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- Considering Juvenescence
- A Short Interview with George Church on Genetics and the Treatment of Aging
- Reviewing the Commercial Application of Longevity Science
- Recent Examples of Research into Protein Aggregates and their Clearance in the Context of Neurodegenerative Disease
- More Evidence for Senolytic Therapies as a Treatment for Lung Fibrosis
- A Few More Details on Juvenescence
- Using Nanoparticles to Vitrify and Rapidly Thaw Fish Embryos
- Linking the Bad Behavior of Senescent Cells with Innate Immune Mechanisms
- Longer-Lived Mice Better Resist Immune System Decline
- Reviewing Epigenetic Inheritance of Longevity
- Do Chimpanzees Suffer from Alzheimer's Disease?
- Converting Effector T Cells into Regulatory T Cells
- AgeX Therapeutics
- Cell Therapy versus Lung Fibrosis
- Optimism without Complacency in the Matter of Rejuvenation Research
As noted this morning, Juvenescence is the new venture fund slash business development company created by investor Jim Mellon and allies as a part of his interest in the development of real, working anti-aging medicine. No-one is getting any younger, and that includes people with the resources to do something about this state of affairs, should they finally wake up to the ongoing revolution in biotechnology and put their shoulders to the wheel. This is the latest instance of a well-heeled group setting forth in earnest to achieve something in aging research and related biotechnology relevant to treating aging as a medical condition. Is it the most promising to date? Perhaps.
Past examples have included Larry Ellison's initiative, Paul Glenn's support of research, Peter Thiel's support of SENS, and Google's California Life Company, among others. In many cases, the rhetoric at the outset gave some hope that these large investments would be more visionary than a funding of the same old dead-end work on pharmaceutical alteration of metabolism to slightly slow aging that has characterized the mainstream for the past fifteen years. But in only one case was there in fact material support for the better, game-changing alternative, rejuvenation research of the sort exemplified by the SENS programs, the only plausible way to greatly extend lives and turn back aging in our lifetimes. If there is caution and a wait and see attitude related to Juvenescence and the rhetoric from its founders, it is because Lucy has snatched away the ball one too many times these past years. Still, this is promising rhetoric, I have to admit that much. It comes from a fellow who has raised talking up his position to something of an art form, so I'm sure we'll be hearing more of it:
Mellon on the Markets: New "highs" for early investors
On the subject of Juvenescence, I am off to San Francisco with my old best friend Anthony Baillieu to meet my new best friend Aubrey de Grey (Google him!) and my dear colleague Greg Bailey. We are all spending the day at the Buck Institute of Aging - not to be rejuvenated ourselves, but to understand more of the amazing science that is coming out of this institution.
One of the key senolytic drugs in development, being trialled by Unity Biotechnology, first emerged at the Buck. In a nutshell, senolytics are among the first of several compounds that will add significantly to human lifespan in the next ten or twenty years. While more fully described in the new book, these are drugs that clear so-called senescent cells from tissues. Senescent cells become more prevalent as we age, and are cells that are neither dead nor healthy, but which exist in a limbo like state. They contribute significantly to inflammatory disease and their removal, at least in part, is demonstrably life extending in animal models.
We are also visiting another company involved in senolytics, and will be looking to make an investment in it for our venture, Juvenescence Limited, which is jointly owned by Greg, Dec Doogan (formerly head of drug development at Pfizer, the world's biggest drug company) and myself. We have collectively recently invested a largish sum in a venture called Insilico Medicine, which uses deep neuronal networks (aka AI) to enhance medical discoveries, and we have capitalised a joint venture with Insilico called Juvenescence AI which will look to discover five new chemical entities a year for several years, using AI. These are exciting times in the field of longevity, and believe me, staying healthy today will allow you to cross a bridge to ultra-long life in the not too distant future.
Alex Zhavoronkov at Insilico Medicine will, I'm sure, forgive me when I say that I haven't been following the Juvenescence work all that closely because the early focus appeared to be fairly standard aging-related drug discovery in areas that I think have little potential. He knows my views on these matters. Should the staff at Insilico Medicine set their sights on senolytics and small molecule glucosepane breakers, I will be the first to laud their efforts, as that is a portion of the SENS rejuvenation research agenda wherein standard issue drug discovery processes, rational drug design, and improvements thereof can shine. But building more marginal geroprotectors that target mTOR or regulators of mitochondrial function or autophagy or other line items associated with the scores of ways to modestly slow aging in mice? Not so promising. We're twenty years in to that sort of work, and what do we have to show for it? More knowledge of the operation of metabolism, yes, but also a distinct absence of ways to add healthy years to life that are any more effectively than eating less and exercising more.
I think that the evidence to date gives us all good reason to think that there is a low ceiling to the utility of such mainstream work in terms of years of life gained at the end of the day, and that the ceiling isn't going to rise significantly with the input of far greater amounts of funding. It is a fundamental aspect of these mechanisms. Aging is damage, and if research doesn't aim to directly repair or remove that damage, then it will always be of low utility. Try keeping any damaged machine running without actually repairing it. Further, stand back for a moment and take an earnest look at calorie restriction mimetic development versus senolytic development. Fifteen years of the former has given us nothing to compare to the reliability and breadth of effects on aging and age-related diseases in animal studies resulting from a mere five years of earnest development in senolytics. This is because calorie restriction mimetics do not repair any form of damage that causes aging, whereas senolytic therapies to clear senescent cells do. It is that simple.
To return to Juvenescence, their clear interest in senolytics, and all of the obvious incentives to be involved in senolytic development now that the commercial side of the field has been validated by large investments in Unity Biotechnologies, makes me more cautiously optimistic for this initiative than I was when Calico launched. Even if the Juvenescence principals do no more than vocally and materially bolster the senolytics industry, that will still be a great good. Will they in fact do more than that for the development of SENS biotechnologies? We shall have to wait and see.
A Short Interview with George Church on Genetics and the Treatment of Aging
The Life Extension Advocacy Foundation volunteers recently interviewed George Church, one of the leaders in the research community who has come around these past few years to speak out in public as being very much in favor of treating aging as a medical condition. I point this out largely because they ask about some of his recent comments regarding timelines in the near future development of anti-aging therapies. He thinks that the first are only a few years away, which is indeed true from my perspective given what is happening in the development of senolytics to clear senescent cells, but Church doesn't have senolytics in mind when he says this. He is one of the luminaries of modern genetic biotechnology, and he sees the future through that lens.
Professor George Church - Turning Back Time to End Age-related Diseases
You recently said that you "predict we are about to end the aging process. In the next five years no less!" Whilst progress has indeed been rapid in the field of rejuvenation biotechnology, could you clarify, is this five years to achieving this in human cells, to clinical trials or what exactly?
Within five years it seems plausible to have some gene therapies in FDA approved clinical trials in dogs - aimed at general aging reversal, but quite likely, labeled for specific diseases (and in humans soon thereafter). This means combinations of gene therapies aimed at most of the known major aging pathways, though there are major challenges in efficient delivery.
Do you agree that epigenetic alterations as described in the Hallmarks of Aging are a primary driver of the aging process, and if so do you think we can safely use cell reprogramming factors OSKM (OCT4, SOX2, KLF4 and MYC) to turn back cellular aging?
Yes. Epigenetics are important drivers, but it are only part of the Hallmarks of Aging - and OSKM would, in turn, be only part of that. Other examples are factors behind heterochronic parabiosis. Efficacy may depend on the various tissue types.
DNA damage is proposed to be a primary reason we age. Can it be repaired by targeting TFAM (Transcription factor A, mitochondrial precursor) to increase NAD (a coenzyme in all living cells that facilitates the production of energy) levels that are known to facilitate DNA repair?
We have targeted TFAM and consequently raised NAD successfully. The NAD-facilitated repair is not the only route - we can prevent DNA damage (via the management of radical oxygen species), prevent the impact of such damage (e.g. duplicating tumor suppressor genes), favor specific types of DNA repair, or induce apoptosis in cells which appear to acquire potentially oncogenic mutations.
Cancer is caused by an unstable genome resulting from DNA damage and could be considered the poster child of aging diseases, can we use CRISPR to defeat cancer?
