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- Crowdfunding Success for SENS Research Foundation, Funds to Aid in Pushing Forward to a Universal Cancer Therapy
- An Open Access Journal Special Issue on Telomerase Activity in Human Cells
- Waking to the Potential of an Age of Biotechnology
- In Search of a Better DNA Methylation Biomarker of Aging
- A Selection of Views on Cryonics from the Cryonics Community
- Latest Headlines from Fight Aging!
- Greater Biological Repair and Maintenance in Long-Lived Ant Queens
- Investigating Differences in Brain Aging in Older Adults
- Hearing Loss Accelerates in Later Old Age
- Pax6 in Regeneration of the Retina in Newts
- Researchers Demonstrate Growth of Yet More Lung Organoids
- An Approach to the Analysis of Differences Between Species in the Matter of Aging and Longevity-Enhancing Interventions
- Considering the Origins of Peto's Paradox
- Estimating the Contribution of Inactivity to Mortality Rates
- Rejuvenation Research should be the Highest of Priorities
- Mitochondria in Muscle Aging and Sarcopenia
Crowdfunding Success for SENS Research Foundation, Funds to Aid in Pushing Forward to a Universal Cancer Therapy
The SENS Research Foundations's latest crowdfunding campaign, hosted by Lifespan.io, was focused on one of a number of vital projects in the development of a universal cancer therapy. I'm pleased to note that the campaign closed successfully yesterday, having raised more than 70,000 for this research initiative from nearly 550 donors. The SENS Research Foundation cancer team will be using the funds for the first rigorous exercise of an alternative lengthening of telomeres (ALT) assay to find potential drug candidates that can suppress the ALT mechanisms used by some cancers to sustain their growth.
All cancers must lengthen their telomeres in order to grow, and to do so they abuse either telomerase or ALT. Shutting down telomere lengthening in tumors is thus an approach that should halt any cancer in its tracks. From a strategic point of view, this is enormous difference when compared to the cancer research and development of recent history, in which most therapies are only applicable to a small number of the hundreds of subtypes of cancer. Progress is necessarily slow in that paradigm. There are too many varieties of cancer and too few researchers to keep doing things that way if the goal is to win, to control cancer in the same way and to the same degree as we control most serious infectious disease. The strategy must change, and a class of therapy that works for all cancers, but costs no more to develop than any of the more limited therapies of the past, is just the sort of thing to aim for.
A number of research groups are working on telomerase suppression in cancer, but next to no-one is working on ALT in anywhere near as meaningful a way. Left to its own devices, cancer tends 90% to telomerase and 10% to ALT. Further, telomerase research is fairly well established as a result of its role in stem cell biology and possibly aging, while ALT is a small field with much more left to discover, so this focus on telomerase is understandable. Unfortunately, suppressing telomerase is quite capable of causing a tumor to evolve to use ALT instead - this has been demonstrated in mice. Therefore any effective universal cancer therapy based on a blockade of telomere lengthening must use both approaches at the same time. Someone has to pick up the slack on ALT research, and this is where the SENS Research Foundation comes in. Funds in hand, the researchers can now start working through the most likely prospects in the standard drug library. This should help to obtain a much better understanding of the best directions to take in order to suppress ALT, and in the best possible outcome finds drugs that might be of some use for patients suffering one of the 10% of cancers that use ALT.
Watching progress day to day from the sidelines, I have to say that this was a tough fundraiser - one of the first we've had these past few years that proved to be a real challenge. The target was reached only because a number of very generous donors stepped up to the plate and put up sizable matching funds when they saw that the outcome was in question. As to why this particular crowdfunding effort was a challenge, why is it suddenly harder now, well, that has been discussed here and there. There are a few hypotheses. The first is simply donor fatigue: this community has given very generously to multiple projects over the past few years, but there are only so many of us at the present time. This year's SENS Research Foundation crowdfunding campaign, unlike last year's, followed immediately on the heels of a successful 50,000 fundraiser for senescent cell clearance work in mice, also via Lifespan.io.
The second hypothesis is that during the fundraiser Michael Greve pledged 10 million to SENS rejuvenation research and the companies that will emerge from that research. There is never a bad time for a large donation to be made, and the SENS Research Foundation has justifiably spent much of their time and effort focused on the Project|21 initiative of which this donation is a part. It is always hard to say whether such large donations are going to inspire or reduce donations from the community in the short term. I've seen it go both ways in the past, and it is just as hard to say after the fact whether that was a factor here. We should all be feeling pretty triumphant after the events of this year, frankly. It is a big boost to ongoing efforts to persuade people who can invest large amounts that SENS is the right path forward, and in the long term more large donations mean more of everything as the years go by: a larger community, more grassroots donations, more research and development.
The third and perhaps most interesting hypothesis is that many members of the community of SENS rejuvenation research supporters don't consider cancer to be their problem, as it were. Perhaps people see the vast sums that go towards cancer research and think that this is an area already adequately covered. Or perhaps it is a cognitive disconnect between aging research and cancer research, seeing them as two separate edifices - which they are in many ways at the level of established funding institutions, charities, and advocacy, but not when it comes to the biochemistry of the situation. On the money front, there is a great deal of funding for aging research as well as cancer research, but that doesn't render efforts like those of the SENS Research Foundation irrelevant. The large scale funds in these fields are almost entirely devoted to the status quo of research, work that is only producing incremental gains at best. These are fields that need to be disrupted and led in a more productive direction. That in turn means that there must be funding for the early stage research and novel lines of work that lead to radical leaps and improvements in medicine, and that funding must almost always come from outside the mainstream - a very large proportion of it is philanthropic, just as in this case.
A tough fundraiser is a sign to change strategy a little, I think. I'm fairly certain that it would be hard to repeat last year's 250,000 success at this point. So this year Fight Aging! will be doing something different to support the SENS Research Foundation as the year comes to a close. More on that later.
An Open Access Journal Special Issue on Telomerase Activity in Human Cells
If you have an interest in telomerase research, and anyone following developments in the science of aging really should pay attention to telomerase research, then you might find a recent special issue of Genes to be worth reading. It collects a dozen or so papers on the subject, adding to a growing number of reviews, calls to action, and discoveries published in the last couple of years in the field of telomere and telomerase biology. You might look at a very readable review from Maria Blasco's lab, published earlier this year, for example. The researchers there are leaders in telomerase gene therapy, and have demonstrated benefits and a slowing of aging in mice via this path. It remains to be seen how well it will translate to humans, though there are certainly people out there willing to try.
It is possible to describe cancer and aging as two sides of the same coin; the evolved systems that act to suppress cancer also suppress tissue maintenance, and the decline in stem cell activity with age that causes a slow decay of tissue function is a trade-off, balancing death by cancer against death by frailty and organ failure. Cellular replication and growth is the commonality in cancer and maintenance: one is uncontrolled growth, the other controlled growth. One of the most important mechanisms in our cellular biochemistry is the Hayflick limit, and telomeres are a part of the system that creates that limit. Telomeres are lengths of repeated DNA that cap the ends of chromosomes. Every time a cell divides some of that length is lost. When telomeres become too short, a cell halts replication and either destroys itself or becomes senescent and is soon thereafter destroyed by the immune system. Healthy tissues are in a state of balance between loss of cells to the Hayflick limit and the delivery of new cells with long telomeres, created by stem cells. How do stem cells constantly create new daughter cells with long telomeres? They use telomerase to maintain long telomeres: the primary function of telomerase is to add more of the repeating telomeric DNA sequences to the ends of chromosomes.
This ornate situation has evolved because it ensures that cancer incidence is kept low enough for it not to impede evolutionary success. The majority of cells have a limited ability to replicate, and only a small number of cells have unlimited replication rights. This greatly reduces vulnerability to cancerous mutations. Still, cancer happens, and it occurs when cells mutate in one of the few ways that can unlock telomerase or alternative lengthening of telomeres activity, or when stem cells mutate in ways that break their regulatory programs. For cancer researchers, interfering in telomere lengthening is the road to the grail of a universal cancer therapy, a single way to shut down all of the hundreds of types of cancerous tissue. On the other side of the coin, for aging, increased telomerase activity is thought to be a way to spur greater tissue maintenance in older individuals, though the processes by which this happens are many, varied, and much debated, just as the full list of mechanisms of action for stem cell therapies is a matter still under investigation. There is some thought that an increased level of telomerase activity will increase cancer risk, as damaged cells will be allowed to replicate far more often than they have evolved to replicate. Though by the same token, stem cell therapies should be similarly risky. So far the benefits look to outweigh the harms. It may be that our evolutionary point of balance has a fair amount of wiggle room.
