Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.
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- A Look Back at the Rejuvenation Research and Advocacy of 2018
- Ambrosia Health and the Downsides of Developing Marginal Therapies
- An Initial Assessment of the Phenotypic Age Metric
- Tau and Amyloid-β Synergize to Impair Neural Activity in Alzheimer's Disease
- Recent Papers on the Cellular Senescence Produced by Visceral Fat Tissue
- The ALZFORUM 2018 Retrospective
- Whether Mitochondrial Genomes are Better or Worse is Circumstantial
- Giant Mole-Rats Exhibit Greater Gene Expression Stability with Aging than Rats
- An Incomplete Survey of Novel Approaches to Alzheimer's Disease
- NAD+ and Cellular Senescence in Intestinal Tissue Organoids
- Towards a Biomarker of Aging Based on the Gut Microbiome
- The Uncertain Details of Retinal Aging
- Considering Mesenchymal Stem Cell Therapy for Atherosclerosis
- Life Extension Advocacy Foundation 2018 Retrospective
- Interfering in the Interaction between Amyloid-β and Prion Protein as a Treatment for Alzheimer's Disease
A Look Back at the Rejuvenation Research and Advocacy of 2018
Another year passes, and we are thus another year closer to our respective graves - or are we? The numbers start to slide and become uncertain as work on the development of rejuvenation therapies progresses. The oldest among us might be in a position to gain a few years or some greater comfort should they avail themselves of the first senolytic therapies. The youngest, on the other hand, may as well put a question mark in place of digits when assessing their remaining life expectancy. The medical capabilities of four decades from now will look like today's science fiction.
A Strange, Productive Year for Funding and Fundraising
The frenzy of money printing and stock market highs that characterized the past decade may have finally come to a close at the end of 2018, and thus the now traditional end of year fundraising efforts for the SENS Research Foundation in our community have been muted in comparison to last year - which, you might recall, was at the height of the cryptocurrency bubble, leading to sizable donations to the SENS Research Foundation, Methuselah Foundation, and others. That bubble deflated shortly thereafter, and the same necessary puncturing of financial excess and fervor looks to occur for the broader market in the year ahead. While the Life Extension Advocacy Foundation successfully crowdfunded a NAD+ enhancer lifespan study in mice earlier in the year, non-profit fundraising is vulnerable to the whims of markets, as the wealth of supporters ebbs and flows. Regardless, it remains the case the there is no better philanthropic cause, no way to save more lives than funding the development of rejuvenation therapies. High net worth philanthropists such as Jim Mellon and Vitalik Buterin who made sizable donations to the SENS Research Foundation this year appear to appreciate this point.
Even now, with the downturn beginning, it has never been easier to start a biotechnology company to work on medical applications of rejuvenation research. Bill Cherman and I did just that earlier this year, launching Repair Biotechnologies and closing our first investment. We have a growing number of fellow travelers, new companies in 2018, and people preparing to launch more in 2019. In fact, investment in the treatment of aging has been something of a theme for the year. Industry leader Unity Biotechnologies raised an enormous sum for senolytic development. Oisin Biotechnologies, funded in its early stages by our core rejuvenation research community, is moving from strength to strength, and spun out a cancer-focused subsidiary this year. Leucadia Therapeutics, supported by the Methuselah Fund in their work on a novel way to clear aggregates in Alzheimer's patients, is also doing well.
The Methuselah Fund itself closed its initial round, and invested in a number of other companies. The leaders of the noted venture organization Y Combinator declared an interest in the field, putting aging at the front of their expansion into biotechnology. Jim Mellon's Juvenescence fund has been leading the way in many investments, such as AgeX Therapeutics, senolytics company Antoxerene, and NAD+ startup Napa Therapeutics. The Longevity Investor Network of interested angel investors has been active over the course of 2018. Among other new companies launched or funded this year are FOXO4-DRI senolytics startup Cleara Biotech, EnClear Therapies and their work on filtration of cerebrospinal fluid, and some of the portfolio companies of Life Biosciences, such as Senolytic Therapeutics. The size of the industry is growing in leaps and bounds, as the volume 1 and volume 2 of the Longevity Industry Landscape Overview illustrate. My comments here really only represent a fraction of what has been taking place.
The Conference Circuit is Booming
There are too many conferences covering the science of aging to easily count these days; there are scores by specialty, such as the 2018 International Cellular Senescence Association Meeting. They are joined now by a growing number of business-focused conferences, bringing together investors, entrepreneurs, and established biotech concerns with an interest in slowing and reversing aging. Closest to our core community of support for SENS rejuvenation research are the new Undoing Aging series from the Forever Healthy Foundation, and the Life Extension Advocacy Foundation's Ending Age-Related Disease conference, both of which launched this year. Another new entry from Jim Mellon's organization is the Longevity Forum in the UK. Older conference series continue: the venerable TransVision, the ongoing spectacle of RAADfest, and a variety of European conferences. More conferences are coming up early next year; it will be a busy first quarter.
Noteworthy Advances in the Science of Aging
One should of course look at annual reports from the SENS Research Foundation and Methuselah Foundation issued earlier in the year before reading the following rambling collection of items that caught my interest. The most important research is that relating to the SENS goals of rejuvenation through repair of cell and tissue damage, but far more than that is taking place in the research community, even through it will largely prove to be less beneficial to patients.
Senolytics and Senescent Cells
Cellular senescence is now undisputed as a cause of aging, and efforts to destroy or control senescent cells are growing rapidly in scope. The first human trials of senolytic therapies to destroy senescent cells have started, and a mouse lifespan study demonstrated 36% extension of remaining life after late life administration in old mice. More life span studies are running, such as the one sponsored by Oisin Biotechnologies. New age-related conditions are linked to the presence of senescent cells seemingly every month, with results over the past year published for vascular dysfunction, Parkinson's disease (and all of the other synucleinopathies), sarcopenia and frailty, osteoporosis, impaired heart regeneration, cardiovascular and metabolic disease, idiopathic pulmonary fibrosis, the degeneration of bile ducts, retinal degeneration, loss of regenerative capacity in the liver, tau aggregation in Alzheimer's disease, autoimmunity, age spots, chronic obstructive pulmonary disease, and loss of hematopoietic stem cell function.
There is suddenly a wealth of funding for basic research into the cell biology of senescence and its mechanisms. A lot of review papers on the subject are being written as well; there is certainly no shortage of work to be accomplished. Earlier this year, evidence was provided for accumulation of senescent cells to be a function of immune system decline, and for lamin A mutation to contribute to normal aging via cellular senescence. Researchers are questioning whether or not senescent cell presence is dynamic in old tissues and the degree to which senescent cells accumulate because of immune system failure in aging. Existing cells are being discovered to be senescent: a well known problem population of monocytes turned out to be senescent, for example. It was also found that senescent cells accelerate the creation of more senescent cells. Researchers in the cancer community are pondering how to better use senescent cells to suppress cancer, given a clear way to remove them afterwards before they cause too much harm. Discovery of new markers and new mechanisms to enable selective destruction of senescent cells is becoming a well-funded, popular line of work. TIGIT, for example, has now been associated with senescent T cells. As another example, TXNIP is implicated in cellular senescence in mice and flies.
New data on senolytic therapies capable of destroying senescent cells is rolling in on a regular basis. Quercetin is not senolytic on its own, rather than in combination with dasatinib. There are plenty of other marginal senolytics in the pipeline, and candidates for which we only have cell data, such as the antibotics azithromycin and roxithromycin. New candidate senolytics with worthwhile effects in animal studies include tetramethylpyrazine, piperlongumine, and, strangely given the failure of quercetin, fisetin. Other approaches to destruction of senescent cells are also moving forward at varying speeds, such as immunotherapies and methods of targeting p16 expression. A research group has also demonstrated the basis for a general drug delivery system that preferentially targets senescent cells, which seems a promising development. Interestingly, calorie restriction suppresses senescent cell levels, though obviously by nowhere near enough.
Assays for level of senescence in humans remain a challenge, though there are some signs of movement; an approach based on blood samples and cell size was demonstrated earlier this year, for example, or the use of CD36 as a cell surface marker. The founders of the CellAge startup are still somewhere in development of their synthetic promoter approach. We shall see where it all leads. The senolytic companies still have little incentive to improve on tissue staining methods that work acceptably well in the lab but are unsuitable for human assays.
Some researchers are more interested in modulating senescence than in destroying these cells, which I can't say I think is a wise course of action at this point in time; it isn't cost effective in comparison to destroying these cells, and no-one has yet produced a compelling reason not to destroy them. MDM2 agonists are suggested as one approach to attenuate some of the harmful signaling produced by senescent cells.