Genome editing (TALENs, CRISPR, etc.) and transgenic methods (CART) are being 'successfully' applied, but proof of generality and long remission is not here yet. Effective alternatives are preventative - vaccines against some of the 11 infectious, cancer-causing agents (e.g. HPV), inherited genome sequencing, genetic counseling, prophylactic surgery and avoiding environmental risk factors. Some strategies which work to preventatively reduce cancer in mice might benefit from engineering germline or more efficient delivery of gene therapies (since single untreated cells matter more for cancer than other diseases).
Do you think we can learn useful knowledge that can be applied to humans from the whole-genome sequencing of long lived species such as the 400-year-old greenland shark?
The most promising sequencing insights will probably come from genomes closest to average humans, such as naked mole rat, bowhead whales and human supercentenarians. Even more crucial is low-cost, high-accuracy testing of hypotheses flowing from those sequences, plus already hundreds of hypotheses from model organisms and cell biology (see the GenAge database).
Genetics is an enormous area, even when you narrow down the scope to genetic biotechnologies that can be used to build therapies relevant to aging. There are numerous different things going on, not all of which we should be equally enthused by. I'll draw some fairly arbitrary lines here to demarcate three classes of genetic therapy. The first broad class of work is very similar to existing pharmaceutical development: the construction of means to temporarily alter the level of a particular protein or interfere in one or more interactions carried out by this protein. Genetic technologies hold the promise of being able to carry out this task with far greater accuracy and control over the size of the outcome. The second class of work involves the creation of permanent effects by adding or removing DNA in a targeted fashion, such as to provide a functional copy of a gene that is broken as a result of an inherited mutation. This is not yet practical for therapies applied to human adults due to challenges in obtaining reliable, comprehensive cell coverage, meaning introducing the new DNA into enough cells, and especially stem cells, to produce a significant and lasting effect. But that goal lies very close in the near future.
The third class of work involves more complicated use of genetic machinery. The production of programmable DNA machines that can read cell state, react, and carry out logical operations to produce different outcomes for different circumstances, for example. The Oisin Biotechnologies approach to targeted cell destruction is one such early, simple machine. Far more complex machinery is obviously possible, given the existence of cells in the first place. This class of more complicated uses also include applications of gene therapy that achieve a more devious and multi-layered goal than just inserting a gene that will result in proteins being produced. For example, allotopic expression of mitochondrial genes involves inserting altered versions of mitochondrial genes into nuclear DNA, their usual sequences wrapped in such a way that cellular transport machinery will pick it up these altered proteins, move them back to the mitochondria, and then import them into mitochondria, ending up with a copy of the original protein at the end of that process.
Now, much of the first category of genetic engineering, tinkering with levels of specific genes, will be just as marginal for the treatment of aging as the pharmaceutical approaches that preceded them. That is inherent in the proteins and genes being targeted. When the goal is mimicking the response to calorie restriction, or increasing autophagy, or similar alterations shown to modestly slow down aging in laboratory animals, then the small size and lack of reliability in the outcome is as much inherent in the target as it is in the method used to manipulate the target. These mainstream efforts are only slightly increasing resistance to the consequences of molecular damage in aging, or slightly slowing the accumulation of that damage. They are not truly effective means of addressing aging.
We should nonetheless expect to find that some targets accessible to genetic methods are a lot better than those that can be or have been manipulated via drugs. There are some promising genetic variants that exist in the wild and have far larger effects on human cholesterol levels than the best drugs, such as statins, for example. There is myostatin and follistatin, that can be targeted to increase muscle growth to a far greater degree than any pharmaceutical method, and thus resist age-related loss of muscle mass. But these are still not repair therapies. They are only ways to better compensate somewhat for the losses and damage of aging. The damage will still win if it is not addressed.
So what George Church describes in the short term is really just the application of genetics to the ongoing pharmaceutical tinkering with metabolism that has achieved little of any practical use in the past few decades. All that has been gained is knowledge. What he describes in the longer term is the much more ambitious project of rebuilding the human genome, one small step at a time, to create packages of changes that result in slower aging, greater resistance to the consequences of aging, and other enhancements to the human condition. This is an immense project of vast scope and complexity. It will happen in the fullness of time, but it cannot possibly produce anywhere near as good an outcome in the next few decades as the alternative approach of keeping the present baseline human genome unmodified, and focusing on periodic repair of the molecular damage that arises as a side-effect of the normal operation of metabolism. The research community has a far better roadmap for this goal, there is far less to achieve, and it is a much easier set of projects, where far more is known of what must be done. Genetics with the goal of improving humanity is seductive, as the long-term potential is truly amazing - but unless we address the damage first, we'll all be long dead before that potential is reached.
Reviewing the Commercial Application of Longevity Science
In the open access paper I'll point out today, João Pedro de Magalhães, a long-standing member of both the transhumanist and aging research communities, casts an unbiased eye over present commercial efforts to treat aging as a medical condition, to slow or reverse its effects. The small online transhumanist community that blossomed with the advent of the web over the course of the 1990s includes many alumni who went on to join the scientific community, found biotechnology companies, write books, become advocates, or in other ways influence the course of today's world, now on the cusp of building rejuvenation therapies. Discussions of radical life extension, technological acceleration, and artificial general intelligence were far more fringe concerns back then than is now the case, but this growth in awareness isn't a coincidence. Visions slowly become reality because people work to make that happen. Technological progress is not accidental: it is led by our desires.
I should say that de Magalhães is here generous in not passing judgement on the value (or lack thereof) of most of the various ventures and classes of approach he surveys. But some approaches are definitely better than others, and to my eyes one the principal challenges at this time is to ensure that the effective (damage repair to reverse aging) rather than ineffective (metabolic alteration to slow aging) lines of research obtain significant support and funding. I think that there is definitely the need for some kind of metric to assess the utility of various efforts to address aging. Given figures for investment in a field, number of life span studies in various species, and average size of effect, one could potentially construct an Effectiveness Score to distinguish between fields that are absorbing a great deal of funding to no effect versus those that are more promising. I'd want an algorithm that clearly differentiates between, say, pharmaceutical targeting of mTOR, development of calorie restriction mimetics as a whole, and senolytics in terms of cost-effectiveness. I would expect the latter to be far more cost effective based on present data and the time and funding required to obtain that data. Sadly I suspect that no-one in the field has much of an incentive to participate in such an assessment, and obtaining the funding numbers wouldn't be an easy task.
The Business of Anti-Aging Science
The dream of fending off old age is as old as human civilization. Given the global aging of the population, developing interventions that preserve health in old age and postpone the onset of age-related diseases is more important than ever. In addition, we now know that it is possible to retard aging in animal models. Various genetic, dietary, and pharmacological interventions have been shown to increase lifespan, in some cases dramatically (tenfold is the current record), in short-lived model organisms like yeast, worms, flies, killifish, mice, and rats. Importantly, life-extending interventions not only increase longevity but can retard the onset of age-related diseases, resulting in the extension of healthspan (i.e., the length of time one lives in good health). These breakthroughs in the biology of aging and its impact on health and disease, referred to by some as 'geroscience', have led to the promise that we will be able to delay or slow human aging, resulting in unprecedented health benefits.
Leading causes of death worldwide, and notably in industrialized countries, are age-related diseases like cardiovascular diseases, cancer, and neurodegenerative diseases. Because of the strong relationship between the aging process and age-related diseases, the benefits emerging from anti-aging science have enormous potential. Using a model of future health and spending in the USA, the effect of delayed aging resulting in 2.2 years additional life expectancy would yield 7 trillion in savings over 50 years; whereas addressing single pathologies such as cancer and heart disease would yield less, mostly due to competing risks. Given its huge potential financial benefits, anti-aging science has tremendous commercial opportunities. The anti-aging industry has struggled in the past in terms of reputation, but driven by more recent scientific breakthroughs it has been growing substantially with several young companies supported by world-leading brands.
