Fight Aging!

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.

Macrophage Polarization

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.

Self-Experimentation

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

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.

Cancer Research

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.

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.

Link: https://doi.org/10.3389/fgene.2018.00593

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.

Link: https://www.alzforum.org/news/research-news/2018-year-research

Cellular senescence is one of the causes of aging. Cells become senescent in response to a variety of circumstances, the most common of which is when a somatic cell reaches the Hayflick limit on replication. Senescence also arises as a result of damage, to shut down cells that might become cancerous. Senescent cells cease to replicate, issue inflammatory signals that attract immune cells to destroy them, and usually self-destruct via programmed cell death mechanisms in any case. The problem with cellular senescence arises from the tiny fraction of senescent cells that evade destruction and linger, polluting surrounding tissue with inflammatory and other signals that evolved for short-term benefit only. When present over the long term, the signals secreted by even a comparatively small number of senescent cells will significantly degrade tissue structure and function, disrupt regeneration, and produce chronic inflammation. This accelerates the development and progression of near all common age-related diseases.

The targeted destruction of senescent cells has been well proven as a rejuvenation therapy in mice in recent years, and human trials are underway for the first senolytic drugs capable of achieving this goal. These initial drugs will be improved upon considerably in the years ahead, as they have side-effects, and only destroy half of the senescent cell burden in some tissues at best, but I expect them to nonetheless produce sizable and broad benefits in older people. Senolytic treatments are a form of repair, clearing away harmful cells that actively maintain a a state of greater dysfunction.

While forging ahead to bring benefits to tens of millions of patients as soon as possible is absolutely the right thing to be doing, there yet remains a great deal to accomplish and investigate as the field expands. On the clinical side of the fence, there are no good commercial assays that quickly and cost-effectively show senescence levels in human tissue, for example. On the scientific side of the fence, it is far from clear as to whether there exist significantly different classes of senescence with meaningful differences in activity and vulnerability to particular senolytic mechanisms. Cataloging past a handful of biomarkers and tissues has barely started. There is also the topic of today's paper, which is the degree to which the presence of lingering senescent cells increases with age because the immune system becomes compromised and falters in its surveillance. Killing senescent cells is a lot easier than restoring the immune system to youthful function, but when that goal is achieved, to what degree will senescence be purged from tissues? The open access paper here is an interesting first attempt to look at the size of this effect.

Impaired immune surveillance accelerates accumulation of senescent cells and aging

Cellular senescence, a central component of aging, is a cell-intrinsic stress response programmed to impose stable cell-cycle arrest in damaged cells, thus preventing them from propagating further damage in tissues. Normally, a sequence of events leads to the clearance of senescent cells and allows regeneration of the tissues that harbor them. In advanced age, however, the efficiency of this process may be compromised, as suggested by the tendency of senescent cells in the tissues of old individuals to accumulate. This accumulation is reportedly conserved across different species, including rodents, primates, and humans. Under such conditions, the beneficial cell-autonomous role of senescence might be outstripped by a negative impact of senescent cells on other cells, an effect mediated via the senescence-associated secretory phenotype (SASP), which has marked pro-inflammatory characteristics.

Senescent cells are subject to immune surveillance by multiple components of the immune system. Senescent cells attract and activate immune cells and serve as highly immunogenic targets for immune clearance. The immune response against senescent cells varies between different pathological conditions. For example, in fibrotic livers senescent cells derived from activated hepatic stellate cells are cleared by natural killer (NK) cells, whereas senescent pre-malignant hepatocytes are eliminated via the adaptive immune system. In other pathological conditions, for example in the case of dysplastic nevi, immune clearance does not occur and senescent cells persist for years. In the context of aging, it is not known to what extent the immune system participates in regulating the number of senescent cells, and whether age-related impairment of immune function contributes to the accumulation of senescent cells in old individuals.

Perforin, a pore-forming protein found in intracellular granules of effector immune cells, is an important mediator of immune cytotoxicity. Upon degranulation, perforin-formed pores enable granzyme penetration and caspase activation to induce apoptosis of the target cell. Perforin-mediated granule exocytosis (but not death-receptor-mediated apoptosis) is essential for the immune surveillance of senescent cells, and disruption of this pathway leads to the accumulation of senescent cells in damaged livers. To investigate the consequences of impaired immune surveillance of senescent cells in aging, we followed the aging process in mice in which granule-exocytosis-mediated apoptosis was disabled as a result of perforin gene knockout (Prf1-/-).

Our data indicates that compared to wild-type (WT) mice, Prf1-/- mice accumulates more senescent cells in their tissues with age. The accumulation of senescent cells in these Prf1-/- mice is accompanied by a progressive state of chronic inflammation, followed by increased tissue fibrosis and other types of tissue damage, as well as compromised organ functionality. The poor health of old Prf1-/- mice is associated with fitness reduction, weight loss, kyphosis, older appearance, and shorter lifespan than that of WT controls. Elimination of senescent cells from old Prf1-/- mice can be achieved by pharmacological inhibitors of the BCL-2 family of proteins, such as ABT-737. This pharmacological approach attenuates age-related phenotypes and gene expression profile in Prf1-/- mice.

Researchers here test a gene therapy that mimics the normal regulatory mechanisms governing BDNF expression in the hypothalamus, enhancing BDNF activity only when it is called for. In aging mice, this slows the expected decline of metabolism, as measured by a variety of metrics and markers. As a basis for a human enhancement therapy, this is intriguing, but not a near term prospect. I think we are at present quite a long way removed from a world of reliable, widely available gene therapies targeted to the brain, even under the most aggressive timelines.

The aging process and age-related diseases all involve perturbed energy adaption and impaired ability to cope with adversity. Brain-derived neurotrophic factor (BDNF) in the hypothalamus plays important role in regulation of energy balance. Our previous studies show that recombinant adeno-associated virus (AAV)-mediated hypothalamic BDNF gene transfer alleviates obesity, diabetes, and metabolic syndromes in both diet-induced and genetic models.

Here we examined the efficacy and safety of a built-in autoregulatory system to control transgene BDNF expression mimicking the body's natural feedback systems in middle-aged mice. The single rAAV vector harbors two cassettes, one expresses human BDNF driven by a constitutive promoter, the other expresses a microRNA targeting BDNF under the control of agouti-related peptide (AGRP) promoter that is activated by weight loss and fat depletion. This dual-cassette vector mimics the body's natural feedback system to achieve autoregulation of the transgene.

Twelve-month-old mice were treated with either autoregulatory BDNF vector or yellow fluorescence protein (YFP) control, maintained on normal diet, and monitored for 28 weeks. BDNF gene transfer prevented the development of aging-associated metabolic declines characterized by: preventing aging-associated weight gain, reducing adiposity, reversing the decline of brown fat activity, increasing adiponectin while reducing leptin and insulin in circulation, improving glucose tolerance, increasing energy expenditure, alleviating hepatic steatosis, and suppressing inflammatory genes in the hypothalamus and adipose tissues. Moreover, BDNF treatment reduced anxiety-like and depression-like behaviors. These safety and efficacy data provide evidence that hypothalamic BDNF is a target for promoting healthy aging.

Link: https://doi.org/10.1111/acel.12846

TGF-β is a problematic protein that is involved in the regulation of chronic inflammation and many other processes important in aging. Unfortunately, presently available means of suppressing TGF-β activity have potentially serious side-effects, as TGF-β has important functional roles in many tissues, even in later life, while it is at the very same time causing a broad set of problems. This is a challenge found in many places in medicine: it is rarely enough to be able to globally increase or diminish the activity of a given protein, as its relationships with the operation of cellular metabolism are usually quite complicated. Here, researchers show that, on top of all of the other issues laid at the feet of TGF-β, it blocks the ability of fibroblasts in aging skin to transform into fat cells and generate antibacterial defenses.

Dermal fibroblasts are specialized cells deep in the skin that generate connective tissue and help the skin recover from injury. Some fibroblasts have the ability to convert into fat cells that reside under the dermis, giving the skin a plump, youthful look and producing a peptide that plays a critical role in fighting infections. Researchers have now discovered the pathway that causes this process to cease as people age.

Don't reach for the donuts. Gaining weight isn't the path to converting dermal fibroblasts into fat cells since obesity also interferes with the ability to fight infections. Instead, a protein that controls many cellular functions, called transforming growth factor beta (TGF-β), stops dermal fibroblasts from converting into fat cells and prevents the cells from producing the antimicrobial peptide cathelicidin, which helps protect against bacterial infections.

"Babies have a lot of this type of fat under the skin, making their skin inherently good at fighting some types of infections. Aged dermal fibroblasts lose this ability and the capacity to form fat under the skin. Skin with a layer of fat under it looks more youthful. When we age, the appearance of the skin has a lot to do with the loss of fat." In mouse models, researchers used chemical blockers to inhibit the TGF-β pathway, causing the skin to revert back to a younger function and allowing dermal fibroblasts to convert into fat cells. Turning off the pathway in mice by genetic techniques had the same result.

Link: https://www.eurekalert.org/pub_releases/2018-12/uoc--usd122118.php

If the research community had a reliable, low-cost method of quickly assessing biological age, the burden of damage and dysfunction, a measure that is distinct from chronological age, then progress towards rejuvenation therapies might be accomplished more rapidly. At present the only reliable way to determine whether or not a given therapy produces a slowing of aging or rejuvenation is to run expensive, slow life span studies in mice. Even when taking the approach of starting the study with old mice, this is still quite a lengthy undertaking. Being able to apply a putative rejuvenation therapy to mice (or dogs, or non-human primates, or people) and then a few weeks later run a brief test to see how well it did would revolutionize the pace of progress.

Based on the past decade of work on biomarkers of aging, it seems plausible that a diverse weighted combination of measures will eventually prove to be good enough to greatly improve the economics of development for rejuvenation therapies. That good enough combination has yet to be established robustly, however. The various epigenetic clocks are promising, but not yet actionable, as researchers cannot say how exactly these clocks relate to the specific forms of molecular damage that cause aging. If the aggregate measure is higher or lower or unchanged following a given treatment, what does that mean? There is as yet no good answer to that question, and the answers will no doubt differ by class of therapy. Different biomarkers will react differently to various forms of biological repair. The same issue also applies to the other approaches beyond epigenetic measures.

Meanwhile, researchers continue to add new biomarkers and new combinations of existing biomarkers to the growing stack. The number of possible options grows on a month by month basis, but it may be that, at this stage, more effort should go towards calibrating the behavior of an existing biomarker approach, following use of interventions to slow or reverse aspects of aging, rather than continuing to pile additional markers onto the heap.

Age is more than just a number: machine learning may be able to predict if you're in for a healthy old age

Researchers focused on a type of skin cell called dermal fibroblasts, which generate connective tissue and help the skin to heal after injury. They chose this type of cell for two reasons: first, the cells are easy to obtain with a simple, non-invasive skin biopsy; second, earlier studies indicated that fibroblasts are likely to contain signatures of aging. This is because, unlike most types of cells that completely turn over every few weeks or months, a subset of these cells stays with us our entire lives.

The investigators analyzed fibroblasts taken from 133 healthy individuals ranging in age from 1 to 94. To get a representative sample, the team studied an average of 13 people for each decade of age. The lab cultured the cells to multiply, then used a method called RNA sequencing (RNA-Seq) to look for biomarkers in the cells that change as people get older. RNA-Seq uses deep-sequencing technologies to determine which genes are turned on in certain cells. Using custom machine-learning algorithms to sort the RNA-Seq data, the team found certain biomarkers indicating aging, and were able to predict a person's age with less than eight years error on average.

Researchers detect age-related differences in DNA from blood

Researchers have discovered age- and health-related differences in fragments of DNA found floating in the bloodstream (not inside cells) called cell-free DNA (cfDNA). These differences could someday be used to determine biological age - whether a person's body functions as older or younger than their chronological age. In a proof-of-concept study, researchers extracted cfDNA from blood samples from people in their 20s, people in their 70s, and healthy and unhealthy centenarians.

They found nucleosomes - the basic unit of DNA packaging in which a segment of DNA is wrapped around a protein core - were well-spaced in the DNA of the volunteers in their 20s but were less regular in the older groups, especially the unhealthy centenarians. Additionally, the signal from nucleosome spacing for the healthy centenarians was more similar to the signal from the people in their 20s than people in their 70s. Nucleosome packing is one aspect of the epigenome. Scientists first found cfDNA in the blood of cancer patients, and the fragments can be useful for diagnosing cancer. Earlier research has found that cfDNA is produced by dying cells, and as the cells die, the DNA is cut in between nucleosomes. "cfDNA is somewhat like a message in a bottle that captures what the cell looked like, epigenetically speaking, before it died."

Blood Markers in Healthy-Aged Nonagenarians: A Combination of High Telomere Length and Low Amyloid-β Are Strongly Associated With Healthy Aging in the Oldest Old

Many factors may converge in healthy aging in the oldest old, but their association and predictive power on healthy or functionally impaired aging has yet to be demonstrated. By detecting healthy aging and in turn, poor aging, we could take action to prevent chronic diseases associated with age. We conducted a pilot study comparing results of a set of markers (peripheral blood mononuclear cell (PBMC) telomere length, circulating Aβ peptides, anti-Aβ antibodies, and ApoE status) previously associated with poor aging or cognitive deterioration, and their combinations, in a cohort of "neurologically healthy" (both motor and cognitive) nonagenarians (n = 20) and functionally impaired, institutionalized nonagenarians (n = 38) recruited between 2014 and 2015.

We recruited 58 nonagenarians (41 women, mean age: 92.37 years, in the neurologically healthy group vs. 94.13 years in the functionally impaired group). Healthy nonagenarians had significantly higher mean PBMC telomere lengths, this being inversely correlated with functional impairment, and lower circulating Aβ40, Aβ42, and Aβ17 levels, after adjusting by age. Although healthy nonagenarians had higher anti-Aβ40 antibody levels, the number of participants that pass the threshold to be considered as positive did not show such a strong association. There was no association with ApoE status.

Researchers here demonstrate that the blood filtration methodology of plasmapheresis results in a temporary reduction in markers associated with aging in the bloodstream. Whether or not this is helpful is another question, and that was not assessed here. Frequently repeated plasmapheresis is an expensive proposition at the present time, far too costly to be worth it for any minor gain. It is, however, an interesting idea in the context of work on parabiosis, the linking of circulatory systems between an old and young animal, where at least one group seems convinced that benefits to the older animal result from dilution of harmful signals in old blood rather than delivery of helpful signals from young blood.

Setting aside the usually considered markers in old blood, what I would consider to be better and more proven targets for filtration based approaches include exhausted and senescent T cells, and molecular waste such as amyloid-β, which exists in the blood in equilibrium with its presence in the brain. It has been shown that clearing it from blood can produce benefits in Alzheimer's disease. Other possible targets include the various forms of oxidized lipid that contribute to atherosclerosis and other age-related issues.

