spent the last fifteen years energetically pushing the research community into paying greater attention to the most plausible, high-value lines of development likely to result in rejuvenation therapies. It is hard to overstate just how influential de Grey and his allies have been in changing the culture of the research community over this time, and in raising the odds of functional rejuvenation therapies coming to pass soon enough to matter to you and I.
So, if you have things you'd like to know regarding the progress of the past couple of years, and the ventures being lined up for the next couple of years, then this is your chance. As matters are moving into the realm of startup companies and other for-profit development in a number of areas relevant to SENS rejuvenation research, the current state of progress can become harder to follow. Biotech startups tend to be much less noisy about their work in comparison to research groups, at least for the first few years, something that is typically forced upon them by regulatory concerns.
On the topic of the work of the de Grey and the SENS Research Foundation, I thought I'd point out a couple of items published online recently. The first detail-free article results from one of de Grey's numerous conference appearances, this one being the latest Virtual Futures event, and demonstrates that the logical consequences of functional rejuvenation technologies continue to make an attractive lure for the publicity industry. If the research and medical communities can move at a sufficient pace in improving the outcome of rejuvenation therapies over time, then even if the first rejuvenation therapies are comparatively poor, the end result is people who live in good health for a very, very long time. The second item is an extended version of the article by de Grey published at the MIT Technology Review recently, and is worth reading even if you're quite familiar with the SENS vision for rejuvenation through repair of cell and tissue damage.
Why This Aging Expert Thinks First 1,000-Year-Old Person is Already Alive
Through his foundation, de Grey is working to solve seven types of aging damage that he believes are the key to a breakthrough. These are tissue atrophy, cancerous cells, mitochondrial mutations, death-resistant cells, extracellular matrix stiffening, extracellular aggregates, and intracellular aggregates. It may sound like a complex salad of jargon, but de Grey claims that because science has an understanding of how to fix all these damages, aging can end for good. "It unequivocally causes far more suffering than anything else that we have to experience, and contrary to the impression that most of humanity has forced itself into, it's indeed a problem which is amenable through technological intervention."
In the future, de Grey imagines humans will develop rejuvenation clinics to regularly combat these seven issues and send people on their way. These clinics may stay in the realm of the super-rich for a short time, but de Grey believes that a movement will very quickly form to bring these technologies to the general public. "It will become impossible to get elected unless you have a manifesto commitment to have a real war on ageing. Not only in getting the therapy developed as quickly as possible, but also putting in place the infrastructure."
Undoing Aging with Molecular and Cellular Damage Repair
The goal of bringing aging under comprehensive medical control is probably humanity's oldest dream - and it is certainly humanity's foremost problem today. However, our progress toward it is lamentably slight. The history of our attempts to control aging can be summarized as a sequence of mis-steps: of misguided approaches that never had a chance of succeeding. They can each be summarized in a single word: disease, design, and deprivation. And the worst of it is that they have not even been sequential: the earlier ones have survived the arrival of the later ones.
The "aging as disease" false dawn, otherwise known as geriatric medicine, rests on the assumption that the diseases of old age are inherently amenable to the same kind of medical assault as the most prevalent diseases of youth, that is, infections. They are not. The "aging as design" false dawn emerged a century or so ago with the proposal that aging serves an evolutionary purpose. It gave rise in the early twentieth century to an approach that relies upon the idea that the genes determining the variation between species are rather few in number, and thus that it is realistic to seek to tweak those of a given species (such as Homo sapiens) so as to extend its healthy lifespan. Does the "aging as design" basis for the pursuit of medical postponement of age-related ill health actually make sense? Is it even remotely compatible with what we know about aging? Again, the painfully obvious answer is no. And yet, just as with geriatric medicine, faith in the existence of some elusive "magic bullet" has persisted in the minds of a depressing number of biologists.
By the third false dawn of "deprivation" I refer, as I hope you have guessed, to calorie restriction (CR), an intervention that was shown as early as the 1930s to extend the lives of mice and rats by as much as fifty percent. To this day, biomedical gerontology research is hugely dominated by the quest for better ways to emulate the effect of calorie restriction by genetic - or, more recently, pharmacological - means. Why is this a third false dawn? Because its true biomedical potential is, and has long been, obviously almost nil. The performance of CR itself varies inversely with the non-CR longevity of the species: longer-lived species derive much less benefit as a proportion of their lifespan, and in fact not much more benefit in absolute time. This should have been expected, since the selective pressure giving rise to the pathways that mediate the response to CR arises from the frequency of famines, which is independent of the lifespan of the organisms experiencing those famines.
But this century, step by painfully small step, things are changing. I first introduced the rejuvenation biotechnology approach to combating aging called SENS, the "Strategies for Engineered Negligible Senescence", about fifteen years ago. Since first proposed in 2002, marked progress has been made in every relevant area of research. SENS is a hugely radical departure from prior themes of biomedical gerontology, involving the bona fide reversal of aging rather than its mere retardation. By virtue of a painstaking process of mutual education between the fields of biogerontology and regenerative medicine, it has now risen to the status of an acknowledged viable option for the eventual medical control of aging. I believe that its credibility will continue to rise as the underlying technology of regenerative medicine progresses.
A High Level View of Progress in SENS Rejuvenation Research in Recent Years
The Life Extension Advocacy Foundation folk have put together a compact summary of some of the progress towards SENS rejuvenation therapies that has taken place in recent years. These treatments, some existing in prototype forms, and some yet to be constructed, are based on repair of the forms of cell and tissue damage known to cause aging. It is a good article to show to a friend who has expressed interest in greater human longevity, or to mine for talking points to use when you next bring up the topic with those unfamiliar with the current state of the science. You might also compare it with my bullet point list of the high points in SENS advocacy, research, and fundraising over the past fifteen years.
Efforts to explain the history and progress to date of SENS rejuvenation research are useful and necessary. The SENS Research Foundation does a good job in summarizing the causes of aging and the research programs that will tackle each cause. The staff also do a good job in listing and explaining the work they carry out year by year, funded by philanthropic donations, in their annual reports. They don't however, tend to publish much that links all of the stories together, to show the scope of progress over the lifetime of the SENS programs, and the positive changes that SENS researchers and advocates have created in the culture of aging research. Fortunately, we can do that, and I think that we must do that: this is some of the most convincing evidence to show that it is all worth it, that the wheel is turning, and that we are much further ahead than we were a decade ago.
Science moves very slowly. It usually takes years for the results of fundraisers and advocacy to bear fruit, and so in this age of instant gratification, it is necessary to show those who are new to SENS that this isn't just another flash in the pan - that present efforts are part of a long upward curve towards the technologies of human longevity, and that past efforts have resulted in success. The dots have to be joined to show that the radical change in the attitudes of the research community with respect to treating aging as a medical condition didn't just happen on its own, that young companies advancing potential rejuvenation biotechnologies didn't just materialize out of nothing. A great deal of work went into these changes, both inside and outside the laboratory, and a sizable fraction of that work was carried out by the SENS Research Foundation and allies such as the Methuselah Foundation.
SENS Research: Progress in the Fight Against Age-related Diseases
Today, there are many drugs and therapies that we take for granted. However, we should not forget that what is common and easily accessible today didn't just magically appear out of thin air; rather, at some point, it used to be an unclear subject of study on which "more research was needed", and even earlier, it was just a conjecture in some researcher's head. Hopefully, one day not too far into the future, rejuvenation biotechnologies will be normal and widespread as aspirin is today, but right now, we're in the R&D phase, so we should be patient and remind ourselves that the fact we can't rejuvenate people today doesn't mean nothing is being done or that nothing has been achieved to that end. On the contrary, we are witnessing exciting progress in basic research - the fundamental building blocks without which rejuvenation, or any new technology at all, would stay a conjecture.
A mitochondrion is a component of the cell in charge of converting food nutrients into ATP, a chemical that powers cellular function. Each mitochondrion is equipped with its own DNA. Mitochondria with damaged DNA may become unable to produce ATP or even produce large amounts of waste that cells cannot get rid of. To add insult to injury, mutant mitochondria have a tendency to outlive normal ones and take over the cells they reside in, turning them into waste production facilities that increase oxidative stress - one of the driving factors of aging.
Cell nuclei are far less exposed to oxidative stress than mitochondria, which makes nuclear DNA less susceptible to mutations. For this reason, the cell nucleus would be a much better place for mitochondrial genes, and in fact, evolution has driven around 1000 of them there. Through a technique called allotopic expression, we could migrate the remaining genes to the nucleus and solve the problem of mitochondrial mutations. The SENS Research Foundation (SRF) team managed to achieve stable allotopic expression of two mitochondrial genes in cell culture. As Aubrey de Grey explains, of the 13 genes SRF is focusing on, it's now managed to migrate almost four. This had never been done before and is a huge step towards addressing this aspect of aging in humans. In the past few months, the SRF team has presented its results around the world and worked on some problems encountered in the project.