As with most diseases, traditional pharmacological approaches are the most straightforward and widely explored way to target aging. Notable examples of anti-aging drug discovery efforts include pharmacological manipulations of sirtuins, sirtuin 1 (SIRT1) in particular (targeted by resveratrol), and TOR (targeted by rapamycin), which are currently being explored. TOR inhibition by rapamycin results in increased lifespan from yeast to mammals. In a small but groundbreaking clinical trial by Novartis, rapamycin improved immune function in elderly volunteers. Because rapamycin has various side effects, companies and laboratories are trying to develop safer analogs, known as 'rapalogs'. Research on resveratrol and sirtuins was high profile in 2008 when GlaxoSmithKline (GSK) purchased the sirtuin-focused biotech company Sirtris (based on work at Harvard Medical School) for 720 million. Enthusiasm for resveratrol and sirtuins as anti-aging compounds has arguably declined in more recent years. Briefly, results have been largely disappointing since then. While Sirtris demonstrated that anti-aging biotech companies could rapidly grow in value and become a financial success for founders and early investors, its more recent problems might have hurt subsequent anti-aging science-based enterprises by discouraging investors and entrepreneurs.
Antioxidants have been historically a major focus of the field. However, currently the idea that antioxidant pathways play a major role in aging is being challenged, and epidemiological studies have largely failed to support the supposed benefits of antioxidants. While many dietary supplements still focus on antioxidants, few companies in the field maintain such a focus.
Telomeres, the protein-bound structures at the ends of chromosomes, shorten with cell division and, at least in some tissues, with age. Although genetic manipulations of telomerase in mice have yielded conflicting results, one study found that overexpression of telomerase in adult mice led to a 24% increase in median lifespan while not increasing the incidence of cancer. Therefore, the idea of activating telomerase as anti-aging remains a powerful one, even resulting in one self-experiment using gene therapy by BioViva.
Telomere shortening, as well as various stressors, can cause proliferating cells to stop dividing and enter a proinflammatory senescent state. There is evidence that senescent cells accumulate with age, at least in some tissues. In a landmark study, drug-induced clearance of p16Ink4a-positive cells (a marker of senescence) once per week from age 1 year extended the median lifespan in two normal strains of mice by 24-27%. Tumorigenesis and age-related deterioration of heart and kidney were delayed or slowed. As a consequence, Unity Biotechnology, a company founded by researchers at the Mayo Clinic involved in the above-mentioned work as well as the Buck Institute, has raised 116 million from investors to develop senolytic (i.e., an agent that destroys senescent cells) treatments. Continuing research by the cofounders has focused on senolytic agents, including the killing of senescent fibroblasts with piperlongumine and ABT-263. Interestingly, they have also acquired a patent related to a senescent cell antibody for imaging and delivery of therapeutic agents.
Other companies focusing on senolytics include Oisin Biotechnologies, although, according to their website, they seem to be developing a genetically targeted intervention to clear senescent cells, suggesting a different approach than Unity. Moreover, Everon Biosciences has shown that a significant portion of cells with p16Ink4a expression may be a subclass of macrophage termed senescent associated macrophages (SAMs). Following this discovery Everon has announced that they will focus on these SAMolytic agents. Last, Siwa Therapeutics' focuses on developing antibodies against senescent cell markers capable of identifying and removing senescent cells.
With a decidedly Silicon Valley-based confidence, venture-capital funded big-data approaches are being pursued in aging and longevity science. High-profile players include Calico and Human Longevity Incorporated (HLI). Started as one of Google's moonshot projects in 2013, Calico is attempting to harness big data to improve understanding of the basic biology that controls lifespan. Not much is known about how this will look in practice. HLI is focused more directly on data than Calico and aims to create the largest database of integrated high-throughput assays - genotype, transcript, and microbiome data - along with deep phenotypic data on patients to fully map genotype to phenotype to inform health care in general. Published efforts have focused on deep sequencing of human genomes. Other companies are using big-data techniques to find new uses for already approved drugs. For one project Insilico Medicine uses deep learning on multiple 'omics' data types to find new relationships between existing drugs and gene regulatory pathways effected in, or otherwise related to, aging-related diseases.
In addition to reasons for spending on basic research in general, anti-aging science has unusual potential to benefit from market forces due to particularly favorable demographics. The median wealth of US families aged 62 years or older is over 200,000, compared with 100,000 and 14,000 for middle-aged and young families, respectively. This may in part be responsible for the increase in investment in even non-traditional therapies and direct to consumer (DTC) products and services aimed at extending healthy lifespan. One high-profile DTC company is Elysium Health, which sells its Basis pill directly to consumers. Basis contains an NAD+ precursor, nicotinamide riboside, that declines with age and is required for sirtuin activity. Elysium has already concluded a preregistered, 2-month randomized, double-blind Phase I trial for Basis using 120 healthy 60-80-year-olds. While results have yet to be published, a company press release claims that participant's blood NAD+ levels were increased by 40% for the duration of the second month. However, the release did not mention the results for health measures.
Caloric restriction (CR) is the most studied and most consistent intervention that increases both health- and lifespan. While a CR diet is too harsh for most people, intermittent fasting (IF) has been proposed as a less-restrictive alternative. Based on this premise, L-Nutra was created to develop and market proprietary fasting-mimetic meals designed to provide the beneficial effects of IF.
A growing number of companies are now focusing on anti-aging science. In a way this is surprising, given that the first high-profile anti-aging company, Sirtris, while a success as an early investment has thus far failed to live up to its anti-aging expectations. Modern advances, abundant aging-related targets and an aging population can arguably be driving the current crop of anti-aging biotechs, but how realistic is it that these will succeed? In a sense there are few assumptions of which we can be confident. At present we can state that: (i) aging is a complex process; (ii) although there are numerous theories of aging with vocal advocates, there is no consensus among scientists regarding the underlying causes of aging; and (iii) aging can be manipulated in short-lived model systems by genetic, dietary, and pharmacological intervention. However, that leaves many open questions, so the uncertainty concerning human anti-aging approaches remains very high.
Although findings from short-lived model organisms, particularly in terms of the plasticity of aging, have been a major breakthrough in the field, the degree to which they are relevant to humans is unknown. Human homologs of genes associated with aging in model organisms have been associated with human longevity in some cases, but these are rare and thus our understanding of the genetic basis of human longevity remains largely unknown. Therefore, it is plausible that most findings from short-lived model organisms will not be relevant to human beings. Briefly, not only may the pathways necessary to extend lifespan in model systems be often irrelevant to the comparatively long-lived human species. Given the above concerns, a major open question is how effective anti-aging interventions can be in humans. Even if they have benefits, how do these compare with mundane lifestyle choices like going to the gym?
Of the 4000 private and 600 public biotech companies worldwide, only a few percent have shown increasing profitability. Historically, only one in 5000 discovery-stage drug candidates obtain approval and only a third of those recoup their R&D costs. Besides, the success rate of clinical trials is not improving, although we have more information, data, and potential targets than ever before. Given the various constraints on the study of aging, including the reliance on short-lived model organisms, long validation times, and poor biological understanding, it would be surprising if most of the companies described here are active a mere 5-10 years from now. Likewise, most companies in the anti-aging biotech sector are startups, and thus riskier. From an investor's perspective this means that investors in anti-aging biotech are expecting to lose money but hoping to win big.
Omics approaches are imperative, as is a multidisciplinary outlook, but while these have augmented the search space, attrition rates remain very high. Perhaps surprisingly, despite the so-far failure of Sirtris, which would be expected to hurt the industry, anti-aging biotech is more vibrant than ever. Clearly even such high-profile failure has not dissuaded investors, including many tech billionaires. No doubt new technologies will be developed and new targets discovered in the coming years and decades, possibly opening new avenues for the commercialization of aging in other directions. The promise of fending off old age remains more powerful than ever and the financial gains for any company delivering on that promise will continue to be extremely attractive. Anti-aging biotech can then be seen as an extreme reflection of the biotech sector: risky and most likely to fail, but if one company is successful the outcomes are monumental.
Recent Examples of Research into Protein Aggregates and their Clearance in the Context of Neurodegenerative Disease
Today the topic is protein aggregation in the aging brain, its consequences, and efforts to both understand and remove these aggregates. I'd noticed a few interesting research notices in the past few weeks, but they were pushed into the backlog by other matters. They are generally representative of the interest in aggregates in the research community, and of the incremental progress towards practical treatments. Removing solid deposits of misfolded or otherwise altered proteins from the brain has proven to be far more challenging than was first hoped when immunotherapies aimed at clearing the amyloid-β associated with Alzheimer's disease began earnest development more than a decade ago. There are signs of progress, and a broadening of different approaches, but it is hard to say when success will arrive in the clinic. Many of the current approaches are clearly very incremental, and even if realized as medical technologies would only produce marginal improvements.