This study is a large-sample cross-sectional study. Based on the comprehensive blood test and analysis, the ageing biomarkers were screened to establish the male and female biological age assessment formulas. From the perspective of prevention, the assessment of ageing is only the starting point. The purpose of the assessment is to screen out high-risk individuals, implement targeted interventions for high-risk individuals to achieve anti-ageing and longevity, and reduce the possibility of chronic diseases caused by ageing. Therefore, on the basis of assessing ageing, we explored the elimination of ageing biomarkers by double filtration plasmapheresis.

Assessing ageing is only the beginning of solving the problem of ageing. The anti-ageing intervention program for high-risk individuals is the end point. In clinical treatment, double filtration plasmapheresis has been approved for the treatment of critically ill patients, but its use in disease prevention has not been reported. This study explored the potential application of double filtration plasmapheresis in anti-ageing. Nine hundred and fifteen subjects underwent biological age assessment before and after intervention. The results confirmed that the biological age of males and females decreased by 4.47 years and 8.36 years after intervention. It is suggested that double filtration plasmapheresis technology might have potential application value in anti-ageing.

Link: https://doi.org/10.1186/s12979-018-0140-9

Stem cell populations maintain tissues in large part by providing a supply of new daughter cells to replace losses and repair damage. This supply diminishes with age, however, as stem cell populations become ever less active. This results from some mix of damage to the stem cells themselves and the more general damage of aging, accompanied by altered signaling as a reaction to that damage. The consensus is that stem cells have evolved to become less active in a damaged environment in order to diminish risk of cancer, but this is by no means settled, given that various approaches to force stem cells into greater activity appear to cause far less cancer than expected.

The decline in stem cell function is perhaps best studied in muscle tissue, but the phenomenon is most likely present in all tissues, each supported by its own varieties of stem cell. Here, researchers painstakingly demonstrate that neural stem cells falter in their delivery of olfactory neurons. The necessary functional tissue will thus deteriorate, and this contributes to the failing sense of smell observed in older individuals.

In mammals, generation of new neurons (neurogenesis) is mainly limited to early childhood and occurs in adulthood only in a few regions of the forebrain. One such exception is olfactory neurons, which develop from stem cells via several intermediate stages. "The production of these neurons diminishes with advancing age. In our recent study we wanted to find out the cellular basis and what role stem cells play in the process. Our approach utilised what are known as confetti reporters to perform lineage tracing: In mouse brains, we induced individual stem cells and all their descendants - called clones - to light up in a specific colour. In this way, we could distinguish clones over time by the different colours."

"In the next step, we compared clones found in young and older mice to find out what contribution individual stem cells and intermediates make to the neurogenesis of mature olfactory cells. We compared the confetti measurements with several mathematical models of neurogenesis. We found that the ability of self-renewal declines in old age, especially in certain intermediate stages called transit amplifying progenitors. In addition, analysis showed that asymmetric cell division and quiescence of stem cells increased in older mice. That means that fewer cells differentiate into olfactory cells in old age as they tend to remain in the stem cell pool and become less active. Therefore, the production comes to a halt."

Link: https://www.helmholtz-muenchen.de/en/aktuelles/latest-news/press-information-news/article/45520/index.html

Researchers recently demonstrated that they could rescue a form of mitochondrial dysfunction in mice by importing a gene from a sea squirt species. This is particularly interesting in the context of aging, as it appears to be possible to use this approach to work around any sort of damage to complexes III and IV in the mitochondrial electron transport chain (ETC). Every cell is equipped with a herd of mitochondria that act as generators, packaging the chemical energy store molecules used to power the cell. The ETC is central to this function.

The protein complexes that make up the ETC are made up of a mix of proteins encoded in both nuclear DNA and mitochondrial DNA. Dramatic mutations, such as deletions, can lead to mitochondria that function poorly or not at all. When this occurs during embryonic development, the result is either death or a much shortened and more uncomfortable life. When a mutation in mitochondrial DNA occurs in a single cell in an adult, on the other hand, as the result of the sort of random damage that takes place constantly in cells, it is usually either promptly repaired or the damaged mitochondrion is recycled.

Some forms of damage can lead to a more insidious result, however, producing a mitochondrion that is both dysfunctional and able to evade quality control mechanisms. Since mitochondria replicate like bacteria, on the rare occasions on which this happens, a cell is quickly overtaken by broken mitochondria. The cell becomes broken itself, exporting harmful oxidative molecules into the surrounding tissue and bloodstream. This has a range of undesirable downstream consequences, one of which is the creation of oxidized lipids that contribute to atherosclerosis.

The SENS Research Foundation's approach to this problem is gene therapy to place backup copies of mitochondrial genes into the better protected cell nucleus. Thus even given damage to mitochondrial DNA, there is still a supply of proteins to ensure that the ETC functions correctly. The paper here represents an alternative but conceptually similar approach, adding novel protein machinery from other species that can do some of the work of ETC protein complexes. It only fixes a portion of the lost functionality in this case, but is nonetheless most intriguing. The researchers are focused on mitochondrial disease, but it would be very interesting to repeat their approach in the context of aging and mitochondrial function.

Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy

Mitochondrial disorders are the most common class of inherited errors of metabolism. However, effective treatments are lacking, and their clinical management remains largely supportive. In patients with electron transport chain complex III (cIII) deficiency, mutations in several genes encoding either cIII subunits or assembly factors have been identified. These compromise cIII enzymatic activity and result in a wide variety of clinical manifestations.

BCS1L mutations are the most common cause of cIII deficiency, with various neonatal and adult phenotypes described worldwide, the most severe and prevalent of them being GRACILE syndrome. BCS1L is a mitochondrial inner membrane translocase required for correct function of cIII. Homozygous Bcs1lc.A232G (Bcs1lp.S78G) knock-in mice bearing the GRACILE syndrome-analogous mutation recapitulate many of the clinical manifestations, and a short survival of 35 days. In the slightly different C57BL/6JCrl substrain, the mice develop the same early manifestations but do not succumb to the early metabolic crisis. This extends their survival to over 150 days and brings additional later-onset phenotypes.

Under physiological conditions, quinols that transport electrons in the mitochondrial inner membrane are efficiently oxidized by cIII, with electron transfer via cytochrome c and cytochrome c oxidase (complex IV, cIV) to oxygen. However, plants and some lower organisms, but not mammals, express alternative oxidases (AOXs) that transfer electrons directly from quinols to oxygen. Their main role is to maintain electron flow when the cIII-cIV segment of the electron transport chain is impaired, limiting production of ROS and supporting redox and metabolic homeostasis.

Ciona intestinalis AOX has been cloned and expressed in human cultured cells, fruit flies, and mice. In these models, AOX is inert under non-stressed conditions, most likely because it accepts electrons only when the quinone pool is highly reduced, such as under inhibition or overload of cIII or cIV. Accordingly, upon inhibition of cIII or cIV by mutations or chemical inhibitors, ectopic AOX can maintain respiration and prevent cell death.

We set out to test whether AOX expression could prevent the detrimental effects of cIII deficiency in a mammalian model, by restoring electron flow upstream of cIII. To this end, we crossed mice carrying a broadly expressed AOX transgene with the Bcs1lc.A232G mice and assessed disease progression, organ manifestations, and metabolism in the homozygotes with and without AOX expression.

The mice expressing AOX were viable, and their median survival was extended from 210 to 590 days due to permanent prevention of lethal cardiomyopathy. AOX also prevented renal tubular atrophy and cerebral astrogliosis, but not liver disease, growth restriction, or lipodystrophy, suggesting distinct tissue-specific mechanisms. Assessment of reactive oxygen species (ROS) production and damage suggested that ROS were not instrumental in the rescue. Cardiac mitochondrial ultrastructure, mitochondrial respiration, and pathological transcriptome and metabolome alterations were essentially normalized by AOX, showing that the restored electron flow upstream of cIII was sufficient to prevent cardiac energetic crisis. These findings demonstrate the value of AOX, both as a mechanistic tool and a potential therapeutic strategy, for cIII deficiencies.

Mortality rises with age. In fact the very definition of aging is that it is a rise in mortality rate due to intrinsic causes, the accumulation of unrepaired damage and subsequent systems failure. Some years ago it was quite robustly established that, after a certain point, aged flies stop aging in this sense. Their mortality rates remain at a very high plateau, and do not further increase over time. Since then, researchers have crunched the numbers and debated back and forth over whether or not human demographic data shows any signs of a similar phenomenon. The challenge is the sparse, poorly gardened nature of the demographic data for people who pass a century of age. The authors of the paper noted here argue that all of the past evidence for a human mortality plateau emerged precisely because the data is problematic, and that systemic issues with data quality will tend to produce this apparent result.

The age-specific probability of death follows diverse, often species-specific curves. In several species, including humans, rates of mortality increase with age have been observed flattening in advanced old age. In some cases, this late-life mortality deceleration (LLMD) is sufficient to cause a levelling off or plateau in the probability of death at advanced ages. LLMD and late-life mortality plateaus (LLMPs) have been proposed to cause the respective slowing or cessation of biological ageing at advanced ages and, respectively, increase and remove the upper limits of survival in humans.

These findings have led to continuing debate on the biological meaning, magnitude, and importance of LLMDs and LLMPs. Several hypotheses and models have been proposed to explain the observation of LLMPs and LLMDs in diverse taxa, such as population heterogeneity, density effects, and evolutionary theories. In parallel, these observations have led to the development and widespread use [of demographic models, such as the Kannisto old-age-mortality model, that assume a priori the existence of LLMPs.

However, there is evidence that LLMPs can result from diverse statistical errors, such as the pooling of human cohorts, choice of mortality rate metric or time interval, and missing death certification or age-reporting errors. Furthermore, in any species with finite upper limits of life, both random and nonrandom error distributions will necessarily favour the inclusion of younger individuals amongst the oldest survivable age categories, reducing the subsequent probability of death calculated for these ages. As a result, deformation of late-life mortality by biodemographic errors may provide a general explanation of LLMDs and LLMPs.

Therefore, understanding late-life mortality patterns requires consideration of the effect of age-coding errors and whether the late-life patterns of mortality rates in humans may represent combined outcomes of measurement and sampling errors. Here, it is revealed how diverse demographic errors deform the age-specific mortality curve and the hazard rate, causing LLMDs and LLMPs in the absence of other effects. In humans, the error rate of demographic sampling, completeness of birth and death records, and development and income indicators all predict the magnitude of LLMD. Correcting for these factors eliminates LLMDs and LLMPs, suggesting these patterns are caused by sampling and measurement error and not by biological or evolutionary factors.

Link: https://doi.org/10.1371/journal.pbio.2006776

This open access review paper surveys the present major areas of interest in the development of therapies expected to slow or reverse aging to some degree. Of the well-funded and popular lines of research and development, only one is unequivocally a form of rejuvenation, the new field of senolytic therapies able to selectively destroy senescent cells. Of the others noted, only stem cell therapies and possibly upregulation of neurogenesis have the potential to become rejuvenation therapies, at the point at which researchers become able to reliably replace damaged cell populations with fresh, functional cell populations. That point has not yet been reached.

The rest of the items, which account for the majority of present research efforts in the treatment of aging, are either (a) the well known lifestyle factors such as exercise and calorie restriction, or (b) attempts to override undesirable cell behavior without actually fixing the damage and dysfunction that underlies that altered behavior in aging. The scope of potential benefits is thus limited; trying to keep a damaged machine running by tinkering with the controls is a challenging way to eke out only incremental gains. The future that must come to pass, if we are to see significant extension of human life span in the decades ahead, is one in which the fields of rejuvenation research not listed in this paper, the other portions of the SENS damage repair agenda beyond senolytics, must become as large and well-funded and popular as senolytics is today.

Finding ways to prevent age-related diseases is important because the aging population is snowballing in the world as a result of better nutrition, effective antibiotics against infectious diseases, and improved healthcare. Development of interventions that slow down the rate of aging and reduce or postpone the incidence of debilitating age-related diseases would be of immense value to improve the quality of life as well as to reduce medical costs. Studies in animal models have demonstrated that a variety of genetic, dietary, and pharmacological interventions enhance lifespan. Some of the anti-aging strategies that extend lifespan may also be useful for delaying the onset of age-related diseases.

Autophagy has a significant role in the modulation of the aging process. The function of autophagy in aging is apparent from numerous studies using yeasts, worms, flies, and mice that elevated expression of autophagy-related genes is a prerequisite for lifespan extension. Some studies have also shown that tissue-specific expression of single autophagy gene is adequate for extending lifespan whereas other studies have pointed out that distinct types of autophagy are critical for longevity as they specifically target dysfunctional cellular components and prevent their aberrant accumulation. Interestingly, slow-down of aging and longevity increase achieved through food deprivation and calorie restriction (CR) are facilitated through upregulation of autophagy. Thus, autophagy enhancing interventions that commence in middle age would likely facilitate successful aging and increased longevity.

Amongst the perpetrators of organismal aging, the function of senescent cells (SCs) has caught significant interest. Senescent cells disrupt the milieu by producing a plethora of bioactive factors that cause inflammation and impede regeneration. Senescent cells actively propel spontaneously ensuing age-related tissue deterioration and thereby promote several diseases associated with aging. In several tissues and organs, senescence is a common feature during the aging process with an age-related increase in the number of senescent cells. From the above, it appears that, the elimination of senescent cells using drugs referred to as senolytics would slow down aging and maintain better function during old age. In mice, senotherapy proved to be effective in models of accelerated aging and also during normal chronological aging. Senotherapy prolonged lifespan, rejuvenated the function of bone marrow, muscle and skin progenitor cells, improved vasomotor function and slowed down atherosclerosis progression.

A new procedure for limiting or reversing aspects of aging in various organs throughout the body is the transfusion of blood from the young to the aged, as molecules circulating in the young blood can rejuvenate the aging cells and tissues. Studies suggested that several soluble factors underlie the rejuvenating effects of the young blood. The growth differentiation factor 11 (GDF11) is one of the well-characterized factors in the young blood. Clinical trials testing the effect of young plasma in patients with Alzheimer's disease are already underway, but careful, placebo-controlled larger clinical trials will be required.

Recently, many studies have shown that intermittent fasting (IF) can have similar effects as CR. Benefits related to cardiovascular health include protection of heart against ischemic injury, reduced body mass index and blood lipids, improved glucose tolerance, and lower incidence of coronary artery disease. The positive effects of IF on brain health in pre-clinical studies comprised improved cognitive function with reduced oxidative stress during middle age when IF was commenced in young adult age and delayed occurrence of age-related brain impairments. In human studies, protocols and interpretations of IF-mediated weight loss trend varied considerably. Most human IF studies did not result in significant weight loss or considerable improvements in metabolic biomarkers. Quite a few questions remain to be dealt with regarding the benefits of IF on human health.