The polarization of macrophages and microglia continues to be a topic of considerable interest in the research community, though it is anyone's guess as when this will make the leap to earnest efforts towards clinical translation. Some researchers have examined possible mechanisms to explain the age-related shift to harmful polarizations, but most are more interested in overriding the polarization state so as to covert harmful inflammatory immune cells into helpful regenerative immune cells. This may be useful as a therapy for heart failure, particularly ventricular hypertrophy, regeneration in the brain, prevention of cancer, or to enhance immunotherapy. Interestingly, oxidized lipids, one of the forms of metabolic waste identified in the SENS rejuvenation research proposals, may steer macropages into their harmful inflammatory polarization. Faltering autophagy may also be involved. Research this year has also shown that polarizations are more favorable in healthier old people.
Breaking Down Metabolic Waste
Clearing metabolic waste products inside and and outside cells is an important arm of the SENS vision for rejuvenation. Researchers this year linked accumulated waste in the lysosome to loss of function in neural stem cells, and in the progression of neurodegeneration in general. Upregulation of lysosomal activity enhances neural stem cell function. A team independent of the SENS Research Foundation made some progress towards finding bacterial enzymes capable of breaking down 7-ketocholesterol. Another group showed USP13 inhibition to clear Lewy bodies in neurons. Antibodies targeting oxidized cholesterols slowed the development of atherosclerosis in mice - as might be expected from the growing evidence for these damaged cholesterols to be a primary cause of atherosclerosis. Various groups are working on approaches to clearing transthyretin amyloid, linked to cardiovascular disease in the population at large, and to mortality in supercentenarians, some more promising than others.
Can the existing technologies of blood filtration be expanded to help with aging? There are all sorts of forms of molecular waste that might be cleaned out on a repeated basis. The costs would have to fall dramatically to make this sort of thing cost-effective, however. What about filtering cerebrospinal fluid (CSF) as well as blood? Even in early aging, CSF has waste in it that we'd be better off without. Evidence accumulates for failing drainage of CSF to be the start of neurodegeneration with age.
Regeneration of the Immune System
Regeneration of the aged immune system is a topic of great interest. New modelling published this year suggest that cancer risk is entirely determined by declines in T cell production. A novel approach to regrowth of the atrophied thymus, where T cells mature, was demonstrated this year, joining a range of others at various stages of development. The company LyGenesis, while initially focused on liver organoids, is working on placing thymus organoids into lymph nodes. Researchers also suggested this year that aged lymph nodes will need to be regenerated in order to restore immune function. Other groups are focused on restoration of hematopoietic stem cell populations, those responsible for generating immune cells, and which decline with age.
There is compelling evidence for cytomegalovirus (CMV) infection to be an important contributing cause of immunosenescence. Too much of the immune system becomes uselessly specialized to CMV, and too little is left to fight novel threats. New evidence in support of this hypothesis turns up every year, and this year was no exception. A study suggests the infectious dose correlates with immune dysfunction, while another group finds a specific immune population that results from CMV infection and contributes to cardiovascular disease. There are always, of course, opposing views, in which CMV is painted as a positive influence, but that is very much a minority viewpoint.
Mitochondrial Damage and Dysfunction
Damage to mitochondrial DNA is an important issue in aging, even though the way in which a single mutation in a single mitochondrial genome can cascades into overtaking all of the genomes cell is poorly understood. The latest mouse models of accelerated mitochondrial mutation are not behaving as expected, but on the other hand it is possible to link mitochondrial mutational damage and loss of stem cell function. More people are giving thought as to how to fix this problem. Sadly the options are still fairly limited, even given this year's proposals for targeted destruction of mutant mitochondrial DNA and use of AOX from non-mammalian species to bypass damaged electron transport chain complexes. The best of the options, the SENS proposal of allotopic expression, is still woefully underfunded in comparison to its potential. Nonetheless, the SENS Research Foundation team is at the point of undertaking mouse studies for their work. That allotopic expression is proven technically is beyond doubt, given that Gensight is at the phase III stage of trials with their focus on a single mitochondrial gene and inherited blindness conditions. Yet the funding for the other twelve genes is still hard to come by.
Beyond this issue of DNA damage, occurring in a small but significant population of cells, mitochondria also become more globally dysfunctional with age, leading to higher levels of oxidative stress, and an energy crisis in muscles and brain. New evidence also shows that mitochondrial dysfunction causes telomere shortening, chronic inflammation, and problems in T cells. There is far less of consensus on why this mitochondrial dysfunction occurs or how to tackle the problem. Specific details are still being uncovered, such as loss of ADP sensitivity, or a role for the mitochondrial transition pore.
Nuclear DNA Damage
Does stochastic nuclear DNA damage cause significant issues in aging beyond cancer risk? Simply counting mutation levels in any given cell population doesn't help to answer this question, and it is impossible to say whether variations in DNA repair contribute meaningfully to natural variations in human longevity. The mainstream consensus is that nuclear DNA damage does significantly disrupt metabolism and tissue function, with some form of clonal expansion necessary to spread a harmful mutation into enough cells to produce these effects. Another argument is that stochastic nuclear DNA damage raises rates of cellular senescence - and we know that it requires only a small number of senescent cells to induce the dysfunctions of aging via their potent inflammatory signaling. An even more unified variant of this argument suggests mitochondrial dysfunction causes the nuclear DNA damage that then produces senescence.
The Quest for a Biomarker of Aging
Is it possible to build a biomarker of biological age that is robust enough to be useful and actionable? Efforts continue, with the epigenetic clock still front and center, and being improved step by step, but researchers are investigating other approaches, such as several attempts at the use of protein levels rather than DNA methylation. There is also a contingent who wish to combine very simple assessments with algorithms to produce a score that correlates better than any single assessment. Any number of new individual biomarkers were noted this year, such as MCP-1 and new oxidative markers. Alone these are not all that accurate, but might be combined into one of the algorithmic efforts.
Telomerase Gene Therapies
Interest in telomerase as the basis for therapy continues apace. Building on work in mice from past years, telomerase gene therapy has been demonstrated to reverse fibrosis, for example. More evidence accumulated this year for increased telomerase not to increase cancer risk in mice, as was originally expected of this sort of approach to pushing damaged cells back to work. Researchers have even proposed a means to enhance the activity of native telomerase to achieve similar effects without delivering more. BioViva Sciences appears to have moved away from building a telomerase gene therapy, but we do now have more of the story of that attempt and more data from the test subject this year. Libella Therapeutics are working now on a gene therapy for human use, and gave a brief overview at RAADfest earlier this year.
The Comparative Biology of Aging
In the comparative biology of aging, researchers attempt to learn from other species, with an eye to eventually perhaps building therapies to port over more favorable biochemistry into humans. Studies of long-lived naked mole-rats are an important part of this field. This species maintains its genome exceptionally well in comparison to other, shorter-lived rodents. The cancer resistance of naked mole-rats was further explored this year, with new mechanisms added to those already known. Naked mole rats apparently suffer cellular senescence, but seem unaffected by it, analogous to the way in which they exhibit high levels of oxidative stress without apparent harm. Beyond naked mole-rats and aging, researchers have reported on investigations of highly regenerative species such as the axolotl, searching for the secrets of organ regrowth, and on the exceptional cancer suppression of elephants.
Well Developed Ways to Modestly Slow Aging
A few approaches to slow rather than reverse aging have picked up steam in the past year. Firstly, there is now a set of mTOR inhibitors in clinical development, most targeted specifically to inhibition of mTORC1 rather than mTOR in general, and a bunch of others waiting in the wings for their turn. Recent research results show mTOR is involved in vascular aging. A clinical trial has shown that mTORC1 inhibition can improve immune function in late life.
Secondly, raising levels of NAD+ in order to improve mitochondrial function is also at the point of showing benefits in clinical trials in the case of nicotinamide riboside. Plain nicotinamide, on the other hand, doesn't do well in mice, suggesting considerable variations in effectiveness in the various methods of NAD+ upregulation on the market. New evidence this year shows that loss of NAD+ is linked to cellular senescence in some tissues, and that increased NAD+ helps hematopoietic stem cell function.
Thirdly, we might consider mitochondrially targeted antioxidants, also intended to improve mitochondrial function, of which several different types are either in development or already approved for treatment of some conditions. This year, researchers provided data for SS-31 to improve cognitive function in mice, while MitoQ improved vascular system function in a human clinical trial. There is also published data for the effects of MitoQ on a variety of biomarkers associated with aging.
That mTOR inhibitors, NAD+ enhancers, mitochondrially targeted antioxidants, and most initial senolytic compounds are cheap and easily available has energized the self-experimentation community. They tend not to be robust in their reporting and care taken in assessing compounds, however. In an attempt to raise the bar a little, I posted a number of guides over 2018. They include chemotherapeutic senolytics, the FOXO4-DRI peptide, mitochondrially targeted antioxidants, and a simple starting example with MitoQ and niagen.