Alzheimer's disease is where the bulk of funding goes in this part of the field, but it is only one of a score of age-related medical conditions that appear to be driven by the buildup of harmful proteins in the central nervous system. If the occasional post on the molecular biochemistry of neurodegenerative conditions here at Fight Aging! interests you, then you should consider adding ALZFORUM to your news feed. It is a good example of what can be achieved in advocacy and education if given sufficient funding. The breadth of mainstream interest in tackling Alzheimer's disease has supplied sufficient resources to fill in all of the areas of a research community, including an education and awareness arm, not just the bare bones.
Arguably this large research community should be viewed not as an effort to produce cures, but as an effort to understand the biochemistry and operation of the brain. The prospect of therapies for neurodegeneration is the rallying flag, the promised application of new knowledge that generates necessary public support. The real goal is knowledge, not treatments. At the large scale, all fields of science work this way: the pure aim of increased knowledge is funded by whatever that knowledge can be used to achieve. Absent advocacy to generate public appreciation of clear, near-future applications, it is very challenging to obtain the funding needed to perform any sort of medical research. Yet medical research is so clearly the greatest determinant of our future health and longevity that I have to see this state of affairs as an important failing of human nature. Important matters never seem to gain the focus that they merit.
Agent Clears Toxic Proteins And Improves Cognition in Neurodegeneration Models
Researchers have found cell receptors abnormally overexpressed in post-mortem brains of those with Parkinson's and Alzheimer's diseases, and that they can be inhibited in animal models to clear toxic protein buildup, reduce brain inflammation, and improve cognitive performance. These dual findings mark the first time that the receptors, discoindin domain receptors (DDRs), have been understood to play a role in Parkinson's and Alzheimer's diseases. They are primarily known as potential targets against cancer. "Activation of these cell receptors appear to prevent brain cells from cleaning out the trash - the toxic buildup of proteins, such as alpha-synuclein, tau and amyloid, common in neurodegenerative diseases."
When DDRs are over-expressed, their actions become destructive. One reason may be that DDRs are protein enzymes known as tyrosine kinases that act as on and off switches of the cell self-cleaning process known as autophagy. Excess DDRs activation may switch off autophagy, resulting in build-up of toxic proteins inside brain cells and possibly breakdown of the blood-brain barrier, common in neurodegenerative diseases. DDRs inhibition with a tyrosine kinase inhibitor appears to insulate the brain via blood-brain barrier repair, which prevents harmful immune cells that circulate in the body from getting into the brain where they can indiscriminately attack and kill healthy and sick neurons, like those that have been unable to perform autophagy. "We studied an experimental tyrosine kinase inhibitor that enters the brain and inhibits DDRs. Inhibition of these receptors with a low dose of the agent, LCB-03-110, or reduction of DDRs expression in several models of Parkinson's and Alzheimer's disease, allows nerve cells to switch on autophagy to clear toxic proteins and help the brain insulate itself from circulating inflammatory cells. This led to cognitive improvement in our animal models."
Gene variant protecting against Alzheimer's disease decreases plasma beta-amyloid levels
New research shows that the APP gene variant protecting against Alzheimer's disease significantly decreases plasma beta-amyloid levels in a population cohort. This is a significant discovery, as many on-going drug trials in the field of Alzheimer's disease focus on decreasing beta-amyloid levels in the brain tissue. According to the study, the APP A673T gene variant, which is a variant in the amyloid precursor protein gene protecting against Alzheimer's disease, leads to an average of 30 per cent decreased levels of the beta-amyloid subtypes 40 and 42. The effects of this previously discovered gene variant were analysed by utilising data from the METSIM (METabolic Syndrome In Men) study.
Approximately 0.3% of the population are carriers of the APP A673T gene variant. Although the variant itself is rare, the observed association with decreased plasma beta-amyloid levels is important from the viewpoint of Alzheimer's drug trials. Several on-going drug trials for Alzheimer's disease focus on decreasing beta-amyloid levels in the brain tissue. The findings from the population cohort in eastern Finland show that a life-long decrease in beta-amyloid levels is not associated with detrimental effects on lipid or glucose metabolism, or on any other metabolically relevant events.
Steering an enzyme's "scissors" shows potential for stopping Alzheimer's disease
Scientists have identified a couple of crucial steps in the formation of a protein called amyloid beta, which accumulates in clumps, or "plaques," in the brains of people with Alzheimer's disease. Those discoveries inspired efforts at disrupting the biochemical carving of amyloid beta's precursor protein into its final, toxic shape. The latest drugs being tested try to silence an enzyme, called BACE1, that cuts the precursor protein. But BACE1 has other functions that are beneficial, so stopping it altogether could bring unwanted side effects - including disrupting the production of myelin, the protective insulation of brain cells. Researchers have found that changing where the cut is made - in effect, guiding the enzyme's scissors to a different point - could achieve the same goal, with less collateral damage.
Researchers built upon two discoveries in the past decade of two rare mutations: one, found in Italian people, that leads to early onset Alzheimer's disease, and another, found in Icelandic people, that staves off Alzheimer's disease. The team was particularly intrigued by the diametrically opposite effects of both mutations because they affected the same point on the precursor protein's chain of 770 amino acids, swapping one acid for another. The researchers injected one set of mice with a virus carrying the Italian gene mutation, and another set with the Icelandic mutation. They found that the amino acid substitution affected where the precursor protein was cleaved. The Icelandic mutation resulted in a shortened form of amyloid beta, which does not become "sticky" and turn into plaque. The Italian mutation produced a longer, "stickier" version of amyloid beta, which ultimately becomes neuron-smothering plaque. Actually, the effects were a matter of degree: Each mutation led to more cuts in one location or more cuts in the other location. But in the gradual degradation of Alzheimer's disease, that could be enough - reducing the levels of the offending toxin could translate into many more years of life before cognitive decline sets in.
More Evidence for Senolytic Therapies as a Treatment for Lung Fibrosis
Research into cellular senescence as a cause of aging and age-related disease has expanded greatly these past few years. Several companies are developing approaches to safely remove these unwanted cells. Very compelling evidence has emerged for the role of senescent cells in aging; a number of research teams have demonstrated reversal of specific measures of aging in various tissues, with one study reporting extended life spans in normal mice in which senescent cells were cleared. The evidence to date is particular interesting in the case of lung conditions, especially those in which inflammation and fibrosis are prominent features. Removing senescent cells from aged mice has been shown to improve lung tissue function and elasticity. Further, senescent cells and their ability to generate inflammation have been strongly implicated in the pathology of fibrotic, inflammatory lung conditions such as idiopathic pulmonary fibrosis.
Senescent cells accumulate with age, a small lingering remnant population of the vast number of cells that every day become senescent and then self-destruct or are destroyed by the immune system. Tissues have a two-tier hierarchy of cells: the vast majority of somatic cells that can only divide a limited number of times before becoming senescent, and the small number of stem cells that can self-renew themselves over the course of a lifetime, and which act as a source of new somatic cells. In most tissues the somatic cell population turns over consistently on a timescale of days to weeks depending on tissue type: countless senescent cells are created as this happens. Near all are quickly destroyed in one way or another, but the very few that fail to achieve that goal become a significant cause of aging over the years.
Senescent cells secrete a potent mix of signals that spurs inflammation, degrades tissue structures, and makes nearby cells more likely to become senescent themselves, among other effects. The signals relate to the normal short-term roles for the senescent cells: to assist in wound healing; to rouse the immune system to clear senescent cells; to halt tissue construction in embryonic development; to suppress the risk of cancer by ensuring that the most at-risk cells become senescent. But left to continue this program for the long-term, and in increasing numbers, the result is age-related disease and failure of tissue function.
The presence of senescent cells appears to be one of the important contributing causes of the dysfunction in regeneration that occurs with aging. Fibrosis is a part of this, in essence a failure to correctly repair and restore tissue structures that involves the formation of scar-like deposits that disrupt normal tissue function. It is at least partially driven by rising levels of inflammation, and a signaling environment that upsets the normal relationship between the immune system and tissue-resident cells. Senescent cells are the most obvious culprit, and a range of studies like the one noted here present evidence in support of the role of cellular senescence in driving fibrosis and fibrotic disease. As the number of senolytic treatments capable of clearing senescent cells increases, and these treatments become more reliable and well-characterized, expect to see more and better studies on this topic in the years ahead. Human trials of senolytics to reverse fibrosis should not be more than a few years distant at this point.