Lysosomes are digestive organelles within cells that dispose of intracellular garbage - harmful byproducts that would otherwise harm cells. Enzymes within lysosomes can dispose of most of the waste that normally accumulates within cells, but some types of waste, collectively known as lipofuscin, turn out to be impossible to break down. As a result, this waste accumulates within the lysosomes, eventually making it harder for them to degrade even other types of waste.
As normal lysosomal enzymes cannot break down lipofuscin, a possible therapy could equip lysosomes with better enzymes that can do the job. The approach suggested by SRF originates with ERT - enzyme replacement therapy - for lysosomal storage diseases. This involves identifying enzymes capable of breaking down different types of intracellular junk, identifying genes that encode for these enzymes, and finally delivering the enzyme in different ways, depending on the tissues and cell types involved.
SRF funded a preliminary research project on lipofuscin clearance therapeutics and another project relating to atherosclerosis and the clearance of 7-ketocholesterol (found in lipofuscin), which eventually spun into human.bio, an early-stage private startup. Another SRF-based approach is currently being pursued by Ichor Therapeutics, where the staff are working on an ERT treatment for age-related macular degeneration. The treatment consists of providing an enzyme capable of breaking down a type of intracellular waste known as A2E. The company earlier this year announced a series A offering to start Phase I clinical trials of its product.
As cells divide, their telomeres - the end-parts of chromosomes protecting them from damage - shorten. Once a critical length has been reached, cells stop dividing altogether and enter a state known as senescence. Senescent cells are known to secrete a cocktail of chemicals called SASP (Senescence Associated Secretory Phenotype), which promotes inflammation and is associated with several age-related conditions. Normally, senescent cells destroy themselves, but some of them manage to escape destruction. The result is that late in life, senescent cells have accumulated to unhealthy amounts and significantly contribute to the development of age-related diseases.
The proposed SENS solution is straightforward: if senescent cells become too numerous, then they need to be purged. Since they are useful in small amounts, the optimal solution would be periodically removing excess senescent cells. This could potentially be achieved by either senolytic drugs or gene therapies that selectively target senescent cells. SRF has funded a number of studies on the subject of cellular senescence, and it's recently begun working on a project in collaboration with the Buck Institute for Research on Aging, which is focusing on the immune system and its role in clearing senescent cells. Another extramural project, again with the Buck Institute, is focused on SASP inhibition. Further, in conjunction with Methuselah Foundation, SRF provided seed funding for Oisin Biotechnologies, a company working on a gene therapy approach to destroying senescent cells.
The extracellular matrix is a collection of proteins that act as scaffolding for the cells in our body. The component parts of this scaffolding eventually end up being improperly linked to each other through a process called glycation. The resulting cross-links impair the function and movement of the linked proteins, ultimately stiffening the extracellular matrix, which makes organs and blood vessels more rigid. Eventually, this leads to high blood pressure, loss of skin elasticity, and organ damage, among other problems.
In order to eliminate unwanted cross-links, the SENS approach proposes to develop molecules that sever the linkages and return tissues to their original flexibility. In order to do this, cross-link molecules need to be available to researchers attempting to combat them with drugs, and especially in the case of glucosepane, this has been a problem for years. The lack of tools to work with glucosepane has been greatly hampering the progress of cross-link breaking research, but thankfully, this problem is now solved thanks to a collaboration between the Spiegel Lab at Yale University and the SENS Research Foundation, which supported the study financially. It is now possible to fully synthesize glucosepane, allowing for researchers to create it on demand and at a cost-effective price. The Spiegel Lab's scientists are now developing anti-glucosepane monoclonal antibodies to cleave unwanted cross-links.
Does Blood Pressure Decrease in Late Life, and Why Would this Happen?
Blood pressure tends to increase with age, ultimately producing clinical hypertension in a sizable fraction of the population. This is driven by the progressive stiffening of blood vessels, which breaks the finely tuned feedback system that reacts to and controls blood pressure. Stiffening of blood vessels is in turn caused by factors such as calcification and inflammation resulting from cellular senescence, as well as cross-linking in the extracellular matrix that degrades tissue elasticity, and dysfunction of the muscle tissue that controls contraction and dilation of blood vessels. Control of blood pressure is considered highly important in modern medicine, and raised blood pressure is one of the most important factors determining risk of cardiovascular disease and mortality.
Given the justifiable focus on high blood pressure and its consequences, it is interesting to note that there is evidence for blood pressure in the population at large to peak and then drop in later life. As the paper here notes, the simple hypotheses for this phenomenon, such as that people with high blood pressure tend to die at a greater rate before reaching older ages, don't in fact explain enough of the phenomenon. My first guess at a mechanism was weight loss in later life due to frailty and pre-clinical levels of age-related disease, but that also doesn't seem to be enough to explain all of the effect.
A second guess might involve the effects of age-related muscle loss, sarcopenia, on the strength of the heart. This is something that doesn't appear to be all that well studied in older individuals without heart disease, and isn't commented on in the paper here. Unfortunately it isn't a straightforward relationship, given all of the ongoing changes in the cardiovascular system; older patients with either healthy hearts or hearts weakened by heart failure can exhibit higher blood pressure, lower blood pressure, or anything in between depending on their specific circumstances.
Blood Pressure Begins to Decline 14 Years Before Death, Study Says
Researchers looked at the electronic medical records of 46,634 British citizens who had died at age 60 or older. The large sample size included people who were healthy as well as those who had conditions such as heart disease or dementia. They found blood pressure declines were steepest in patients with dementia, heart failure, late-in-life weight loss, and those who had high blood pressure to begin with. But long-term declines also occurred without the presence of any of these diagnoses.
Doctors have long known that in the average person, blood pressure rises from childhood to middle age. But normal blood pressure in the elderly has been less certain. Some studies have indicated that blood pressure might drop in older patients and treatment for hypertension has been hypothesized as explaining late-life lower blood pressures. But this study found blood pressure declines were also present in those without hypertension diagnoses or anti-hypertension medication prescriptions. Further, the evidence was clear that the declines were not due simply to the early deaths of people with high blood pressure.
Blood Pressure Trajectories in the 20 Years Before Death
Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) follow progressive upward trajectories from childhood to middle age, but blood pressure (BP) trends at older ages are unclear. Several studies reported flattening of the upward trend or a decrease in BP at advanced ages, although a few have reported continued BP increases. Blood pressure decreases in older age have been associated with poorer health, onset of dementia, and excess mortality. Hypothesized explanations for BP decreases in later life include (1) advancing age; (2) increasing end-of-life disease, especially heart failure, suggesting a link to the years before death rather than to age; (3) more intensive use of antihypertensive medications; or (4) that excess mortality of hypertensive individuals leaves healthy survivors with lower BP. Data to test these hypotheses are currently limited.
Observing individuals with multiple repeated BP measures over time could help clarify the causes underlying trends. If increasing end-of-life disease explains BP changes, then similar downward BP trajectories should not be observed in age- and sex-matched controls who die much later. In this study, we used the Clinical Practice Research Datalink (CPRD) to estimate clinically measured SBP and DBP trajectories for 20 years prior to death, for individuals dying at 60 years and older. Second, we compared the linear SBP trends for years 10 to 3 years before death in patients who died and age- and sex-matched controls who survived at least 9 years. These approaches aimed to separate age from end-of-life associations, and avoid healthy survivor biases.
Twenty years before death, estimated mean SBPs increased with increasing age at death (60-69 years, 139.5 mm Hg; ≥90 years, 150.0 mm Hg). All age-at-death groups initially experienced increasing SBP, reaching peak values and then declining with proximity to death. Peak SBPs occurred 14 years before death in those dying aged 60 to 69 years (mean peak SBP, 146.3 mm Hg) to 18 years before death for those dying aged at least 90 years (mean peak SBP, 150.8 mm Hg). Overall, 64.0% of individuals experienced SBP decrease of more than 10 mm Hg following the peak.
Antihypertensive medication was prescribed to 85.1% of patients for at least 1 year during the analysis period: mean SBP changed by -20.8 mm Hg from peak to year of death in those treated vs -11.2 mm Hg in those not treated. Peak SBP occurred at a mean of 15 years before death in the treated vs 14 years in those not treated. Adjustment for antihypertensive treatment made little difference to the main model results. Smoking status, alcohol consumption, and levels of physical activity measured in the 20 years prior to death had little association with SBP decreases. Weight loss (the difference between the maximum weight during the first 10 years of follow-up and weight in the final year) findings showed that patients losing at least 20 kg experienced a bigger absolute SBP decrease (mean, -24.87 mm Hg) compared with those who did not lose weight.