Special Issue "Telomerase Activity in Human Cells"
The activity of the reverse transcriptase telomerase is a canonical function to maintain telomeres, the ends of linear chromosomes. Telomeres shorten in the absence of telomerase, causing senescence and ageing. In contrast to other organisms, telomerase activity is downregulated early in development in many somatic human tissues. However, some cell types, such as lymphocytes, adult stem cells, and endothelial cells retain, or can upregulate, telomerase activity. Importantly, this activity is strongly controlled by physiological conditions. In contrast, telomerase activity is continuously expressed at a high level in the majority of cancer cells, contributing to their indefinite proliferation potential. Although telomerase activity has been vigorously investigated over the last few decades, many questions still remain open regarding the mechanisms of physiological regulation in normal cells, as well as its up-regulation during tumourigenesis. The complex regulation at the levels of transcription, splicing, and posttranscriptional activation certainly contribute to that. Recently, interventions into its activation to counteract telomere shortening in healthy tissues, as well as its inhibition as tumour therapy, have been suggested and trials have been started with no final breakthrough yet. Thus, we still need to better understand the biology and regulation of telomerase activity in order to interfere with it successfully.
Telomerase Regulation from Beginning to the End
The vast body of literature regarding human telomere maintenance is a true testament to the importance of understanding telomere regulation in both normal and diseased states. In this review, our goal was simple: tell the telomerase story from the biogenesis of its parts to its maturity as a complex and function at its site of action, emphasizing new developments and how they contribute to the foundational knowledge of telomerase and telomere biology. Telomeric integrity has implications in both cancer and aging, as telomere attrition serves as a key checkpoint in the control of cell proliferation by triggering replicative senescence. There are two broadly defined mechanisms of telomere maintenance in humans: telomerase-mediated maintenance and ALT (alternative lengthening of telomeres). However, the complexity of each of these mechanisms becomes more evident with every new publication in the field of telomere biology. Approximately 80% of cancers are immortalized by constitutive activation of telomerase to maintain telomeres throughout rapid cellular proliferation. Additionally, defects in telomerase and other telomere maintenance components cause premature aging syndromes like dyskeratosis congenita (DC), due to progressive telomere shortening and subsequent proliferative blocks. As such, greater knowledge of telomerase regulation and its contribution to telomere homeostasis will contribute to our understanding of human disease and natural cellular processes alike.
The Telomere/Telomerase System in Chronic Inflammatory Diseases. Cause or Effect?
Many chronic conditions in humans are associated with chronic inflammation, immune system impairment and accelerated aging. In addition, abnormalities in telomere/telomerase system of these patients have been reported in many of these disorders. Since telomerase, an enzyme directly associated with aging, is inactive in most cell types in a mature organism and active in immune system cells, one can easily hypothesize that the immune system dysfunction/accelerated aging observed in chronic conditions is connected with telomeres and telomerase biology. Indeed, a connection of this nature seems to exist since shortened telomeres, observed in aged cells, cause an inflammatory cascade whereas, at the same time, NF-κB, a master regulator of inflammation, seems to directly induce telomerase transcription as stated above. Moreover, many researchers documented correlations between lower telomerase activity and/or shorter telomeres in immune system cells and elevated cytokines in blood serum from patients with chronic disorders. One should also bear in mind that, although aging is a multifactorial and complex procedure, healthy aging and longevity are believed to be associated with longer telomeres and lower inflammation profiles among older individuals. Despite all of the above, and despite the accumulating data of a strong interconnection between telomerase regulation/activity and inflammation, the mechanistical details and the molecular pathways of this connection have not been uncovered yet.
Telomerase: The Devil Inside
Emerging evidence over the last decade supports the idea that telomere length-independent functions of telomerase are also important for its function, both in normal and tumor cells. Interestingly, current research also revealed that telomeres may sense cellular stress (such as genotoxic stress, oncogenic or aneuploidy-inducing mutations) that result from harmful mutations that lead to genome instability and induce senescence in cells with intact checkpoints. Although the mechanistic details of the 'sensing' process are yet to be revealed, this new function of telomeres, thought to be a result of accumulating replication stress at the telomeres, seems to be independent of telomere length. In this context, telomerase relieves this cellular protective mechanism by mitigating telomere replication stress and this function of telomerase apparently is separate from its telomere elongation activity. In light of the recent discoveries hinting at novel, telomere length-independent roles of telomeres and telomerase, attempts at modulating telomerase activity to improve organ function and longevity must be seriously reconsidered. In this line, interfering with telomerase activity and its extracurricular functions for cancer therapy seems to be an attractive strategy again but new concepts need to be taken into account.
Role of Telomerase in the Cardiovascular System
Aging is one major risk factor for the incidence of cardiovascular diseases and the development of atherosclerosis. One important enzyme known to be involved in aging processes is telomerase reverse transcriptase (TERT). It has been proposed for a long time that telomerase activity is absent from human somatic cells. However, there is accumulating evidence that substantial telomerase activity is present in differentiated, non-dividing somatic cells of the cardiovascular system. This is of particular importance since cardiovascular diseases (CVD) are still the leading cause of death worldwide. All of these diseases have a primary defect in the heart or in the blood vessels, and there is emerging evidence that telomerase has a protective effect against CVD. Understanding this enzymes' functions in these tissues could, in the long run, help to reveal the therapeutic potential of activating TERT in cardiovascular diseases.
Waking to the Potential of an Age of Biotechnology
I see that the Zuckerbergs have set themselves the ambitious goal of ending disease over the course of this century. Don't forget that these are the spokespeople for an organization, not a few individuals making choices. Billionaires are effectively each the head of their own small state with its own politics and varied goals, the center of circles of delegation and machination, and frequently have less freedom to direct resources than you might think they do. Nonetheless:
Chan Zuckerberg Initiative announces 3 billion investment to cure disease
The Chan Zuckerberg Initiative just announced a new program informally called Chan Zuckerberg Science to invest 3 billion over the next decade to help cure, prevent, or manage all disease. The money will bring together teams of scientists and engineers "to build new tools for the scientific community." Part of the 3 billion will go to a 600 million investment in Biohub, a new physical location that which will unite researchers from Stanford, Berkeley, and UCSF with elite engineers to find new ways to treat disease. The majority of deaths are caused by heart disease, infectious disease, neurological disease, and cancer, so those are the areas where the program will concentrate its efforts. Mark Zuckerberg showed visible gusto, noting how our country spends 50x more on treating people who are sick than curing diseases so people don't get sick. "We can do better than that!" he exclaimed. To change this, Zuckerberg explained there must be a shift towards long-term thinking for research that requires more funding than typical academic grants can sustain. That's where his 45 billion fortune comes in.
Ambitious goals are good; far too few people with significant resources also choose to aim high, and the simple possession of wealth certainly doesn't magically grant vision. It is welcome to see that at least some of the wealthy of the world are waking up to the fact that this is an age of biotechnology in which the sky is the limit. The cost of medical research and development has plummeted over the past three decades. Yes, it is true that the straitjacket of regulation ensures that it is ever more costly to actually deploy medicine to the clinic, and that all to many promising lines of research never even get to that point since they couldn't be profitable. That fact serves to hide the reality from casual observers, which is that the actual research itself has become very cheap, and the state of the art in the lab is moving ever further ahead from the state of the art in the clinic. Any line of work using the tools of the biotechnology industry has experienced the same curve in costs and capabilities over the past few decades as computing and telecommunications, the result of advances in materials science and processing power. This is a time to aim high.
You might recall that Sean Parker is funding cancer immunotherapy at a fairly large scale, and then there is the Gates Foundation, funding work on a number of infectious diseases, Paul Allen's large-scale funding for mapping a range of human biochemistry, the Google founders' Calico Labs venture, Larry Ellison's past funding for aging research, and so forth. Where disease and the cause of disease is the target most of these are neither ambitious nor visionary exercises, however. While they bring a large amount of money to the table, very few manage to blaze a new path with that funding. They largely follow the current mainstream strategy, fund later stage scientific work, more development than research, and tend to only incrementally improve outcomes. The Ellison Medical Foundation essentially become a small arm of the National Institute on Aging, for example, and we can point to nothing that changed greatly as a result of those years of additional budget. There is a good chance, given the way things tend to go, that Calico and the Parker Institute for Cancer Immunotherapy will end up at the same destination - incremental increases in funding for existing projects, no meaningful change in strategies that have produced only small gains over the years, no bold steps, no radical advances. It often seems that the more funding one can bring to bear, the more one is constrained to do nothing new with it. To be sure more funding for research is better than less funding for research, but there is a very large difference between investing intelligently and taking calculated risks for a shot at large gains in medical capabilities and simply investing in the current mainstream, whatever that might be. Real, radical progress and the foundation for the next generation of medicine tends to come from the fringes of a field, not the established institutions.