Alzheimer's research is so massively funded that it generates an outsized amount of news and research results. Ask most scientists who toil within the field, and they are suspicious that much of this effort is wasted. There is open rebellion against the amyloid hypothesis and the recent history of relentless failure of clinical trials of immunotherapies. Researchers are looking at other approaches, such as cell therapies, targeting herpesviruses or infection in general as a cause of amyloid aggregation, destroying or replacing microglia, targeting all protein aggregates in the aging brain and not just one, focusing on tau (this is a popular one), use of anti-amyloid small molecules, slowing progression of Alzheimer's via NSAIDS, or addressing changes in drainage of cerebrospinal fluid, including via the glymphatic system. Ironically, this is occurring right at the time at which the original course of immunotherapies to clear amyloid from the brain is finally starting to work, and in a couple of different ways. Was this all a waste, or the price of progress? There you will find disagreement and debate. Other interesting research from the year includes signs that Alzheimer's is reversible until major cell death occurs.
Stem Cell Therapies and Tissue Engineering
First generation stem cell therapies achieve their results via cell signaling, as the transplanted cells do not survive long. But which signals? Most signaling between cells is carried by means of vesicles, membrane-bound packages of molecules. The class of vesicle known as exosomes is gaining more attention these days, as researchers have found they are fairly easy to harvest. Why deliver cells when you can deliver vesicles? The first tests have been intriguing: vesicles of young cells can reverse measures of aging in old stem cells in cell culture, and similarly in old mice. Vesicles promote heart regeneration in rats, brain regeneration and intestinal regeneration in pigs. Exosomes from stem cells make skin cells more resilient.
Tissue engineering and regenerative medicine is too large and energetic a field by far to do more than note a few of the high points as they race by. This year a human trial showed that mesenchymal stem cell transplant reduced frailty in older patients. Some very promising progress is being made on ensuring survival of transplanted cells in the heart and in the retina, actually realizing the original goal of delivering useful, functional cells to support aged tissues. Researchers are also demonstrating the ability to grow patient matched tissue sections via induced pluripotency. The production of small functional sections of tissue, organoids, is progressing apace, as is bioprinting. Bioprinting efforts are in fact consuming large-scale venture funding in the production of factory operations now. Examples of tissues created by the research community include corneas, liver sections, salivary glands, and intervertebral discs. The development of decellularized organs for transplantation is also moving more rapidly. Researchers recently demonstrated transplantion of decellularized lungs in pigs. This year also saw the beginning of a contentious debate over whether adult neurogenesis happens in humans as it does in mice; the implications are important for near term progress in regenerative therapies for the brain.
The cancer research industry is another vast field in which it is impossible to do more than sample the output of the scientific community. The important part of cancer research, to my eyes, is progress towards technologies that can be applied - with little alteration - to most or all cancers. This is the path to meaningful progress, given the vast array of cancers that exist. This year researchers noted that it may be possible to starve any cancer cell given the way they alter circadian rhythm mechanisms. Paligenosis has been noted as a process that might give rise to broadly applicable cancer therapeutics capable of suppressing cancer cell proliferation. Mechanisms of Huntington's disease might be used to suppress all cancers. Genes essential to metastasis have been identified as possible targets. There are suggestions of a potentially exploitable mechanism linking p53 and DHEAS. Meanwhile, CAR-T therapies, while not applicable to all cancers without a fair amount of work to adapt to each new type, are still proving to be a major advance over the prior state of the art.
Blood Pressure and Cholesterol
Blood pressure and cholesterol levels are important topics in the present practice of medicine. One of the great successes of medicine in recent decades, against all the odds, has been to find that blood pressure and cholesterol are so important to mortality that overriding bodily systems to bring them under control can significantly reduce mortality rates even given the fact that none of the underlying causes are being addressed, and even given ongoing debates over their importance. Research is progressing towards novel ways of achieving these goals, such as via ANGPTL3 blockade, PCSK9 inhibition, or any number of other gene therapies that reduce cholesterol levels or blood pressure. Researchers have also tried training the immune system to attack cholesterol transport mechanisms.
The Cryonics Community
Cryonics is ever controversial in the mainstream, but the press seems more respectful of late. The cryonics community advances and changes slowly, but nonetheless it does advance. Progress at a faster pace requires greater investment in research and development, which in turn is unlikely to arise absent commercial success in offering cryopreservation services. This chicken and egg is nothing new, and the bootstrapping process of incremental growth is a slow one - though with the occasional unexpected and welcome development, such as the donation of 5 million to Alcor this year to support cryonics research. That research is now moving more rapidly towards viable reversible cryopreservation of organs, something that would greatly improve the standing of the cryonics industry. Small molecule alternatives to cryoprotectant to minimize ice formation during cooling are under investigation, for example.
The long-standing tension between those who care only to see a copy of their mind running in the future versus those who want their living brain restored and repaired continues to be debated. This influences support for specific technical approaches, as noted by the Brain Preservation Prize going towards a vitrifixation method that is advantageous for copying the structure of the preserved brain, but makes restoration of the tissue far more challenging, one step removed from being impossible. The company Nectome was founded to commercialize this approach with the explicit aim of providing data for later whole brain emulation. From my perspective, it would be good to see the pendulum swing back to favor improvement in reversible vitrification preservation options.
Short Essays From 2018
A handful of short free-form essays appeared at Fight Aging! over the past year. If you like them, share them.
- Aging Research Half a Lifetime Ago: the Lost Decades of the 20th Century
- How Would One Go About Building a Company to Bring Cheap Senolytics to the World?
- Can Two Dozen Marginal Ways to Treat Aging be Combined into One Useful Therapy?
- A Nuanced Opposition to the FDA and Similar Regulatory Agencies
- When I am Eighty-Five
- Ladies and Gentlemen, We Are All Dying
- The Hedonistic Imperative, Followed to the Ends of Paradise Engineering
- Blind Upon the Eve of Apotheosis
- For Senolytics Companies, an Effective Piperlongumine would be a Greater Competitive Threat than Dasatinib
- Without an End to Aging, Every New Technological Advance is Just Another, Greater Monument to the Dead
- When Someone Has to Spend Millions on Small Molecule Screening to Get Things Moving
Interesting Presentations and Interviews
Many of the interviews with members of the community, advocates, entrepreneurs, and scientists, given over the past year may be worthy of a second glance. If Aubrey de Grey of the SENS Research Foundation dominates this list, it is because he gives a lot of presentations and interviews.
- Aubrey de Grey on Ending Aging and the Relative Merits of Various Approaches
- Aubrey de Grey on Rejuvenation Research: How Big and How Near are the Benefits?
- Aubrey de Grey on Progress and Timescales in Rejuvenation Research
- An Interview on the Unknowns of the Epigenetic Clock
- An Interview on Mitochondrial Decline in Aging and Neurodegeneration
- The Rise of Oisin Biotechnologies
- An Interview with Vitalik Buterin, Patron of SENS Rejuvenation Research
- Undoing Aging: an Interview with Aubrey de Grey
- An Interview with a Buck Institute Neuroscientist
- Undoing Aging: an Interview with Michael Greve of the Forever Healthy Foundation
- A Three Part Discussion of Mitochondrial Hormesis as an Approach to Slow Aging
- Cornelis (Cees) Wortel, Ichor Therapeutics Chief Medical Officer, on Rejuvenation Research and Its Engagement with the Established Regulatory System
- An Interview with a Programmed Aging Theorist
- An Interview with Reason at the Life Extension Advocacy Foundation
- An Interview on Mitochondrial Damage and Dysfunction in Aging
- An Interview with Vadim Gladyshev on Research into the Causes of Aging
- An Interview with Jim Mellon, and Update on Juvenescence
- A Lengthy Interview with Aubrey de Grey of the SENS Research Foundation
- An Interview with Peter de Keizer of Cleara Biotech
- Didier Coeurnelle on Advocacy and the Transition Years for Rejuvenation Therapies
- An Interview with Researcher João Pedro de Magalhães
- Alex Zhavoronkov on Funding and Priorities in Longevity Science
- An Interview with David Gobel of the Methuselah Foundation
- Judith Campisi on Senolytics
- A Biotech Industry CEO on mTOR Inhibitors and the Treatment of Aging
- An Interview with James Peyer of Apollo Ventures
- An Interview with Aubrey de Grey at the Longevity World Forum
- Thoughts on Near Term Rejuvenation Therapies
- Questioning the Validity of Jeanne Calment's Age
A Community Looking to the Future
What is past is prologue, as they say. The acceleration of biotechnology is starting to reach our field of rejuvenation research, with newfound funding and interest in treating aging as a medical condition growing year by year. There is much to look forward to, and we should remain rightly focused on building the better future that we all want to see, a future in which aging is controlled and no-one is forced against their will into suffering, frailty, and a drawn out death of mind and body.
Ambrosia Health and the Downsides of Developing Marginal Therapies
One of the many good reasons to be guided by the SENS approach to aging, meaning a focus on repairing molecular damage as close to the causes of aging as possible, is that it has a greater likelihood of resulting in a viable therapy. Benefits should turn out to be sizable, broadly applicable to many age-related conditions, and reliable. The present best example of the type is provided by senolytic therapies that clear senescent cells. The more prevalent and popular strategy of tinkering with metabolism or adjusting the late-stage, dysfunctional disease state, throwing signals into the mix to override cellular reactions to damage, or upregulate stress responses, and while hoping for the best, has a high failure rate in larger human trials. With few exceptions, benefits tend to be unreliable, narrowly applicable to just a handful of conditions, and small.