More work is needed to elucidate the specific mechanisms involved in late-life BP dynamics. Such studies may also be useful in addressing ways of optimizing the clinical care of older patients who experience decreasing BP. Also, downward BP trajectories before death have the potential to introduce reverse causation or "reverse epidemiology" effects in risk analyses, yielding misleading associations between BP and outcomes in older patients.
mTOR and the Age-Related Decline in Stem Cell Activity
As a companion piece to an earlier post on the relationship between the mechanistic target of rapamycin (mTOR) gene and cellular senescence in aging, you might take a look at the research here that investigates the relationship between mTOR and the characteristic decline in stem cell activity that occurs with advancing age. In addition to the large body of research focused on insulin and growth hormone metabolism, work on mTOR is among the most active areas of study resulting from investigations of calorie restriction. The practice of calorie restriction has been shown to slow aging in near all species and lineages studied to date, so insofar as the response to calorie restriction is partially mediated through mTOR, we should expect mTOR to have some connection to most of the causes of aging.
Unfortunately, calorie restriction has only a small effect on life span in our species. The research community doesn't yet know exactly how small, but it would be very surprising for it to be greater than five years or so. It would be hard for an effect much larger than that to remain hidden over the length of human history. The health effects are worth it in all other respects; calorie restriction greatly reduces the risk of age-related disease in our species, just as in others. Why are the effects on longevity so much less in humans than in mice? The response to calorie restriction most likely evolved because it grants a greater chance of survival through seasonal famine. The famine is the same length regardless of species, and thus short-lived species evolve under selection pressure to develop a proportionally greater extension of life span, while longer-lived species do not. The result is mice that live 40% longer if they eat less, and humans that do not.
Stem cells of many varied types are responsible for maintaining our tissues in good condition. Their activity declines with age, however, due to some combination of (a) intrinsic damage of the sort listed in the SENS view of aging, and (b) reactions to rising levels of damage elsewhere. It is thought that stem cells become less active with age because this acts to reduce the risk of cancer; the more cells that replicate, the greater the risk that one of those cells acquires mutations that lead to a tumor. That risk rises as the damage of aging grows, as the environment becomes more inflamed and dysfunctional, and the immune system, responsible for destroying potentially cancerous cells, falters. Our life span, longer than that of other primates, came to its present position by balancing the slow decline due to failing tissue maintenance against the fast end due to cancerous growth.
In calorie restricted individuals, the decline in stem cell activity tends to be a little bit slower. So if this effect is in part mediated by mTOR, what exactly is going on under the hood? It is a complex business, trying to reverse engineer the operation of metabolism. Even when it is possible to identify lynchpin genes, such as mTOR, it usually turns out that they are influential in dozens of important low-level cellular operations that can in turn slightly speed or slow the aging process in any number of ways. That just means it is challenging work, however. I think my greater objection to putting such a large focus on this way forward towards potential therapies to treat aging is that, based on what is known of calorie restriction, we shouldn't expect the results in mice to in any way translate to similarly sized results in humans. The effects should be analogous to one another, but in humans the size of those effects will be small.
Inhibiting TOR boosts regenerative potential of adult tissues
In most of our tissues, adult stem cells hang out in a quiet state - ready to be activated in case of infection or injury. In response to such injury, however, stem cells have to be able to rapidly divide, to generate daughter cells that differentiate into cells that repair the tissue. Previous research showed that TOR needs to be maintained at a low level in order to preserve stem cells in a quiet state and prevent their differentiation. But in this study, researchers discovered that TOR signaling becomes activated in many stem cell types when they are engaged in a regenerative response.
This activation is important for rapid tissue repair, but at the same time it also increases the probability that stem cells will differentiate, thus losing their stem cell status. This loss - in this case in the fly intestine, mouse muscle and mouse trachea - is particularly prevalent when the tissue is under heavy or chronic pressure to regenerate, which occurs in response to infections or other trauma to the tissue. During aging, repeated or chronic activation of TOR signaling contributes to the gradual loss of stem cells. Accordingly, by performing genetic or pharmacological interventions to limit TOR activity chronically, the researchers were able to prevent or reverse stem cell loss in tracheae and muscle of aging mice.
Mice were put on differing regimens of the mTOR inhibitor rapamycin starting at different stages of life. Rapamycin was able to rescue stem cells even when given to mice starting at 15 months of age - the human equivalent of 50 years of age. "In every case we saw a decline in the number of stem cells, and rapamycin would bring it back." Whether this recovery of tissue stem cell numbers is due to a replenishment of the stem cell pool from more differentiated cells, or due to an increase in "asymmetric" stem cell divisions that allow one stem cell to generate two new ones, remains to be answered.
mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance
The balance between self-renewal and differentiation ensures long-term maintenance of stem cell (SC) pools in regenerating epithelial tissues. This balance is challenged during periods of high regenerative pressure and is often compromised in aged animals. Here, we show that target of rapamycin (TOR) signaling is a key regulator of SC loss during repeated regenerative episodes. In response to regenerative stimuli, SCs in the intestinal epithelium of the fly and in the tracheal epithelium of mice exhibit transient activation of TOR signaling.
Although this activation is required for SCs to rapidly proliferate in response to damage, repeated rounds of damage lead to SC loss. Consistently, age-related SC loss in the mouse trachea and in muscle can be prevented by pharmacologic or genetic inhibition, respectively, of mammalian target of rapamycin complex 1 (mTORC1) signaling. These findings highlight an evolutionarily conserved role of TOR signaling in SC function and identify repeated rounds of mTORC1 activation as a driver of age-related SC decline.
Highlights from Yesterday's /r/futurology AMA with Aubrey de Grey
Aubrey de Grey of the SENS Research Foundation took a few hours from his packed schedule yesterday to answer questions from the community at /r/futurology. It is a pity that we can't get a full day of his time at some point - clearly there are way too many interested folk with questions and not enough hours to answer more than half of them. It is a sign of progress, I hope, that ever more people recognize that the SENS approach to the development of rejuvenation therapies is promising, and understand enough of the science to ask intelligent questions about the details.
SENS is simple enough to explain at the high level: identify the cell and tissue damage that (a) appears in old tissues but not in young tissues, and (b) is caused by the normal operation of metabolism, not by some other form of damage. The resulting short list includes the causes of aging. It may include some other things as well, that in the end turn out not to need fixing, but why take the chance? In modern biotechnology and life science research, it is faster and cheaper to develop a repair therapy and see what happens than it is to painstakingly figure out how everything fits together.
When de Grey first evaluated the field of aging research, back before the turn of the century, he found that the causes of aging by the above definition were largely known, with a good deal of evidence in support of each one. Yet next to no-one was working on fixing them. Since then, he has campaigned tirelessly to build organisations, assemble allies, raise funding, and persuade researchers, and all of that to ensure that the scientific and biotechnology communities do in fact move ahead with a repair-based approach to building functional rejuvenation therapies. It has been surprisingly hard work, given a research community that was hostile towards the idea of treating aging as a medical condition versus merely observing it, and a public at large who seem disinterested in living longer in good health. Nonetheless, here we are today, on the verge of the first rejuvenation therapies making it into the clinic, and with a growing number of research, investment, and business interests showing great interest in treating aging.
Aubrey de Grey, AMA, December 7th at /r/futurology
I've noticed in the last year you seem a lot more optimistic about the timeline.
I wouldn't say a LOT, but yeah, it's been a good year. Basically just the cumulative progress, both on the science and on the public attitude and funding stream. I'm still cautious, because for sure we are still really struggling for funds, but I'm hopeful.
If you were to find all the funding you'd ever need, how long until you make major breakthroughs in all 7 areas and essentially completely remove aging?
50% chance: 20 years.
What do you think were the biggest wins of the last couple of years in SENS-relevant advocacy, research, and development? What has moved the needle?
There have been lots. On the research I would highlight our paper in Science two years ago showing how to synthesize glucosepane and our paper in Nucleic Acids Research one year ago showing simultaneous allotopic expression of two of the 13 mitochondrial genes. Both those projects have greatly accelerated in the meantime as a result of those key enabling breakthroughs; watch this space. On advocacy I think the main win has been the arrival of private capital; I would especially highlight Jim Mellon and his Juvenescence initiative, because he is not only a successful and energetic and visionary investor, he is also a highly vocal giver of investment advice.