Cell aging in lung epithelial cells
Pulmonary fibrosis causes the patient's lung tissue to scar, resulting in progressive pulmonary function deterioration. In particular, the surface of the alveoli (called the alveolar epithelium) is often affected. If the disease's origin is unknown, the condition is called idiopathic pulmonary fibrosis, or IPF for short. "The treatment options for IPF have been few and far between. We are therefore attempting to understand how the disease comes about so that we can facilitate targeted treatment." In the current work, researchers have now succeeded in solving another piece of the puzzle. "In both the experimental model and in the lungs of IPF patients, we were able to show that some cells in the alveolar epithelium have markers for senescence. Because the occurrence of IPF increases with age, this was already suspected. We have now succeeded in proving this hypothesis."
Senescence impairs lung function in two ways: It prevents lung cells from dividing when they need to be replaced. And senescent cells secrete mediators that further promote fibrosis. Since this effect also plays a role in cancer, the scientists were able to access an already existing group of medicines, the so-called senolytic drugs that selectively kill off senescent cells. In order to test possible treatment strategies, the scientists placed the affected cells into a three-dimensional cell culture and examined the drugs's effect ex vivo. "We observed that this caused a decline in the quantity of secreted mediators and additionally a reduction in the mass of connective tissue proteins, which are greatly increased in the disease." Altogether, the study shows that senescence in the cells of the alveolar epithelium can contribute to the development and worsening of IPF.
Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo
The incidence of idiopathic pulmonary fibrosis (IPF) increases with age and accumulating evidence strongly suggests ageing as a crucial contributor to IPF initiation and progression. In support of ageing as one proposed driver of disease pathogenesis, normal and accelerated-aged mice are more susceptible to experimentally induced fibrosis. A landmark paper in 2013 described nine hallmarks of ageing, and importantly, all nine hallmarks have been found to contribute to IPF pathogenesis, albeit to a variable degree. Cellular senescence, representing one of these hallmarks, is characterised by stable cell cycle arrest accompanied by secretion of mediators, including pro-inflammatory cytokines and metalloproteinases, collectively termed the "senescence-associated secretory phenotype" (SASP). While the detrimental effects of senescence are thought to be a result of stem or progenitor cell depletion or of the SASP components, senescence has also been described to be beneficial in tumour suppression and wound healing.
In the lung, as in other organs, the number of senescent cells increases with age and cellular senescence has been linked to the pathogenesis of chronic lung diseases such as chronic obstructive pulmonary disease or IPF. The contribution of senescent cells to disease onset and progression remain unclear. Some studies have suggested a link between increased senescence and fibrotic burden, while others report that attenuation of lung fibrosis correlates with lung fibroblast senescence. In addition to lung fibroblasts, evidence has emerged that alveolar epithelial cells can become senescent in IPF. However, lung epithelial cell senescence and its potential pathogenic role in IPF remains largely unexplored. Here, we aimed to investigate whether senescence of this cell population is detrimental or beneficial to lung repair. We utilised senolytic drugs on fibrotic lung epithelial cells in vitro and ex vivo in three-dimensional lung tissue cultures and demonstrated that senolytic treatment attenuates fibrotic mediator expression, while stabilising epithelial cell marker expression and function. These findings suggest that senescence contributes to development of lung fibrosis and that treatment of pulmonary fibrosis with senolytic drugs might be beneficial.
A Few More Details on Juvenescence
Jim Mellon is making a high profile investment in the development of therapeutics to treat aging, and this article offers a few more details on the company founded to carry this forward, Juvenescence. It is good to see new funding and vigor joining the field, but by the sound of it most of the proposed work is not actually all that interesting. It will be more of the standard drug development to try to slightly slow the aging process: consider the present panoply of work on calorie restriction mimetics, enhancement of autophagy, exercise mimetics, and so forth. Billions have been spent in this area in the past two decades with essentially nothing of practical use to show for it, because this approach to treating aging cannot possibly either produce significant rejuvenation or add decades to life spans. It fails to directly address the root causes of aging, does nothing more than tweak the operation of metabolism to slightly slow the consequences, and after twenty years of this work, the results still cannot even perform near as well as either actual calorie restriction or exercise.
Aside from the promise of investment in senolytic development, this initiative appears to be largely the Longevity Dividend approach so far; pour vast investment into perhaps adding a couple of years of life by 2030 or 2040. It is underwhelming, especially in comparison to the animal studies arising out of even just a few years of serious work on the alternative, which is to repair the forms of damage that cause aging. If Juvenescence focuses on senolytic drugs to clear senescent cells, it will be useful - the more the merrier in that part of the field. This is one of the few places where SENS rejuvenation research overlaps significantly with long-standing drug discovery practices, and not coincidentally it is also where results on aging and age-related disease in animal studies these past few years are both reliable and exciting in their magnitude - more has been achieved here in a few years than in the past two decades of work on calorie restriction, and at far less cost. Beyond these overlaps with SENS, all of the other usual suspects in the drug discovery agenda for slowing aging will, I predict, continue to produce little to no meaningful outcome no matter how much is invested in their development.
When British billionaire Jim Mellon wants to map out an investment strategy, he likes to write a book first. Out of that process came his most recent work - Juvenescence: Investing in the Age of Longevity. Now he and some close associates with some of the best connections in biotech are using the book as inspiration to launch a new company - also named Juvenescence - with plans to make a big splash in anti-aging research. "We are at an inflection point for the treatment of aging," says Greg Bailey, who likes to highlight some of the new cellular pathways that are pointing to new therapies that can counter the effects of aging. "I think this is going to be the biggest deal I've ever done. It will need repetitive financing. Five to 600 million was raised for Medivation. As we hit inflection points, we will need to raise a dramatic amount of money."
Bailey, the CEO of Juvenescence, was one of the early backers of Medivation, where he was a board director for 7 years - before Pfizer stepped in to buy the biotech for 14 billion. The primary game plan at Juvenescence is to come up with various operations engaged in developing new anti-aging drugs. Juvenescence AI is a joint venture they've just set up with Alex Zhavoronkov, who runs Insilico Medicine. Mellon met Zhavoronkov while he was researching his book, and believes that the tech the scientist developed can illuminate new programs with a better chance of success. "They are going to take up to 5 molecules from us every year for development," says Zhavoronkov, an enthusiastic advocate of AI in drug research who's also been working on some alliances with big pharma players. The group has invested about 7 million in the technology so far getting the joint venture set up. More will follow.
Aside from the cellular pathways that have attracted their attention, the biotech will look to effect change in the mitochondria, the cell's powerhouse, as well as clean up senescent cells that accumulate as the body grows older. And Bailey expects he'll be working some Biohaven-like deals to develop an advanced pipeline at a rapid pace. The principals chipped in the seed millions for the company and invested in the joint venture with Zhavoronkov. Bailey says you can expect to see 20 million to 50 million more in funding from a friends-and-family raise before the end of the year. And it's expected to grow from there.
Using Nanoparticles to Vitrify and Rapidly Thaw Fish Embryos
Not so long ago, researchers demonstrated that infusing tissues with nanoparticles could allow for safe and rapid thawing following low-temperature vitrification, avoiding damage that can occur due to ice crystal formation during a slower warming process. In the research noted here, a different scientific group is working on the nanoparticle approach as a way to cryopreserve fish embryos. They have achieved a proof of principle demonstration, but clearly have a way to go in terms of the quality of the result - it isn't yet as good as the earlier work on tissue sections. Taken as a whole the nanoparticle approach has the potential to help expand the use of vitrification for tissue storage, something that could greatly improve the logistics of organ donation, tissue engineering, and many areas of research by allowing indefinite storage of large sections of tissue. Greater use and development of tissue vitrification should in turn also help to advance the state of the art in human cryopreservation, the most important backup plan for those who will not survive to benefit from the rejuvenation therapies of decades to come, and a field in need of far greater investment and attention.
Zebrafish embryos have for the first time been frozen, thawed, and brought back to life. Researchers have been working on cryopreservation of zebrafish embryos for decades. It's never been done before. Over the past 60 years, scientists have had success preserving the sex cells and embryos of humans, cattle, mice, and many other animals. Trying to freeze and thaw fish embryos, however, has been more difficult because of their size and structure. The embryos are relatively large, bigger than a human egg. Fish embryos also have different compartments that freeze and thaw at different speeds. That can lead to the development of ice particles, which can damage the embryo.