Studies in animal models have shown that hippocampal neurogenesis decreases during aging, and the overall decrease is exacerbated in Alzheimer's disease. The precise mechanistic causes underlying age-related decline in neurogenesis are unclear. Overall, it appears that age-related reductions in stem cell mitogenic factors, microvasculature and cerebral blood flow, and low-grade inflammation influence reduced neurogenesis in aging because increased neurogenesis could be obtained through interventional strategies that upregulate the concentration of neural stem cell (NSC) mitogenic factors or improve the microvasculature density and diminish inflammation. Pharmacological mimetics of exercise capable of enhancing both hippocampal neurogenesis and BDNF appear to be useful for improving cognitive function, and thus combined neurogenesis and BDNF boost during adulthood and middle age may postpone cognitive aging and onset of Alzheimer's disease.

The benefits of regular physical exercise (PE) for conserving the function of the cardiovascular, musculoskeletal and nervous systems are well known. Regular PE commencing from young or middle age appears to be a necessary lifestyle change for maintaining good health in old age. Since drugs that significantly prevent age-related cognitive decline are yet to be discovered, it is vital to start PE regimen early in life when the neural reserve is still adequate, to completely avoid or at least postpone the cognitive decline. However, the amount of PE required in young or middle age to maintain healthy cognitive function in old age is yet to be ascertained.

The efficacy of intracerebral transplantation or peripheral injection of a variety of stem cells including mesenchymal stem cells (MSCs), NSCs or glial-restricted progenitors (GRPs) has been examined in animal models to improve the function of the aging brain. Stem cell therapy has been shown to mediate beneficial effects in several age-related neurodegenerative disease models. Studies revealed that the mechanism underlying a better cognitive function involved improved hippocampal synaptic density mediated by BDNF. In addition to stem cell grafting approach, activation of endogenous cells in some regions of the body has promise for mediating regeneration during aging.

In conclusion, there are many anti-aging strategies in development, some of which have shown considerable promise for slowing down aging or delaying the onset of age-related diseases. From multiple pre-clinical studies, it appears that upregulation of autophagy through autophagy enhancers, elimination of senescent cells using senolytics, transfusion of plasma from young blood, neurogenesis and BDNF enhancement through specific drugs are promising approaches to sustain normal health during aging and also to postpone age-related diseases. However, these approaches will require critical assessment in clinical trials to determine their long-term efficacy and lack of adverse effects on the function of various tissues and organs.

Link: https://doi.org/10.14336/AD.2018.1026

The well-known difference in longevity between genders, in which females live longer than males, is not peculiar to our species. It is present in most gendered species examined to date, which strongly suggests that these differences in the pace of aging arise quite robustly from the interaction of evolutionary pressures with gender roles in mating and reproduction. Males can achieve reproductive fitness by investing resources into mating sooner rather than later, while for females greater fitness arises through investing resources to retain the capacity to mate successfully over time. The male candle burns brighter and less long. This is an overly simple summary of a complicated and much debated area of research, however.

The research reported here is an interesting addition to the literature on this topic. Some years ago the scientific community engineered mouse lineages with a mix of sex chromosomes and gonads, so as to obtain physically male mice with female sex chromosomes, and vice versa. Most mammals have two sex chromosomes, X and Y, producing XX chromosome females and XY chromosome males. This allows researchers to split out the contribution of sex chromosomes versus gonads for most gender differences, and determine relative level of importance. Here the researchers have chosen to focus on differences in the pace of aging, running a lifespan study on mice with different combinations of sex chromosomes and gonads. Unsurprisingly, both female sex chromosomes and gonads provide a modest survival advantage. The sex chromosome effect is larger, however, which might not be the expected outcome for many observers.

This is all, of course, a matter of purely scientific interest rather than a matter of relevance to the future of aging. The introduction of rejuvenation therapies will make any of the existing disparities in aging irrelevant, and the mechanisms that produce gender differences in longevity have no role to play in the development of rejuvenation therapies. These therapies will work through repair of the molecular damage that causes aging, which is exactly the same in both genders. When it becomes possible for everyone to use medical science to live decades longer in good health, few people will care about evolved difference that might add or subtract a few years from human life spans.

Female XX sex chromosomes increase survival and extend lifespan in aging mice

Women live longer than men around the world, regardless of culture or socioeconomic status. Female longevity is also observed in the animal kingdom due to causes that may be extrinsic, intrinsic, or both. Extrinsic causes of sex difference in invertebrates can signal antagonistic survival strategies: female pheromones reduce male lifespan in Drosophila, and male secretions shorten hermaphrodite lifespan in C. elegans. Intrinsic effects - operating within the organism - underlie longer life in organisms following removal of reproductive cells or organs in C. elegans hermaphrodites, male and female dogs, and possibly men as suggested by a study of eunuchs. Nonetheless, causes of intrinsic sex difference in lifespan remain largely unknown. The pervasive nature of female longevity in humans, even in early death during severe epidemics and famine, suggests a role for innate biology in the survival gap between the sexes. Here, we sought to identify intrinsic causes of female longevity in mammalian lifespan.

Sex chromosomes or gonads cause intrinsic sex differences in mammals, but whether they directly contribute to increased female lifespan is unknown in mammalian aging. To dissect these etiologies, we used four core genotypes (FCG) mice. In mice and humans, the Sry gene normally resides on the Y chromosome and codes for a protein (testicular determining Y factor) that induces development of testes and perinatal masculinization. In FCG mice, Sry resides instead on an autosome, enabling inheritance of Sry - and thus male, testicular phenotype - with or without the Y chromosome. The genetic manipulation of SRY generates XX and XY mice, each with either ovaries (O) or testes (T): XX(O), XX(T), XY(O), XY(T). Gonadal hormone levels in FCG mice with the same gonads are comparable, regardless of their sex chromosomes. In FCG model mice, a sex difference with a main effect that statistically differs by genotype (XX vs. XY) is sex chromosome-mediated; one that differs by phenotype (ovaries vs. testes) is gonadal sex-mediate. Examples of age-relevant FCG mouse studies show that XX improves blood pressure regulation and attenuates experimental brain injuries.

To explore sex-based differences in lifespan, we generated and aged over 200 mice from the FCG model on a congenic C57BL/6J background and investigated aging-dependent mortality from midlife to old age (12-30 months). We first examined whether mortality in "typical" females (XX,O) and males (XY,T) recapitulates the pattern of female longevity. Indeed, aging females (XX,O) lived longer than aging males (XY,T). We next measured main effects of sex chromosomes and gonads on survival in aging. XX mice with ovaries or testes lived longer than XY mice of either gonadal phenotype, indicating a main effect of sex chromosomes on lifespan. Mice with ovaries (XX and XY) tended to live longer than those with testes (XX and XY), suggesting a gonadal influence on lifespan. Collectively, these data indicate that the XX genotype increases survival in aging - and suggest a protective effect of ovaries.

Does the adult brain produce and integrate new neurons into its neural circuits, in a process known as neurogenesis? Near all of the evidence for this process to take place in adults has been established in mice, and over the past year a few new studies have suggested that this process doesn't in fact occur in humans. This is something of shock to the research community, as a fair number of regenerative medicine projects are progressing under the hope that existing neurogenesis can be increased in scope and pace, in order to repair and restore the aged brain to greater degrees than presently occurs naturally. If the neurogenesis so well characterized in mice doesn't exist in humans, then those projects will all fail. It is an important topic, but we shouldn't expect resolution of this debate to arrive in the near term. Conflicting data that is so carefully produced and so directly opposed tends to require years of work to resolve, particularly when human tissues are vital to the end goal.

Just a generation ago, common wisdom held that once a person reaches adulthood, the brain stops producing new nerve cells. Scientists countered that depressing prospect 20 years ago with signs that a grown-up brain can in fact replenish itself. The implications were huge: Maybe that process would offer a way to fight disorders such as depression and Alzheimer's disease. This year, though, several pieces of contradictory evidence surfaced and a heated debate once again flared up. Today, we still don't know whether the fully grown brain churns out new nerve cells.

In March of this year, contradicting several landmark findings that had convinced the scientific community that adults can make new nerve cells, researchers described an utter lack of dividing nerve cells, or neurons, in adult postmortem brain tissue. A return volley came a month later, when a different research group described loads of newborn neurons in postmortem brains, in an April paper. Scientific whiplash ensued when a third group found no new neurons in postmortem brains, describing the results in July. Still more neuroscientists jumped into the fray with commentaries and perspective articles.

This ping-ponging over the rejuvenating powers of the brain is the most recent iteration of a question on neurogenesis that still hasn't been answered. Despite the more recent negative results, many scientists still hold on to the notion that new growth happens. "The negative findings were very controversial. It's always very difficult to put aside a phenomenon just by not finding it. Let's face it: it's not easy to label and detect adult neurogenesis in human postmortem tissue. This year's studies provide a push to the field to develop more advanced tools and models."

Link: https://www.sciencenews.org/article/neurogenesis-brain-neurons-2018-yir

Dietary fiber is known to reduce chronic inflammation; the modest but reliable degree to which it does so is well studied. In recent years researchers have been turning their attention to the diverse microbes of the gut in order to understand how this and other dietary effects on the immune system and tissues are mediated. Some attention has been given to the production of butyrate by gut bacteria involved in digesting fiber, for example. Researchers here find an analogous mechanism in the bacterial production of propionate from fiber, and make some inroads into understanding how exactly it functions to reduce inflammation.

To a large extent our well-being depends on what bacterial guests in our digestive tract consume. That's because gut flora help the human body to utilize food and produce essential micronutrients, including vitamins. Beneficial gut microbes can produce metabolites from dietary fiber, including a fatty acid called propionate. This substance protects against the harmful consequences of high blood pressure. Researchers have now shown why this is the case. The researchers fed propionate to mice with elevated blood pressure. Afterwards, the animals had less pronounced damage to the heart or abnormal enlargement of the organ, making them less susceptible to cardiac arrhythmia. Vascular damage, such as atherosclerosis, also decreased in mice.

"Our study made it clear that the substance takes a detour via the immune system and thus affects the heart and blood vessels." T helper cells, which enhance inflammatory processes and contribute to high blood pressure, were calmed. This has a direct effect on the functional ability of the heart. The research team triggered heart arrhythmia in 70 percent of the untreated mice through targeted electrical stimuli. However, only one-fifth of the animals treated with the fatty acid were susceptible to an irregular heartbeat. Further investigations with ultrasound, tissue sections, and single-cell analyses showed that propionate also reduced blood pressure-related damage to the animals' cardiovascular system, significantly increasing their survival rate. But when researchers deactivated a certain T cell subtype in the mice's bodies, known as regulatory T cells, the positive effects of propionate disappeared. The immune cells are therefore indispensable for the substance's beneficial effect.

Propionate still has to prove itself in everyday clinical practice. The research team now hopes to validate their findings by examining the substance's effects on human subjects. It is already known that propionate is safe for human consumption and can also be produced economically: The substance has been used for centuries as a preservative, for example. It is already approved as a food additive. "With these favorable conditions, hopefully propionate will soon make the leap from the lab to patients who need it."

Link: https://www.mdc-berlin.de/news/press/how-dietary-fiber-and-gut-bacteria-protect-cardiovascular-system

Inflammatory signaling disrupts all sorts of normal tissue functions. In the short term this is usually beneficial; inflammation is a necessary part of wound healing, defense against pathogens, and even destruction of errant cells. It is required to mobilize the immune system and coordinate the activities of various classes of immune cell with those of other cell populations. Unfortunately inflammation becomes chronic in later life, and the constant inflammatory signaling - and cellular reactions to that signaling - degrades normal function and produces lasting damage as a result. This particularly noteworthy when it comes to loss of regenerative capacity and generation of harmful fibrosis.

Chronic inflammation in aging and disease has long been a topic of interest for the research community, and a great deal of effort has been put into trying to understand the fine details of inflammation and means to control it. The newfound acceptance of the past few years that accumulation of senescent cells and growth in their potent inflammatory signaling is a significant cause of degenerative aging has only reinforced this part of the field.

"Inflammatory signaling" is, however, a very broad category. The processes of inflammation are very complicated, as is true of any situation in which multiple types of cell are interacting with one another. It is rarely the case that researchers can point to any one protein and say that more of it is always a bad thing. Context and timing and location all matter. Further, many inflammatory signal proteins have roles other than that related directly to the immune system - evolution is very much in favor of promiscuous reuse of component parts that happen to be lying around. TGF-β1 is a good example. It can increase or decrease inflammatory activity in specific contexts, and while it is definitely a prominent part of the problem of chronic inflammation in later life, it cannot simply be suppressed without unwelcome side-effects, the loss of activities that are still beneficial even in the context of a damaged immune system.

It is challenging (meaning expensive and slow) to unravel the complexity of metabolism, even in the context of a well researched single protein, in order to arrive at therapies that override dysfunction in some way. This is precisely why we should avoid messing with metabolism, investing in this process of trying to find overrides in a poorly understood, complex system. Instead, the focus should be on examining the root causes of this dysfunction. Find ways to repair or remove the cell and tissue damage that leads to chronic inflammation and the pathological state of the aged immune system. When damage is meaningfully repaired, then a complex system will revert on its own to a more functional, youthful state.

Central Role of Transforming Growth Factor Type Beta 1 in Skeletal Muscle Dysfunctions: An Update on Therapeutic Strategies

Transforming growth factor type beta 1 (TGF-β1) is a growth factor and cytokine belonging to a superfamily of ligands, including bone morphogenetic proteins (BMPs), growth and differentiation factors, activins and myostatin, which are pleiotropic factors with important roles in inflammation, cell growth, and tissue repair. TGF-β1 mediates many of its intracellular actions by changes in the gene expression to regulate the synthesis of extracellular matrix (ECM) proteins, cell motility and several cellular processes, including differentiation, renewal, and quiescence. In skeletal muscle, TGF-β1 can be activated and/or up-regulated by different stimuli, such as acute skeletal muscle injury, or in other cases by chronic stimulus generated in different types of skeletal muscle diseases in which fibrosis and/or atrophy is produced.

Skeletal muscle is a tissue that has the capacity to regenerate after damage, with the replacement of injured tissue by healthy and functional tissue. The regenerative capacity of adult skeletal muscle is attributed to a population of resident stem cells called satellite cells (SC). In normal conditions, SCs are in a quiescent status. However, after damage or in response to degenerative stimuli, the activation of SCs is induced. The formation of mature myofibers and the regeneration process can be impaired or arrested by several mechanisms, such as the inhibition of cell cycle entry, increment of cell death and/or premature terminal commitment. TGF-β1 is a typical inhibitor of the myogenic differentiation process because it can cause SC apoptosis and potently inhibit its proliferation and fusion, negatively affecting muscle regeneration. In this context, in aged regenerating skeletal muscle, TGF-β1 signalling is abnormally elevated and considered to inhibit SC activation and terminal myogenic differentiation.