Can give your thoughts on Mark Zuckerberg's plan to "cure all diseases" within his child's lifetime? I suspect there's a lot you could talk about regarding that.
Mark is (as far as I can tell) not well-informed about this area. Unlike Page and Brin, who were quite assiduous more than a decade ago in educating themselves on matters technovisionary including medical (I first met them both in that era), Zuckerberg seems to be reluctant to reach out to those who actually know stuff. Anyone who can get me an hour of his time, you could save a lot of lives.
Is there anything new you are able to say about the breaking of cross-links in the extracellular matrix?
Absolutely. Short story, we now have a bunch of glucosepane-breaking enzymes, and we are within a few months of spinning the work out into a startup.
The SENS strategy to migrate mitochondrial DNA (mtDNA) into the nucleus seems to be preventive engineering approach rather than a maintenance approach. In light of new techniques like killing senescent cells, why wouldn't killing off cells that have given in to mutant mitochondria make more sense?
Great question - see my early papers on the subject. Basically the issue is that the majority of mutant mtDNA in an aged body is in muscle fibres, which do not get completely taken over, only segments a millimeter or so long, so we would do much more harm than good if we zapped the whole fibre.
RepleniSENS describes the thymus rejuvenation project. How does this approach compare to directly injecting stem cells into the recipient's thymus?
Actually we have discontinued that work, mostly because we were basically overtaken. A raft of approaches seem to be working: our approach of building a new one, or growth factors to regrow the old one, or even tricks to repopulate the T cell pool by proliferation in the periphery (i.e. without a thymus).
Some researchers attempt to eliminate mutated mitochondrial genomes from the cell. Would you reckon these approaches have a chance of success?
The work you referenced is terrific, but it is intrinsically limited to mitochondriopathies that are caused by inherited, single mutations, whereas in aging we have different ones in different cells. There are some ideas out there for tipping (reversing) the selective advantage enjoyed by mutant mtDNA without being sequence-specific, but they are not all that promising yet.
Once we have an efficient senolytic drug and we can get rid of a significant number of senescent cells in the body, do we also have to clear the senescence associated secretory phenotype (SASP) that has been secreted over the years or is it something that the metabolism can naturally get rid of?
The latter. The SASP molecules have a short half-life.
Aside from funding, what do you consider to be a burden or delay for your type of research?
Nothing. Seriously, nothing at all. We have the plan and we have the people. It's all about enabling those people, giving them the resources to get on with the job.
How come the epigenetic changes and changes to our microbiome that accumulate with age are not a part of the categories of damage? When do you predict that rejuvenation approach as a solution to the problem of aging will become accepted by clear majority of scientists?
The microbiome is basically a highly dynamic population of cells, hence it is virtually certain to become right on its own when we fix everything else (even assuming that there is anything suboptimal about it in old age in the first place). For epigenetic changes, this is also the case if you mean coordinated ones that happen across all cells of a given type. If you mean drift, i.e. epimutations, my explanation for that is protagonistic pleiotropy (see my 2007 paper with that title). Rejuvenation is already accepted as a solution by most scientists, and it is being reinvented by other people. See for example the 2013 "Hallmarks of aging" paper.
How confident are you still in your previous prediction that humans will be able to control aging by 2029?
I think we've slipped a few years, entirely because of lack of funding. The tipping point will be when results in mice convince a critical mass of my curmudgeonly, reputation-protecting expert colleagues that rejuvenation will eventually work, such that they start to feel able to say so publicly. I think that's on the order of five years away.
Given current funding, how far away from robust mouse rejuvenation do you think you are?
My estimate is 5-7 years, but that's not quite "given current funding". My overoptimism in saying "10 years" 13 years ago consisted entirely of overoptimism about funding - the science itself has not thrown up any nasty surprises whatsoever - but nonetheless I am quite optimistic as of now about funding, simply because the progress we have made has led to a whole new world of startups (including spinouts from the SENS Research Foundation) and investors, so it's not only philanthropy any more. Plus, the increase in overall credibility of the approach is also helping to nurture the philanthropic side. We are still struggling, that's for sure, but I'm feeling a lot surer that the funding drought's days are numbered than I felt even two or three years ago.
It was some time ago that you guys published your paper on inserting the enzyme into white blood cells to help them break down 7-ketocholesterol, I know a company was spun out not to long after that. Are they making good progress?
Actually, of all our (so far five) spinouts, that's the one that has rather lost its way. We are working to reboot that work and get it moving more promisingly. A lot of the problem was that it was bankrolled by one wealthy person, so that (rather like Calico) it had no incentive to let the world (or even me) know what it was doing.
When would you guess that we will have the first, direct evidence of human rejuvenation through removal of senescent cells (also considering self-experimenting individuals, which could get there first)?
To start at the end: if it works, the first evidence will indeed quite probably be from self-experimentation. Of course it will be n=1 so it will be very provisional evidence, but you knew that. So, when? - that mostly depend on the extent to which humans reproduce what has been seen in rodents, where the benefits of removing senescent cells were a lot broader than I (or anyone, I think) would have anticipated. We just don't know.
You have recently accepted a position as Vice-President of New Technology Discovery at BioTime Subsidiary AgeX Therapeutics. Can you give an overview of why you accepted this position and how it affects your current work at SENS?
I'm still defining my role there, but it is a big deal. I am there 30% so my primary affiliation remains SENS Research Foundation. But the emergence of the private-sector component of the rejuvenation biotech effort is a hugely important recent advance, and for me to have an official foot in both camps makes a strong statement. Also, it is a huge thing for me to be finally working closely with Mike West, who has been a hero of mine for 20 years. The two roles will certainly dovetail a lot: at AgeX my basic task is to come up with new therapeutic ideas, and naturally that will feed off what we are doing and have done at SRF.
Given that cells can reverse their age through induced pluripotency, do you see this as a viable strategy for reversing aging in humans, or is it too difficult and dangerous to do in vivo?
As of now it's definitely dangerous in terms of its carcinogenicity. However, we may be able to reduce that soon. I am particularly excited by the recent work of the awesome researcher Vera Gorbunova on the difficulty of dedifferentiating cells from naked mole rats; I suspect that that work may uncover ways to be more selective and controlled with in vivo dedifferentiation.
Has your position on the relative importance of the stem cell side of aging changed over the years? I know that in earlier years I was somewhat convinced that stem cell decline was fairly secondary to other parts of SENS.
It very much remains to be seen. In some tissues, like the substantia nigra where cell loss causes Parkinson's disease, I'm pretty sure we will indeed need stem cell therapy. In other places, the failure of stem cells to maintain their numbers and/or their proliferative vigour seems to be quite largely determined by the systemic environment, i.e. by what is and is not present in the circulation, and there I agree that recovery is quite likely to be largely spontaneous once we fix other stuff.
It seems likely that artificial intelligence will be a necessary tool in order to reach longevity escape velocity. I was wondering how much of a role does artificial intelligence play in your research? Is this something you devote many resources to?
We don't, but that is because other major players in this field (and good friends of mine), such as Alex Zhavoronkov and Kristen Fortney, are doing it so well already (with Insilico Medicine and BioAge respectively). They are both awesome and massively committed crusaders for this mission. Check out the BioData West conference that will occur in San Francisco a couple of days before our Undoing Aging conference in Berlin; I will be chairing a session on this.
With the recent departure of Calico's Head of R&D for GSK, do you think that there is a chance that Calico might now redirect its efforts in a more productive direction?
No. A good approximation to how Calico operates is as two entities: one that is essentially Genentech 2.0, setting itself up to make massive money from big deals with other traditional pharma, and one that is to pursue its actual remit, namely to defeat aging. Barron was squarely on the former side. The latter side is led by David Botstein, who is as pure a basic scientist as they come and has no time whatsoever for "dreamers" who think we might actually know enough already to be able to develop therapies. His philosophy is unfortunately permanent: no amount of progress will make him become translational and cease to be 100% discovery-focused. I don't remotely blame him - he is who he is. I only slightly blame Levinson: there was nothing wrong with hiring a chief science officer to do discovery, the only thing he got wrong was not also to hire a chief technology officer (me, obviously) alongside him. The people who have all the blame are Larry and Sergey, for allowing their billions to be wasted like this and not having the guts to step in and impose a change of direction.
Given that it's such an emotionally charged field how do you personally, and SENS in general, remain objective and keep hope from interfering with your work?
That's not so hard as you might think. Ultimately, we are driven by the desire to increase the chance of success, or equivalently to reduce the likely time until success - but from what to what is secondary. If we hasten the defeat of aging by a year, who cares whether it's from 2050 to 2049 or from 2030 to 2029? - it's still 40 million lives.