Unfortunately, once development has reached the stage of a funded company focused on developing a particular therapy, it is hard for anyone involved to back down and admit failure to achieve good results. A few companies, Ambrosia and Alkhahest, are currently in this position when it comes to the use of blood and plasma transfusions to try to recreate the benefits observed in parabiosis studies. In these animal studies, the circulatory systems of old and young mice are linked; the young mice suffer accelerated measures of aging and they old mice gain some reversal of measures of aging. Unfortunately, research completed after these companies were established, and then the data generated by the companies themselves, shows that there is nothing here of interest. If there is an effect resulting from transfusion, it is small and unreliable. For one, transfusion is a terrible way to try to recreate the effects of a complete joining of circulatory systems, and secondly the evidence now strongly indicates that benefits in the old mice in parabiosis studies are more a matter of dilution of harmful factors in old blood rather than the delivery of beneficial factors in young blood.
The media are sharks and will cheerfully build a narrow pedestal for a company and its founders one day, uncritically accepting all company statements as fact without challenge, and then turn on a dime to knock all it down the moment that the data fails to live up to unrealistic expectations. They will be unkind about failure, regardless of how deserving the people involved actually are; they will mix together all possible reasonable and unreasonable accusations while constructing their narrative, as illustrated in today's article below. This is another thing to bear in mind when considering what sort of medical biotechnology to pursue, and how to pitch it at the outset.
The article here assembles a grab-bag of complaints about Ambrosia, some of which are valid and useful, and some of which are quite pernicious, such as the leading presentation of the death of an aged trial participant, or the way the authors played the public opinion game with blood banks. Most of the technical complaints about lack of effect for the therapy could just as well be leveled at Alkahest, but Ambrosia is an easier target given their non-traditional approach to trials and present diminished position. For my part, I see nothing wrong with patient paid trials that are responsibly conducted. It allows for tests of potential therapies that might otherwise never happen. There is an unseemly hostility to this approach to trials, sad to say, both in the research community and in the media. Objections on that front when a company fails to produce good results are irrelevant and unhelpful. On the other hand, calling out the founders of companies that continue with a failed program because no-one has the moral courage to admit failure and call a halt is a good thing, and it is a pity that it isn't done in most such cases.
Jesse Karmazin, the founder of the startup Ambrosia, had a pitch journalists couldn't resist: For a fee, he could help his clients combat aging and its related ills with infusions of blood plasma from the young. Teen donors, vampiric undertones, a serious-sounding study, an 8,000-per-person price tag and rumors that venture capitalist Peter Thiel might be interested earned Ambrosia more than 100 press mentions in just two years.
But despite declaring the study a success and announcing plans this week to accept new clients, Karmazin never showed any proof that the transfusions actually helped people. In the media, he touted impressive results, but almost a year after his study officially concluded in January 2018, he hasn't released them. Scientists have criticized the study as flawed and the procedure as medically unnecessary and not without risk; in rare cases, transfusion complications can be fatal. One of the doctors Karmazin hired had previously been disciplined by a state medical board for unprofessional conduct.
Karmazin himself cannot legally practice medicine in any state; he is explicitly prohibited from practicing in Massachusetts by authorities. Ambrosia's president and chief operating officer quietly left the company in late December, leaving Karmazin as the sole employee. And the only patient who spoke publicly about Ambrosia's transfusions - treatments he hoped would help him live healthier into old age - died at 65 after going into cardiac arrest.
We found that at least some of Karmazin's young plasma came from a nonprofit blood bank in Texas that recruited teenage donors for "saving lives," but noted on a consent form that their blood components could also be used for "any other medical purpose." The bank abruptly decided to stop selling young plasma after we reached out, according to an employee email.
Ambrosia, which declined to comment on whether the company has any investors, is only one of many firms investigating how to help people feel younger for longer. But Ambrosia's ability to attract paying clients and years of positive press coverage - without providing scientific data to back up its claims - shows just how easy it can be for promises to outpace the research when Silicon Valley gold-chasing mixes with Americans' fear of death.
An Initial Assessment of the Phenotypic Age Metric
Today's open access paper adds to the growing number of attempts to construct a useful biomarker of aging from a combination of simple, available metrics. The Phenotypic Age measure described here uses a few fairly standard measures from blood samples as a basis, which might lead us to suspect it is heavily biased towards measuring immune system aging. Insofar as immune system function is important to overall health, and immune system function declines with age, then so far so good. The challenge with all of these potential biomarkers is less how well they do in the world of natural aging, to predict who will have a higher mortality in the years ahead, and more how they respond to specific classes of rejuvenation therapy.
The primary rationale for spending any time on the development of a biomarker of aging is to produce a fast, low-cost way of assessing the results of an alleged rejuvenation treatment. At present only life span studies can reliably determine how well such a treatment performs. Such studies are expensive and slow in mice, and out of the question in humans. This is a major impediment to progress. What is needed is an approach that enables researchers to treat older animals and people, and then a month later run a quick test to assess the results. That would speed up development in this field immensely. The work carried out in recent years on epigenetic clocks suggests that a robust biomarker of aging is a feasible goal.
The most important question remains to be answered, however: how will all of the various potential biomarkers of aging react to specific classes of rejuvenation therapy, such as senolytic drugs to clear senescent cells? A biomarker heavily based on immune cell characteristics may provide results that are of little relevance to changes taking place in the tissues of important inner organs, and vice versa. Until these interactions are well quantified by researchers, the biomarkers are not terribly useful - the output will provide a number, but what does that number really mean? Building biomarkers and building rejuvenation therapies will, at least at the outset, have to proceed in parallel, with the two sides incrementally validating one another.
A new aging measure captures morbidity and mortality risk across diverse subpopulations from NHANES IV: A cohort study
One method for determining whether a person appears younger or older than expected on a biological or physiological level is to compare observable characteristics, reflecting functioning or state, to the characteristics observed in the general population for a given chronological age. A number of aging measures have been proposed using molecular variables, the most prominent being epigenetic clocks (expressed as DNA methylation age, in units of years) and leukocyte telomere length. We and others have previously shown that while these measures are phenomenal age predictors - especially DNA methylation age - their associations with aging outcomes above and beyond what is explained by chronological age is weak to moderate. Conversely, aging measures based on clinically observable data, or phenotypes, tend to be more robust predictors of aging outcomes.
The differences in prediction between these two types of measures could reflect that molecular measures may only capture one or a small number of changes involved in the multifactorial aging process, while on the other hand, clinical measures may represent the manifestations of multiple hallmarks of aging occurring at the cellular and intracellular levels. While composite scores based on traditional clinical chemistry measures are not mechanistic, their better performance and relative affordability and practicality compared to current molecular measures may make them more suitable for evaluating the effects of aging interventions on an organismal scale, and/or identifying groups at higher risk of death and disease.
Among the existing clinical measures, the majority were generated based on associations between composite variables and chronological age - with no integration of information on how the variables influence morbidity and mortality. Given that individuals vary in their rate of aging, chronological time is an imperfect proxy for building an aging measure. Recently, we developed a new metric, Phenotypic Age (in units of years), that incorporates composite clinical chemistry biomarkers based on parametrization from a Gompertz mortality model. Rather than predicting chronological age - as previous measures have done - this measure is optimized to differentiate mortality risk among persons of the same chronological age, using data from a variety of multi-system clinical chemistry biomarkers.
In general, a person's Phenotypic Age signifies the age within the general population that corresponds with that person's mortality risk. For example, two individuals may be 50 years old chronologically, but one may have a Phenotypic Age of 55 years, indicating that he/she has the average mortality risk of someone who is 55 years old chronologically, whereas the other may have a Phenotypic Age of 45 years, indicating that he/she has the average mortality risk of someone who is 45 years old chronologically.
All analyses were conducted using NHANES IV (1999-2010, an independent sample from that originally used to develop the measure). Our analytic sample consisted of 11,432 adults aged 20-84 years and 185 oldest-old adults top-coded at age 85 years. We observed a total of 1,012 deaths, ascertained over 12.6 years of follow-up. Proportional hazard models and receiver operating characteristic curves were used to evaluate all-cause and cause-specific mortality predictions. Overall, participants with more diseases had older Phenotypic Age. For instance, among young adults, those with 1 disease were 0.2 years older phenotypically than disease-free persons, and those with 2 or 3 diseases were about 0.6 years older phenotypically.
After adjusting for chronological age and sex, Phenotypic Age was significantly associated with all-cause mortality and cause-specific mortality (with the exception of cerebrovascular disease mortality). Results for all-cause mortality were robust to stratifications by age, race/ethnicity, education, disease count, and health behaviors. Further, Phenotypic Age was associated with mortality among seemingly healthy participants - defined as those who reported being disease-free and who had normal BMI - as well as among oldest-old adults, even after adjustment for disease prevalence.