Fibrosis is formed by the accumulation of ECM proteins, such as fibronectin, collagen, elastin, and laminin, among others, which are produced within the tissue via activation of different fibrogenic factors or cytokines, such as TGF-β1. In several muscular dystrophies, the synthesis and accumulation of ECM components produce the progressive replacement of functional muscle tissue by connective tissue, with the consequent loss of muscle function. Several reports have shown that TGF-β1 has a key role in the inflammatory process in skeletal muscle and induces muscle fibrosis by increasing collagen, fibronectin and other profibrotic factors, such as connective tissue growth factor (CTGF).

The increased knowledge about the participation of TGF-β1 in several muscular pathologies has attracted great interest in the evaluation of therapeutic alternatives to neutralise or diminish the deleterious effects of TGF-β1. Among the possible strategies to inhibit TGF-β signalling are blocking antibodies for TGF-β1, and the different components of RAS and several inhibitors of the TGF-β1 receptors or signalling pathway have been proposed. The main problem with the use of therapies aiming at inhibiting TGF-β1 signalling is the lack of specificity of the compounds and therefore the development of side effects. The challenge is to develop therapy that can specifically promote muscle regeneration while decreasing fibrosis and atrophy without altering the normal function of TGF-β in other tissues, such as regulation of proliferation, haematopoiesis, migration, or inflammation.

Both quality control and pace of production of proteins in cells are linked to aging. When comparing species and lineages with different life spans, long-lived mutants of short-lived species such as nematode worms exhibit a slower rate of protein synthesis. The same is true in yeast. Equally, the long-lived naked mole-rat exhibits highly efficient quality control in protein synthesis when compared to short-lived rodent species of a similar size. It is also the case that for any given individual, the quality control of protein synthesis becomes worse with age, and this - like stochastic mutation of DNA, and for similar reasons - is thought to be a contributing factor in the progression of degenerative aging. That said, where exactly it sits in the long chains of cause and effect between first cause of aging and final downstream outcome of aging is up for debate.

Aging is characterized by the accumulation of various forms of damage as well as by other age-related deleterious changes. These changes generally have negative, deleterious consequences for organisms as they age. Different living systems differ in their metabolic strategies, resulting in different types and levels of damage production, therefore have evolved both unique and common mechanisms to counteract some of these deleterious changes. These mechanisms also limit the transfer of damage to progeny. The damage-producing and protective mechanisms are mostly genetically controlled, differ among taxonomic groups and are important in defining the lifespan of organisms. Nevertheless, the general principles of cell and organismal organization make damage accumulation inevitable for most multicellular organisms.

In this review, we discuss age-related changes in one of the most important and abundant components of any cell, and therefore of the whole organism - the proteome. Functionality of the whole system of proteins in any organism requires maintenance of a precise balance of synthesis, degradation and function of each and every protein, while aging often shifts this balance, resulting in pathology. Being the end-point of the implementation of genetic information, the proteome accumulates damage generated during this process. The effectiveness of proteostasis control systems, which maintain and recycle the proteome, is diminished with age, leading to the accumulation of damaged proteins and molecules, which in turn inhibit cell functionality and thus cause age-related dysfunction.

Every step in protein lifecycle, most notably protein synthesis and degradation, is relevant to the aging process and, indeed, has been shown to change with age and likely define lifespan. While changes in protein degradation systems during aging are relatively well studied, alterations in protein synthesis still remain to be elucidated. Does the overall level of protein synthesis change with age? Which components of the translation apparatus are affected by aging? Do errors in protein synthesis increase in older organisms? Is there age-dependent regulation of protein synthesis at the level of translation? Answering these questions is necessary for understanding the mechanisms of aging and lifespan control.

Link: https://doi.org/10.18632/aging.101721

Reprogramming of ordinary somatic cells into induced pluripotent stem cells (iPSCs) capable of generating any cell type is very much a going concern these days. The first cell therapies based on the transplantation of patient-matched cells derived from iPSCs are entering trials. More recently, however, researchers have been experimenting with the more radical idea of reprogramming cells in situ, in tissues. At first glance (and later consideration) this seems enormously risky, a fast path to cancer. Yet in mouse studies it appears, at least initially, to be quite beneficial. It will take a great deal more data to overcome skepticism about the cancer risk, but it seems there is a faction of researchers ready to work towards that goal.

Equally intriguing is the evidence for reprogramming to reset some of the markers of cell and tissue age, such as mitochondrial dysfunction. A complete catalog of what is fixed and what is not fixed by this process, and which of those items are more or less important than the others, has yet to be assembled. This is a comparatively recent development in the field, and, accordingly, comparatively little exploration has taken place. Will reversal of aspects of aging hold up when cells are put back into tissue? Which of the changes are lasting versus transient? A great deal of work lies ahead.

To our knowledge, the first study reporting cell rejuvenation was published in 2011. It was known that cells from old individuals display a typical transcriptional signature, different from that of young counterparts. It was also known that fibroblasts from old donors have shortened telomeres as well as dysfunctional mitochondria and higher levels of oxidative stress. The researchers first explored the effect of cell reprogramming on the above features. In order to efficiently reprogram fibroblasts from healthy centenarians and very old donors, the authors added the pluripotency genes NANOG and LIN28 to the Yamanaka OSKM reprogramming cocktail. This six-factor combination efficiently reprogrammed fibroblasts from very old donors into typical induced pluripotent stem cells (iPSCs).

These blastocyst-like cells showed a higher population-doubling (PD) potential than the cells of origin as well as elongated telomeres and a youthful mitochondrial metabolism (estimated by measuring mitochondrial transmembrane potential and clustering transcriptome subsets involved in mitochondrial metabolism). Using an appropriate differentiation cocktail, the iPSCs were differentiated back to fibroblasts, whose transcriptional profile, mitochondrial metabolism, oxidative stress levels, telomere length, and PD potential were indistinguishable from those of fibroblasts from young counterparts. Taken together, the data revealed that the cells had been rejuvenated.

Until late 2016, it was believed that although cells taken from old individuals could be fully rejuvenated, rejuvenation in vivo was not possible as a continuous expression of the Yamanaka OSKM genes in animals had been shown to cause multiple teratomas. However, then it was reported for the first time that cells and organs can be rejuvenated in vivo. The authors used transgenic progeric mice. After 6 weeks of partial reprogramming cycles, the experimenters could observe some improvements in the external appearance of experimental mice, including a reduction in spine curvature as compared with untreated counterparts (controls).

A subgroup of the experimental and control mice was sacrificed and some of their tissues and organs analyzed (skin, kidneys, stomach, and spleen). Controls showed a variety of alterations at an anatomical and histological level in the above organs whereas some of these aging signs disappeared or were attenuated in the experimental mice. Some aging signs remained unchanged by the treatment. Furthermore, although the experimental animals kept aging, they showed a 50% increase in mean survival time as compared with wild-type progeric controls. If the treatment was interrupted, the aging signs came back.

Link: https://doi.org/10.1186/s13287-018-1075-y

While the causes of aging are comparatively well mapped, supported by a great deal of solid evidence, the field more than ready for the development of rejuvenation therapies to begin in earnest, the biochemical details of the progression of aging remains a vast and poorly explored forest. This is also true of cellular metabolism as a whole: to fully understand aging, one must fully understand the inner workings of the cell to the finest level of detail. The research community is a lifetime removed from that goal, even taking into account a rapid pace of future progress in the capabilities of biotechnology.

Still, some parts of the overlap between aging and the operation of metabolism are mapped, at least at the high level. One of the most explored areas relates to the control of growth, the relationships between insulin, insulin-like growth factor 1, growth hormone, growth hormone receptor, and a broad collection of related proteins. Many of the earliest approaches to slowing aging via genetic engineering used these mechanisms. It remains the case that lineages of dwarf mice, engineered to exhibit disabled growth signaling, still hold the record for longevity in that species, living 70% or so longer than their unmodified peers.

Despite this record, modification of growth signaling is a false grail. Alongside research into the mechanisms of calorie restriction, it has led the research community to expend enormous effort on approaches that are technically challenging, make slow progress, and cannot greatly extend the healthy human life span. If billions in funding and entire scientific careers are to be spent on attempts to treat aging as a medical condition, why work on approaches that are incapable of producing more than a few extra healthy years? We know what disabled growth hormone signaling can achieve in humans: the small Laron syndrome population don't live appreciably longer than any of the rest of us, and suffer a range of undesirable side-effects. Perhaps they exhibit a lower incidence of cancer and diabetes, but not so much lower that it leaps out of the data. Or consider the size of life span differences between short people and tall people; it isn't large.

This is the great roadblock for all of the more established ways to alter metabolism in order to reach states in which aging is slowed, whether by disabling growth signaling or via calorie restriction mimetics. The effects are sizable in mice, and tiny in humans. The longer-lived the species, the less plastic its lifespan in response to metabolic changes induced by the environment, or through engineered genetic alterations that touch on the same regulatory mechanisms. This is a dead end, and is not where the research community should focus if the goals are rejuvenation and sizable extension of life span.

Impact of Growth Hormone-Related Mutations on Mammalian Aging

Much of the work in our laboratory during the last 30 years was directed at identifying mechanisms of extended longevity of mice with growth hormone (GH)-related mutations and answering the question how major reduction or absence of normal endocrine signals can have major beneficial impact on healthspan and lifespan. Both GH-deficient and GH-resistant mice have many phenotypic characteristics that presumably account for, or contribute to, healthy aging and extended longevity and, thus, represent likely mechanisms of these effects.

These characteristics include increased resistance to multiple stressors such as free radicals and toxins, reduced chronic low grade inflammation, senescent cell burden, and expression of pro-inflammatory cytokines in the central nervous system, reduced mTORC1 and increased mTORC2 signaling, as well multiple adaptations of carbohydrate, lipid, and energy metabolism. Many of the physiological characteristics of GH-related mutants interact, forming a complex network of mechanisms.

For example, reductions in the levels of pro-inflammatory cytokines, the number of senescent cells, the secretory capacity of pancreatic beta cells, and mTORC1 signaling, interact with increased levels of adiponectin and reduced GH signaling to improve insulin sensitivity, while each of these factors also influences aging by other mechanisms. We believe that the remarkable extension of longevity in mice with genetic GH deficiency or resistance results from alterations in multiple mechanisms of aging and interactions among these alterations.

Growth Signaling and Longevity in Mouse Models

Reduction of insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) extends the lifespan of various species. So far, several longevity mouse models have been developed containing mutations related to growth signaling deficiency by targeting growth hormone (GH), IGF1, IGF1 receptor, insulin receptor, and insulin receptor substrate. The gene expression profiles of these mice models have been measured to identify their longevity mechanisms.

GH signal-deficient mice, including Snell, Ames, Little, GHR-/- , and Fgf21 Tg dwarf mice, showed increased lifespans and smaller body masses than wild type (WT) mice. Therefore, body size was strongly dependent on GH action. This consistent trend suggests an inverse correlation between size and lifespan. However, small size can not be used as a general indicator of longevity, because Kl Tg, Irs2 +/-, p66 Shc-/-, and mtor +/-; mlst8 +/- mice had normal body masses like WT mice, but showed longer lifespans than WT. In addition, GHA Tg mice had normal lifespans like WT mice, and Kl -/- and Irs2 -/- mice showing dramatically shorter lifespans also had a dwarfism phenotype. Therefore more work is needed to elucidate factors contributing to the lifespan of these mice.

Older people have a lot of metabolic waste in their cerebrospinal fluid, of which the amyloid-β associated with Alzheimer's disease is probably of greatest interest at the present time. It is an interesting question as to why this increase over time occurs, particularly considering the point that the presence of amyloid-β and other molecules is dynamic, a constant process of creation and destruction. A number of groups, such as Leucadia Therapeutics, make the case for failure of mechanical systems of drainage by which cerebrospinal fluid leaves the brain. Without that drainage to act as a sink for metabolic waste, the waste accumulates.

EnClear Therapies is a company pursuing a path analogous to that of Leucadia Therapeutics, but instead of restoring drainage they seek to filter cerebrospinal fluid. Increasingly sophisticated filtration of blood for various purposes is fairly common, albeit expensive. The challenge with cerebrospinal fluid is that it is locked away inside the spine and skull. If a suitable mechanical approach could be assembled to safely and reliably access and filter cerebrospinal fluid on a regular basis, which sounds like a tough job, then there are all sorts of things that might be built upon that foundation.

While the company is not initially focused on removal of amyloid-β, that is a possibility for the future, given success. Overall, I'd say that this is a most interesting approach: a worse strategy than restoration of drainage in the sense that each new target requires a development program to build a suitable filter to fit into the machinery, but on the other hand a better strategy for some conditions as it might be possible to clear more of a given target molecule.

EnClear Therapies was conceived with the purpose of developing novel device-based therapies to treat patients with neurodegenerative disease. Toxic proteins are generated in ALS and FTD patients with C9orf72 mutations. These proteins travel through the brain and spinal fluids and are taken up by neurons of the motor system that are very sensitive to their toxicity which leads to degeneration of these neurons leading to paralysis.

EnClear has developed a technology which clears these toxic proteins from the brain and spinal fluids of C9orf72 ALS and FTD patients. We are now developing this technology into a device that will recirculate the brain and spinal fluids while the toxic proteins are rendered harmless. With this technology Enclear aims to stop or significantly slow down the neuronal degeneration in ALS and FTD patients with C9orf72 mutations. This technology can potentially be used for other forms of ALS and FTD in which toxic prion like proteins propagate through the brain and spinal fluids.

Similar to ALS, Progressive Supranuclear Palsy (PSP) is hallmarked by the buildup of toxic proteins (in this case tau) in the brain. As with ALS, the toxic proteins travel through the brain and spinal fluids and are taken up by neurons that are very sensitive to their toxicity which leads to degeneration of these neurons leading to paralysis. EnClear Therapies aims to halt the progression of PSP by rendering the tau harmless through the same mechanism used for ALS.

Link: https://www.encleartherapies.com

In this modern age of transport machinery, desk jobs, and idle leisure, few people exercise as much as they should. A perhaps surprisingly large fraction of the physical and mental decline characteristic of later life is the result of an increasingly sedentary lifestyle. One doesn't have to look much further than a comparison with physically active hunter-gatherer populations to see as much. As a result, exercise looks like a therapy in the context of an older, sedentary population, an intervention that can reverse aspects of aging to some degree. Yet consider that a cessation of neglect always looks good in comparison to continued neglect. Better not to become sedentary in the first place, given the serious risks to long-term health that arise as a result.