You have been wrong in the past with your expectation of peoples willingness to get onto this idea. Thus I can easily see a path where this technology is proven enough to be clearly happening but most people just don't care and the funding is still very hard to come by. Have you given much thought to this potential scenario?
You're right that I was overoptimistic in the past about the willingness of other high net worth individuals to follow in the wake of Peter Thiel, who started funding us in 2006. However, when it comes to support from scientists, I have never made such a mistake - I always knew it would take robust mouse rejuvenation. I have the advantage in that regard that the community in question is just the most credentialed, authoritative biogerontologists - no one else. Thus, they are (a) really few in number (truly, we are talking about something like a dozen people), (b) scientists (hence I know how they think, unlike billionaires) and (c) people I know well, personally. So I have very strong confidence regarding what determines what they say publicly.
Many wealthy celebrities and smart individuals can easily afford to invest into SENS. How come they are not?
Everyone has rationalisations. The key thing to remember is that humanity has been hoping against hope for a cure for aging since the dawn of civilisation, and it has been suckered time and time again into believing we had one, so there is a rather strong incentive not to get hopes up. And if something is impossible, its desirability is irrelevant: there is still no basis for funding it. So it falls to the small minority of wealthy people who are also truly independent-minded to support this work. Yes, people like Elon Musk may well feel rather ashamed a decade or two from now that they didn't do more earlier. But we're working on it.
How do you feel about the impact of groups like LEAF advocating and reporting on rejuvenation biotech? Has the advocacy and reporting of these groups made your life any easier?
Massively! A huge thing that I say all the time is that advocacy is one thing that absolutely relies upon diversity of messenger. Different people listen to different forms of words, different styles of messaging, etc. The more the better.
George Church Discusses Gene Therapies as a Basis for Therapies to Control Aging
George Church is one of the more noteworthy business-oriented scientists whose work touches on aging and longevity science. He is involved in a number of different companies, and while his primary focus is genetics, his interests include tissue engineering, farming engineered pigs for xenotransplantation, and a range of other items. Just about everyone of note in the scientific community has a different view on aging: the theory, the plausibility of various endeavors, and how best to go about tackling it as a medical challenge. This interview illuminates a little more of Church's viewpoint, which is, as one might expect, quite focused on using gene therapies as the primary tool for delivery of therapeutic effects. In principle, though not yet in reality, a gene therapy can do everything a drug can, more effectively and more accurately. There is a little way to go yet in generating the necessary methodologies and a reliable technology platform, probably built atop CRISPR.
Is there an accepted causal or ultimate theory of aging? There are hypotheses and different schools of thought. It's not so mature that there's total consensus. There are relatively few exciting fields of biology where there's total consensus. In aging, there's a school of thought that it's all about damage and you have to repair that damage. There's another school it's all about regulation and epigenetics, and if you get the cell in the right epigenetic state then it can repair its own damage; a young cell is much more powerful at repair than an old cell.
Then there's hallmarks of aging - about nine components - and maybe you have to get all of them pushed back for rejuvenation. I like this version where they talk about specific biological mechanisms. If you fight or leverage those mechanisms you get your best shot at treating aging. Why we age is less useful than the mechanisms, but having some intuition for why the mechanisms are the way they are can help you manipulate them. And very often you want to manipulate them in an unnatural way, and that requires a deeper understanding. If you're trying to do something totally natural your protocol is clear. If you find that in the western world we're eating a lot of marbled cow that didn't exist in the ancient days, all you have to do is get rid of the marbled cow and you're all set. On the other hand if you're trying to get people to live past 150, there's no precedent for that.
Certainly if you could fix all nine hallmarks at once that would do well to solve aging. Reversal of aging has been demonstrated in simple animals. Some people will dismiss those as too simple - because they have such a short life already, it's not surprising you can make them live longer. But I think it's quite clear that aging is programmed in some sense. It's not like you've been programmed to die at some age, but the laziness of evolution has resulted in your program to not avoid dying. Over evolutionary time, to use analogy, it was not cost effective to invest a lot of your precious food to live longer because you're going to get eaten by a wolf anyway.
To address the hallmarks of aging, the idea is to take the subset of genes that has been demonstrated to work for longevity or aging reversal in smaller organisms and reconfigure them into something that's usable in gene therapy. You change it from longevity that requires introducing it into the germ line, which is not really a good strategy for humans because most of us that want longevity are already past the zygote stage, and we're reconfiguring it as a adeno-associated virus gene therapy.
How far off is age reversal? The simple answer is, I don't know. Probably we'll see the first dog trials in the next year or two. If that works, human trials are another two years away, and eight years before they're done. Once you get a few going and succeeding it's a positive feedback loop. The FDA doesn't need to classify aging as a disease in order to treat it. If you actually have something that causes aging reversal, they'll approve it. You'll frame it in conventional terms, but it can have additional benefits. In other words If you have something that fixes one disease problem and happens to fix a bunch of others, you don't need to put them all on the label. The FDA doesn't stop you for using things off label or curing two things at once.
Low Cost Biotechnologies can be Inconvenienced but not Halted by Regulators
The coming era of gene therapies will be considerably more distributed and bottom-up than the advent of stem cell therapies. This will be a dynamic industry in which many small groups compete to set up distribution of mail order kits and clinics to provide widespread access to therapies. Regulators will attempt to suppress all of this, and will largely fail, as money talks and many regions will choose to host the businesses that offer gene therapies. This will come to pass because gene therapy technologies are many times cheaper, more easily managed, and capable of centralization and mass production than stem cell technologies. You might look at how medical tourism for stem cells progressed over the past twenty years, and expect the gene therapy industry to grow many times faster once the spark is lit. It will also be far more accessible to members of the public in its earlier stages: cost of the product drives the character of an industry.
There are several very promising targets for the first gene therapies, the best of which, in my opinion, are follistatin and myostatin, which control muscle growth, and are well studied. There are even a few natural human myostatin mutants, to accompany the many well-muscled myostatin mutants in other mammalian species, both natural and engineered. A number of other genes will be targeted in the first years of the industry, such as those that can dramatically lower blood cholesterol, and which also either have thriving human mutants or are already targeted by drug-based therapies. The only thing holding back an explosion of activity is the fact that current methodologies, even those based on CRISPR, are not yet up to scratch. They don't reliably introduce the therapy into a large enough number of cells in adults, and particularly into stem cells in order to make it truly lasting. When that changes, we'll all be in for an interesting ride.
Two companies say they'll continue offering DNA-altering materials to the public. The companies, The Odin and Ascendance Biomedical, both recently posted videos online of people self-administering DNA molecules their labs had produced. Following wide distribution of the videos, the FDA last week issued a harshly worded statement cautioning consumers against DIY gene-therapy kits and calling their sale illegal. A growing number of cases of DIY gene therapy are putting the health regulator in a difficult situation as individuals argue that no law stops them from self-administering the substances. In fact, there is a long history of scientists carrying out experiments on themselves, including some Nobel Prize winners. Last month, Josiah Zayner, CEO of The Odin, which sells DIY biology kits and supplies through its website, posted a video in which he injected himself with the gene-editing tool CRISPR during a biohacker conference.
The problem facing regulators is that interest in biohacking is spreading, and it's increasingly easy for anyone to obtain DNA over the internet. It's also easy to get hold of the recipes necessary to carry out gene editing using CRISPR, a potent new technique for modifying DNA. In October, Zayner's website began selling $20 copies of a DNA molecule containing the necessary genetic information to deactivate the human gene for a certain protein, myostatin, using CRISPR. Human DNA can be purchased through a number of other companies that cater to research labs. The difference is The Odin markets its DNA to amateur biologists. The materials sold by The Odin also can't be directly used to alter a person's genes. Instead, they contain DNA that would have to be produced in larger amounts, purified, and then delivered to the body using methods well beyond the skills of most consumers.
At least one other company appears to have begun offering finished gene-therapy preparations directly to patients for their own use. In October, an HIV patient was filmed injecting himself with a gene therapy designed to generate antibodies that he believed would help his body destroy cells infected with the virus. The material he used was supplied by Ascendance Biomedical, an until recently unknown startup company that promotes "decentralized" testing of new drugs. The company is also developing a herpes vaccine, as well as a follistatin gene therapy to boost muscle mass and reduce fat. Aaron Traywick, the CEO of Ascendance, says Ascendance plans to make both of those therapies available for self-administration by early next year.