Tau and Amyloid-β Synergize to Impair Neural Activity in Alzheimer's Disease
The mainstream of the Alzheimer's research community remains primarily interested in clearing deposits of amyloid-β from the aging brain. That said, there is a growing interest in tackling tau aggregation as well, particularly given the long years of failure to achieve meaningful results through clinical trials of immunotherapies that target amyloid-β. The current consensus on the development of the disease is that increased amyloid-β, leading to solid deposits of amyloid in and between cells, is an early phenomenon, and may in and of itself do little more than create mild cognitive impairment. However, amyloid-β aggregation sets the stage for the later production of neurofibrillary tangles, consisting of an altered form of tau protein, and these are far more harmful to brain function.
Both tau and amyloid-β protein aggregates are biochemically complex, with a surrounding halo of many varieties of harmful molecule. It is the halo rather than the deposits that do the damage to brain cells and their function, or so present thinking goes. Further, more recent research suggests that while tau is the more harmful of the two, tau synergizes with amyloid-β to causes greater damage than it would on its own.
This view of the condition may explain why attempting to intervene late in the process with anti-amyloid therapies fails to produce sizable benefits, but nonetheless does appear to help to some degree, particularly in animal models. So perhaps amyloid-β clearance as an approach is best harnessed for prevention or slowing of early development of the condition. Still, that leaves the challenge of treating later stages of the condition for present patients, and thus a growing number of researchers are working on ways to remove tau aggregates. Many of those scientists advocate for the development of therapies that clear both tau and amyloid-β at the same time, a strategy that seems very reasonable given the evidence to date.
Tau protein suppresses neural activity in mouse models of Alzheimer's disease
A new study sheds light on how the hallmarks of Alzheimer's disease - amyloid-beta (A-beta) plaques and neurofibrillary tangles containing the protein tau - produce their damaging effects in the brain. The findings suggest that strategies directed against both pathologic proteins, rather than one or the other, might be promising therapeutic options. "Our current study reinforces growing evidence suggesting that A-beta and tau work together to impair brain function and that, for certain aspects of that impairment, tau predominates. We are intrigued to learn how they are interacting at a molecular level, in order to find ways of blocking that synergy."
Studies with two mouse models that overexpress different forms of tau found, for the first time, that elevated levels of the protein were associated with a significant reduction in neural activity whether or not tau had aggregated into tangles. Experiments with a novel mouse model that overexpresses both A-beta and tau found that, in the presence of both pathological proteins, A-beta-associated hyperactivity was abolished and tau's neuronal silencing effect predominated. The findings were duplicated in mice regardless of their age, including animals too young to exhibit the loss of neurons typically seen in animals that only overexpress tau.
The authors note that their findings could help explain why clinical trials of A-beta-blocking therapies have had difficulty improving symptoms of patients with Alzheimer's disease. "One implication of our work is that approaches combining anti-A-beta and anti-tau therapies might be more effective than either alone, at least from the perspective of neural activation. Finding that tau and A-beta work in a synergistic fashion opens the doors to new research into understanding exactly how that interaction works."
Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo
The coexistence of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the neocortex is linked to neural system failure and cognitive decline in Alzheimer's disease. However, the underlying neuronal mechanisms are unknown. By employing in vivo two-photon Ca2+ imaging of layer 2/layer 3 cortical neurons in mice expressing human Aβ and tau, we reveal a dramatic tau-dependent suppression of activity and silencing of many neurons, which dominates over Aβ-dependent neuronal hyperactivity.
We show that neurofibrillary tangles are neither sufficient nor required for the silencing, which instead is dependent on soluble tau. Surprisingly, although rapidly effective in tau mice, suppression of tau gene expression was much less effective in rescuing neuronal impairments in mice containing both Aβ and tau. Together, our results reveal how Aβ and tau synergize to impair the functional integrity of neural circuits in vivo and suggest a possible cellular explanation contributing to disappointing results from anti-Aβ therapeutic trials.
Recent Papers on the Cellular Senescence Produced by Visceral Fat Tissue
Today, I thought I'd point out a couple of papers that touch on different aspects of the overlap between visceral fat tissue and senescent cells in aging. In the first paper, researchers show that the ability of visceral fat tissue to generate the markers of senescence is suppressed when the circulatory system of an old mouse is linked to a younger mouse. All of the ongoing, unresolved arguments over why this sort of modest rejuvenation occurs apply here; my money is still on it being dilution of harmful factors in an aged bloodstream. In the second paper, researchers link yet another aspect of dysfunction in the brain to the presence of senescent cells, in this case disorders such as anxiety and depression that are linked to fat tissue. The senescent cells can be used to explain that association with excess fat tissue.
Excess visceral fat tissue is harmful in many different ways, damaging the body and the brain. It is metabolically active, distorting the normal operation of cellular metabolism and tissue functions throughout the body. Further, it generates chronic inflammation via what appears to be quite a wide variety of mechanisms, from inappropriate cell signaling to DNA debris from dead fat cells. Short bursts of inflammation are a normal part of the response to injury and infection. When those mechanisms become stuck, however, activated without cease for the long term, then they become very damaging. Chronic inflammation accelerates the progression of all of the most common disabling and ultimately fatal age-related conditions. Being overweight speeds up that process.
As ever more of the research community becomes convinced (finally) that senescent cells are an important root cause of degenerative aging, more attention is being directed to all of the inflammatory conditions and states, searching for the senescent cells that no doubt cause a sizable fraction of that inflammation. Even in very old people, it is thought that there are only a small number of senescent cells present in tissues - perhaps a few percent of all cells at most. Yet these errant cells have a sizable detrimental effect, as the damage they do is mediated by the signal molecules that they generate, influencing the behavior of countless other cells near and far. Pro-inflammatory signals are one of the better understood consequences of cellular senescence, and the reason why these cells are a significant cause of inflammatory disease in old age.
Thus fat tissue doesn't have create many more senescent cells, in absolute numbers, in order to place a significant burden of damage and dysfunction on the rest of the body. Sadly, it does indeed create those cells. We can quite accurately say that being overweight results in an acceleration of aging, a consequence reflected in mortality rates, disease risk, and medical expenditure. The overweight and the obese have shorter, less healthy, more expensive lives, with all of those disadvantages scaling with the amount of excess visceral fat tissue, and the length of time it is carried. That isn't all down to senescent cells - there are plenty of other issues to consider in the harmful biochemistry of large amounts of fat tissue. I am sure that the development of senolytic therapies to destroy senescent cells will lead to a quantification of just how much of the damage done by being overweight is down to cellular senescence. Building therapies is the fastest way to obtain answers to this sort of question.
Adipose tissue senescence and inflammation in aging is reversed by the young milieu
Visceral adipose tissue (VAT) inflammation plays a central role in longevity and multiple age-related disorders. Cellular Senescence (SEN) is a fundamental aging mechanism that contributes to age-related chronic inflammation and organ dysfunction, including VAT. Recent studies using heterochronic parabiosis models strongly suggested that circulating factors in young plasma alter the aging phenotypes of old animals. Our study investigated if young plasma rescued SEN phenotypes in the VAT of aging mice.
With heterochronic parabiosis model using young (3 months) and old (18 months) mice, we found significant reduction in the levels pro-inflammatory cytokines and altered adipokine profile that are protective of SEN in the VAT of old mice. These data are indicative of protection from SEN of aging VAT by young blood circulation. Old parabionts also exhibited diminished expression of cyclin dependent kinase inhibitors (CDKi) genes p16 (Cdkn2a) and p21 (Cdkn1a/Cip1) in the VAT.
In addition, when exposed to young serum condition in an ex-vivo culture system, aging adipose tissue-derived stromovascular fraction cells (SVFs) produced significantly lower amounts of pro-inflammatory cytokines (Mcp-1 and IL-6) compared to old condition. Expressions of p16 and p21 genes were also diminished in the old SVFs under young serum condition. Finally, in 3T3 pre-adipocytes culture system; we found reduced pro-inflammatory cytokines (Mcp-1 and IL-6) and diminished expression of CDKi genes in the presence of young serum compared to old serum. In summary, current study demonstrates that young milieu is capable of protecting aging adipose tissue from SEN and thereby inflammation.
Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis
Cellular senescence entails a stable cell-cycle arrest and a pro-inflammatory secretory phenotype, which contributes to aging and age-related diseases. Obesity is associated with increased senescent cell burden and neuropsychiatric disorders, including anxiety and depression. To investigate the role of senescence in obesity-related neuropsychiatric dysfunction, we used the INK-ATTAC mouse model, from which p16Ink4a-expressing senescent cells can be eliminated, and senolytic drugs dasatinib and quercetin.
We found that obesity results in the accumulation of senescent glial cells in proximity to the lateral ventricle, a region in which adult neurogenesis occurs. Furthermore, senescent glial cells exhibit excessive fat deposits, a phenotype we termed "accumulation of lipids in senescence." Clearing senescent cells from high fat-fed or leptin receptor-deficient obese mice restored neurogenesis and alleviated anxiety-related behavior. Our study provides proof-of-concept evidence that senescent cells are major contributors to obesity-induced anxiety and that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders.