The study involved 160 people with an average age of 65 and risk factors for heart disease, such as hypertension, who did not have dementia but reported problems with thinking skills. All participants were identified as having cognitive impairments without dementia and were sedentary at the start of the study. Researchers examined the effects of both exercise and diet, specifically the Dietary Approaches to Stop Hypertension (DASH) diet, which is a low sodium, high fiber diet rich in fruits and vegetables, beans, nuts, low fat dairy products, whole grains, and lean meats. The DASH diet was designed specifically for individuals with high blood pressure.

Participants were randomly assigned to one of four groups: aerobic exercise alone; DASH diet alone; both aerobic exercise and the DASH diet; or health education, which consisted of educational phone calls once every one or two weeks. People assigned to the exercise groups exercised three times a week for 45 minutes each session which included 10 minutes of warm-up exercises and 35 minutes of aerobic exercise, such as walking, jogging, or cycling on a stationary bicycle. At both the beginning and end of the six-month study, researchers evaluated participants' thinking and memory abilities with standardized cognitive testing, cardiorespiratory fitness with treadmill stress testing, and heart disease risk factors with screenings for blood pressure, blood glucose and lipids. They also used questionnaires and food diaries to measure how closely the participants followed the DASH diet.

Researchers found that participants who exercised showed significant improvements in thinking skills when compared to those who did not exercise. Those who took part in both the exercise and diet had average scores of nearly 47 points on the overall tests of executive thinking skills, compared to an average score of about 42 points for those with exercise and diet alone and about 38 points for those who just received health education. There was no improvement in participants who only consumed the DASH diet, although those who exercised and consumed the DASH diet had greater improvements compared to health education controls.

At the start of the study, the participants had average scores for select subtests of executive function for people who were age 93, which was 28 years older than their actual chronological age. After six months, participants who exercised and followed the DASH diet saw their average executive function scores correspond with people who were age 84, a nine-year improvement. For those who received only health education, their performance on executive function tests worsened by a half year from their scores at the start of the study.

Link: https://www.aan.com/PressRoom/Home/PressRelease/2684

The SENS approach to the treatment of aging is explicitly engineering, in the sense that engineering is the application of science to produce useful technology in absence of full knowledge of the systems influenced. It is right there in the name: Strategies for Engineered Negligible Senescence. In fact all medicine is engineering, as no-one yet has access to the full map of cellular biology that would allow for complete knowledge of how any particular therapy actually functions. SENS is merely a particularly obvious example, perhaps because of the great divide that exists in the aging research community.

Firstly, there are those who think that far greater understanding of the progression of aging at the detail level is needed, and that any intervention should be a matter of slowing aging by changing the operation of metabolism. They believe that meaningful progress towards greater human life spans is still remote, and only small gains are possible in our lifetimes, if then. Secondly, on the other side of the divide, there are those who wish to use the known catalog of forms of cell and tissue damage that lie at the root of aging in order to bypass the need for full understand of how aging progresses, and to produce rejuvenation rather than merely a slowing of aging. If damage has no other contributing source than the normal operation of healthy metabolism, then let us just repair it and observe the results - that is how we find out what is relevant and what is not. This is a much more cost-effective approach, but despite tremendous and demonstrable success in the form of senolytic therapies that destroy senescent cells, it remains unpopular as a strategy within the research community.

Damage repair to produce rejuvenation is popular with engineers, however, and for the obvious reasons. People with a technical background can look at the summary above (or more detailed summaries, or the scientific literature on SENS-based approaches to rejuvenation therapies) and find it obviously true that the cheaper, faster path with larger and more reliable gains should be the one receiving the greatest attention. Engineering is all about producing that sort of gain in effectiveness, applying what is known to produce benefits, and understanding where the details matter and where the details do not matter when it comes to development, safety, and efficiency. If researchers can repair a form of damage, such as the accumulation of senescent cells, and show it to be safe, and to produce rejuvenation, then the scientific community can thereafter spend as much time as they like in finding out how exactly it works. Meanwhile, there is a working treatment in existence that can benefit the world.

The software engineering community has long been supportive of the SENS program of advocacy and research. Software engineers make up an outsized proportion of the donors to the SENS Research Foundation and Methuselah Foundation. They appear everywhere in the broader community of supporters; there is a lot of history here if you look back along the timeline of the transhumanist communities of the thirty years past and what has become of those involved since then - also a lot of software engineers. Where the software engineering community overlaps with the venture capital community, particularly in California, there too is a sizable level of support for rejuvenation research after the SENS model. It is no accident that the SENS Research Foundation is based in the Bay Area, California; that is as much connections to capital and support as for the aging research laboratories that are nearby.

An interesting side-effect of this core constituency of support has arisen with the development of blockchain implementations and the cryptocurrency goldrush; suddenly a lot of younger, more idealistic and optimistic software engineers have a lot of wealth, even following the recent bursting of the bubble. When you have wealth you can start to make the world better in the ways that matter to you - if you have the vision and the will, which is something that seems to go with youth more than age, sad to say. it is perhaps a measure of this that the lion's share of donations to the SENS Research Foundation and Methuselah Foundation in the last 18 months have arrived in the form of cryptocurrencies. Indeed, Ethereum founder Vitalik Buterin donated $2.4M last year, and has now donated another $350,000 to the present SENS year end fundraiser. Such fellow travelers are greatly appreciated as we strive to make human rejuvenation a reality.

Vitalik Buterin donates $350,000 to the SENS Research Foundation

SENS Research Foundation would like to send a huge thank you to Vitalik Buterin for donating $350,000 worth of ethereum to our end of year campaign!

The Bitcoiners Who Want To Defeat Death

The office of Aubrey de Grey, chief science officer of SENS (short for the very catchy Strategies for Engineered Negligible Senescence), is my first stop in my journey into the strange and surprisingly overlapping worlds of cryptocurrency and life-extension. But de Grey is not like most tech entrepreneurs, nor is he like most longevity researchers. He doesn't buy into the health fads popular amongst his peers, like calorie restriction. He's not hoarding the blood of spritely teenagers (though tech billionaire Peter Thiel, who may or may not be interested in youthful blood infusions, is a SENS donor). And, while he says that cryonics - in which bodies are preserved at low temperatures - is "an extremely valuable and neglected area of medicine," the whole freezing-and-thawing process is not where his still-beating heart lies.

De Grey's plan is more ambitious than resurrection: He wants to reverse aging all together. As he outlines in his 2007 book Ending Aging, his strategy is to discover therapies that address the "diseases and disabilities of aging." Whereas most biogerontologists focus on the complex metabolic processes that cause aging damage, de Grey argues that the focus should be on the forms of damage themselves - like nuclear mutations, or the intracellular "junk" that forms as we get older. In short: Focus on treating the underlying causes, not the symptoms of aging.

Though he has plenty of critics, de Grey's bold approach has also garnered him scores of devoted fans. As he sits stroking his Rip Van Winkle-worthy beard, it's easy to see how de Grey's achieved this "kind of a spiritual leader status," as he calls it. He dives easily into intricate explanations of two research projects unfolding in the lab down the hall, eagerly describing how one studies mitochondrial mutations, which are thought to cause an increase in oxidative stress. The other looks at atherosclerosis, the narrowing and hardening of artery walls. If we understood more about this buildup, the logic goes, we could better clean it up before too much damage is done.

Though he attends lab meetings and oversees the SENS Research Foundation's research, his primary task is convincing the general public that death is, in fact, bad and that we should be doing everything we can to stop it. This focus on messaging suits him just fine. Back in April, at a San Francisco blockchain conference called Block 2 the Future, de Grey began his talk with a disclaimer: "I probably ought to start by emphasizing that I don't know fuck-all about cryptocurrencies. I am really only here because I have apparently quite a significant fan base in this community, and I am delighted that I do." He was referring to the intertwining relationship between blockchain enthusiasts and life-extension advocates, which can feel less like a Venn diagram and more like overlapping circles. There's a history of members of the blockchain community donating to life-extension efforts. Billionaire and cryptocurrency investor Michael Novogratz donated to the organization that predated SENS in the early 2000s, and the number of cryptocurrency donors has increased exponentially since. In the past year or so, SENS has received more than $6.5 million in cryptocurrency donations, including $2.4 million from Ethereum cofounder Vitalik Buterin last December.

Pine, the anonymous individual behind the Pineapple Fund who donated $55 million worth of bitcoin to various charities last year, gave 2 million of those dollars to SENS. A few other anonymous crypto donors gave around $1 million each, says de Grey. And other cryptocurrency heavy-hitters have long-term involvements with SENS, too. De Grey believes that crypto's philanthropic donors skew younger, like with Buterin, just 24, who became a fan after reading Ending Aging as a teenager. De Grey likes to call this new generation of donors "Children of the Revolution" - and he's called out older people for not doing their part. "It's a huge embarrassment to the kind of wealthy individuals of my age, like Peter Thiel or Jeff Bezos or the Google Twins or whatever, who are ostensibly really supportive of all of this, but who have put very small, if any, proportions of their net worth into supporting it. Peter is a shining example of someone who has put some money in - but let's face it, he could have put more in."

For now, the business of life extension is still a business - even nonprofits like the SENS Research Foundation need to fund their research. Despite the techno-spiritual affinity, the main reason life-extension proponents are regulars on the blockchain circuit is economic: They're chasing crypto's money.

I think it fair to say that GDF11 was the first concrete target to emerge from the modern reinvention of parabiosis research, in which the circulatory systems of an old mouse and a young mouse are joined. The old mouse rejuvenates a little, and the young mouse is aged a little, most of which seems to emerge from effects on inflammation and stem cell activity. Researchers thereafter started looking for specific signals carried in the bloodstream that might mediate this effect.

There has been no shortage of debate in this part of the field, such as over whether or not it is possible that beneficial factors from young blood can exist, given the evidence. Or whether the early work on GDF11 holds up at all. Work has continued, however, and matters have progressed to the point at which a well-funded biotech company, Elevian, has been launched. The Elevian researchers claim to have resolved the early conflicting evidence and confusion regarding GDF11, and are now well underway to building a regenerative therapy.

Cardiac hypertrophy is a prominent pathological feature of age-related heart failure. Using the parabiosis model, it has been demonstrated that age-related cardiac hypertrophy can be reversed via exposure to a young circulatory environment. These experiments revealed that age-related cardiac hypertrophy is at least in part mediated by circulating factors, such as GDF11, which is able to reverse the condition.

The reversal of cardiac hypertrophy in old mice exposed to a young circulation cannot be explained by a reduction in blood pressure in the older mice. An extensive proteomics analysis was performed on the serum and plasma of the animals. GDF11 was reduced in the circulation of aged mice and its levels were restored to those in young animals by parabiosis. A significant decrease was also found in both GDF11 gene expression and GDF11 protein levels in the spleens of old mice. These results suggest exciting therapeutic approaches for the management of age-related cardiac hypertrophy by restoring youthful levels of circulating GDF11.

Recently, the goal of a study in old mice was to reexamine the possibility to restore youthful levels of GDF11 by injecting recombinant GDF11 (rGDF11) and thus reversing cardiac hypertrophy and imparting a young phenotype to the old heart. The conclusions were that recombinant GDF11 (rGDF11) had no effect on cardiac structure and cardiac pump function; these results do not support the concept that GDF11 could be an anti-aging compound.

Muscle satellite cells are responsible for the postnatal growth and major regeneration capacity of adult skeletal muscle. Previous studies demonstrated that impaired regeneration in aged muscle can be reversed by parabiosis, which exposes aged tissues to a youthful systemic environment and restores injury-induced satellite cell activation by the up-regulation of Notch signaling. To determine whether supplementation of GDF11 from the young partner might underlie changes in skeletal muscle in the condition of heterochronic parabiosis, aged mice were treated with daily intraperitoneal injections of rGDF11 to increase systemic GDF11 levels.

After 4 weeks, satellite cell frequency, determined by flow cytometry, and function increased in the muscles of rGDF11-treated mice, whereas other myofiber-associated mononuclear cell populations were unaffected. Aged mice treated with rGDF11 also showed increased numbers of satellite cells with intact DNA. These results indicate that GDF11 is able to regulate muscle aging and may be therapeutically suitable for skeletal muscle dysfunction.

Link: https://dx.doi.org/10.3390/ijms19123998

Researchers here outline what is possibly a new point of intervention in the processes that maintain the myelin sheath that wraps nerves. This sheath is vital to the correct operation of the nervous system, and as a consequence demyelinating conditions such as multiple sclerosis are unpleasant and fatal. Loss of myelin isn't just restricted to named conditions, however: some degree of degradation occurs over the course of aging, and is thought to contribute to the progression of cognitive decline. Thus therapies that can boost myelin maintenance may be of greater interest than it might at first appear.

Myelin is maintained by oligodendrocyte cells, and the slow disruption of this cell population and its maintenance activities is the major cause of issues in aging. All cell populations exhibit loss of effectiveness or pathological behavior with the rising levels of inflammation and molecular damage present in older individuals. This research suggests a novel way to attempt to override the cellular reactions to the damage of aging in order to generate more oligodendrocytes and put them back to work. You might compare it with previous efforts that have focused on delivering greater numbers of oligodendrocytes in other ways.

Researchers have found that activation of a specific transcription factor induces in adult stem cells a phenomenon called pathological quiescence. This is when adult stem cells are rendered incapable of responding to injury by producing myelin-forming oligodendrocytes. The failure to remyelinate is the key feature of multiple sclerosis (MS). The work defines the role of the previously undescribed transcription factor known as PRRX1 in human oligodendrocyte progenitor cells, the cells that generate myelin-forming oligodendrocytes.

Current MS research focuses largely on drugs that induce the differentiation of human oligodendrocyte progenitors. In contrast, the UB research presents a novel concept for the development of new drugs based on blocking the pathological quiescence of progenitors. The research demonstrated that PRRX1 expression results in the cell cycle arrest and quiescence of oligodendrocyte progenitors, which disabled the production of myelin. In an animal model of leukodystrophy, the group of genetic disorders in which myelin fails to form or is destroyed, pathological quiescence induced by PRRX1 prevented cell colonization of white matter and effective myelin regeneration by transplanted human oligodendrocyte progenitors.

The researchers also found that blocking expression of this transcription factor prevented the negative effects of proinflammatory cytokines, such as interferon-γ, which regulates its expression. "Blockade of PRRX1 expression prevents the negative effects of interferon-γ, suggesting that PRRX1 expression might be a viable target in inflammatory diseases, such as multiple sclerosis, where interferon-γ may prevent successful myelin regeneration."