The Zuckerberg vision is a good one, but we shall see how that translates to reality in the years ahead. There is only one way to bring an end to heart disease and the other diseases of aging, and that is to control the causes of aging - to repair or make irrelevant the molecular damage that gives rise to degeneration, decline, and disease, as outlined in the SENS proposals. I will be pleasantly surprised to see that approach showing up anywhere in practice in this venture, however, as it isn't yet reflected in the mainstream consensus on strategy in the research community. The bold visions of past ventures largely gave way to work that was prosaic and mediocre in ambition, subsumed by the short-term targets of small, incremental gains. So on the one hand I'm not optimistic that this, rather than any other past or existing venture, will be the one to break the mold. On the other hand there's a lot to cheer about when people with access to world-changing levels of resources acknowledge that ending disease is a viable goal for this age of biotechnology, and set their sights on it, in word at least. That is a part of the persuasion that must continue to happen in order to bring ever more resources to bear on progress in medicine, and in order to have a decent chance at realizing the potential of medical science to bring an end to all of the presently common causes of death. The more funding that there is in general, the more of that funding that we can persuade to go towards SENS-like strategies that stand a real chance of producing radical improvements in health and longevity, rather than the mainstream research strategies that largely cannot achieve such goals soon enough to matter.
In Search of a Better DNA Methylation Biomarker of Aging
In the open access paper I'll point out today, the authors dig into some of the details of DNA methylation changes that occur with aging, seeking to build a better biomarker of aging. This methylation is one of the epigenetic decorations to DNA that act to alter the expression of particular genes, determining whether or not the encoded proteins are produced. The methylation status of genes changes constantly in response to circumstances, differently in every tissue, one small portion of the countless interacting feedback loops that drive the behavior of cells. The cell and tissue damage of aging is the same for everyone, however, and so are the reactions to that damage, even though happenstance, lifestyle choices, and genes conspire to create some variation in the pace at which aging progresses. Thus there are patterns of DNA methylation that are distinctive for people at a given point in the progression of degenerative aging, and those patterns can be picked out of the constant changes that occur due to other environmental factors. Some of these patterns better reflect chronological age, others better reflect biological age, but there is much left to be done to expand and improve upon the existing discoveries in this field.
Why is this important? Primarily for economic reasons. At present it costs a great deal of time and money to assess whether or not a potential therapy that might produce a slowing or reversal of aging in fact works. Researchers have to run life span studies, and as the focus moves from lower animals into mice the cost per study rises to millions and the time taken rises to years. Yet without those studies, obtaining the proof and support to justify further development is impossible. You might look at the progress towards senescent cell clearance, one of the SENS approaches to rejuvenation biotechnology, over the past decade as an example. Despite the established body of evidence for the role of senescent cells in aging, that line of research didn't start to pull in meaningful support until researchers managed, against all the odds, to raise enough funding to run a study in mice and demonstrate extended life span through removal of senescent cells. Now, five years after those results were published, there are funded startups and numerous research groups working on building a variety of senescent cell clearance therapies. Looking ahead for the field of aging research as a whole, imagine that these lengthy and expensive mouse life span studies could be replaced with very short studies that assess a biomarker of aging, apply the therapy, wait a few weeks, then assess the biomarker again. That would dramatically reduce the cost, get many more research groups into the field, and allow many more approaches to be proved or disproved fairly rapidly. The iterative process of research and development would speed up considerably.
So, to the degree that DNA methylation is a path to a good biomarker of biological age, one that will change quickly and predictably when a real, actual, working rejuvenation therapy is applied, we should all be cheering progress in DNA methylation research. The present DNA methylation clocks are not as accurate as researchers would like them to be, however. There is definitely room for improvement, and all such improvement will - in the end - be reflected in the bottom line: the cost of running studies to assess potential treatments for aging, and thus the cost of progress in the treatment of aging as a whole. Greater reductions in costs will bring larger increases in the output of the research and development communities. The more progress here the better, as no-one is getting any younger yet. All of that said, I should note that the publicity materials here make what is to my eyes a complete hash of the meaning and significance of this research, so you might want to just skip straight to the paper.
Youthful DNA in old age
The DNA of young people is regulated to express the right genes at the right time. With the passing of years, the regulation of the DNA gradually gets disrupted, which is an important cause of ageing. A study of over 3,000 people shows that this is not true for everyone: there are people whose DNA appears youthful despite their advanced years. The researchers charted the regulation of the DNA of over 3,000 people by measuring the level of methylation at close to half a million sites across the human DNA. They were looking for sites where the difference in regulation increased between people as life progressed. Unexpectedly, these sites were closely linked to the activity of genes that were known from studies in worms and mice to play a central role in the ageing process. Not everyone in the study showed equal evidence of an age-related dysregulation of the DNA. Some elderly people had DNA that was regulated as if they were still 25 years old. In these individuals, genes characteristic of the ageing process were much less active. The next step will be to find out whether such people stay healthier for longer. "Obviously, health depends on more than just the regulation of our DNA. But we do think that the dysregulation of the DNA is a fundamental process that could push the risk of different diseases in the wrong direction. In cancer cells, we found changes in the regulation of the DNA at the same sites as if the differences occurring with ageing were a precursor of the disease. We therefore want to study whether a dysregulated DNA increases the risk of different forms of cancer and, conversely, a "youthful" DNA is protective."
Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms
Studies of model organisms such as yeast, nematodes, and mice have shown that the accumulation of cellular damage is a fundamental cause of ageing across species. Epigenetic dysregulation is thought to play a key role in this process. Numerous human population studies have now shown that changes in DNA methylation of CpG dinucleotides, a key epigenetic mechanism, are strongly associated with chronological age. Although these epigenetic changes are in part a by-product of age-related changes in the cellular composition of the studied tissue, many age-related differentially methylated positions (aDMPs) observed in blood samples are independent of cell composition, and aDMPs have proven to be a useful tool to predict chronological age. However, aDMPs may not be the most informative marker of the ageing process since they were discovered as close correlates of chronological age instead of biological age. Moreover, only a small proportion of aDMPs are associated with expression changes, suggesting that their functional implication may be limited. In contrast, DNA methylation changes that increasingly diverge from chronological age may reflect the increasing inter-individual variation in health that occurs with increasing age. Initial studies, although small or lacking a genome-wide view, indicated that an increasing variability of DNA methylation with age indeed exists.
In the current study, we charted the occurrence of age-related variably methylated positions (aVMPs) across the genome. We evaluated the methylation at 429,296 CpG sites for increased variability with age in whole blood samples from 3295 individuals aged 18 to 88 years. We discovered and validated 6366 age-related variably methylated positions (aVMPs). While aVMPs were commonly associated with the expression of (neuro)developmental genes in cis, they were linked to transcriptional activity of genes in trans that have a key role in well-established ageing pathways such as intracellular metabolism, apoptosis, and DNA damage response. Of interest, tumors were found to accumulate DNA methylation changes at CpG sites of aVMPs, thus supporting the long-standing notion that ageing and cancer are in part driven by common mechanisms.
Our data show that the genomic regions accumulating variability in ageing populations are highly specific and reproducible. Hence, although the increase in variability may have a stochastic component, the regions affected by this phenomenon are well-defined and not stochastic. Intriguingly, associations of aVMP methylation with gene expression in trans extended to genes known to play a role in ageing. In older individuals who had an aged DNA methylation profile as compared with young individuals, we observed a downregulation of genes involved in metabolism. The upregulation of ageing pathways, as observed in old individuals with an aged methylome, has been reported previously in hematopoietic stem cells in mice and humans, for which macromolecular or DNA damage may be the driving force. Of note, many of the trans-genes we identified are involved in the DNA damage response and are frequently mutated in various cancers. Hence, genomic stress, due either to hyperproliferation or DNA damage, may drive upregulation of well-established ageing pathways, downregulation of intra-cellular metabolism, and altered regulation by proteins associated with increased variability of DNA methylation. In contrast to aDMPs, aVMPs show a striking variability in DNA methylation at higher ages. Two individuals of the same age may display highly distinct methylation patterns across aVMPs, where one of them may have a DNA methylation profile at aVMPs that is similar to that of young individuals. Therefore, aVMPs fulfill a primary prerequisite for a biomarker of biological age.