The ALZFORUM 2018 Retrospective
ALZFORUM should be on your reading list. It is a shining example of what can be accomplished online in focused patient advocacy, given sufficient funding and a good team. The Alzheimer's research community and its surrounding institutions represent a sizable fraction of all funding for the investigation and treatment of age-related disease these days, at least for public funding where such data is more reliably tracked. There is thus more money to go around for supporting initiatives like ALZFORUM than is the case in other fields, but it - of course - still requires a quality team to produce quality work. In this lengthy post, developments in Alzheimer's research over the course of 2018 are reviewed in detail. It is an exciting time for the field, given the first signs of progress after long years of failure in attempts to clear amyloid-β from the brain, and also given the rise of radical new directions in the development of therapies.
In 2018, a mix of positive and negative trial data left the field with a sense of unease that, in order to meet its goal of a game-changing treatment by 2025, everything has to go right from now on. On the up side, the SPRINT MIND trial indicated that keeping systolic blood pressure under 120 mm Hg in a person's 60s reduced mild cognitive impairment four years later by 19 percent, while in a Phase 2B trial, the anti-Aβ protofibril immunotherapy BAN2401 seemed to both mop up Aβ plaques from the brain and slow cognitive decline in people with early Alzheimer's disease (AD). Both trials generated optimism about early intervention.
BAN2401 joins the aducanumab, gantenerumab, and N3pG antibodies in removing amyloid plaques in the brain. Up to half the participants fell below the threshold for amyloid positivity over the course of one to two years. Convinced that their early antibody efforts were too timid, researchers at boosted dosing of gantenerumab, crenezumab, and N3pG, respectively, but as yet, none of these treatments has been shown to slow or halt dementia.
Taking a different tack, researchers claimed they cleared Aβ from the brain in a procedure akin to an engine oil change. They removed Aβ from blood by way of plasmapheresis, in which a person's plasma is exchanged for a solution of 5 percent albumin, the principal carrier of Aβ in the blood, and in some cases also containing blood immunoglobulins that bind Aβ. These carrier proteins indirectly coax Aβ from the brain, the theory goes. The Phase 2b/3 AMBAR (Alzheimer's Management by Albumin Replacement) trial missed its endpoint, but subgroup analysis suggested cognitive decline slowed in participants with moderate, though not mild, AD. Whether the albumin or the immunoglobulins did the trick is unclear, and the company plans to run a new trial to clarify. A related approach of soothing the "inflammaging" brain, either with whole plasma or defined fractions from the blood of young adults, is in early stage trials.
Whether Mitochondrial Genomes are Better or Worse is Circumstantial
Mitochondria, the power plants of the cell, come equipped with their own small genome. It is a remnant, left over from the ancient symbiotic bacteria that later became mitochondria, containing the few genes that failed to migrate to the cell nucleus over evolutionary time. Every species exhibits numerous different mitochondrial haplogroups, and given that these lead to variance in the performance and activities of mitochondria, one might be tempted to think that some haplogroups are objectively better than others. This study suggests that advantages and disadvantages vary by environment and diet, however, which might explain why evolution has selected for multiple haplogroups rather than one dominant haplogroup.
This is all interesting, but none of it stops the research community from engineering a globally better-than-natural human mitochondrial genome, and then copying it into the cell nucleus as a backup to prevent the well-known contribution of mitochondrial DNA damage to aging. Further, nothing stops us from keeping the haplogroups we have and rendering the effects of variants small and irrelevant through the development of other forms of enhancement biotechnology. The natural world handed over to us after billions of years of evolution is a starting point, not the bounds of the possible.
Mitochondrial DNA (mtDNA) and the dietary macronutrient ratio are known to influence a wide range of phenotypic traits including longevity, fitness and energy production. Commonly mtDNA mutations are posited to be selectively neutral or reduce fitness and, to date, no selectively advantageous mtDNA mutations have been experimentally demonstrated in adult female Drosophila. Here we propose that a ND V161L mutation interacted with diets differing in their macronutrient ratios to influence organismal physiology and mitochondrial traits, but further studies are required to definitively show no linked mtDNA mutations are functionally significant.
We utilized two mtDNA types (mitotypes) fed either a 1:2 Protein: Carbohydrate (P:C) or 1:16 P:C diet. When fed the former diet, Dahomey females harboring the V161L mitotype lived longer than those with the Alstonville mitotype and had higher climbing, basal reactive oxygen species (ROS) and elevated glutathione S-transferase E1 expression. The short lived Alstonville females ate more, had higher walking speed and elevated mitochondrial functions as suggested by respiratory control ratio (RCR), mtDNA copy number and expression of mitochondrial transcription termination factor 3. In contrast, Dahomey females fed 1:16 P:C were shorter lived, had higher fecundity, walking speed, and mitochondrial functions. They had reduced climbing.
This result suggests that mtDNA cannot be assumed to be a strictly neutral evolutionary marker when the dietary macronutrient ratio of a species varies over time and space and supports the hypothesis that mtDNA diversity may reflect the amount of time since the last selective sweep rather than strictly demographic processes.
Giant Mole-Rats Exhibit Greater Gene Expression Stability with Aging than Rats
A number of African mole-rat species live significantly longer than similar-sized rodents, and show very little age-related decline until very late life. Where examined in detail, their biochemistry is an odd mix. In some respects they exhibit the usual signs of damage and dysfunction associated with mammalian aging, such as raised oxidative stress and the presence of senescent cells, but don't appear all that affected by it. Elsewhere they exhibit clearly superior mechanisms, such as improved protein quality control, a layered set of anti-cancer mechanisms that provide near immunity to cancer, and - the topic of this paper - a well preserved pattern of gene expression. This latter case may be something of a tautology: dysregulation of gene expression, or changes in gene expression that are reactions to underlying damage, are a downstream consequence of the causes of aging. When an organism ages more slowly, or exhibits only a lesser degree of aging until very late life, then one would naturally expect gene expression patterns to remain more stable over time.
Compared to short-lived mammals, long-lived mammals have repeatedly been shown to exhibit fewer age-associated changes in numerous physiological parameters related to the functional decline during aging. Recent RNA-seq studies have suggested that much of the remarkable lifespan diversity among mammals is based on interspecies differences in gene expression. However, those studies focused on identifying particular genes and pathways that are differentially expressed between species with divergent longevities. Whether short-lived and long-lived species differ at the transcript level with respect to their amount of differentially expressed genes (DEGs) during aging (hereinafter referred to as "gene expression stability") has, to the best of our knowledge, not been explored yet.
Here, we examined age associated transcriptome changes in two similarly sized rodent species with different longevities: the laboratory rat (Rattus norvegicus), which has a maximum lifespan of 3.8 years, and the giant mole-rat (Fukomys mechowii), which has a maximum lifespan of more than 20 years. In giant mole-rats, longevity is significantly correlated with the reproductive status. Breeding animals outlive non-breeders by far. In the current study, we examined only non-breeding males. Male non-breeding giant mole-rats have a maximum lifespan of approximately 10 years and an average lifespan of approximately 6 years, still clearly exceeding the life expectancy of the laboratory rat.
For both species, we performed RNA-seq on tissue samples from five organs (blood, heart, kidney, liver, and skin; hereinafter called simply tissues) of young and elderly adults. The tissues were collected from young and elderly cohorts of laboratory rats (0.5 and 2.0 years) and giant mole-rats (young: approximately 1.5 years at average; elderly: approximately 6.8 years at average). For each species, we determined DEGs between the two respective time points and searched for enriched functional categories.
Our findings show that giant mole-rats exhibit higher gene expression stability during aging than rats. Although well-known aging signatures were detected in all tissue types of rats, they were found in only one tissue type of giant mole-rats. Furthermore, many differentially expressed genes that were found in both species were regulated in opposite directions during aging. This suggests that expression changes which cause aging in short-lived species are counteracted in long-lived species. Taken together, we conclude that expression stability in giant mole rats (and potentially in African mole-rats in general) may be one key factor for their long and healthy life.
An Incomplete Survey of Novel Approaches to Alzheimer's Disease
This open access paper is illustrative of a dogmatic mainstream of Alzheimer's disease research in which treatments must be immunotherapy approaches to clearance of amyloid-β or tau, or lifestyle changes and other means of management of risk factors such as blood pressure. Little else is acceptable. Yet many other lines of investigation do exist, such as drainage or filtration of cerebrospinal fluid, or tageting viral causes of amyloid-β accumulation, and some have progressed as far as development in biotech startups. They are nowhere to be found in this review paper.
Alzheimer's disease (AD), the most prevalent neurodegenerative disease of aging, affects one in eight older Americans. Nearly all drug treatments tested for AD today have failed to show any efficacy. There is a great need for therapies to prevent and/or slow the progression of AD. The major challenge in AD drug development is lack of clarity about the mechanisms underlying AD pathogenesis and pathophysiology. Several studies support the notion that AD is a multifactorial disease.