Link: http://www.buffalo.edu/news/releases/2018/12/018.html

The puzzle of aging is less how it happens, given that the scientific community has a good catalog of the forms of cell and tissue damage that cause aging, and can work to prove relevance by repairing that damage, but rather why it happens. Serious attempts to intervene in the aging process have long been a minority concern when compared to the funding and careers devoted to explaining the existence of aging. Understanding why evolution has led to a world dominated by species that age, alongside a tiny number of species that do not, is a thorny problem.

This is in part the case because arguments over the evolution of aging proceed by thought experiment and modeling rather than by examination of data. There is the world as it exists today, a few slim hints about the past, and researchers must deduce how this fantastically complex array of systems came into being over hundreds of millions of years from the minuscule sliver of information provided. There is a great deal of room in which to be wrong. Indeed, everyone involved in any given debate on the evolution of aging may be dramatically incorrect in the details of their models, and there is little that can be done in the short term to prove or disprove their positions.

Insofar as there is any consensus in the field on why we age, it might be found somewhere in the vicinity of the antagonistic pleiotropy hypothesis. Evolution selects for reproductive success in an environment in which mortality from disease and predation is an ugly reality - so the sooner that reproductive success occurs, the better. Selection pressure is much stronger in early life than in later life, and thus mechanisms that achieve early life resilience and success at the cost of later decay are selected for, while the additional expense of long-term resilience and success is selected against, outcompeted. The result is age-related decline. This, needless to say, is an overly simplistic and very high-level description of an area of theory within which are found many variants and dissenting opinions.

The adaptive immune system is a good example of antagonistic pleiotropy. It remembers past threats, making it highly effective in earlier life. But that act of memory consumes resources, requiring cells to be devoted to memory rather than action against new threats. Eventually there is no room left; the system runs out of space and its function declines. We can envisage an adaptive immune system that could work more effectively over longer spans of time, given just a few comparatively simple alterations to the way in which it manages its resources. That didn't evolve, as there is insufficient selection pressure in later life for mechanisms that would make old adaptive immune systems more functional, and no gain in having those mechanisms in younger life where selection pressure is strong.

Is antagonistic pleiotropy ubiquitous in aging biology?

The logic of evolution by natural selection is straightforward. Within any population, the alleles of individuals that produce the most breeding descendants will increase in frequency in successive generations at the expense of the alleles of individuals less successful at reproduction. To be successful at leaving descendants requires that organisms also be successful at surviving - so that they live long enough to reach reproductive age and afterward continue reproducing. By this logic and process, natural selection ultimately produces individuals superbly designed to survive and reproduce in their environment.

From this perspective, aging presents an evolutionary puzzle. If continued survival and reproduction should always be favored by natural selection, why is aging - which in evolutionary terms can be defined as the age-related decline in survival rate and reproduction - nearly ubiquitous in the natural world? Or as George Williams put it, "it is remarkable that after a seemingly miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed." Why doesn't evolution, in other words, mold the biology of organisms such that aging never occurs?

One possible solution to this conundrum is that evolution does in fact mold the biology of organisms such that they never age in their natural environment, that is, the environment in which they evolved. Aging might seldom occur in nature and only become evident when animals live much longer than they ever would in the wild, such as when we protect them from natural hazards by making them pets or livestock, keeping them in zoos or, as in the case of ourselves, organizing them into climate controlled, predator-free civilizations. Some biomedical gerontologists believe this hypothesis to be the case. But it is not and, in fact, dozens of field studies to date have identified that aging in wild animals is rampant if not close to ubiquitous.

Thus, there is a real puzzle to be solved as to how aging develops in natural populations. Fortunately, evolutionary biologists have cracked this mystery. An evolutionary mechanism of aging was hypothesized 60 years ago to be the genetic trade-off between early life fitness and late life mortality. Genetic evidence supporting this hypothesis was unavailable then, but has accumulated recently. These tradeoffs, known as antagonistic pleiotropy, are common, perhaps ubiquitous. George Williams' 1957 paper developed the antagonistic pleiotropy hypothesis of aging, which had previously been hinted at by Peter Medawar. Antagonistic pleiotropy, as it applies to aging, hypothesizes that animals possess genes that enhance fitness early in life but diminish it in later life and that such genes can be favored by natural selection because selection is stronger early in life even as they cause the aging phenotype to emerge.

No genes of the sort hypothesized by Williams were known 60 years ago, but modern molecular biology has now discovered hundreds of genes that, when their activity is enhanced, suppressed, or turned off, lengthen life and enhance health under laboratory conditions. Does this provide strong support for Williams' hypothesis? What are the implications of Williams' hypothesis for the modern goal of medically intervening to enhance and prolong human health? Overall, whenever antagonistic pleiotropy effects have been seriously investigated, they have been found. However, not all trade-offs are directly between reproduction and longevity as is often assumed. The discovery that antagonistic pleiotropy is common if not ubiquitous implies that a number of molecular mechanisms of aging may be widely shared among organisms and that these mechanisms of aging can be potentially alleviated by targeted interventions.

After controlling for other factors, hypertension risk increases as excess fat tissue increases, according to the data from a recent epidemiological study. The more overweight you are, the greater your blood pressure, all other things being equal. Hypertension is no small thing: raised blood pressure damages delicate tissue throughout the body, such as via ruptures in tiny blood vessels in the brain, and it leads to the growth and weakening of heart muscle that ends in heart failure. Hypertension also accelerates the progression of atherosclerosis, and it raises the risk that blood vessels compromised by atherosclerotic plaque will rupture, causing a fatal stroke or heart attack.

It isn't hard to suggest mechanisms that might link visceral fat tissue to hypertension. Visceral fat produces chronic inflammation through a range of mechanisms: inflammatory signaling by fat cells; greater numbers of inflammatory senescent cells; the creation of oxidized lipids; debris from dead fat cells; and more. Chronic inflammation in turn is thought to impair the operation of smooth muscle responsible for constriction and relaxation of blood vessels. When blood vessels cannot react to the environment as well as they should, when they stiffen, then hypertension follows. This seems the most plausible mechanistic link between weight, aging, and blood pressure.

The present study was undertaken to provide a better insight into the relationship between different levels of body mass index (BMI) and changing risk for hypertension, using an unselected sample of participants assessed during the Longevity Check-up 7+ (Lookup 7+) project. Lookup 7+ is an ongoing cross-sectional survey started in June 2015 and conducted in unconventional settings (i.e., exhibitions, malls, and health promotion campaigns) across Italy. Candidate participants are eligible for enrollment if they are at least 18 years of age and provide written informed consent. Specific health metrics are assessed through a brief questionnaire and direct measurement of standing height, body weight, blood glucose, total blood cholesterol, and blood pressure.

The present analyses were conducted in 7907 community-living adults. According to the BMI cutoffs recommended by the World Health Organization, overweight status was observed among 2896 (38%) participants; the obesity status was identified in 1135 participants (15%), with 893 (11.8%) participants in class I, 186 (2.5%) in class II, and 56 (0.7%) in class III. Among enrollees with a normal BMI, the prevalence of hypertension was 45% compared with 67% among overweight participants, 79% in obesity class I and II, and up to 87% among participants with obesity class III. After adjusting for age, significantly different distributions of systolic and diastolic blood pressure across BMI levels were consistent. Overall, the average systolic blood pressure and diastolic blood pressure increased significantly and linearly across BMI levels. In conclusion, we found a gradient of increasing blood pressure with higher levels of BMI. The fact that this gradient is present even in the fully adjusted analyses suggests that BMI may cause a direct effect on blood pressure, independent of other clinical risk factors.

Link: https://dx.doi.org/10.3390/nu10121976

Why do people with the APOE4 variant of APOE have a much greater risk of Alzheimer's disease? Past work has focused on its role in accelerating amyloid-β accumulation by disrupting recycling mechanisms in some way. Evidence is provided here for the relevant mechanisms to trace back to the acidity of the environment within parts of the cellular recycling system which APOE operates. APOE4 is more prone to dysfunction in that environment than is the case for other APOE variants. Manipulating the regulators of acidicity may thus enable Alzheimer's disease to be slowed down at its very earliest stage - though the size of that effect in patients is a question mark. It seems plausible that it will have little effect on people with variants other than APOE4, for example.

ApoE is a lipid and cholesterol carrying protein that is primarily produced by the liver and is responsible for plasma lipid homeostasis. It occurs in three major isoforms in humans known as ApoE2, ApoE3 and ApoE4, with ApoE3 being the most frequent allele (~77% homozygosity) followed by ApoE4 (~15-20% allele frequency) which is present in more than 50% of late onset Alzheimer's disease patients. The effect of ApoE4 on amyloid-β (Aβ) accumulation through impaired Aβ turnover, increased aggregation, and thus plaque formation is allele dosage-dependent and this can partly explain its effect on the earlier age of disease onset. However, ApoE4 can independently impair synapse function and Ca2+ homeostasis by disrupting the endocytic transport and recycling of synaptic ApoE receptors and the excitatory AMPA and NMDA type glutamate receptors that are regulated by those ApoE receptors and that are consequently trapped with them in the same vesicles.

The molecular basis by which ApoE4 causes the disruption of normal endosomal vesicle transport and recycling is most likely the result of its propensity to unfold and assume a 'molten-globule' conformation upon entering an acidic environment. ApoE4 differs from ApoE3 by a single amino acid, which alters its isoelectric point to coincide with the pH of ~6.5 that is present in the early endosome. We hypothesized that this isoelectric charge neutralization would make ApoE4 prone to aggregation, which could be the molecular basis for the ApoE4-induced and gene dosage-dependent recycling defect.

pH in the early endosome is maintained by the opposing functions of the proton pump, which decreases vesicular pH, and the Na+/H+ exchanger NHE6, which increases it. Here, we have investigated the role of NHE6 inhibition as a means of lowering endosomal pH, away from the isoelectric point of ApoE4. We found that this simple pharmacological intervention releases the endosomal ApoE4 block, restores the normal trafficking of ApoE receptors and glutamate receptors in neurons and corrects the functional defects in vitro and in vivo. Together these findings suggest that drugs that make vesicles in neurons more acidic may have the potential to help prevent individuals that carry the ApoE4 protein from developing Alzheimer's disease. Current drugs that target NHE6 also affect other molecules, which can often lead to side effects. A next step will be to develop tailor-made, small molecule drugs that can enter the brain efficiently and selectively block NHE6.

Link: https://doi.org/10.7554/eLife.40048

A golden future is ahead of us. Humanity will build wonders upon the Earth, cities on the moon and Mars. There will be arcologies to touch the skies, artificial general intelligences that surpass the minds of humanity, molecular assemblers constructing the necessities of life from soil, resurrected dinosaurs grazing alongside de novo unicorns, and probes departing for the nearest stars. There will be wealth beyond measure, in an age of plenty for all. Hunger and disease will be banished, even as we engineer all of the greatest dreams of past visionaries into reality.

But what does any of this matter without longevity, without radical life extension, without an end to aging? The present, seen from the perspective of futurists two or three centuries past, already appears a golden age of staggering, near-magical machineries. An era of grand wealth and comfort, in which even the poorest of the wealthy nations live the lives of nobility, immune to famine and pestilence. But our cities and our achievements, the towering spires and the internet, the freeways and clinics, are little more than monuments to their originators. The engineers and the creators and the visionaries of this modern world of ours are long dead or even now dying of old age.

It is a noble thing to build a greater technology, to generate the wealth of choice and capability that will aid billions in years to come. To contribute to the construction of the golden future, one step at a time, is right and proper. Yet without biotechnologies to control aging, whatever you or I choose to build will be nothing more than a bigger and better monument to our passing, one increment greater than the monuments of our predecessors, and what difference that to the dead? It will become one of the countless tombstones of our age, of the all too short span of years in which we and our fellow travelers lived. Then we will be gone, and only the tombstones remain, and then even those will crumble.

We put fences around graveyards. That is a foolish thing, a wished-for separation of concerns that does not and cannot exist. Every city, every building, every road is a marker of the dead. Every last cultivated part of our environment was touched by someone who is now no more, gone to oblivion. When we walk into the doorways, or drive over the asphalt, it becomes a marker for us as well. For our generation. This will be the way of it. Whatever we strive to build, no matter how noble, no matter how useful, it will be nothing more than a tombstone, a monument, a marker destined to be worn down to nothing while we no longer exist. What is the point to this?

The true value of building a better future can only exist when we are all assured of living to participate in that future, in health and vigor, of sound mind and body. A house can only be a house and not a tomb if its architect and resident is alive. Yes, we should build wonders, because we can, because we can dream into existence a far better world. But of greater importance than any other technology, we must build the means to end aging, to enable life to continue for as long as desired. Until we do, we are merely marking time amidst grave sites that will all too soon be our own, and therefter the grave sites of the next generation, and ever on until we break this cycle. Until we do, all that we achieve is ultimately meaningless. There is no continued story, there is no progression, there is simply death, oblivion, and an end, too soon, over and over again.

We can divide aging into primary aging and secondary aging. Primary aging is inherent to the operation of our biochemistry, a relentless accumulation of damage that historically we could do little about, while secondary aging is driven by the environment, such as the pathogens we encounter, particulate air pollution, bad choices in diet, and a sedentary lifestyle. There is a very large gray area where primary aging meets secondary aging, and indeed it is far from settled where the line lies. The commentary here, proposing the concept of the envirome, falls into this area of inquiry.

To determine what is primary and what is secondary in aging, we would need a comprehensive model of the detailed progression of aging. I don't expect that model to be produced any time soon. Firstly, it is a truly massive undertaking that will only be completed in this century given significant technological progress over the next few decades. Secondly, the progression of aging will become a moving target in the near future era of rejuvenation therapies. Who will care about the degree to which a specific mechanism of damage results from primary or secondary aging when it can be controlled near completely through periodic repair? The impetus to fund the deep, detailed investigation of aging will fade with the control of aging.

Although variations in the rate of aging across species suggests a strong role of genetics, the heritability of lifespan observed within each species is less than 35%, indicating that the environment plays an predominant role in aging. The reliability theory of aging portrays organisms as mechanical systems that contain components with varying probabilities of failure. Complex organisms have redundancy in vital systems (perhaps better understood as the capacity to self-repair) so that every occurrence of damage does not result in death, but rather, the organism accumulates defects (due to inefficient repair) that ultimately exhaust reparative capacity.

While, in the context of this theory, the frequency and severity of damage has been thought to be determined, at least in part, by the environment, there are few, if any, conceptual models with robust explanatory power and predictive capacity to account for the influence of the environment on the rate of aging. In this regard, the concept of the envirome, analogous to the genome, could provide a useful ontological model for studying the relationship between the environmental circumstance and genetic predisposition.