A Selection of Views on Cryonics from the Cryonics Community
Here I'll point out a good article on cryonics and its nuances in the online press; it includes thoughts from people working at cryonics providers, people signed up for cryopreservation, and advocates with various viewpoints. Like any community there are a range of opinions on what constitutes progress and the best strategy for moving ahead, and just as many motivations as there are individuals involved. What is cryonics? It is the low-temperature preservation of at least the brain as closely following death as possible. Early preservations in the 1960s and 1970s were a matter of straight freezing, and thus the preserved individuals are most likely characterized by extensive tissue damage due to ice crystal formation. Later preservations have used increasingly better forms of vitrification, in which cryoprotectants are perfused into tissues during the cooling process, resulting in the near absence of ice crystals and high quality preservation of fine structures. This is a technology that scientists are nowadays seeking to bring to the organ transplant industry, a way to revolutionize the logistics of that field by allowing indefinite reversible storage of donated organs for later use. It has been a few years since the reversible vitrification of a rabbit kidney followed by transplant and a few hours of function was demonstrated: work proceeds on pushing forward the state of art to the quality needed for everyday medical use, but this demonstrates the basic viability of the approach, provided the initial vitrification is of good quality. Similarly, maintenance of long term memory through vitrification and thawing has been shown in lower animals.
The point of this is life: the data of the mind is stored in fine structures in the brain, and at some point, future technology will include the necessary capabilities to restore a vitrified individual to life. That will require, at the least, a very mature and sophisticated regenerative medicine industry, incorporating rejuvenation biotechnologies after the SENS model, and equally capable applications of molecular nanotechnology to deal with the cryoprotectant and forms of damage that cells cannot handle on their own. For so long as the data is intact, the option remains for rescue at some future date. It is an open question as to the degree to which earlier cryopreservations have managed to save the individual. Ultimately reconstruction of a frozen, ice-crystal-damaged brain and its data will probably be possible, but will that be the same person if considerable extrapolation is required? Continuity of identity through the same structure associated with the data of the mind seems important, or else you become one of those folk who believe a copy of the self is the self - a dangerous idea, to my eyes. The technological side of the future of cryonics seems a safe bet. The risks all lie in whether or not you manage to obtain a good cryopreservation, and whether or not the storage company survives the intervening years. A lot of thought and effort has gone into these matters over the four decades that cryonics has been a professional concern; you can peruse the materials at Alcor's website for a sampling of it.
Thus cryonics is a wager as well a so far small industry, a bet on technology continuing its upward trend. The odds are unknown, but infinitely better that those provided by any other end of life choice. We are heading into an era of rejuvenation therapies, but all too many people will run out of time before those therapies arrive. Are we barbarians, writing off these countless individuals? I would hope not. A fallback plan that offers some chance is better than a certainty of oblivion, and the more people who choose to sign up for cryonics, the better the chances become. A larger industry means more research and development, faster progress towards improved preservation techniques, more effective lobbying to change laws on euthanasia so as to make preservation a reliable, scheduled, low-cost event, and so forth. There is much that can be done to improve present matters, just as there is much that has been accomplished to make present day cryonics much advanced over its beginnings.
Generation Cryo: Fighting Death in the Frozen Unknown
Alcor Life Extension Foundation is the first and largest cryonics firm in the world. Its only true competitors are the Cryonics Institute located near Detroit - a 7,000-square-foot facility that currently hosts 100 preserved individuals - and KrioRus near Moscow - the world's first cryonics firm based outside the United States. Futurist Robert Ettinger came up with the idea of cryonics in the 1960s, but it was Frederick and Linda Chamberlain who formed a nonprofit organization in 1972 dedicated to cooling recently deceased people down to liquid nitrogen temperatures, and maintaining their bodies until it was possible to "reanimate" them. They called their new California-based organization the Alcor Society for Solid State Hypothermia - "Alcor" being a faint star in the Big Dipper. After dealing with some uncomfortable political squabbles and bureaucratic hurdles in California, the organization moved its operations to Arizona in 1990. Arizona offered a stable environment, free from earthquakes, floods, and other natural disasters, and state laws that were more amenable to Alcor's unconventional activities.
Alcor may be a not-for-profit 501(c)(3), but it needs to be profitable to survive, and to ensure the long-term prospects of those preserved at the facility. The core staff of Alcor - all of whom are signed up - have a vested interest in the success of the company. Alcor CEO Max More says, "We want this for ourselves." Registering with Alcor comes at a price. To help pay for it, most clients take out a second life insurance policy and name Alcor as the beneficiary. To ensure that Alcor can take possession of the deceased, clients donate their bodies to the organization for scientific study. And yet, very few people are actually ready to go the distance. Around 2.6 million people die each year in the United States. Alcor, the world's leading cryonics institute, has only 1,569 full members after four decades - and that includes the 148 patients currently in cryostasis. Undaunted, More says that there will be a tipping point, that cryonics will "eventually be the norm" and even "a regular fixture of medical care." He sees hospitals of the future having the expertise and facilities to perform their own cryopreservations. He compared the slow buy-in to the length of time it took germ theory and open heart surgery to be accepted. "The current problem is that it's hard to sell something without a guarantee. We make absolutely no promises about our offering-and in fact, we even provide our clients with a lengthy list of all the things that could go wrong."
A surprising number of things can and do go wrong, from the moment death is declared to the lowering of a body into the shiny dewar. With advance warning of death, a standby team is dispatched to wait until clinical death has been declared. Within seconds, the patient is placed in an ice bath to start cooling, and a mechanical respirator is used to restart circulation. The goal is to maintain normal bodily processes, even after "clinical death" has been declared. Decomposition starts almost immediately. The team then administers 16 different kinds of medication, including propofol to suppress consciousness in the event that cardiopulmonary support unintentionally revives the patient. Even at this early stage in the process, the line that divides life and death is blurred. The other medications work to reduce metabolism and stave off other problems that occur when the body stops functioning. The idea isn't to freeze the body, but to take it down to slightly above the freezing point of water to prepare it for transportation to Alcor. This is the ideal scenario, but there can be catastrophically long delays. Each passing hour or day following clinical death means preservation will be that much lower in quality. As Alcor likes to say, "Time is trauma."
Sometimes, disapproving family members deliberately refrain from alerting Alcor that one of their clients has passed away, in direct violation of the recently deceased's wishes. If a person was crushed by a streetcar, there may not be much left to preserve. Likewise, an autopsy will almost certainly result in a seriously compromised cryopreservation. And if the person died of an aggressive brain tumor or neurodegenerative disorder, any memories or aspects of personality that were damaged by the disease will almost certainly not be restored at a future date. Once the body arrives at Alcor, it's quickly taken to the operating room. For whole-body preservations, surgeons connect all the major blood vessels of the heart to a heat exchanger (a device that lowers the patient's body temperature to a few degrees above the freezing point of water), and a perfusion machine, which delivers chemicals to the body. The idea is to wash out the body's blood and other fluids as quickly as possible, and replace them with a cryoprotectant. This high-tech gel is gradually added to the body to prevent ice crystal formation - the mortal enemy of biological sustainability. The quality of this process varies according to the state of the patient. Things tend to go smoothly for people with a fully-functioning circulatory system, but for others, who have had prior surgery or other conditions, this can lead to less than ideal conditions. Aneurysms and bleeding in the brain are not good.
Alcor prides itself on transparency and commitment to "evidence based cryonics," and it publishes detailed case reports for each preservation. These reports include notes about deficiencies and problems that happened during the process. Despite Alcor's strict protocols, there's no proof that its method of cryopreservation is actually working. For all we know, every single person at the facility is a goner. Alcor has published micrographs of cryogenically preserved brain cells on its website, and claim the images "demonstrate good structural preservation with dehydration artifacts, but no ice damage." But as More himself admits, they haven't been able to prove that the neural connections have remained intact, though he remains hopeful. Kenneth Hayworth, president and co-founder of the Brain Preservation Foundation and an expert in the burgeoning science of connectomics, is critical of Alcor's micrographs. Hayworth says that chemical fixation, in conjunction with cryonics, is the future of brain preservation, and that Alcor has it all wrong. Alcor, on the other hand, steadfastly believes that chemical fixation is a catastrophe. The process uses aldehyde to fix the brain in place, preventing any shrinking on account of dehydration (a serious problem during the cooling process). More says this is a big no-no because it's irreversible, and that this "destructive" form of preservation is not a true form of survival. He and others believe this process will essentially kill the individual - and all their biological bits - for all time. More admits that the resulting brain scans could help future scientists reconstruct an individual, but many Alcor members argue that it would be a mere copy of that individual. "Not a lot of people will accept that."