Building on work by other scientists, researchers tweaked an existing cryopreservation method by injecting gold nanoparticles into zebrafish embryos, along with a cryoprotectant. The team froze the embryos in about one second using liquid nitrogen, then, after a few minutes, warmed them using a laser. The gold nanoparticles, which were distributed evenly throughout the embryos, absorbed the laser light and turned it into heat. The laser, which shown on the embryos for a millisecond, warmed developing fish so rapidly that they may have avoided being damaged by ice formation or other untoward effects of the quick-chill and thaw technique.
In the trials, only about 10 percent of the embryos survived to 24 hours. At this point, survivors started squirming and wiggling as their hearts, eyes, and nervous systems developed, proving their viability, yet none survived to day five, the final time point the team used. The advance is important for the field of genetics. Zebrafish have become an important model organism for studying the genetics of vertebrates and humans. Being able to preserve the different genetic lines of zebrafish generated in these studies means researchers wouldn't need to maintain live populations or run the risk losing irreplaceable research lines. It is also the most cost-effective method for this kind of research. The team is continuing to work on the technique to improve the viability of the embryos. Tweaks to the laser, gold nanoparticles, and even the cryoprotectant could make the method more suitable for embryos with a diameter of a millimeter or smaller. That would mean there would be one way of cryopreservation for all organisms with embryos of that size.
Linking the Bad Behavior of Senescent Cells with Innate Immune Mechanisms
Senescent cells accumulate in tissues with age, and while they make up a comparatively small fraction of all cells even in late life, they nonetheless cause great harm. These cells actively secrete a potent mix of signals, the senescence-associated secretory phenotype (SASP), that spurs chronic inflammation, degrades extracellular matrix structures, promotes fibrosis, disarrays regenerative processes, and generally changes the behavior of nearby normal cells for the worse. This materially contributes to age-related degeneration and disease. Recently, researchers have linked regulation of the SASP with mechanisms related to the innate immune system, suggesting that there may be opportunities here to sabotage the SASP. There is certainly a faction in the research community who would like to proceed towards therapies on the basis of modulating the SASP without removing senescent cells, but it has to be said that the evidence to date strongly supports the more direct approach of destroying these cells - it is much easier to achieve, and definitively removes all aspects of the SASP, not just a few of them.
Cells in the body or in cultures eventually stop replicating. This phenomenon is called "senescence" and is triggered by shortening of telomeres, oxidative stress or genetic damage to the cells, either acute or simply due to the cell growing "old". Understanding the causes and impact of senescence can give us deep insights into the development of cancer and ageing. When cells senesce, they undergo profound changes, including the secretion of several inflammation-mediating proteins (cytokines, chemokines, extracellular-matrix proteins, growth factors). The production of this "senescence-associated secretory phenotype" controls a number of biological processes such as wound healing and tissue repair, but also tumor formation and some age-related disorders. But although we know how senescence increases the activity of the genes for these proteins, we know very little about how the entire process begins in the first place.
Researchers have now found that senescing cells use a mechanism of the innate immune system to regulate the secretion of inflammation-mediating molecules. The innate immune system includes fast-acting but non-specialized cells (macrophages, neutrophils, mast cells, etc.) that provide the first line of defense against the millions of potential pathogens to which humans are constantly exposed. The innate immune cells use a host of pattern recognition receptors to sense and identify foreign parts of an invading pathogen, such as the DNA of a virus. DNA-sensing is accomplished through a two-receptor system comprising an enzyme called cGAS and an adaptor molecule called STING. Once activated, the cGAS-STING pathway triggers the production of inflammatory proteins that help fight off the pathogen.
Unexpectedly, the researchers now found that senescent cells in the body use the cGAS-STING pathway to regulate and facilitate their secretion of inflammation mediators. But in the context of senescent cells, it is the cell's own DNA that activates cGAS because of defects in the integrity of the nuclear envelope. Examining the relevance of this fundamental mechanism, the study found that the cGAS-controlled secretion of cytokines appears to play a role in various contexts of senescence such oxidative stress, oncogene signaling, and irradiation. The scientists also observed that at least irradiation and oncogene activation exert these actions through cGAS-STING in vivo as well. The study shows that DNA sensing through the cGAS-STING pathway is an important regulator of senescence and the release of inflammatory mediators, and could also serve as surveillance system that protects the organism against neoplastic cells, which opens up new insights for our understanding of the development of cancer. Moreover, since the inflammatory response of senescent cells also promotes ageing, the cGAS-STING pathway could serve as new drug target to tackle age-related diseases.
Longer-Lived Mice Better Resist Immune System Decline
In this open access paper, researchers examine the functionality of the immune system in old mice. They find a correlation between greater longevity and more successful compensation for age-related changes. Longer-lived mice tend to have immune systems capable of better, less disrupted function in later life. Given the importance of the immune system to many aspects of tissue function, over and above its role in defending against pathogens, this should perhaps not be all that surprising. Open questions remain on the relevant mechanisms and the degree to which sustained immune performance is a matter of resisting damage versus better compensating for damage versus stochastic differences in the load of molecular damage between individuals.
Aging of the immune system, which is known as immunosenescence, involves a striking rearrangement of almost every component, leading to changes including enhanced as well as diminished functions. In addition, the functioning of the immune system has been demonstrated to be an excellent marker of health, given that several age-related changes in immune functions are predictive of mortality and lifespan. Thus, long-lived individuals seem to exhibit a high degree of preservation of several functions of the immune system with values similar to those observed in adult individuals. This may be essential to reach a very advanced age in a healthy condition.
Among all the age-related changes that the immune system undergoes, the most obvious is the involution of the thymus gland. Accordingly, one of the most marked age-related alterations in the immune cells has been reported in the T lymphocytes, specifically in the lymphoproliferative response to mitogens, which is decreased in old subjects for both humans and experimental animals. The study of the proliferative response of leukocytes to a given stimulus has become an important issue given that a low lymphoproliferative response to mitogens has been linked to an increased mortality, and together with other parameters, defines the immune risk phenotype in humans.
Cytokines are principal mediators of interactions among immune cells. They are responsible for the development and resolution of immune response and are greatly affected by the aging process. In fact, an age-related loss of homeostasis in cytokine networks can contribute significantly to health impairment in old age. In this context, together with the previously mentioned age-related loss of functionality in immune cells, aging is characterized by a chronic low-grade inflammatory status, so-called "inflammaging". Thus, it has been described that an age-related increase in release of pro-inflammatory cytokines in resting cells leads to a sterile inflammation. This is accompanied by an elevation of circulating levels of cytokines in old subjects, such as IL-6, which in addition has been related to a higher risk of mortality. However, cells from old subjects produce lower pro-inflammatory cytokines when needed to do so, i.e., after a mitogenic stimulus, compared to those of adult subjects. Again, long-lived individuals, despite having high levels of pro-inflammatory markers, have a postponed disease onset, making it difficult to understand whether "inflammaging" is beneficial or detrimental.
Based on the striking facts regarding lymphoproliferation and cytokine release by immune cells in long-lived individuals, it was hypothesized that these individuals could present different proliferative as well as cytokine release dynamics as an adaptive mechanism. Moreover, given that all the studies in long-lived individuals previously mentioned have been cross-sectional, it is still not known if they reach those advanced ages due to the maintenance of optimal immune cell function during their whole life (as if they were adults) or whether they experience an age-related impairment in these functions but are able to compensate for it. In order to address these questions, an individualized longitudinal study was performed on female ICR-CD1 mice analyzing the proliferation as well as the cytokine secretion profile of leukocytes obtained from animals at different ages. The study was performed starting at the adult age, 40 weeks old, and followed each animal individually until its death.