Broadly, the envirome could be thought of as an integrated set of natural, social, and personal environmental domains. The natural domain of the environment consists of ecological and geographic conditions, whereas the social environment, which lies within the natural environment, includes the built environment, social networks, and culture. Lastly, the personal environment lies within the social environment and includes the factors specific to an individual. In this model, interactions of the natural and social domains of the envirome with the genome could be viewed as the major determinants of aging. Aging, in turn, could be viewed as a progressive accrual of damage or unrepairable injury that results from a mismatch between the envirome and the genome and from exposure to adverse environmental conditions such as low socioeconomic status, smoking, or air pollution.

Link: https://doi.org/10.18632/aging.101709

Researchers here report on a mechanism that increase the regenerative capacity of brain cells following the damage of a stroke, at least in mice. There are now a few similar approaches demonstrated in the laboratory, but it remains to be seen whether any of them will lead to therapies in the near future. It is certainly the case that mammalian cells do not respond to structural damage and loss of blood supply in the most optimal way; many of their reactions make matters worse, not better. Perhaps that can be adjusted safely and soon, though it would be far preferable to focus on potential ways to prevent that sort of event from occurring at all, such as better maintenance of blood vessels, control of atherosclerosis, and the like.

Stroke is a leading cause of death and chronic disability in adults, causing a heavy social and economic burden worldwide. However, no treatments exist to restore the neuronal circuitry after a stroke. The mammalian brain has only a limited ability to regenerate neuronal circuits for functional recovery. While most neurons are generated during embryonic brain development, new neurons continue to be produced in the ventricular-subventricular zone (V-SVZ) of the adult brain.

In a rodent ischemic stroke model induced by transiently blocking the middle cerebral artery, the most commonly affected vessel in human patients, some V-SVZ-derived neuroblasts migrate toward the lesion, where they mature and become integrated into the neuronal circuitry. However, the number of these new neurons is insufficient to restore neuronal function. Within a few days after stroke, astrocytes, a major population of macroglia, in and around the injured area become activated, exhibiting larger cell bodies, thicker processes, and proliferative behavior. The migrating neuroblasts must navigate through this astrocyte meshwork to reach the lesion.

The research team demonstrated that neuroblast migration is restricted by the activated astrocytes in and around the lesion. In normal, olfaction-related migration, neuroblasts secrete a protein called Slit, which binds to a receptor called Robo expressed on astrocytes. Slit alters the morphology of activated astrocytes at the site of neuroblast contact, to move the astrocyte surface away and clear the neuroblast's migratory path. However, in the case of brain injury, the migrating neuroblasts actually down-regulated their Slit production, crippling their ability to reach the lesion for functional regeneration. Notably, overproducing Slit in the neuroblasts enabled them to migrate closer to the lesion, where they matured and regenerated neuronal circuits, leading to functional recovery in the post-stroke mice.

Link: https://www.eurekalert.org/pub_releases/2018-12/nion-ans120918.php

As the year draws to a close, more than half of the SENS Patron 2018 challenge fund remains to be claimed. Fight Aging! and the other fund donors challenge you to make a commitment to the SENS Research Foundation and progress towards rejuvenation therapies that can bring an end to the suffering and debility that accompanies aging. Become a SENS Patron by setting up a monthly donation to the SENS Research Foundation, and we will match the next year of your gifts in support of the research programs ongoing in the network of labs and scientists dedicated to aging research.

It has never been as easy as it is today to help ensure that the decline and death of late life ceases to be inevitable. Competent, proven organizations such as the SENS Research Foundation and Methuselah Foundation offer reliable ways to direct funds to this goal, and making a charitable donation takes just a few moments online. Become a SENS Patron to support the SENS Research Foundation with regular donations, or join the Methuselah 300 to do the same for the Methuselah Foundation programs. Thanks to the efforts of the past twenty years, the first rejuvenation therapies are accepted and on their way to the clinic. No longer must we argue over the plausibility of turning back aging; now we only argue over how best to go about it.

As it happens, the best way forward in the matter of treating aging as a medical condition, a condition that can be controlled and minimized, is outlined by the SENS rejuvenation research programs. It involves building new therapies that can repair the well-known and well-cataloged forms of cell and tissue damage that lie at the root of aging. Yet even as easy as it is to make charitable donations to support this work, most of the SENS agenda is still poorly funded and little worked on when compared with the mainstream of medicine, in which tens of thousands of scientists and physicians engage in heroic, futile efforts to stave off aging, failing because they are not focused on repairing its causes. The consistent failures of the past have led to a culture in which failure is expected - but this is only the result of a bad choice of strategy. It can be changed.

The first rejuvenation therapies, involving senolytic drugs to selectively destroy senescent cells, are a going concern, but we are far from where we should be when it comes to the rest of the rejuvenation biotechnology toolkit. The philanthropic research programs that aim to unblock and open up important lines of research into repairing the causes of aging are still very important and very necessary. They still lack sufficient funding and support for meaningful progress. Our bodies are packed with scores of forms of metabolic waste, and few of the approaches needed to clear that waste are close to the point at which clinical development can begin. We have a lot of work to do!

This is how I can, on alternate days, first celebrate our progress (and we should celebrate, as we have achieved a great deal since the days in which rejuvenation therapies based on repair of damage were only a tenuous vision) and then the very next day bemoan the state of funding and limited focus. Collectively, our community has launched the senolytic revolution in medicine, but another dozen revolutions in the treatment of aging must still be brought to the point of readiness. All of the damage must be repaired, not just one thin fraction of it. So please, help us to move faster towards this goal.

The Life Extension Advocacy Foundation recently published an interview with Aubrey de Grey of the SENS Research Foundation, on the occasion of the Longevity World Forum in Valencia, Spain. This interview ties in nicely with recent questions regarding whether we should be optimistic or pessimistic about progress toward human rejuvenation over the next ten to twenty years. It is not easy to predict the future, and it is true that even people closely connected to specific ares of work tend to overestimate the progress of a decade and underestimate the progress of two decades. For my part, I am of the opinion that, given the accelerating pace of the underlying science, when moving out to longer time frames the enormous, unnecessary costs and slowdown imposed by regulation of medicine becomes the largest determining factor governing clinical availability of new classes of medical biotechnology.

It was published recently that a therapy to reverse aging will be a reality within five years. What will be its mechanism of action, roughly?

There will not be just one medicine; there will be a lot of different medicines, and they will all have different mechanisms of action. For example, some of them will be stem cells, where we put cells back into the body in order to replace cells that the body is not replacing on its own. Sometimes, they will be drugs that kill cells that we don't want. Sometimes, they will be gene therapy treatments that give cells new capabilities to break down waste products, for example. Sometimes, they will be vaccines or other immune therapies to stimulate the immune system to eliminate certain substances. Many different things. In five years from now, we will probably have most of that working. I do not think that we will really have it perfect by then; probably, we will still be at the early stages of clinical trials in some of these things. Then, we will need to combine them, one by one, to make sure that they do not affect each other negatively. So, there will still be some way to go. But, yes, I think it's quite likely that in five years from now, we will have everything, or almost everything, in clinical trials.

Then clinical trials for seven years until it's perfected. Don't clinical trials usually take a long time?

It depends. For example, in aging, because there is this progressive accumulation of damage, you could have therapies that slow down the rate at which damage accumulates, or you could have therapies that repair the damage that has already happened. The second type of therapy is what we think is going to be most effective and is going to be easiest to do, and you can see results from that very quickly, like in one or two years. Now, of course, you still want to know what happens later on, but the first thing is to determine whether this is working at all, and as soon as it starts to work, then you can start to make it available. Clinical trials are changing in that way. Historically, clinical trials had to be completed before anybody could get these drugs, but now we are getting new policies; there is a thing called adaptive licensing, which is becoming popular in the US and elsewhere, where the therapy becomes approved at an earlier stage, and then it's monitored after that.

Beyond the humanitarian perspective of avoiding the pain and suffering that comes with old age, if increasing the years of healthy life in people will significantly reduce health care spending by governments, why don't they promote research in this area?

You're absolutely right. It's quite strange that governments are so short-sighted. But, of course, the real problem is psychological: it's not just governments that are short-sighted. Almost everybody in the world is short-sighted about this. The reason I believe why that's true is people still can't quite convince themselves that it's going to happen. Since the beginning of civilization, we have known that there is this terrible thing called aging, and we have been desperate to do something about it, to get rid of it. And people have been coming along, ever since the beginning of civilization, saying, "Yes, here's the solution, here's the fountain of youth!" And they've always been wrong. So, when the next person comes along and says they think they know how to do it, of course, there is going to be some skepticism until they have really shown that it's true. Of course, if you don't think it's going to work, then you're not going to support the effort financially. It's very short-sighted, but it's understandable.

Why do you think that the pharmaceutical industry does not devote its research and development efforts to this area, which causes the death of 100,000 people every day?

Today, the pharmaceutical industry is geared toward keeping old people alive when they are sick. It makes its money that way. It's not just the pharmaceutical industry, it's the whole of the medical industry. And so, most people say that they are worried that maybe the pharmaceutical industry will be against these therapies when they do come along. I don't think that's true at all. I think they will be in favor because people will be in favor, but people are not really in favor yet. People don't really trust preventive medicine. They think "Okay if I am not yet sick…" They don't trust medicine in general; they know that this is experimental. So, when they are not yet sick, they think "Well, I'll wait until I am sick," but we can change that. Eventually, people will understand that it's going to be much more effective to treat yourself before you get sick, and then the whole medical industry will just respond to that; they will make the medicines that people want to pay for.

Link: https://www.leafscience.org/aubrey-de-grey-valencia/

Researchers here find that the beneficial effects of regular exercise on bone density and strength are mediated in part by irisin, which acts on a receptor found on the surface of osteocytes. Osteocytes are a class of cell responsible for the constant remodeling of bone tissue that takes place throughout life, alongside osteoclasts and osteoblasts. The loss of density and strength in bone that occurs in later life, known as osteoporosis, is an imbalance between creation and destruction of bone. It might be reduced by means of modifying the behavior of the cells responsible for these activities, though to my eyes it would be preferable to identify the forms of underlying damage in aging that lead to this imbalance and then work to repair them.

Researchers have proposed that the irisin hormone serves as a link between exercise and its beneficial effects on health, including burning fat, strengthening bones, and protecting against neurodegenerative diseases. Until now, however, researchers hadn't identified a specific molecular receptor for irisin - in effect, a docking structure allowing irisin to bind to cells and tissues. They are now reporting that the irisin receptor is a group of proteins called integrins situated on the surface of osteocytes.

Osteocytes are cells that act as the "command and control unit" for bone remodeling - that is, the loss and replenishment of bone that occurs both normally and in pathological states. Some research previously found that intermittent injections of irisin increased bone density and strength in mice. Now that it has shown that irisin targets the osteocyte through a specific receptor, the irisin-bone connection can be explored more mechanistically.

Osteocytes gradually die off with age, and their loss is believed to be a cause of age-related osteoporosis, the thinning and weakening of bones. In cell culture, the scientists observed that treating osteocytes with irisin protected them from being killed by hydrogen peroxide - a simulation of age-related death. The experiments also showed that treating osteocytes with irisin increased their production of sclerostin, a protein that triggers bone remodeling, and injecting irisin into mice raised their sclerostin levels. Sclerostin actually triggers the breakdown of bone, which might seem harmful rather than helpful. However, the intermittent breakdown of bone seems to be interpreted as a signal to remodel and build bones. So how could manipulating irisin be used therapeutically? Some form of intermittent irisin treatment might work.

Link: https://www.dana-farber.org/newsroom/news-releases/2018/exercise-related-hormone-irisin-found-to-target-key-bone-cells/

In older mice and humans, the immune system becomes dysfunctional. It is overactive, producing chronic inflammation that leads to harmful cellular behavior throughout the body, but at the same time it is much less capable when it comes to destroying pathogens and errant cells. In today's open access research, scientists investigate the incapacity of naive T cells in older mice. This population of T cells is necessary for a strong immune response, but their numbers decline due to the involution of the thymus. T cells begin life as thymocytes in the bone marrow, and then migrate to the thymus where they mature into T cells of various types. With advancing age the thymus atrophies, and the active tissue needed for T cell maturation is replaced with fat. The supply of new T cells diminishes, and thus so does the fraction of the overall immune cell population that is made up of naive T cells capable of meeting new threats.

In the research here, it is found that those naive T cells that do remain in old mice are dysfunctional, far less capable than their young counterparts. The mitochondria, the power plants of the cell, are altered and diminished. Many important mechanisms are thus likely compromised, or operating at levels far beneath what is minimally required for adequate cellular function. This mitochondrial malaise is observed in all tissues, but possibly best studied in the context of muscle and brain, both energy-hungry tissues that are greatly affected by a reduced supply of chemical energy store molecules packaged by mitochondria. Clearly similar problems exist in all cells.

Fixing this age-related alteration in mitochondrial structure and function is an interesting challenge. The problem is only peripherally related to the mitochondrial DNA damage of the SENS rejuvenation research program, and appears to be a downstream consequence of some combination of other molecular damage and altered signaling inside and outside cells. There is no clear view of which forms of repair would be most effective, as there is no solid link established between any of the known forms of molecular damage that lie at the root of aging and this general mitochondrial decline. Thus efforts to override specific mitochondrial mechanisms are further ahead as of the moment; providing additional NAD+ to cells, for example, perks up mitochondrial activity. That can be enough to provide incremental benefits to tissue function, as recently demonstrated in a small human trial. There are no doubt other similar possibilities. These are all limited in their upside by the fact that they don't address the underlying causes; there is a great need for more research and development focused on repair of those underlying causes.

The 'Graying' of T Cells

Researchers looked for overall differences between old and young T cells. They isolated T cells from the spleens of young and old mice and noticed that, in general, older mice had fewer T cells. Next, to gauge the cells' immune fitness, the researchers activated the T cells by mimicking signals normally turned on by pathogens during infection. The older T cells showed diminished activation and overall function in response to these alarm signals. Specifically, they grew more slowly, secreted fewer immune-signaling molecules and died at a much faster rate than young T cells. The researchers also observed that aged T cells had lower metabolism, consumed less oxygen and broke down sugars less efficiently. They also had smaller than normal mitochondria, the cells' power-generators that keep them alive

To pinpoint the metabolic pathways behind this malfunction, the scientists analyzed all the different proteins in the cells, including those that might be important for coaxing a T cell from dormancy into a fighting state. The team found that the levels of some 150 proteins were lower-than-normal upon activation of the aged T cells, compared with young T cells. About 40 proteins showed higher than normal levels in aged versus young T cells. Many of these proteins have unknown functions, but the researchers found that proteins involved a specific type of metabolism, called one-carbon metabolism, were reduced by nearly 35 percent in aged T cells.