Aschwin de Wolf, the editor of Cryonics Magazine and CEO for Advanced Neural Biosciences, says it's good that Hayworth and others are holding Alcor to a high standard, because it pushes the science of cryonics forward. Having said this, he worries that Hayworth is rehashing old misconceptions about Alcor's techniques. "For a long time cryonicists were criticized for causing ice formation in the brain and now that we have eliminated this phenomenon through vitrification we are told that electron micrographs do not look like controls yet. We know this! Hayworth's position seems to be that a cryonics organization should only offer cryopreservation services if its electron micrographs are indistinguishable from controls. That seems an extreme and ethically troublesome position to me. As long as we have good reason to believe that the original state of the brain can be inferred from the altered state, offering cryonics services is not only reasonable but an ethical mandate."
Robin Hanson, an economist at George Mason, has been an Alcor member since the 1990s, and he says it rarely crosses his mind. "It hasn't occupied very much of my attention or thought over the years. It's not some kind of part-time job that requires your constant attention." Simon Smith, a Toronto-based digital health marketer, husband, and father of two, has been an Alcor member for nearly a decade, and he concurs. "I think it's like a life insurance policy. A lot of people have life insurance policies, but they don't walk around thinking about them everyday." Smith is disheartened at the slow pace of technological development. An avid futurist and life extension advocate, he'd like to see more emphasis placed on technologies that will prolong human life, whether it be advances in pharmacology, biotechnology, molecular nanotechnology, or improvements to cryogenic techniques. But he remains optimistic. "The odds of reanimation being successful are better today than they've ever been and are continuously getting better, while the odds of coming back from burial, cremation or every other alternative remain the same."
Latest Headlines from Fight Aging!
Greater Biological Repair and Maintenance in Long-Lived Ant Queens
Eusocial insects are distinguished by queens that share the same genes as the workers but that, in many species, have a far longer life span. The expression of genes associated with aging is very different in queens, something that has been observed in both ants and bees. Given this, these species can serve as a laboratory in which to gather evidence for and against a variety of hypotheses about aging, its causes, and the degree to which specific causes are important. This paper is one example among many:
Since senescence is a detrimental process with important societal and economic impacts, substantial effort has been invested into understanding its causes and many theories have been proposed to explain its origins. One of these theories proposes that senescence is caused by macromolecular damage that accumulates with age due to incomplete somatic maintenance. Lifespan is thus expected to be modulated by investment into physiological processes of damage prevention and repair. So far, investigations of somatic maintenance have mostly focused on systems of damage prevention such as anti-oxidants, and have for the most part refuted the hypothesis that longevity is achieved through damage prevention. A possible explanation for this patterns is that there is a limited potential to freely modulate the amount of reactive oxygen species because they are important signalling molecules. Such constraints are unlikely to apply to systems of macro-molecular repair, which may effectively affect lifespan by modulating the accumulation of damage with age.
Various forms of macromolecular damage have been linked to senescence. For example, DNA may be damaged or mutated in several ways, and there is evidence from mammalian studies that mutations to genes involved in DNA repair accelerate senescence. Similarly, the cellular accumulation of damaged proteins can be toxic and a range of maintenance mechanisms exist to keep this accumulation in check, many of which have been linked to ageing and longevity. One such mechanism is the Ubiquitin Proteasome System (UPS), which degrades mis-folded or damaged proteins by labelling them with ubiquitin and subsequently degrading them. Subunits of the proteasome involved in the UPS have been found to be associated with lifespan and stress resistance in a range of species, from yeast to humans.
The aim of this study is to investigate whether natural variation in lifespan is associated with differential expression of genes involved in the repair of DNA and proteins. To study the role of these somatic repair genes, we take advantage of the striking variation found in social insects, where queens and workers can differ in their lifespan by more than an order of magnitude. Importantly, the difference in lifespan must be due to differences in gene expression, since there are usually no genetic differences between castes. A particularly interesting species for studies of ageing is the ant Lasius niger, where queens can survive as long as 29 years whereas workers live for only one or two years even in laboratory conditions. Since lifespan is expected to be modulated by investment into somatic damage repair, we test the prediction that queens of L. niger have higher expression of somatic repair genes than workers.
Our analysis of 20 somatic repair genes revealed that queens and workers did not differ in their pattern of expression in 1-day-old individuals. The level of expression of these genes increased with age and this up-regulation was slightly greater in queens than in workers, resulting in significantly queen-biased expression of the 20 somatic repair genes in 2-month-old individuals in both legs and brains. Similarly, analysis of 244 genes related to DNA repair revealed no effect of caste on expression in 1-day-old individuals, but a greater up-regulation with age in queens than workers, resulting in significant queen-biased expression in the legs of 2-month-old individuals. Overall, the combination of these analyses indicates a lack of concerted differences in somatic repair gene expression between 1-day-old queens and workers, but a significantly higher level of expression in queens than workers in 2-month-old individuals.
Overall, the differences in somatic repair gene expression that we have identified between queens and workers are consistent with the hypothesis that longevity is associated with investment into somatic repair. This contrasts with results from studies investigating the process of damage prevention through anti-oxidant enzymes in social insects, where expression of antioxidant genes was found to be higher in workers than queens, perhaps to compensate for workers' the increased levels of activity. Our results suggest that damage repair may be more relevant to lifespan than removal of antioxidants. One reason for this could be the important role that antioxidants play in critical biological processes, which prevents them from being freely modulated.
Investigating Differences in Brain Aging in Older Adults
We all grow old and all lose cognitive function, but different people of the same age exhibit quite a wide range of variation in losses and remaining capabilities. Most researchers are far more interested in investigating relative differences in natural aging, as this aids in the mapping of exactly how aging progresses, than they are interested in building treatments for aging, sad to say. So we see a lot of studies of this sort, generating a greater understanding that is both irrelevant and useless for the age of rejuvenation therapies to come. It won't meaningfully contribute to the production of treatments that can repair the causes of cognitive aging, and after those treatments are widely available no-one will get to the point of suffering this form of degeneration.
A study examines a remarkable group of older adults whose memory performance is equivalent to that of younger individuals and finds that certain key areas of their brains resemble those of young people. While most older adults experience a gradual decline in memory ability, some researchers have described older adults - sometimes called "super agers" - with unusually resilient memories. For the current study, the team enrolled 40 adults ages 60 to 80 - 17 of whom performed as well as adults four to five decades younger on memory tests, and 23 with normal results for their age group - and 41 young adults ages 18 to 35. "Previous research on super aging has compared people over age 85 to those who are middle aged. Our study is exciting because we focused on people around or just after typical retirement age - mostly in their 60s and 70s - and investigated those who could remember as well as people in their 20s."
Imaging studies revealed that these super agers had brains with youthful characteristics. While the cortex - the outermost sheet of brain cells that is critical for many thinking abilities - and other parts of the brain typically shrink with aging, in the brains of super-agers a number of those regions were comparable in size to those of young adults. "We looked at a set of brain areas known as the default mode network, which has been associated with the ability to learn and remember new information, and found that those areas, particularly the hippocampus and medial prefrontal cortex, were thicker in super agers than in other older adults. In some cases, there was no difference in thickness between super agers and young adults. We also examined a group of regions known as the salience network, which is involved in identifying information that is important and needs attention for specific situations, and found preserved thickness among super-agers in several regions, including the anterior insula and orbitofrontal cortex."
Critically, the researchers showed not only that super-agers had no shrinkage in these brain networks but also that the size of these regions was correlated with memory ability. One of the strongest correlations between brain size and memory was found in an area at the intersection of the salience and default mode networks. Previous research has shown that this region - the para-midcingulate cortex - is an important hub that allows different brain networks to communicate efficiently. Understanding which factors protect against memory decline could lead to important advances in preventing and treating age-related memory loss and possibly even various forms of dementia. "We desperately need to understand how some older adults are able to function very well into their seventh, eight, and ninth decades. This could provide important clues about how to prevent the decline in memory and thinking that accompanies aging in most of us."