In the present study, it has been found that old mice exhibit a significant increase in the basal proliferation of immune cells, what takes place in the absence of a proliferative stimulus, with respect to when they were younger. In contrast, long-lived mice show basal proliferative levels similar to when they were adults. The high proliferation in the absence of stimulus seen in old mice implies a deregulation of the immune system. Those mice that naturally achieve high longevity are the ones that not only maintained lower levels of basal proliferation and higher levels of proliferation after stimulation during their whole lifetime, but are also those that achieve a better control of the effects of aging on the immune functions. Thus, long-lived mice are those that maintained a lower secretion of pro-inflammatory cytokines and a higher secretion of anti-inflammatory cytokines in unstimulated conditions as well as a higher one upon stimulation when they were old, compared to their age-matched counterparts. This is the first study to demonstrate that the animals reaching high longevity experience immune-senescent changes (to a lesser extent than those which do not reach advanced ages), but they are able to compensate for them by showing optimal levels when they are long-lived.
Reviewing Epigenetic Inheritance of Longevity
Natural variations in longevity can be inherited to some degree, but one of the more interesting findings in recent years is that induced longevity as a result of environmental circumstances such as calorie restriction or gene therapies applied to adults only, and thus not inherited, can also produce extended longevity in offspring. Researchers were initially quite surprised to find that even limited forms of Lamarkian inheritance could exist. The proposed mechanism is inheritance of epigenetic markers, decorations to DNA that control the degree to which specific proteins are produced from their genetic blueprints. This open access paper reviews what is known on this topic.
Until recent years, a basic assumption in biology was that mutations in the DNA sequence were the only source of heritable phenotypic variation. It is commonly believed that genetic information may be transmitted to the next generations by germ cells only, while somatic cells do not have any inheritance function. The core of this theory is the idea that information is not capable of being transferred from somatic to germline cells and, respectively, to the next generations. This concept is commonly referred to as the Weismann's barrier. According to this concept, a strict distinction exists between innate and acquired characters. There is, however, significant empirical evidence to suggest that the Weismann's barrier is not entirely impermeable and can be crossed.
Examples for non-DNA sequence-based inheritance across generations have been obtained in a variety of species, including microbes, plants, worms, flies, fish, rodents, pigs, and humans. Many recent papers highlight the role of epigenetic mechanisms in mediating these effects. These processes include modified patterns of DNA methylation and histone posttranslational modifications, replacement of canonical histones with histone variants, as well as altered noncoding RNA expression causing changed local accessibility to the genetic material and modified gene expression. In several recent studies, the potential importance of non-genomic transgenerational effects in the inheritance of age-related characteristics has been highlighted. However, the transgenerational effects on longevity have been reported only rarely to date. Most of the papers reviewing and discussing such effects are focused solely on data obtained from the nematode Caenorabditis elegans, although similar findings were obtained in other species as well.
In evolutionary terms, the transmission of the adaptive transcriptional patterns acquired throughout the parental life course in subsequent generations via the mechanism of epigenetic memory can enable the organism to better survive in potentially adverse environments. In particular, it has been repeatedly reported that offspring of parents exposed to nutritional stresses exhibit altered expression of genes related to metabolic functions including those implicated in pro-longevity metabolic pathways. The mechanisms potentially responsible for such inter- and transgenerational effects are currently the subject of active investigation. In most studies on short-lived models such as nematodes and flies, the role of histone modifications in transgenerational transmission of epigenetic information was highlighted, while in rodent models changes in DNA methylation have been mainly detected.
Do Chimpanzees Suffer from Alzheimer's Disease?
Researchers here report on the presence of protein aggregates characteristic of Alzheimer's disease in old chimpanzees. This may not result in any meaningful new lines of investigation, however, given that studies of this species are now heavily restricted. In principle, comparative biology studies using similar, related species can be useful in helping to understand specific mechanisms and cellular behaviors. In the case of Alzheimer's disease, any of the benefits that might result from such a research program may well be overtaken by success in any one of the numerous forms of therapy currently under development. Comparative biology is a useful approach, but successfully removing a possible cause, such as one type of protein aggregate, and then observing the effects is even better as a source of new information.
Researchers have discovered tell-tale signs of Alzheimer's disease in 20 elderly chimpanzee brains, rekindling a decades-old debate over whether humans are the only species that develop the debilitating condition. Whether chimps actually succumb to Alzheimer's or are immune from symptoms despite having the key brain abnormalities is not clear. But either way, the work suggests that chimps could help scientists better understand the disease and how to fight it - if they could get permission to do such studies on these now-endangered animals.
A definitive diagnosis of Alzheimer's includes dementia and two distortions in the brain: amyloid plaques, sticky accumulations of misfolded pieces of protein known as amyloid beta peptides; and neurofibrillary tangles, formed when proteins called tau clump into long filaments that twist around each other like ribbons. Many other primates including rhesus monkeys, baboons, and gorillas also acquire plaques with aging, but tau tangles are either absent in those species or don't fully resemble those seen in humans. In the new study, and thanks to a newly founded center that collects brains from chimps that die at zoos or research centers, the team was able to examine the brains of 20 chimps aged 37 to 62 - the oldest recorded age for a chimp, roughly equivalent to a human at the age of 120. Of these chimps, 13 had amyloid plaques, and four also had the neurofibrillary tangles typical of more advanced stages of Alzheimer's in humans.
But so far, only humans are known to show the Alzheimer's trifecta of plaques, tangles, and dementia. The 20 chimps whose brains were studied had not been tested for cognitive or behavioral changes. As a result, "we can't say these chimps had Alzheimer's, but we can say for sure that they are the only other species with its pathologic hallmarks." Some scientists aren't persuaded that the chimp brains really do match those of human Alzheimer's patients. In human brains, amyloid plaques are associated with neuron death, which wasn't measured in the new study. The researchers plan to go back to the same chimp brains to calculate neuron death, but proving that chimps develop dementia will require research on living animals.
Converting Effector T Cells into Regulatory T Cells
Slow progress is being made in the development of means to adjust the operation and configuration of the immune system, especially when it comes to damping inflammation. Present approaches used in the clinic are blunt, suppressing immune activity as a whole, or at least large swathes of it, and have significant side-effects. More sophisticated ways to adjust immune cell behavior may have applications in reducing some of the consequences of the disarray of the immune system that occurs with age. In particular, if the chronic inflammation and overactivity of the aged immune system could be reduced, some benefits might be realized. In the longer term, however, the real relevance of this sort of work is as a stepping stone towards a greater capacity to arbitrarily adjust the immune system in situ, changing or destroying very specific subpopulations of immune cells in order to achieve desired effects. It is possible that this could lead to the prevention of misconfiguration and change in relative numbers of immune cells that occurs with age.
Scientists have revealed, for the first time, a method to reprogram specific T cells. More precisely, they discovered how to turn pro-inflammatory cells that boost the immune system into anti-inflammatory cells that suppress it, and vice versa. The researchers studied two types of cells called effector T cells, which activate the immune system to defend our body against different pathogens, and regulatory T cells, which help control the immune system and prevent it from attacking healthy parts of its environment.
By drawing on their expertise in drug discovery, the team identified a small-molecule drug that can successfully reprogram effector T cells into regulatory T cells. Their study describes in detail a metabolic mechanism that helps convert one cell type into another. This new approach to reprogram T cells could have several medical applications. For instance, in autoimmune disease, effector T cells are overly activated and cause damage to body. Converting these cells into regulatory T cells could help reduce the hyperactivity and return balance to the immune system, thus treating the root of the disease. In addition, the study could improve therapies using stem cells. At least in theory, producing regulatory T cells could promote immune tolerance and prevent the body from rejecting newly-transplanted cells.
"Our work could also contribute to ongoing efforts in immunotherapy for the treatment of cancer. This type of therapy doesn't target the cancer directly, but rather works on activating the immune system so it can recognize cancer cells and attack them." Many cancers take control of regulatory T cells to suppress the immune system, creating an environment where tumors can grow without being detected. In such cases, the team's findings could be used to transform regulatory T cells into effector T cells to strengthen the immune system so it can better recognize and destroy cancer cells.
AgeX Therapeutics is a spin-off of BioTime, one of the earliest of the present generation of stem cell therapy companies, and run by a fairly vocal supporter of the idea that stem cell treatments have the potential to help address aging. Considered as a whole, the stem cell field, for all of the tremendous progress made to date, actually hasn't moved far towards the classes of therapy that would be required to address the roots of stem cell population decline in aging. Treatments have instead been compensatory, or attempts to enhance regeneration, or attempts to reduce inflammation, or tissue engineering for transplant, or attempts (largely failed so far) to increase the numbers of a specific cell type in situ. All of these have some small overlap with issues involving age-related tissue damage and stem cell decline, but only a small overlap.