Another Study to Suggest that the Harms of Excess Fat Tissue are Understated
As a companion piece to a recent sizable study on weight and risk of age-related disease, here is another set of data to suggest that the existing consensus on the harms done by excess visceral fat tissue are, if anything, an underestimate. There is a large body of research that covers the many mechanisms by which the visceral fat packed around internal organs causes damage, such as through inflammation and immune dysfunction, the presence of raised numbers of senescent cells, the metabolic disarray that leads to diabetes, and so forth. Collectively it is a lengthy cautionary tale for those living far enough along the upward curve of technological progress to have reliable access to cheap calories, but not far enough to have reliable technological means to prevent the consequences of consuming those calories.
The harmful effects of being overweight have been underestimated, according to a new study. Previous studies have suggested that the optimum body mass index (BMI), at which the risk of death is minimised, appears to be above the range normally recommended by doctors, leading to claims it is good for health to be mildly overweight. However, scientists suspect these studies do not reflect the true effect of BMI on health, because early stages of illness, health-damaging behaviours, such as cigarette smoking, and other factors can lead to both lower BMI and increased risk of death. This makes it difficult to estimate how BMI actually influences risk of death (the causal effect), as opposed to the observed association between BMI and risk of death. This aim of this study was to assess the causal link between BMI and risk of death.
Using HUNT, a Norwegian population-based health cohort study based in a rural county with 130,000 residents, researchers were able to see how mortality in the parents related to both their own BMI (the conventional approach) and to the BMI of their adult children. Because BMI of parents and their offspring is related, due to genetic factors, offspring BMI is an indicator of the BMI of the parents. The BMI of adult children is not influenced by illness among the parents, therefore using offspring BMI avoids the problems inherent in simply relating the BMI of the parents to their risk of death.
The health records of around 30,000 mother and child pairs and 30,000 father and child pairs were assessed to examine the extent to which BMI may influence mortality risk in a situation that is not biased by "reverse causation" - illness leading to low BMI rather than BMI influencing illness. The team found that when offspring BMI was used instead of the parent's own BMI, the apparent harmful effects of low BMI were reduced and the harmful effects of high BMI were greater than those found in the conventional analyses. Importantly, the results suggest that previous studies have underestimated the harmful effects of being overweight. The current advice from doctors to maintain a BMI of between 18.5 and 25 is supported by this study, and the widely reported suggestion that being overweight may be healthy is shown to be incorrect.
Adrenomedullin is Involved in Age-Related Memory Loss
Researchers have identified adrenomedullin as a contributing factor in age-related memory loss in mice, and in the open access paper here note that levels of adrenomedullin increase with age in humans as well. This research is a fair distance from a rigorous proof of the relevance of adrenomedullin to human memory loss, but it is nonetheless quite interesting. The observed correlations suggest that the important connection is between adrenomedullin and the aggregated tau protein that gives rise to tauopathies, and consequently that tau is influential in the lesser degree of mental decline with age that occurs in people without full-blown neurodegenerative conditions. Aggregation of altered tau protein is a fairly fundamental form of age-related damage, something that occurs as a side-effect of the normal operation of metabolism, so it might be expected to contribute to declining function in proportion to its presence.
Memory loss is a common characteristic of normal aging, and is greatly accelerated in some neurodegenerative diseases. The causes of memory loss during normal aging are not completely understood. Atrophy of some brain areas has been shown in normal aging and changes in intrinsic neural electrical excitability associated with oxidative stress have been hypothesized as potential causes. Subtle perturbations in stabilization of neuronal cytoskeleton, reminiscent of those occurring during Alzheimer's disease (AD) neurodegeneration, may also be an important underlying cause of age-associated neuronal dysfunction and cognitive decline. In this line, modifications of tau expression and status akin to those of tauopathies are also typical of normal aging and their distribution pattern correlates with memory capabilities.
In the search for predictive blood biomarkers of AD cognitive decline, some studies have found that mid-regional proadrenomedullin is elevated in the plasma of AD patients and that the concentration of this peptide could have predictive value in the progression from predementia to clinical AD, although a recent study found no correlation. The proadrenomedullin gene, adm, generates two biologically active peptides: proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (AM).
Expression of these peptides is widespread and several functions have been ascribed to them, including vasodilatation, bronchodilatation, angiogenesis, hormone secretion regulation, growth modulation and antimicrobial activities, among others. In the central nervous system (CNS), AM is expressed throughout the whole brain and spinal cord where it acts as a neuromodulator. It has been shown that plasma levels of AM increase with normal aging.
Knockout studies have shown that total abrogation of adm results in embryo lethality. To circumvent this problem, we generated a conditional knockout model where adm was eliminated just from neurons. Consequently, we have shown that aged mice that lack neuronal AM have better contextual and recognition memory than their wild type littermates. In parallel, the brain cortex and hippocampus of these mice have a lower accumulation of phosphorylated tau, suggesting that tau may be the link between lack of AM and memory preservation, although we cannot rule out other alternative molecular pathways. In addition, we also showed that older human individuals present higher levels of AM and lower levels of acetylated tubulin in their brains than younger controls.
Our data suggest that reducing AM/PAMP levels may constitute a novel path to preventing or delaying memory loss. A few years ago, a particular single nucleotide polymorphism (SNP) close to the adm gene was found to be responsible for a natural reduction in the circulating levels of AM and to correlate with cancer susceptibility. Therefore, it would be interesting to test whether carriers of this SNP are more protected from developing memory impairment. Also, several physiological inhibitors of AM have been proposed for clinical development, and some of these inhibitors may be used for the pharmacological prevention of age-related memory loss.
Towards a Mass Production System for Liver Organoids
Researchers can create functional organ tissue in small quantities, building few-millimeter-sized structures known as organoids. Yet because there is still no reliable approach to the creation of the capillary networks required to support thick tissue sections, this cannot yet scale up to the production of full-size replacement organs. That may not be a roadblock for organs such as the liver and kidney, which are responsible for what are essentially chemical manufacture and filtration tasks; in this case the large-scale structure of the organ isn't as important as the small-scale structure, and much of the organ might be thought of as countless tiny factories operating independently in response to circumstances. The arrangement of those factories can vary.
Thus it should be possible to rescue a failing liver or kidney by transplanting scores or hundreds of functional organoids grown from the patient's own cells. The organoids will integrate with the existing tissue, and blood vessel networks will growth into and through them - that much has been demonstrated in animal studies for single organoids in a number of different organs. The only challenge standing in the way of this vision for the near future is the cost and time required to create organoids, a process that has yet to be scaled up for mass manufacture.
Researchers report creating a biologically accurate mass-production platform that overcomes major barriers to bioengineering human liver tissues suitable for therapeutic transplant into people. The new process allows researchers to bioengineer single batches of up to 20,000 genetically matched, three-dimensional and highly functional liver micro-buds. When combined, the batch has a sufficient quantity of liver cells and size feasibility for transplant into a person with liver failure, or for drug testing. The liver tissues were also generated entirely from human induced pluripotent stem cells (iPSCs), making the process free of animal feeder byproducts used to make cells for research purposes - a barrier to the cells being used therapeutically.
"Because we can now overcome these obstacles to generate highly functional, three-dimensional liver buds, our production process comes very close to complying with clinical-grade standards. The ability to do this will eventually allow us to help many people with final-stage liver disease." The researchers stress continued research and refinement of their process is required before initial clinical trials could begin, and estimate this might occur in the next two to five years.
Over the past five years the reseearch published several studies that made continuous progress into defining the precise genetic and molecular blueprints needed to mimic natural human development. This allows the researchers to develop and bioengineer functional, three-dimensional human mini livers in the laboratory. To help overcome the biological challenge of animal-product feeder cells in the current study, the team used their fine-tuned formula of genetic and molecular components to generate the liver tissues in custom-designed, U-shaped bottom micro-well cell plates. The plates use a combination of chemistry techniques to form a finely structured film inside the micro-wells, designed to nurture the developing liver buds.
But prior to this step, the researchers started mass production by initially using the donor-derived iPSCs to grow three critical types of liver progenitor cells needed to generate healthy livers. These include hepatic endoderm cells and both endothelial and septum mesenchyme cells. Study data show this generates robust and highly functional progenitor cells that are placed into the custom-designed, film-coated micro-wells. The progenitor cells then engage in high levels of molecular cross-communication to form into self-organizing, three-dimensional liver buds.
ANGPTL2 Knockout Reduces Inflammation and Slows Muscle Loss in Mice
The gene ANGPTL2 is starting to look like an interesting basis for therapy, something to bump closer to the top of the lengthy list of targets to consider for first generation human gene therapies. In animal studies, lowering the level of protein produced by this gene has been shown to reduce chronic inflammation in older individuals and slow progression towards heart failure. These effects might be mediated through the presence of senescent cells in the cardiovascular system, in that it is these cells that are the primary producers of ANGPTL2. One of the most easily measured consequences of the growing numbers of senescent cells in older tissues is a higher level of inflammation.