While there is abundant evidence that amyloid plays a role in AD pathogenesis, other mechanisms have been implicated in AD such as neurofibrillary tangle formation and spread, dysregulated protein degradation pathways, neuroinflammation, and loss of support by neurotrophic factors. Therefore, current paradigms of AD drug design have been shifted from single target approach (primarily amyloid-centric) to developing drugs targeted at multiple disease aspects, and from treating AD at later stages of disease progression to focusing on preventive strategies at early stages of disease development.
Here we focus on current AD therapeutic strategies which comprise of mechanism-based approaches including amyloid-beta (Aβ) clearance, tau protein deposits, apolipoprotein-E (ApoE) function, neuroprotection and neuroinflammation, as well as non-mechanism based approaches including symptomatic cognitive stimulation, AD prevention, lifestyle modifications, and risk factor management including non-pharmacological interventions.
NAD+ and Cellular Senescence in Intestinal Tissue Organoids
Organoids are a useful intermediary step between cell cultures and animal studies, allowing for investigations to be carried out in a structured tissue that is much closer to the real thing than cells in a petri dish. Researchers here use intestinal tissue organoids derived from old mice to show that raised levels of NAD+ suppress markers of cellular senescence - which most likely indicates suppression of activity rather than outright destruction of senescent cells to any great degree, given what we know of how calorie restriction affects NAD+ and senescent cells.
NAD+ levels are connected to mitochondrial function, and fall with age. A growing industry is now selling various means to raise NAD+ in order to improve mitochondrial function and thus tissue function. Some of these appear to be beneficial in early trials, while others seem ineffective. Past research has connected NAD+ with cellular senescence, or mitochondrial function with cellular senescence, but rigorous data on the size of the effect has yet to be produced. This narrow slice of the benefits of increased mitochondrial function is unlikely to compare favorably with the effects of senolytics, the outright destruction of senescent cells in large numbers.
Here we have demonstrated that the important stem cell marker Lgr5 was epigenetically silenced by trimethylation of histone H3K27, inducing suppression of Wnt signaling and a decrease of cell proliferation in intestinal epithelial organoids derived from aged mice. In these organoids, we also observed accumulation of SA-β-gal, a decrease in the expression of DNA methyltransferases and an increase in the expression of p21, indications of cellular senescence.
Epigenetic silencing of Lgr5 and induction of senescence occurs in aged intestinal organoids. The stem cell marker Lgr5 was substantially expressed in young intestinal epithelial organoids, whereas it was faintly expressed in aged intestinal organoids. Examination of DNA methylation levels around the Lgr5 promoter region revealed no significant difference in DNA methylation between young and aged intestinal organoids. Since Lgr5 is an activator of the Wnt signaling pathway, epigenetic silencing of Lgr5 results in suppression of Wnt signaling, which may lead to decreased cell proliferation and activation of senescence-associated genes such as p21 due to suppression of DNA methylation.
Recently, calorie restriction experiments have highlighted Sirt1 as a possible longevity gene. Sirt1 has histone acetyl transferase activity and its expression is regulated by the concentration of NAD+. Aging leads to a reduction of NAD+ in the body, and it has been reported that supplementation of NAD+ induces longevity and stem cell activation. Here, intestinal epithelial organoids derived from aged mice grew larger, forming crypt-like structures after treatment with NMN, a key NAD+ intermediate. The aged intestinal epithelial organoids treated with NMN showed an increase of proliferative activity, activation of Lgr5 and Sirt1, and suppression of p21 and p16, suggesting that treatment with NMN was able to ameliorate senescence-related changes in intestinal epithelia and could have potential application as an anti-aging intervention.
Towards a Biomarker of Aging Based on the Gut Microbiome
A low-cost, low-effort way to accurately assess biological age, meaning the burden of molecular damage and the countless harmful cellular reactions to that damage, would greatly speed development of rejuvenation therapies. Ideally researchers would be able to apply a therapy and then within a month obtain a measure of how greatly it affects aging. At present the only reliable way to fully assess means of slowing or reversing aging is to run life span studies, which are slow and expensive in mice, and simply not feasible in humans.
Thus a fair amount of effort is presently devoted to the development of biomarkers and combinations of biomarkers that might one day serve this purpose. In this preprint paper, researchers outline their work on the use of the gut microbiome as a basis for a biomarker of aging. It is known that characteristic changes occur in the microbiome with age, many of them detrimental and associated with the development of age-related disease, but there is a high degree of variability between individuals and study populations. Thus these results will certainly need a much broader replication as a part of any further development.
Although infant microbiome succession is well studied and can be used to assess the risks of various health conditions, its transition to adult microbiome is less understood. More so, composition variability attributed to geographic location, medical history, diet, and other factors make it hard to analyze adult microbiomes as effectively as those of infants. Age-related studies of human microbiome have failed to produce a straightforward theory of gut flora aging.
Some studies indicate decreasing biodiversity in the elderly gut. However, that is not the case for all data sets, and elderly healthy people may have microbiomes as diverse as the younger population. Other findings include changes in specific taxa abundance in aging microbiota. Such bacterial genera as Bacteroides, Bifidobacterium, Blautia, Lactobacilli, Ruminococcus have been shown to decrease in the elderly, while Clostridium, Escherichia, Streptococci, Enterobacteria increase. However, these patterns are not strictly established as results vary greatly across different studies. This may be attributed to different methodologies as well as unbalanced data sets that may contain people of different lifestyles.
Despite these complications, the consensus is that the elderly gut has lower counts of short chain fatty acid (SCFA) producers such as Roseburia and Faecalibacterium and an increased number of aerotolerant and pathogenic bacteria. Such shifts can lead to dysbiosis, which in turn contributes to the onset of multiple age-related diseases.
The standard way of separating the gut microbiome into three chronological states - child, adult, and elderly microbiomes - lack a clear set of rules. Among them, adult microbiome remains the greatest mystery. It has no established succession stages, as in newborns, and does not normally reflect gradient detrimental processes typical for an old organism. This poses a question whether normal adult microbiome progresses at all or it is in a state of stasis. Considering the aging process is gradual and involves accumulation of damage and other deleterious changes (as also indicated by a number of biomarkers such as DNA methylation clocks), it is logical to suppose that gut microbiome succession is also gradual. However, attempts to use microbiome-derived features to predict chronological age have been inconclusive.
Here, we developed a method of predicting the biological age of the host based on the microbiological profiles of gut microbiota using a curated dataset of 1,165 healthy individuals. Our predictive model, a human microbiome clock, has an architecture of a deep neural network and achieves the accuracy of 3.94 years mean absolute error in cross-validation. The performance of the deep microbiome clock was also evaluated on several additional populations. This approach has allowed us to define two lists of 95 intestinal biomarkers of human aging. We further show that this list can be reduced to 39 taxa that convey the most information on their host's aging. Overall, we show that (a) microbiological profiles can be used to predict human age; and (b) microbial features selected by models are age-related.
The Uncertain Details of Retinal Aging
This open access paper examines what is known of the aging of the retina, and notes the difficulties inherent in relating any of those changes to specific declines in vision. The research community has an increasingly detailed view of exactly what differentiates an old retina from a young retina, structurally, chemically, and in the changing behavior of the various types of cell that make up retinal tissue. It is a challenge to relate data obtained in laboratory animals to loss of specific aspects of visual function, however, particularly the more subtle ones. One can't ask mice and rats to sit through the same test procedures as humans undergo, and obtain useful feedback via that approach.
Visual aging is linked to a decline in functional activity causing lower visual acuity, lower contrast sensitivity and impaired dark adaptation. However, although it has been reported that the age-related visual impairment is mainly due to a neuronal malfunction together with cell loss, the specific reasons of aging are still uncertain. How, and at what level, are the diverse neuronal populations affected? And how much are other retinal players involved?
By characterizing retinal aging in experimental animals (pigmented and albino rats) under controlled and healthy conditions, we found that the retinal function, as measured with full field electroretinograms, decreased ~50% at 22-months compared with 2-month-old rats. Whether neuronal malfunction or cell loss is mainly responsible for this reduced functionality is still an open question, even though structural changes in the optical components may contribute to this reduction. Interestingly, several studies suggest cell loss based on the retinal thinning that occurs with aging. However, although when we measured the retinal layers in vivo we observed a decrease in thickness ~14%, we also saw that the constant retinal growth was responsible for the retinal thinning, since volumetric and quantification analyses indicated that the thinning did not involve neuronal loss.
The retina is a highly organized and specialized tissue. The light-sensitive photoreceptors are essential for an effective signal transduction and to initiate the efficient transmission of impulses through the retina. They are vulnerable to light-induced damage and many publications have shown the degeneration of outer segments during aging. The central retina probably receives greater light exposure triggering different metabolic requirements that increases metabolic stress. In fact, a deficiency in DNA repair enzymes, damage induced by excitatory amino acids, specific age-related metabolic changes, a general decline in autophagy activity, and reduced energy production by mitochondrial metabolism collectively result in oxidative stress that may affect photoreceptor functionality. All that in addition to lipofuscin accumulation, morphological alterations and damage in the retinal pigmented epithelium accompanied by a para-inflammatory response are the signature signs of aging in the retina.