Hearing Loss Accelerates in Later Old Age
Aging is not a linear process, and different causes and consequences of aging run at different paces at different times in later life. In most cases, the rate of decline accelerates. All of our biological support systems, large-scale and small-scale, interact with one another. Damage and dysfunction in one speeds up the progression of damage and dysfunction in others. Just look at failure of cellular maintenance operations, degrading the effectiveness of all tissues, or the decline of the immune system, which is responsible for culling dangerous cells, assisting in healing, and numerous other jobs beyond the better known function of defense against invading pathogens. Here, researchers provide one example among many of the way in which specific manifestations of aging speed up as the years pass:
Presbycusis, or age-related hearing loss (ARHL), affects approximately two-thirds of adults older than 70 years and four-fifths of adults older than 85. It is a major public health concern that is associated with numerous deleterious effects. Currently, there is a global demographic change that has resulted in an increase in the number of older adults. In the United States, the population of individuals older than 80 years is expected to double in the next 40 years. The majority of research in ARHL, however, groups participants older than 70 years into a single category, thus obscuring changes in the severity of hearing loss as individuals live to 80 years or older.
This study included 647 patients 80 to 106 years of age who had audiometric evaluations at an academic medical center (141 had multiple audiograms). The degree of hearing loss was compared across the following age brackets: 80 to 84 years, 85 to 89 years, 90 to 94 years, and 95 years and older. From an individual perspective, the rate of hearing decrease between 2 audiograms was compared with age. The researchers found that changes in hearing among age brackets were higher during the 10th decade of life than the 9th decade at all frequencies for all the patients (average age, 90 years). Correspondingly, the annual rate of low-frequency hearing loss was faster during the 10th decade. Despite the universal presence of hearing loss in this sample, 382 patients (59 percent) used hearing aids. "More attention should be on counseling patients on accepting hearing aids in a longitudinal primary care setting, especially in the population living to 80 years or older."
The scientists here urge greater use of existing compensatory mechanisms, but should also be urging greater funding for work on regenerative medicine for the causes of age-related deafness. There are a number of promising lines of research focused on neurodegeneration in the connections between ear and brain on the one hand and regrowth of hair cells in the ear on the other, for example.
Pax6 in Regeneration of the Retina in Newts
A fair number of researchers are mining the biochemistry of highly regenerative species in search of the differences that enable regrowth of damaged organs. There is the hope that these differences are in at least some cases small enough that human tissues could be adjusted to perform far greater feats of regeneration. At this point it is far too early to say how likely this is, how long the mapping process will take, or how difficult it will be to build therapies when the relevant differences are identified. There have been a few interesting discoveries in recent years, and this is the latest of these:
In contrast to other vertebrates including humans, the newt can regenerate, even as an adult, an entire retina from retinal pigment epithelium (RPE) cells. In adult vertebrate eyes, the RPE is a highly differentiated monolayer-cell-sheet laminating the back of the neural retina (NR) and functions as a partner of the NR for vision. Mature RPE cells, as a rule, do not proliferate under physiological conditions. In the adult newt, RPE cells in the intact eye are also mitotically inactive, but when the NR is removed from the eye by surgery, RPE cells lose their epithelial characteristics and detach from each other as well as from the basement membrane (Bruch's membrane), giving rise to the aggregates of mesenchymal-like cells with multipotency, named RPE stem cells (RPESCs), in the vitreous cavity. RPESCs are subsequently divided into two cell populations which undergo proliferation, so that they can differentiate into two epithelial layers of progenitor cells (named pro-NR and pro-RPE layers) that eventually regenerate new functional NR and RPE, respectively.
It remains unknown how such a sophisticated mechanism for retinal regeneration evolved in the newt. It would be difficult to understand this mechanism solely by the mechanisms underlying RPE-to-NR transdifferentiation which can be induced in a restricted time frame during embryonic development. In these cases, the RPE does not lose its epithelial characteristics, but directly switches into the neuroepithelium, giving rise to the NR while losing the RPE. On the other hand, our recent studies revealed a similarity in early behaviour of RPE cells between adult newt retinal regeneration and human retinal disorders such as proliferative vitreoretinopathy (PVR). In PVR, when the NR suffers a wound from a traumatic injury, RPE cells - as in the newt - start to lose their epithelial characteristics while acquiring the ability to migrate and proliferate. However, unlike in the newt, these cells eventually transform into myofibroblasts, a major component of both the epi- and sub-retinal membranes which close the wound of the NR, but finally withdraw the NR by contraction, leading to a loss of vision. In this process of transformation (classified as the epithelial-mesenchymal transition, or EMT), it has been suggested that RPE cells pass through a multipotent state. Such multipotent RPE cells in humans, which were also named RPESCs, are regarded as the cells corresponding to the newt RPESCs.
Perhaps, in the newt, something may have happened in early processes of retinal disorders like PVR during evolution, so that the fate of RPESCs was directed toward retinal regeneration. If this is the case, when retinal regeneration in the newt is impaired in early processes, symptoms of PVR would become apparent. In this study, we examined this hypothesis. For this, we created for the first time a transgenic newt enabling RPE-targeted gene regulation and successfully hindered retinal regeneration by knocking down the expression of Pax6 in RPESCs.
It would be difficult to understand by comparison with eye development how normal reprogramming by Pax6 prevents RPE cells from transforming into myofibroblast-like cells. This issue would be of mature RPE cells. Pax6 may function even as a key factor that revises a default program which is booted in mature RPE cells after retinal injury and leads them to EMT. It must be noted here that Pax6 may be expressed in human RPESCs which give rise to myofibroblast cells in PVR. In the newt, something might have happened in RPE cells during evolution so that Pax6 can work properly for retinal regeneration while inhibiting EMT. Further understanding of how Pax6 works in reprogramming RPE cells in the adult newt in comparison with the homologous system in humans is necessary not only to uncover the changes that occurred in the newt during evolution but also to unlock the potency of in vivo retinal regeneration from RPE cells in humans. These findings would lead, in the future, to a novel clinical treatment of RPE-mediated retinal disorders that inhibits the EMT of RPE cells while promoting retinal regeneration in the eyes of patients.
Researchers Demonstrate Growth of Yet More Lung Organoids
The tissue engineering community is making rapid progress in discovering techniques to reliably grow functional tissue structures from cells. The challenge of producing blood vessel networks remains, however, so these tissues are small in size. Any larger and the inner cells would not receive sufficient oxygen and nutrients. This is not to say that these organoids are useless - far from it. They will revolutionize many areas of research by replacing the use of animal models and greatly speeding up activities such as drug discovery and testing. Further, for many tissues the transplantation of multiple organoids to be integrated into an existing organ is a potentially viable approach to improving function and treating degenerative conditions: consider that many organs function as filtration devices or chemical factories, and these functions are only loosely connected to the present shape and location of the organ. To mention one example from recent years, there is nothing to prevent liver, pancreas, and thymus organoid tissue from usefully functioning inside lymph nodes rather than their usual location. Lungs are a less flexible situation, but it is still the case that organoids may be the basis for a useful transplantation strategy in addition to benefiting research efforts:
By coating tiny gel beads with lung-derived stem cells and then allowing them to self-assemble into the shapes of the air sacs found in human lungs, researchers have succeeded in creating three-dimensional lung organoids. The laboratory-grown lung-like tissue can be used to study diseases including idiopathic pulmonary fibrosis, which has traditionally been difficult to study using conventional methods. "While we haven't built a fully functional lung, we've been able to take lung cells and place them in the correct geometrical spacing and pattern to mimic a human lung." The researchers started with stem cells created using cells from adult lungs. They used those cells to coat sticky hydrogel beads, and then they partitioned these beads into small wells, each only 7 millimeters across. Inside each well, the lung cells grew around the beads, which linked them and formed an evenly distributed three-dimensional pattern. To show that these tiny organoids mimicked the structure of actual lungs, the researchers compared the lab-grown tissues with real sections of human lung. "The technique is very simple. We can make thousands of reproducible pieces of tissue that resemble lung and contain patient-specific cells."
Moreover, when researchers added certain molecular factors to the 3-D cultures, the lungs developed scars similar to those seen in the lungs of people who have idiopathic pulmonary fibrosis, something that could not be accomplished using two-dimensional cultures of these cells. Idiopathic pulmonary fibrosis is a chronic lung disease characterized by scarring of the lungs. The scarring makes the lungs thick and stiff, which over time results in progressively worsening shortness of breath and lack of oxygen to the brain and vital organs. After diagnosis, most people with the disease live about three to five years. Though researchers do not know what causes idiopathic pulmonary fibrosis in all cases, for a small percentage of people it runs in their families. To study the effect of genetic mutations or drugs on lung cells, researchers have previously relied on two-dimensional cultures of the cells. But when they take cells from people with idiopathic pulmonary fibrosis and grow them on these flat cultures, the cells appear healthy. Using the new lung organoids, researchers will be able to study the biological underpinnings of lung diseases including idiopathic pulmonary fibrosis, and also test possible treatments for the diseases. To study an individual's disease, or what drugs might work best in their case, clinicians could collect cells from the person, turn them into stem cells, coax those stem cells to differentiate into lung cells, then use those cells in 3-D cultures. Because it's so easy to create many tiny organoids at once, researchers could screen the effect of many drugs.