Here researchers show that loss of ANGPTL2 can slow the age-related decline in muscle mass that takes place in later life, a condition known as sarcopenia. They also consider cellular senescence to be a plausible mediating mechanism for the detrimental effects of ANGPTL2 when it is present, and certainly there is plenty of evidence to link sarcopenia with chronic inflammation. Raised levels of inflammation and other activities of senescent cells derail the normal processes of tissue maintenance. If this is the case, and ANGPTL2 does cause harm due to increased levels of cellular senescence or increased activity of senescent cells, then senolytic therapies that destroy senescent cells should capture all of the benefits of reduced levels of ANGPTL2, rendering gene therapy approaches redundant in this case. That is a proposition that could be tested in mice now, given the present state of the field.
Sarcopenia is defined as age-related loss of skeletal muscle mass and strength, a condition that worsens subjects' quality of life. Clarification of molecular mechanisms underlying sarcopenia development is important to devise effective approaches to treat this condition. Several lines of evidence support the idea that in skeletal muscle chronic inflammation and reactive oxygen species (ROS) accumulation due to redox imbalance contribute to sarcopenia development, and chronic inflammation in aging skeletal muscle is positively correlated with sarcopenia development in humans and mice.
The pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-1β (IL-1β) both decrease skeletal muscle mass by causing inflammation and subsequently facilitating muscle proteolysis, ROS accumulation, and growth hormone resistance. Moreover, excess ROS accumulation causes oxidative damage to skeletal muscles, resulting in myofibers loss. Both inflammation and ROS accumulation inactivate "satellite cells", the precursors of skeletal muscle cells, thereby accelerating sarcopenia development.
Previous studies reveal that expression and secretion of angiopoietin-like 2 (ANGPTL2) significantly increase in cells stressed by pathophysiological stimuli, such as hypoxia and pressure-overload. ANGPTL2 expression also increases in cells undergoing senescence, suggesting that ANGPTL2 is a senescence-associated secretory phenotype (SASP) factor. Moreover, excess ANGPTL2 signaling is pro-inflammatory in pathological states and contributes to development of aging-associated diseases.
Although ANGPTL2 hyperactivation is associated with age-related diseases, ANGPTL2 function in sarcopenia development remains unknown. Here, we investigated the roles of ANGPTL2 in sarcopenia development using aging mice. We report that ANGPTL2 expression increases in skeletal myocytes of aging mice and that running exercise decreases that expression, suggesting that excess ANGPTL2 signaling in aged skeletal muscular myofibers accelerates sarcopenia development. Moreover, ANGPTL2 deficient mice showed attenuated loss of skeletal muscle by reduced muscular inflammation and ROS accumulation and increased satellite cell activity. To the best of our knowledge, this is the first report showing that ANGPTL2 signaling may accelerate sarcopenia pathologies.
Boosting Mitochondrial Function Reduces Plaque and Improves Cognitive Function in a Mouse Model of Alzheimer's Disease
Mitochondria, the power plants of the cell, suffer a general malaise in older individuals. Their dynamics change and their production of energy store molecules declines. This is distinct and separate from the damage to mitochondrial DNA outlined in the SENS vision for rejuvenation therapies, in that it occurs across all cells rather than in a small but significant number of cells. It is probably a secondary or later consequence of other forms of cell and tissue damage, an inappropriate reaction that makes things worse. This decline in mitochondrial function is implicated in neurodegenerative diseases; the brain requires a great deal of energy to function, and some portion of the changes and symptoms of cognitive decline are due to insufficient energy store production.
Researchers here make some inroads to putting numbers to that portion, at least in mice, but the challenge inherent in the use of animal models of Alzheimer's disease is that they are very artificial. Mice don't normally suffer from Alzheimer's, and their neural biochemistry must be altered significantly in order to produce any of the protein aggregates seen in Alzheimer's disease. The current models only recapture a slice of the full human condition, focusing on amyloid aggregation rather than the full biochemistry of the Alzheimer's. Thus there is always the question for any specific finding as to whether it will also apply to humans, or whether it is a quirk of the model, no matter how plausible the assumptions.
Alzheimer's disease is the most common form of dementia and neurodegeneration worldwide. A major hallmark of the disease is the accumulation of toxic plaques in the brain, formed by the abnormal aggregation of a protein called beta-amyloid inside neurons. Most treatments focus on reducing the formation of amyloid plaques, but these approaches have been inconclusive. As a result, scientists are now searching for alternative treatment strategies, one of which is to consider Alzheimer's as a metabolic disease.
Researchers looked at mitochondria, which are the energy-producing powerhouses of cells, and thus central in metabolism. Using worms and mice as models, they discovered that boosting mitochondria defenses against a particular form of protein stress, enables them to not only protect themselves, but to also reduce the formation of amyloid plaques. During normal aging and age-associated diseases such as Alzheimer's, cells face increasing damage and struggle to protect and replace dysfunctional mitochondria. Since mitochondria provide energy to brain cells, leaving them unprotected in Alzheimer's disease favors brain damage, giving rise to symptoms like memory loss over the years.
The scientists identified two mechanisms that control the quality of mitochondria: First, the "mitochondrial unfolded protein response" (UPRmt), which protects mitochondria from stress stimuli. Second, mitophagy, a process that recycles defective mitochondria. Both these mechanisms are the key to delaying or preventing excessive mitochondrial damage during disease. "These defense and recycle pathways of the mitochondria are essential in organisms, from the worm C. elegans all the way to humans. So we decided to pharmacologically activate them." The team started by testing well-established compounds that can turn on the UPRmt and mitophagy defense systems in a worm model (C. elegans) of Alzheimer's disease. The health, performance and lifespan of worms exposed to the drugs increased remarkably compared with untreated worms. Plaque formation was also significantly reduced in the treated animals.
Most significantly, the scientists observed similar improvements when they turned on the same mitochondrial defense pathways in cultured human neuronal cells, using the same drugs. The encouraging results led the researchers to test in a mouse model of Alzheimer's disease. Just like C. elegans, the mice saw a significant improvement of mitochondrial function and a reduction in the number of amyloid plaques. But most importantly, the scientists observed a striking normalization of the cognitive function in the mice.
mTOR and Cellular Senescence
Now that the research community has finally woken up to the significance of cellular senescence in aging, a point long advocated for by the SENS Research Foundation and Methuselah Foundation, scientists are busily patching it in to their existing understanding and models of aging. This is just as true for studies of mechanistic target of rapamycin (mTOR) as elsewhere. This is one of the more popular areas of research to emerge from the study of calorie restriction, an intervention that slows aging in near all species tested to date. There is a sizable contingent of researchers interested in finding ways to mimic some fraction of the benefits of calorie restriction through therapies that target mTOR.
Since calorie restriction slows aging, albeit to a much larger degree in short-lived animals than in humans, it is generally agreed that it also slows the accumulation of senescent cells, one of the causes of aging. Thus to the degree that mTOR is involved in the calorie restriction response, we should also expect mTOR to be relevant in some ways to the harms done by cellular senescence: either reducing the number of cells that become senescent, or reducing the harm done by cells once they are senescent. Since we know that calorie restriction doesn't greatly extend life in humans (though it is very good for long term health), we should not expect these effects to be large. Certainly, senolytic therapies that clear out senescent cells should have a much greater positive impact on health and longevity.
The mechanistic target of rapamycin (mTOR) is an evolutionary conserved serine-threonine kinase that senses and integrates a diverse set of environmental and intracellular signals, such as growth factors and nutrients to direct cellular and organismal responses. The name TOR (target of rapamycin) is derived from its inhibitor rapamycin. We now know that the role of mTOR goes far beyond proliferation and coordinates a cell-tailored metabolic program to control cell growth and many biological processes including aging, cellular senescence, and lifespan.
Rapamycin is currently the only known pharmacological substance to prolong lifespan in all studied model organisms and the only one in mammals. Rapamycin was shown to extend the lifespan of genetically heterogeneous mice at three independent test locations by about 10-18% depending on sex. Interestingly, treatment was only started late when the mice were 600 days of age equivalent to roughly 60 years of age in a human person. This proposes that inhibition of mTOR in the elderly might be enough to prolong life. The findings were confirmed and extended in mice, in which rapamycin treatment started earlier. However, they failed to substantially observe larger effects on longevity.