To preserve visual function, the eyes and brain require precisely tuned machinery. Any of the above-mentioned changes related to aging, including synapse remodelling or neuronal loss in response to age may contribute or play a crucial role in the continuous and irreversible decline in vision. Importantly, age may end causing a partial or complete distorted image formation, more so in a timeframe where our lifespan is increasing. So, could this retinal dysfunction be prevented or restored?
Considering Mesenchymal Stem Cell Therapy for Atherosclerosis
Mesenchymal stem cell (MSC) therapies as presently practiced, even given considerable differences in what exactly is meant by "mesenchymal stem cell", fairly reliably reduce the chronic inflammation of aging for an extended period of time. They are much less reliable at inducing regeneration of tissues, and where that does occur it probably results from dampened inflammation. One of the many detrimental consequences of the always-on inflammatory signaling that arises with age is a disruption of regenerative capacity. Given the ability of MSC transplantation to suppress inflammation, it is possible that this could be at least marginally useful as a therapy for any age-related condition in which inflammation is an important component.
Here, researchers consider MSC therapies as a way to slow down atherosclerosis, as inflammation strongly influences the pace at which this condition progresses. They also suggest that atherosclerosis is linked to the age-related failure of native MSCs to regulate inflammation. There are several possible reasons for this. Firstly, inflammation goes hand in hand with oxidative stress, the presence of greater levels of oxidizing molecules. This means it also leads to more of the oxidized lipids that cause macrophages attempting to clean up atherosclerotic lesions to become harmful foam cells that instead accelerate growth of the lesions. Secondly, macrophage behavior is influenced by the state of inflammatory signaling. Macrophages that are normally helpful can be coerced into amplifying inflammation, switching to an aggressive inflammatory mode rather than assisting in repair of lesions.
Atherosclerosis, a chronic inflammatory disease of the wall of large- and medium-sized arteries, is the most common pathological process leading to cardiovascular disease (CVD). The hallmark lesion in atherosclerosis is the atherosclerotic plaque. An alternative strategy to target inflammatory pathways for CVD therapy could be enhancing physiological mechanisms that antagonize inflammation. Key cellular targets for this approach are multipotent mesenchymal stromal cells (MSC). MSC are non-hematopoietic clonogenic perivascular multipotent stromal cells that can be induced to differentiate in vitro into osteoblasts, chrondrocytes, or adipocytes. MSC function as pivotal regulators of inflammation by modulating innate and adaptive immune cells. This does not require long-term engraftment of MSC in target tissues. The crosstalk between MSC and immune cells is mainly mediated by secreted bioactive molecules.
Limited data are available for MSC from patients with atherosclerosis. Specifically, the contribution of MSC dysfunction to the persistence of chronic inflammation and plaque progression are ill-defined. This relates in part to the lack of specific markers that can identify MSC in vivo in human arteries. We have overcome this obstacle by using an alternative approach. Thus, we have characterized adipose derived MSC from atherosclerotic patients (i.e. subjects undergoing coronary artery bypass graft surgery) and compared their function with MSC from non-atherosclerotic patients. Immunopotency (i.e. the MSC capacity to suppress the proliferation of allogenic activated T-cells) was used as the main readout of MSC function. Initial findings confirmed that atherosclerotic-MSC have impaired immunomodulatory capacity and a pro-inflammatory secretome, both contribute to the state of chronic low-grade inflammation that promotes atherosclerosis progression. Moreover, we demonstrated that MSC immunopotency can indeed be enhanced by modulating inflammatory components of the MSC secretome.
There are multiple potential implications of these data. First, the therapeutic effectiveness of atherosclerotic-MSC is likely compromised when compared to their non-atherosclerotic counterparts. Accordingly, only non-atherosclerotic MSC should be used in clinical trials. Second, the ability to modulate the redox state of MSC is a possible strategy to enhance the therapeutic efficacy of autologous atherosclerotic-MSCs. Third, increasing age is an established independent risk factor for the development of atherosclerosis. Notably, mitochondrial dysfunction is not only associated with aging, but also with premature or accelerated atherosclerosis. Our study was not designed to address the contribution of MSC dysfunction to atherosclerosis onset or progression. However, our results strongly suggest this link, and we have set the stage to test this hypothesis in the future.
Life Extension Advocacy Foundation 2018 Retrospective
The Life Extension Advocacy Foundation (LEAF) staff members have grown their efforts considerably over the past year, including the launch of a yearly conference series and a network of angel investors focused on startup companies engaged with the aging process. The LEAF blog should probably be on your reading list. Insofar as a position on aging goes, the Life Extension Advocacy Foundation folk appear more guided by the Hallmarks of Aging view than the SENS view, but there is a significant overlap, and many of their past fundraising efforts have directly supported the SENS Research Foundation. The more fellow travelers the better; there is certainly the need for a great deal more patient advocacy for the treatment of aging than presently takes place.
In May, we officially announced our first conference held in New York City, Ending Age-Related Diseases: Investment Prospects and Advances in Research, which would then be held in July. The Longevity Investor Network, LEAF's own initiative to foster a flourishing rejuvenation biotech ecosystem, was also launched in May under the lead of Javier Noris; speaking of investments, at around the same time, a generous anonymous donor decided to invest both money and trust in us by becoming a Lycium-level Lifespan Hero and pledging 2,000 a month. We'd like to express our most sincere gratitude to this donor as well as to all our Heroes for all they do for us.
Although organizing the upcoming New York City conference took a great deal of effort and time, we still got quite a few interviews out in July. This was not all, as one of our most important projects was also launched in July - the Rejuvenation Roadmap, a curated database of hallmark-categorized, work-in-progress rejuvenation therapies, the companies developing them, and their current state of development. The Roadmap is our way of answering the question, "How far are we from defeating aging?", and it has grown quite a bit since it was first announced; hopefully, it'll grow much more in 2019!
In August, Michael Kope from SENS Research Foundation joined our newly formed Industry Advisory Board (IAB) and will provide business guidance and advice to LEAF as our organization continues to grow and develop. Michael and the other members of the IAB will be a great asset in helping us to achieve our goals. The AgeMeter biomarker scan, which was successfully crowdfunded in late 2017 on Lifespan.io, became available for purchase on its own website near the end of August. We also should have an update regarding data access for project backers early in the new year.
In mid-September, we launched our most recent crowdfunding campaign on Lifespan.io, the NAD+ Mouse Project which was aimed at studying whether the administration of the NAD+ precursor nicotinamide (NMN), in both normal and accelerated-aging mice, confers the rejuvenative benefits that were first observed in previous studies.
As we look back on the year, we have published over 400 articles, with a corresponding 10-fold increase in traffic from our readers over the previous year. We have also hosted 10 pitch meetings to help young rejuvenation startups connect with investors as part of the Longevity Investor Network, a project aimed at bringing together researchers and investment funding. We hope that 2019 will be at least as intense as its predecessor, and given the all-around progress in the field and the growing interest in it, we're sure that we can look forward to it.
Interfering in the Interaction between Amyloid-β and Prion Protein as a Treatment for Alzheimer's Disease
The damage of Alzheimer's disease mediated by aggregation of amyloid-β and tau protein deposits isn't so much due to the aggregates, but rather the surrounding halo of complex interactions and related proteins. One of those thought to be important is between oligomeric amyloid-β and cellular prion protein, the latter of which is also of note in transmissible spongiform encephalopathy. Researchers here sought to interfere in this interaction, and achieved interesting results, at least in a mouse model of Alzheimer's disease. The usual caveats apply, in that Alzheimer's mouse models are highly artificial constructs, since nothing resembling Alzheimer's naturally occurs in that species. The relevance of these varied models to the real condition is very dependent on the details of the model and the details of the treatment - there is plenty of room for later failure even given good results in mice.
Researchers have identified a drinkable cocktail of designer molecules that interferes with a crucial first step of Alzheimer's and even restores memories in mice. The binding of amyloid beta peptides to prion proteins triggers a cascade of devasting events in the progression of Alzheimer's - accumulation of plaques, a destructive immune system response, and damage to synapses.
Researchers screened tens of thousands of compounds looking for molecules that might interfere with the damaging prion protein interaction with amyloid beta. They found that an old antibiotic looked like a promising candidate but was only active after decomposing to form a polymer. Related small polymers retained the benefit and also managed to pass through the blood-brain barrier. They then dissolved the optimized polymeric compound and fed it to mice engineered to have a condition that mimics Alzheimer's. They found that synapses in the brains were repaired and mice recovered lost memory.
A collaborating team reported a positive response when they delivered the same cocktail to cells modeled to have Creutzfeldt-Jakob Disease, a devasting neurological condition caused by infection with misfolded prion protein. The next step is to verify the compounds aren't toxic in preparation for translation to clinical trials for Alzheimer's disease.