AgeX Therapeutics is perhaps of interest to our community for the fact that Aubrey de Grey of the SENS Research Foundation has taken a position there, more than his usual presence on the advisory board of a relevant venture. In addition, the company has recently raised funding from investors that include Jim Mellon's and Michael Greve's funds. So it seems worth looking more closely at the lines of development here than one would for the average stem cell therapy startup, to speculate on how this would lead to classes of therapy closer to the SENS vision for addressing cell loss and stem cell dysfunction in aging. We shall see how it progresses.
AgeX Therapeutics, Inc. is a biotechnology company formed in 2017 as a subsidiary of BioTime, Inc. Its mission is to apply technology related to cell immortality and pluripotency to human aging and age-related disease. The Company's technology platform has three facets: Pluripotent stem cell-derived progenitor cell lines representing over 200 types of cells in the body (PureStem technology); HyStem matrices; and induced tissue regeneration (iTR) - the latter being an emerging technology directed at inducing the immortal regeneration of tissues in the body.
Through BioTime, AgeX has license to a large consolidated technology and patent estate including technologies invented at Geron and subsequent companies. AgeX is leading off with cell-based regenerative therapeutics for significant unmet needs in age-related disease such as type II diabetes and ischemic disease. In addition, it will also be advancing products based on an entirely new technology platform aimed at the central molecular processes of aging itself designated "induced Tissue Regeneration (iTR)." AgeX scientists believe that the combination of telomerase therapy and iTR may unlock the potential of immortal tissue regeneration in humans.
Some naturally-occurring animals such as the Mexican salamander can profoundly regenerate damaged tissues. Humans also have this potential, but only in the first weeks of development. Using advanced molecular and artificial intelligence technologies, we have identified pathways we believe may provide means of unlocking this profound biology in human medicine. The pathways suggest that they may also be integral to the biology of aging and cancer as well. Patents relating to this emerging technology have been filed and animal studies are currently underway. The combination of pluripotent stem cell and iTR technology may provide AgeX with a valuable platform to address large markets associated with chronic degenerative age-related disease.
Cell Therapy versus Lung Fibrosis
In recent years the research community has made some progress towards the use of cell therapies to treat fibrosis in lung tissue, the basis for a number of ultimately fatal conditions that present cannot be effectively controlled. Fibrosis is a disruption of the structure of tissue, the formation of scar-like structures that degrade tissue function. This line of research may soon be overtaken by the use of senolytic treatments to remove senescent cells, given that senescent cells appear to be a significant cause of the age-related failures in regenerative processes that cause fibrosis. Nonetheless, prior to recent work on cellular senescence and fibrosis, cell therapies were the most promising approach. Here, researchers report on recent progress in this part of the field:
Promising research points towards a possible stem cell treatment for several lung conditions, such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cystic fibrosis. These diseases of the lung involve the buildup of fibrous, scar-like tissue, typically due to chronic lung inflammation. As this fibrous tissue replaces working lung tissue, the lungs become less able to transfer oxygen to the blood. In the case of IPF, which has been linked to smoking, most patients live for fewer than five years after diagnosis. The two drug treatments for IPF reduce symptoms but do not stop the underlying disease process. The only effective treatment is a lung transplant, which carries a high mortality risk and involves the long-term use of immunosuppressive drugs.
Scientists have been studying the alternative possibility of using stem cells to treat IPF and other lung fibrosis diseases. Some types of stem cells have anti-inflammatory and anti-fibrosis properties that make them particularly attractive as potential treatments for fibrotic diseases. Researchers have focused on a set of stem cells and support cells that reside in the lungs and can be reliably cultured from biopsied lung tissue. The cells are called lung spheroid cells for the distinctive sphere-like structures they form in culture. Lung spheroid cells showed powerful regenerative properties when applied to a mouse model of lung fibrosis. In their therapeutic activity, these cells also outperformed other non-lung-derived stem cells known as mesenchymal stem cells, which are also under investigation to treat fibrosis.
Researchers showed that they could obtain lung spheroid cells from human lung disease patients with a relatively non-invasive procedure called a transbronchial biopsy. They cultured lung spheroid cells from these tiny tissue samples until they were numerous enough - in the tens of millions - to be delivered therapeutically. When they infused the cells intravenously into mice, they found that most of the cells gathered in the animals' lungs. The researchers then induced a lung fibrosis condition in rats that closely resembled human IPF. Then the researchers injected the new cultured spheroid cells into one group of rats. Upon studying this group of animals and another group treated with a placebo, the researchers saw healthier overall lung cells and significantly less lung inflammation and fibrosis in the rats treated with lung spheroid cells.
Optimism without Complacency in the Matter of Rejuvenation Research
In this article, the Life Extension Advocacy Foundation volunteers offer thoughts on the middle road for expectations regarding the near future of research and development in longevity science. There are all too many people who are either overly pessimistic or overly optimistic. While it is true that the optimists of today are not in the same terrible position as the optimists of the last generation, who completely misjudged the scope of what was possible via pharmaceutical approaches to aging, it is still the case that a great deal must be accomplished in order to bring effective rejuvenation biotechnologies to the clinic. There is too little funding for many of the necessary areas of work based on the SENS vision of damage repair, and even in very well-supported and active fields such as cancer and stem cell research, comparatively little effort goes towards the most effective approaches. So while we can look back at considerable progress made in past years towards the realization of SENS-like rejuvenation therapies, and the clinical development of the first line of such therapies in the form of senolytics is forging ahead, the work has in many ways only just started.
In the last year or so we have seen remarkable progress with a number of interventions that target the aging processes to prevent and treat age-related diseases. There is plenty to be excited about, and with all this good news recently it is tempting to become overly optimistic. I have seen a significant number of people suggest that everything will be fine now, because the first technologies are starting to arrive in the repair based approach to aging, but this is a dangerous mindset to fall into. We should not think we are close to bringing the aging processes under medical control. The metabolism of the human body is a highly complex interconnected machine and anyone with an understanding of biology understands that controlling this complexity is likely the work of decades if not longer. However, there is an approach that seeks to sidestep this complexity - rejuvenation biotechnology.
Rejuvenation biotechnology is a multi-disciplinary field of science whose aim is the prevention and reversal of age-related diseases by targeting the aging processes that cause them. This is a dramatic deviation from traditional medicine and in particular geriatrics which aims to treat the consequences, often by attempting to tweak metabolism far downstream from the actual root causes, rather than prevent it happening in the first place by focusing on where the damage begins. This traditional approach of treating the symptoms and not the cause is an approach doomed to fail, and considering people continue to die from age-related diseases it is time to admit that this approach has been a spectacular failure. Repairing the underlying damage, whilst itself not trivial, is considerably less complex than attempting to tweak metabolism or treating the consequences as traditional geriatrics does. Regardless of how you categorize the damages of aging, be it the seven damages model of SENS or the Hallmarks of Aging model, they are much the same and both advocate the repair approach to aging. The damage repair approach is becoming a realistic goal in the next couple of decades and that is very good news indeed.
Some parts of the damage repair approach are now far advanced and enjoying a great deal of attention and hype in the media. But there are a number of approaches to damage that are yet to reach this level of attention. Because aging comprises of a number of interlinked but distinct processes, addressing only one or two of them is unlikely to yield significant increases in healthy lifespan. This is confirmed in rodent experiments where a single damage has been addressed. We see increased lifespans as a result of addressing these hallmarks of aging and a delay of age-related diseases, which is the aim of rejuvenation biotechnology. And yet, these animals ultimately still die of the age-related damages that are not being addressed. Believing that addressing just one form of damage will make a dramatic difference puts us in serious danger of becoming overly optimistic and thus complacent. Quite simply, there are no magic bullets.
At the risk of stating the completely obvious: we should be focusing the greatest efforts now on the areas where progress is the least advanced. We need to help these approaches that are lagging behind catch up with the rest that are more advanced. Areas like crosslink breaking, mitochondrial gene transfer and the destruction of misfolded proteins are all areas that are in need of support. As it stands these and other critical research areas that are needed to realize full medical control of the aging processes to address age-related diseases are yet to reach a proof-of-concept stage. That leaves the basic science and early-stage development of these technologies entirely in the hands of philanthropy.