It is now accepted that mTOR inhibition increases lifespan; yet, the mechanism through which this occurs is still uncertain. mTORC1 inhibition may not delay aging itself, but may delay age-related diseases. However, many researchers directly link the longevity effects of mTOR inhibitors to a decrease in aging. Conserved hallmarks of aging have recently been proposed and include telomere attrition, epigenetic alterations, genomic instability, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The mTOR network is known to regulate some of these aging hallmarks. Ultimately, the prominence of mTORC1 signaling in aging likely reflects its exceptional capacity to regulate such a wide variety of key cellular functions.
Cellular senescence has been suggested to function as a tumor suppressor mechanism and promotor of tissue remodeling after wounding. However, senescent cells may also directly contribute to aging. Senescent cells show marked changes in morphology including an enlarged size, irregular cell shape, prominent and sometimes multiple nuclei, accumulation of mitochondrial and lysosomal mass, increased granularity and highly prominent stress fibers that are accompanied by shifts in metabolism and a failure of autophagy. Interestingly, many of these phenotypes are regulated by mTORC1 in various cell types. The secretion of proinflammatory mediators by senescent cells contributes to aging and has been termed senescence-associated secretory phenotype (SASP). Recent data identified a main role of mTORC1 to promote the SASP. Rapamycin blunts the proinflammatory phenotype of senescent cells by specifically suppressing translation of IL1A.
Despite maintaining a nondividing state, senescent cells display a high metabolic rate. Metabolic changes characteristic of replicative senescence often show a shift to glycolytic metabolism away from oxidative phosphorylation (which is also observed in proliferative cells), despite a marked increase in mitochondrial mass and markers of mitochondrial activity. This might stem from a rise in lysosomal pH as a consequence of proton pump failure, which leads to an inability to get rid of damaged organelles such as mitochondria caused by a failure of autophagy. Dysfunctional mitochondria not cleared by autophagy in senescent cells produce reactive oxygen species, which cause cellular damage including DNA damage. mTORC1 has been postulated as main driver of these metabolic changes. Hence, rapamycin treatment prevents metabolic stress and delays cellular senescence.
Covalent Bioscience is One of the Current Crop of SENS Rejuvenation Biotechnology Startup Companies
Covalent Bioscience is the company formed to carry forward work on catalytic antibodies capable of clearing aggregated proteins found in old tissues, such as transthyretin amyloid. This type of amyloid, a misfolded protein that disrupts normal tissue function when present in large enough amounts, is associated with cardiovascular mortality and osteoarthritis, and is thought to be a prevalent cause of death in supercentenarians. The advantage of catalytic antibodies over normal antibodies is that they bind to the target site on a protein, then destroy that site, then move on. One antibody can attack thousands of targets, making low doses potentially highly effective.
Covalent Bioscience is one of a handful of startups and young companies working on science funded in part by the SENS Research Foundation, the foundation for rejuvenation therapies based on repairing and reversing the fundamental cell and tissue damage that causes aging, such as the presence of amyloid. There are a now a number of serious investors and venture firms interested specifically in SENS strategies to treat aging, including figures such as Jim Mellon, Peter Thiel, Michael Greve, James Peyer, and so forth - far more than was the case just a few years ago. This is the time for SENS startup companies to flourish, and gain the funding needed to bring the first batch of rejuvenation therapies to the clinic.
We are a development stage company with intellectual property rights to novel therapeutic antibodies and chemically activated vaccines in all major markets. These rights have been developed from discoveries indicating the power of the immune system to use covalent bonding as the basis for synthesizing antibodies that neutralize and remove target antigens with efficacy and safety superior to conventional antibodies.
The two classes of therapeutic monoclonal antibodies (MAbs) being developed by Covalent, Inc are: (a) irreversible MAbs (iMAbs), which bind and neutralize the target antigen with virtually infinite affinity, (b) catalytic MAbs (cMAbs), which hydrolyze and destroy the target antigen in an enzyme-like manner. Covalent, Inc has proof-of-principle for superior efficacy and diminished side effects of the cMAbs/iMAbs compared to conventional MAbs that bind the target antigen reversibly. Covalent's cMAbs/iMAbs are isolated from the innate immune repertoire that has developed by Darwinian evolution, and immunization with Covalent's electrophilic antigen analogs induces the synthesis of the cMAbs/iMabs adaptively.
Covalent is in a position to generate cMAbs/iMAbs to diverse antigen targets for development as immunotherapies. In addition, Covalent is developing the electrophilic antigen analogs as therapeutic and prophylactic vaccine for unmet medical needs. Covalent has in hand: (a) candidate immunotherapeutic cMAbs to amyloid proteins for treating central nervous system and systemic amyloidosis, and (b) a candidate electrophilic vaccine for treating and preventing HIV infection.
Increased Autophagy Improves Stem Cell Activity and Restores Bone Loss in Mice
Researchers here provide evidence for increased autophagy, achieved via targeting mTOR to mimic some of the response to calorie restriction, to improve stem cell function in old mice. As a result some of the loss of bone mass and strength that occurs with age was reversed. Autophagy is the collection of maintenance processes responsible for clearing out broken proteins and structures in the cell, but like most of our biochemistry it declines in effectiveness with age. Increased levels of autophagy have been shown to be necessary for the gains in health and longevity provided by calorie restriction in short-lived species, and mTOR is one of the regulatory genes through which the calorie restriction response works. It is not surprising to find that inhibiting mTOR improves autophagy, and thus also improves the function of many systems in the body that benefit from having less garbage and breakage in their cells.
The overall slowing of aging produced by calorie restriction touches on all aspects and measures of aging, and that includes a reduction in the usual rate of decline in stem cell activity in old age. So the study here illustrates that calorie restriction, stem cell activity, autophagy, and mTOR all link together nicely. Unfortunately, we should not expect the same size of effect in humans as is observed in mice: calorie restriction is very good for health, but it certainly doesn't extend human life span by 40%, as is the case in mouse studies. This is generally the case for all longer-lived species, as the size of the life span increase produced by calorie restriction and its mechanisms under the hood scales down as life span scales up.
Mesenchymal stem cells (MSCs) are pluripotent cells that play crucial roles in tissue maintenance, repair, and regeneration. However, data suggest that beneficial functions of MSCs may become compromised with age; this is closely associated with age-related loss of repair and regenerative capacity of different tissues. Bone marrow-derived mesenchymal stem cells (BMMSCs) decline in number with aging and show degenerative properties including reduced osteogenic differentiation capacity, increased adipogenic differentiation capacity and reduced proliferative ability; these are partially caused by bone aging.
Autophagy is a process in which cellular components such as proteins and damaged mitochondria are engulfed by autophagosomes and delivered to lysosomes to be degraded and recycled in order to maintain cellular homeostasis. Autophagy has been widely studied as a mechanism for anti-aging effects and in alleviating age-related diseases. Recent studies have indicated that autophagy is required for maintaining the stemness and differentiation capacity of stem cells. It has been reported that autophagy is a crucial mechanism in the maintenance of the young state of satellite cells, and failure of autophagy causes declines in the number and function of satellite cells. Autophagy can protect BMMSCs from oxidative stress, which indicates that autophagy plays a protective role in cell aging. Conversely, autophagy also has been proven to be a requirement for maintenance of replicative senescence of MSCs. Therefore, whether and how autophagy regulates MSC aging remains unclear.
Bone marrow-derived mesenchymal stem cells have been regarded as the main source of osteoblasts for skeletal repair. It has been reported that degenerative changes of BMMSCs in humans and rodents during aging are associated with bone aging. Bone marrow-derived mesenchymal stem cells tend to partially lose their self-renewal capacity and differentiate into adipocytes instead of osteocytes with aging, which causes bone loss and fat accumulation. Our findings showed that aged BMMSCs had decreased osteogenesis, elevated adipogenesis and decreased proliferation compared with young BMMSCs; these results are in line with the previous findings.
We speculate that decreased autophagy in aged BMMSCs might be one of the causes of degenerative changes of aged BMMSCs, and bone loss by decreased autophagy could be a potential new mechanism of bone aging. The results of the manipulation of autophagy in both young BMMSCs and aged BMMSCs confirmed our speculations. As an autophagy inhibitor, 3-MA was used on young BMMSCs; the results showed that inhibition of autophagy not only reduced osteogenesis and promoted adipogenesis but also inhibited proliferation of young BMMSCs, which indicated that decreased autophagy could turn young cells into an aged state with degenerative properties. Meanwhile, the autophagy inducer rapamycin could partially convert aged BMMSCs to a young state by increasing osteogenesis, reducing adipogenesis and promoting proliferation. In summary, we conclude that activation of autophagy can restore degenerative properties of aged BMMSCs via regulating oxidative stress and p53 expression.