An Approach to the Analysis of Differences Between Species in the Matter of Aging and Longevity-Enhancing Interventions
Most research into the mechanisms of aging starts with cells and then moves to short-lived species such as flies or nematode worms - easier to manage than mice, and the short life spans mean that more work can be carried out for a given amount of funding and time. Only later do more promising projects move to the use of mice. At each stage of the process, from cells to worms, from worms to mice, from mice to people, many research results fail to prove relevant. Worms are not mice, and mice are not people. There are significant differences, for all that many of the most fundamental aspects of aging and cellular biochemistry are remarkable similar in all of these species. The paper here, the full text in PDF format only I'm afraid, is an interesting attempt to put some numbers to the degree to which nematodes and mice are different in the matter of aging and interventions that slow aging.
Given the existence of subtle but important differences that can produce the results outlined here, then it may well be the case that the development of reliable biomarkers of aging should be prioritized to a greater degree and work in nematodes and the like largely abandoned in favor of short mouse studies that assess effects on aging through the use of biomarker tests. The discussion below should be considered in the context of the comparatively small changes in life span achieved by most interventions, where it is reasonable to ask how that change came about and whether it was due to an influence on aging or some other factor. The future of the field, assuming that SENS rejuvenation research prospers, is to create increases in life span and health span so large that there is no room for debate as to what is taking place.
It has been argued that an extension of lifespan may not necessarily be concrete evidence of a retardation of the aging process. In this view, a lifespan-extending intervention may simply remedy deficiencies in the environment or in the genetic make-up of one particular strain. The intervention would therefore extend lifespan by correcting specific flaws rather than altering the aging process. These considerations create a conundrum: if lifespan is not a reliable measure of aging, how can we confirm that a particular manipulation truly affects the aging process? One approach is to assess physiological phenotypes which are known to deteriorate with age, such as cognition or the functioning of the cardiovascular or immune systems, in order to detect similarities or discrepancies with the patterns observed in control strains. An alternative criterion is to consider whether a particular manipulation changes how mortality rates increase with age. This is based on the hypothesis that the increased incidence of the age-related pathological changes that characterizes the aging process is reflected in changing mortality rates.
In the Gompertz model of mortality, 'G' describes the rate at which mortality rates accelerate with age and 'A' represents the initial mortality rate at time 0. 'A' is strictly theoretical as a mortality rate, since there can be no actual mortality at time 0. Instead, it can be determined by extrapolation from mortality rates at greater ages, and does not necessarily correspond to true mortality rates at birth or during youth. Decreasing 'A' extends lifespan by shifting the inflection point of the curve rightwards, such that it occurs proportionally later in age, relative to maximum lifespan. There is no change in the apparent "slope" of the curve. In contrast, decreasing 'G' extends lifespan by decreasing the slope. 'A' has been described as measuring the vulnerability to disease unrelated to the onset of aging, or the effect of the environment on mortality. Changes to 'A' will alter mortality rates evenly across the lifespan of the population. In contrast, since the parameter 'G' can be considered a rate constant for the age-related increase of mortality of a sample or population, it is often given a pre-eminent role as an indicator of the "rate of aging". This is a logical hypothesis, since an increased or decreased 'G' would likely reflect the rate at which physiological conditions are declining with age. Therefore it is often assumed that interventions that extend lifespan by slowing aging, rather than by alleviating some age-independent pathology, will be associated with a decreased 'G'.
Since a substantial number of studies reporting changes in mouse lifespan resulting from genetic manipulations have now been published, we hypothesized that a correlation-based approach may be a more powerful technique to search for patterns in Gompertz parameter shifts. For example, a negative correlation between lifespan and 'G' across long-lived lines of mice would suggest that their extended longevity was due to a decreased rate of aging. By the straightforward method of plotting Gompertz parameters against lifespan we found that most of the genetically-driven variability in lifespan between normal- or long-lived groups of mice was due to changes in 'A', not in 'G'. In fact, 'G' remained remarkably invariant for different groups of wild-type mice as well as for mice with genetic variations that extend lifespan. The only exceptions to this trend were some interventions which acutely shortened lifespan. We also found this to be true for a collection of inbred mice strains studied under uniform conditions as part of the Mouse Phenome Database. Thus, with the exception of some severe lifespan-shortening interventions, lifespan in laboratory mice is largely determined by factors that affect initial vulnerability, rather than age-dependent mortality rate acceleration. In contrast to mice, we found lifespan to be associated with changes in 'G', not 'A', among long-lived C. elegans mutants. This was true as a trend across long-lived mutants, and was also observed by analysing changes to Gompertz parameters among numerous replicate studies of the well-characterized daf-2, isp-1, and eat-2 mutants.
Considering the Origins of Peto's Paradox
If cancer results from mutation, then why don't species with more cells have more cancer? That is clearly not the case. Whales, for example, have a lower rate of cancer than humans despite having something like a thousand times as many cells as we do. Mice have a much higher rate of cancer than we do. This is Peto's paradox in a nutshell, and the observation is the basis for a range of fundamental research that seeks to understand large variations in cancer rates across mammalian species, and then perhaps do something with that understanding. This paper looks at the evolutionary origins of this variation between species of differing sizes:
Multicellularity is risky. Every cell could, in principle, escape the checks and balances of healthy organisms that keep individual cells from proliferating in an uncontrolled manner and cause cancer. If having many cells is risky, then having even more cells should be even riskier. If the hazard rate increases with age, then a longer life should progressively increase cancer risk. Hence, large, long-lived organisms are expected to suffer a higher lifetime cancer risk than small, short-lived organisms. This does not seem to be the case; an apparent contradiction known as Peto's paradox. There is significant recent interest in Peto's paradox and the related problem of the evolution of large, long-lived organisms in terms of cancer robustness. Peto's paradox, however, is circular. The paradox relies on assuming a certain lifespan, after which the cancer risk during that lifetime is evaluated. This seems the wrong procedure. Lifespan is a function, among others, of cancer robustness: organisms are long-lived because they are cancer robust. If not, then they would be short-lived. One cannot next expect that they are not cancer robust and should therefore have a higher lifetime cancer risk, based on the very same lifespan that derives from high cancer robustness. Similarly, large organisms exist because they are cancer robust; one cannot next expect that they are not.
Because no set of competing risks is generally prevalent, it is instructive to temporarily dispose of competing risks and investigate the pure age dynamics of cancer. In addition to augmenting earlier results, I show that in terms of cancer-free lifespan large organisms reap greater benefits from an increase in cellular cancer robustness than smaller organisms. Conversely, a higher cellular cancer robustness renders cancer-free lifespan more resilient to an increase in size. This interaction may be an important driver of the evolution of large, cancer-robust organisms. Large, long-lived animals can exist if and only if they are cancer robust; one cannot next expect them to have a higher lifetime cancer risk because they are not cancer robust. The observation that (cells of) large, long-lived organisms must be more cancer robust than (those of) small, short-lived organisms is shrewd and of great importance, but should have been the endpoint. The expectation that large, long-lived animals should have a higher lifetime cancer risk than small, short-lived organisms is an unnecessary and faulty extra step, as is the resulting paradox when that prediction remains unconfirmed. Given that whales live up to 200 years and weigh up to 200,000 kg, their cancer dynamics differ from those of humans, and the "promise of comparative oncology" stands.
Estimating the Contribution of Inactivity to Mortality Rates
One observation that has emerged in recent years from large epidemiological studies of health and longevity is that greater time spent sitting correlates with a higher risk of death and thus shorter life expectancy. This even seems to be independent of amount of exercise carried out while not sitting, though that aspect of the findings needs further reinforcement to rise to the level of evidence for the more general association between level of inactivity and mortality rates. As for most statistical human studies it is a challenge to move from correlation to understanding the directions and mechanisms of causation, though as ever we can reference the numerous animal studies in which it is shown that increased activity is very definitely a cause of reduced mortality. This latest paper to look at the "chair effect" is more food for thought on the topic. The national differences suggest that this, like most correlations, reflects the operation of numerous interacting environmental factors:
Exercising and not spending so much time on the couch tend to be some of these good intentions. 31% of the worldwide population does not meet the current recommendations for physical activity according to several studies. In addition, a lack of exercise is associated with major noncommunicable diseases and with deaths of any cause - inactivity is the culprit behind 6% to 9% of total worldwide deaths. Today's lifestyle has an impact on these numbers. In fact, various studies over the last decade have demonstrated how the excessive amount of time we spend sitting down may increase the risk of death, regardless of whether or not we exercise. A new study now estimates the proportion of deaths attributable to that 'chair effect' in the population of 54 countries, using data from 2002 to 2011. "It is important to minimise sedentary behaviour in order to prevent premature deaths around the world, cutting down on the amount of time we sit could increase life expectancy by 0.20 years in the countries analysed."
The results reveal that over 60% of people worldwide spend more than three hours a day sitting down - the average in adults is 4.7 hours/day - and this is the culprit behind 3.8% of deaths (approximately 433,000 deaths/year). The highest rates were found in Lebanon (11.6%), the Netherlands (7.6%) and Denmark (6.9%), while the lowest rates were in Mexico (0.6%), Myanmar (1.3%) and Bhutan (1.6%). Spain falls within the average range with 3.7% of deaths due to this 'chair effect'. The authors calculate that reducing the amount of time we sit by about two hours (i.e., 50%) would mean a 2.3% decrease in mortality (three times less), although it is not possible to confirm whether this is a causal relationship. Even a more modest reduction in sitting time, by 10% or half an hour per day, could have an immediate impact on all causes of mortality (0.6%) in the countries evaluated.
Rejuvenation Research should be the Highest of Priorities
In this op-ed, Aubrey de Grey of the SENS Research Foundation argues that finding effective ways to treat the causes of the aging process should be the highest priority for our societies. No other single thing causes anywhere near as much suffering, loss, and death, and yet few resources are devoted to bringing an end to aging. Few people seem to realize just how plausible it is to build rejuvenation therapies in the near future given the present advanced state of biotechnology and medical research. Some of those therapies are under development in startup companies even today, but much more work remains ahead, at present supported only by a low level of funding. So much more could be achieved, and far more rapidly, given sufficient material support.
What is medicine for? Surely an easy question, right? Apparently not. I have always believed that the purpose of medicine is to alleviate the suffering caused by ill-health and death. One must include both, because death itself is very effective in ending the suffering caused by ill-health, and even though there is vibrant debate concerning the appropriate access to assisted suicide, society overwhelmingly adopts the policy that life is sacred and must be extended at virtually all cost. Or does it? There is a bizarre contradiction in our collective approach to the ill-health of old age. On the one hand we are happy to allocate billions upon billions to the quixotic pursuit of extended but functionally impaired life, under the banner of geriatric medicine, but on the other hand we overwhelmingly express deep ambivalence, if not outright opposition, to the idea of future medicine that would actually work - that would entirely abolish those ailments and maintain youthful mental and physical function to much greater chronological ages. When asked to consider such a world, most people are far more inclined to raise concerns about how society would manage the likely side-effect of increased average longevity, than to pay any attention whatever to the prospective alleviation of so much suffering.
The ill-health of old age currently accounts not only for over 70% of deaths worldwide but also for a similar proportion of medical expenditure. In the industrialised world, these numbers are in the region of 90%. What if we had medicine that would prevent the conditions on which all that money is spent? The money would be saved! Sure, the medicines that achieved this prevention would themselves cost money, but there is no reason (not even any hypothetical reason) why prevention should not be better (i.e. cheaper) than cure in this case as it usually is. And that's just the start. Do you, or does anyone you know, have a parent with advanced Alzheimer's or any other age-related chronic disease? How much productivity is lost from the burden of caregiving as a result? It's astronomical. And beyond that, consider the wealth that the elderly could contribute to society if only they remained able-bodied. The economic benefit would be unimaginable.
How is this not completely obvious to everyone? My only explanation is that the powers that be are just as irrational about aging as the rest of society. There can be no doubt that policy-makers are acutely aware of the economic realities that I summarise above, but their decisions are based on their perceptions of the impact on their priorities. And it seems that policy-makers remain convinced that it is not in their interests to inject relatively minuscule sums into research that could pay for itself literally millions of times over. Why? Only two explanations seem available. One is that the reward is further in the future than the current electoral cycle, such that whatever the logic of such a course, it would be against the nearer-term vested interests of the political elite. The other is that these decision-makers truly feel, in spite of all the scientific evidence trumpeted by biogerontologists every day, that the probability of actual success (i.e., of a substantial hastening of the defeat of ageing) from such expenditure really is less than one in a million, thus outweighing the benefit that success would bring. Neither such attitude is remotely excusable.
Mitochondria in Muscle Aging and Sarcopenia
This review paper takes a look at some of what is known of the contribution of mitochondrial dysfunction to age-related loss of muscle mass and strength, progressing towards the condition known as sarcopenia. The hundreds of mitochondria packed into every cell act as power plants; these evolved descendants of symbiotic bacteria are responsible for, among many other things, generating chemical energy stores to power cellular operations. This process also produces potentially disruptive reactive oxygen species as a byproduct, but the structures most likely to take the brunt of that disruption are the mitochondria themselves. Mitochondrial damage is important in the aging process, producing a growing population of dysfunctional cells that export harmful reactive molecules into surrounding tissues, giving rise to damaged proteins that contribute to a range of age-related conditions. Declining energy store production is also a significant problem in tissues that need greater amounts of energy to function and maintain themselves, such as muscles:
Loss of muscle mass and muscle wasting are clinical symptoms associated with many chronic diseases as well as with the aging process. The loss of muscle mass accompanied by a decrease in muscle strength and resistance which occurs in the elderly is termed sarcopenia. In the population over 65 years of age, this decay in muscle function is particularly associated with increased dependence, frailty, and mortality. In fact, sarcopenia is the main cause of disability among the elderly. Among the mechanisms that contribute to sarcopenia have been described the decrease in physical activity, the decrease in anabolic hormones, and an increase in proinflammatory cytokines as well as the increase in catabolic factors. Further, recent studies have also identified that not only mitochondrial metabolic dysfunction but mitochondrial dynamics and mitochondrial calcium uptake too could be involved in the degeneration of skeletal muscle mass. A growing body of evidence suggests that muscle quality plays a systemic role in the aging process. Thus, it has become apparent that mitochondrial status in muscle cells could be a driver of whole body physiology and organism aging.
Reactive oxygen species (ROS) are produced in the mitochondria as a byproduct of an inefficient transfer of electrons through the electron transport chain (ETC). During the aging process, ROS production increases as well as mitochondrial damage and dysfunction. These phenomena have also been observed in age-associated diseases. In fact, it is supposed that the observed increase in ROS is derived from a decline in mitochondrial function. Interestingly, in flies, the development of genetic sensors which can be targeted specifically to a tissue or to an organelle within the cell is helping to reveal which tissues are subject to redox dysregulation during aging. Increased production of ROS in aged and age-related phenotypes has also been observed to be accompanied by alterations in mitochondrial DNA (mtDNA) quality and quantity. It has been proposed that increases in ROS could easily target the mtDNA which lacks histone protection. Furthermore, it is argued that with aging, DNA repair mechanisms efficiency decline and could lead to mutations in mtDNA.
Consistent with the paradigm, in mice, it has been found that ROS production is increased in aged muscles and directly affects the complex V (ATP synthase) of the ETC, oxidizing, thereby preventing the synthesis of ATP by the oxidized protein. One possible consequence of this process is that the damaged mtDNA promotes the biogenesis of damaged mitochondria, in turn producing more ROS, enabling a vicious cycle to continue. Contrasting these results, recent deep sequencing of mitochondrial genomes in mice suggests, otherwise, that mutations in the mtDNA arise from replication errors during early life. Increased ROS species in the cell have also been associated with diminished ROS scavengers activities during aging. Interestingly, recent evidence has demonstrated that genetic manipulation of mitochondrial antioxidants, given by the overexpression of human mitochondrial catalase in old mice, protects from oxidative damage and age-associated mitochondrial dysfunction, together with protecting from energy metabolism diminution in age. Several questions remain open regarding the behavior of ROS during organism and muscle aging. For example, when in lifespan do ROS first appear in the muscle? Or which concentrations of ROS are required to alter the gene and protein networks that ensure mitochondria and muscle quality functions? These are still matters to be addressed.