One-carbon metabolism comprises a set of chemical reactions that take place in the cell's mitochondria and the cell cytosol to produce amino acids and nucleotides, the building blocks of proteins and DNA. This process is critical for cellular replication because it supplies the biologic material for building new cells. The team's previous work had shown that one-carbon metabolism plays a central role in supplying essential biological building blocks for the growing army of T cells during infection. So, the scientists wondered, could adding the products of this pathway to weakened T cells restore their fitness and function?

To test this hypothesis, the team added two molecules - formate and glycine, the main products of one-carbon metabolism - whose levels were markedly reduced in aged T cells. Indeed, adding the molecules boosted T cell proliferation and reduced cell death to normal levels. The researchers caution that while encouraging, the effects were observed solely in mouse cells in lab dishes rather than in animals and must be confirmed in further experiments.

Defective respiration and one-carbon metabolism contribute to impaired naïve T cell activation in aged mice

T cell-mediated immune responses are compromised in aged individuals, leading to increased morbidity and reduced response to vaccination. While cellular metabolism tightly regulates T cell activation and function, metabolic reprogramming in aged T cells has not been thoroughly studied. Here, we report a systematic analysis of metabolism during young versus aged naïve T cell activation.

We observed a decrease in the number and activation of naïve T cells isolated from aged mice. While young T cells demonstrated robust mitochondrial biogenesis and respiration upon activation, aged T cells generated smaller mitochondria with lower respiratory capacity. Using quantitative proteomics, we defined the aged T cell proteome and discovered a specific deficit in the induction of enzymes of one-carbon metabolism. The activation of aged naïve T cells was enhanced by addition of products of one-carbon metabolism (formate and glycine). These studies define mechanisms of skewed metabolic remodeling in aged T cells and provide evidence that modulation of metabolism has the potential to promote immune function in aged individuals.

Earlier this year, researchers provided evidence for expression of TIGIT to mark senescent and exhausted T cells in the immune systems of older individuals. Here, new results reinforce the point that TIGIT-expressing T cells are a burden. These cells cause issues, contributing to the inflammatory and weakened state of the aged immune system. Selectively destroying them should help, and senolytic drugs may achieve this goal, as least insofar as the biochemistry of TIGIT-expressing T cells overlaps with that of better studied varieties of senescent cell in tissues. To what degree this is the case remains to be determined; researchers in the cellular senescence field have far more analysis of this nature in front of them than can possibly be accomplished over the next few years, and this particular case is probably still a fair way down the list by priority.

Researchers have identified that an immune cell subset called gamma delta T cells that may be causing and/or perpetuating the systemic inflammation found in normal aging in the general geriatric population and in HIV-infected people who are responding well to drugs. The team measured many markers on the surface of immune cells in the blood of people either with or without HIV (uninfected controls) that were sub-divided into two groups: younger (less than 35 years) and older (over 50 years) and compared that data with levels of inflammatory proteins in their plasma.

Researchers found a marker on these gamma delta T cells, called TIGIT, that tracked significantly with plasma inflammatory markers in both the HIV+ and uninfected subject groups, and therefore could be targeted to potentially stop this "inflammaging" found in both HIV+ people and the general geriatric population. "Our study indicates that there's a previously uninvestigated cell subset new player in the immune landscape that could be driving widespread illnesses and with targeted gamma delta therapeutics maybe there may be a chance of reducing onset, symptoms, and/or severity of inflammation-related diseases."

Link: https://www.eurekalert.org/pub_releases/2018-12/buso-rdu121118.php

At this year's RAADfest event, the interviewer noted here was taking an informal survey of optimistic versus pessimistic attitudes towards progress in the decades ahead. Apparently I was on the pessimistic end of the spectrum. Once past the present highly active development of senolytic therapies to remove senescent cells from old tissues, I think it quite plausible that we'll see a gap of a decade before the next class of SENS-like rejuvenation therapy arrives at the point of availability via medical tourism. The likely candidates include clearance of cross-links and restoration of the immune system via thymic regrowth.

Surprise progress in advance of the end of the 2020s seems implausible, with the exception of the discovery that an existing small molecule drug or otherwise widely available low cost compound breaks down significant amounts of some form of molecular waste, such as oxidized cholesterol or glucosepane cross-links. That is possible to engineer, given the resources, but so far as I know next to no-one is screening the compound libraries with this in mind. It is an expensive task with uncertain chances of success. This present state of the market, that there is a gulf of further required development ahead, is perhaps a little obscured by the excitement over senolytics. There is, however, a continued need for philanthropic support of lines of research that remain poorly funded. If senolytics are to be closely followed by the rest of the rejuvenation toolkit, then we still have a great deal of work to do.

What are the most promising near-term therapies that may actually turn back the clock on biological aging?

Senolytic treatment, obviously, is the one that is here already and is presently available. It is fortunate that some of the first drugs identified to have this effect are, to a significant degree, already widely used and cheap. The animal results are far better in terms of robustness and reproducibility than any of the calorie restriction mimetic and other stress response tinkering work. The first human data from formal trials will arrive late this year or in early 2019. These first-generation approaches are killing only about half of the senescent cells at best (and far fewer than that in some tissues) but are nonetheless very effective in comparison to any other approach to age-related inflammatory disease.

The next approach to arrive that will likely have a similar character and size of effect is breaking of glucosepane cross-links, but since that involves a completely new enzyme-based therapy, we're unlikely to see it in people any sooner than a decade from now. If there is interest in that field, someone might uncover a useful small molecule prior to then, but it seems unlikely.

Other than that, over that same timeframe: (a) advances in stem cell medicine, moving beyond the simple transplantation therapies that do little other than suppress inflammation towards ways to actually replace damaged populations and have them get to work; (b) removal of amyloids through means other than the immunotherapies that are the present staple of that field; (c) forms of immune system restoration, such as via thymic regrowth, replacement or enhancement of hematopoietic stem cells, and clearance of problem immune cells.

I'm not convinced that there is an enormous benefit to be realized from approaches to enhance mitochondrial function, such as NAD+ precursors and mitochondrially targeted antioxidants, that get a lot of hype and attention. They may have a small positive effect on metabolism in later life, which would make them worth taking when cheap and safe. They are not in any way reversing aging - they are forcing a damaged machine to work harder without addressing any of the causes of failure. One can paint the same picture when discussing ways to enhance stem cell function without addressing the underlying damage, such as telomerase therapies and the use of signaling molecules. It may meet the cost-benefit equation, but it also may not, since these are much more expensive propositions.

Why is breaking extracellular crosslinks so important?

This is important because cross-links cause stiffening of tissues. The stiffening of blood vessels is the cause of hypertension, and hypertension is (like inflammation) a major way in which low-level biochemical damage is translated into many different forms of structural damage: pressure damage to delicate tissues; rupture of capillaries in the brain; remodeling and weakening of the heart; increased risk of atherosclerotic lesions causing stroke or heart attack. High blood pressure is very damaging. It is so harmful that ways to reduce blood pressure that work by overriding signaling systems - which do absolutely nothing to eliminate the root cause, the biochemical damage of aging - can still produce large reductions in mortality risk.

All of that can be greatly reduced by cross-link breaking, and there is only one major class of cross-links in humans that needs targeting to obtain that benefit: those involving glucosepane. Thus, like senolytics, once there is some motion towards achieving this end, we should see a very rapid expansion of the industry and delivery of benefits to patients. Glucosepane is hard to work with, so very few groups have done anything meaningful - the first big advance that the SENS Research Foundation achieved in this field was to fund the creation of the tools needed to move forward at all in this part of the field. Even now, there is really only one group working earnestly on it that I know of, David Spiegel's team at Yale, with a couple of others doing some investigative work around the edges of the challenge. The Spiegel approach is to mine the bacterial world for enzymes that degrade glucosepane and then refine the successes into therapeutic drugs. His team is a fair way along, and work is progressing in a funded startup company at this point.

Link: https://www.leafscience.org/an-interview-with-reason-near-term-life-extension-therapies/

There are any number of reasons why promising lines of research get stuck. Simple abandonment is a surprisingly common one; people outside the scientific community have little appreciation of the degree to which the floor of the forest is littered with valuable raw materials, just waiting for someone to spend the effort to forge them into useful goods. Many researchers have little interest in implementation, or fail to convince funding sources to continue their initial exploration, or the people involved move on, or the tools are hard to use and no-one else wants to make the effort to replicate the discoveries. It is sometimes amazing that anything is accomplished, watching the way in which most academic labs organize themselves.

Another common problem is the lack of suitable tools to manipulate a mechanism of interest, related to disease or aging. Once researchers find a mechanism, and have the means to probe its operation, the next step is to build ways to influence it. Some of the most common traditional tools are genetically engineered animal lineages, in which genes of interest are inserted or removed in the germline, gene therapies that increase or decrease protein levels in cells and adult animals, and small molecules that can increase or decrease protein levels, or interfere in or enhance protein interactions. Of those, only small molecules have traditionally resulted in clear path to clinical application, though gene therapies are starting to become more practical for those purposes.

What happens when researchers have an interesting mechanism, but don't have a small molecule that can manipulate that interesting mechanism? Well, they are stuck when it comes to moving closer to the clinic, unless they can raise a fairly sizable amount of funding for screening, as well as produce a sufficiently cheap screening methodology to allow a very large number of compounds from the standard libraries to be tested. The cost of a comprehensive screening exercise to find candidate small molecule drugs can be a few million dollars, which is why there are a sizable number of companies working on ways to reduce that cost and raise the odds of success. Expending these sizable resources offers no guarantee of finding a viable compound, or even a viable starting point. That is why many projects just stop right there, and remain halted until the slow grind of grant-writing and incremental discovery leads to a potential candidate compound in some other way.

In recent years, the new ability to cultivate arbitrary bacterial species from soil, rather than the tiny minority that has traditionally been the case, has unlocked the door for compound discovery relating to destruction of problem molecules. Every molecule in the human body can be consumed and broken down by at least one species of soil bacteria. Finding the tools that bacteria use for that purpose is low-cost and reliable in comparison to old-style screening from compound libraries: just grab a soil sample, separate the bacteria, drop in the protein that needs destruction, and see which of the bacteria thrive on that diet. A number of research groups have produced proof of principle results with modest budgets.

While that works just fine for targets such as the 7-ketocholesterol associated with atherosclerosis, as well as glucosepane cross-links, both of which are implicated in the aging process, and that we'd be far better off without, the approach doesn't work when the objective is to alter rather than destroy aspects of cellular metabolism. For example, it would be very useful to have drugs that interfere in the operation of alternative lengthening of telomeres (ALT), a mechanism that is only active in cancer cells. All cancers must lengthen their telomeres constantly in order to maintain rampant growth. If both ALT and telomerase-based telomere lengthening could be suppressed, then cancers would wither.

Work on finding ways to manipulate ALT is essentially stuck on the point that someone needs to spend a few million dollars in order to buy a chance at finding a candidate small molecule drug. No-one really wants to take that wager, and would much rather wait on incremental progress in the field to turn up a possible path forward. Perhaps that will happen in a year, perhaps not for twenty years, no-one can tell. It seems to me that for those areas of research blocked in this way, and where success would be very valuable, then paying for the screening would be a sensible act of high net worth philanthropy. For that to take place, however, it would require either a good understanding of the field on the part of more wealthy individuals, or a good packaging of the ideas involved on the part of a non-profit entity.

Macrophages of the innate immune system play an important role in coordinating the intricate dance of cell populations that takes place during regeneration from injury. Differences in macrophage behavior may be key to the exceptional regenerative capacities of species such as salamanders that can regrow entire organs, and possibly also in the few mammalian species and genetically altered lineages capable of noteworthy feats of regeneration.

Researchers here make a most interesting discovery, finding that in mice there are populations of macrophages capable of coordinating greater than normal regeneration following injury to the heart, such as that resulting from a heart attack. This regeneration doesn't take place because the macrophages arrive too late to prevent the formation of scar tissue; regeneration is already well advanced by the time they are present in any significant number. This suggests that regenerative therapies based on manipulation of macrophage behavior are plausible for the near future, as it is always easier to adjust an existing mechanism than it is to build something completely novel.

Macrophages are white blood cells that live in organs and are key components of our immune system. They have a well-established ability to fight infections, but more recently, have been shown to help promote repair and regeneration of tissues. Researchers have found that instead of a single type of macrophage, there are at least four types that live within the uninjured heart, and that number increases to 11 after a heart attack, which indicates the immune system behaves in much more complex fashion than was imagined.

First, they found that neonatal-like macrophage cells are lost after a heart attack in adults, which could explain why the adult heart may not heal itself as well as the neonatal heart. In very young animals, neonatal macrophages increase in number and are very effective at triggering the regrowth of heart muscle and blood vessel cells. "Genetically removing neonatal-like macrophages at the time of the heart attack in adult animals worsens heart function most profoundly at the region of the heart separating injured and uninjured heart muscle - the only zone of the adult heart where they increase in number."

Researchers also found large numbers of macrophages are attracted to the heart after a heart attack, and a small number enter into the neonatal state, except, too late. By the time they arrive on site after a heart attack, a scar has formed in the heart in the place of heart muscle. "Each cell has a unique role to play in the human body, but our next question is: how can we guide a cell that enters the heart into a neonatal state more efficiently and, ultimately, more effectively?"

Link: https://www.uhn.ca/corporate/News/Pages/Study_finds_macrophage_cells_key_to_helping_heart_repair_and_potentially_regenerate.aspx

One way to identify the important mechanistic links between metabolism and longevity is to examine the genomes of unusually long-lived species. This has long been underway for naked mole rats and some smaller bats, species that live many times longer than similarly sized near relatives. The same sort of longevity occurs in parrots; other birds of their size live for perhaps a decade or two, but parrots exhibit a similar life span to that of humans, given a safe and supportive environment. Scientists here report on their initial investigations of the parrot genome, and a comparison with less long-lived birds. As for the case for all similar research, it remains an open question as to whether any of the findings will turn out to be of practical use when it comes to developing the means to significantly lengthen healthy human life spans.

Parrots are one of the most distinct and intriguing groups of birds, with highly expanded brains, highly developed cognitive and vocal communication skills, and a long lifespan compared to other similar-sized birds. Yet the genetic basis of these traits remains largely unidentified. To address this question, we have generated a high-coverage, annotated assembly of the genome of the blue-fronted Amazon (Amazona aestiva) and carried out extensive comparative analyses with 30 other avian species, including 4 additional parrots.

We identified several genomic features unique to parrots, including parrot-specific novel genes and parrot-specific modifications to coding and regulatory sequences of existing genes. We also discovered genomic features under strong selection in parrots and other long-lived birds, including genes previously associated with lifespan determination as well as several hundred new candidate genes. These genes support a range of cellular functions, including telomerase activity; DNA damage repair; control of cell proliferation, cancer, and immunity; and anti-oxidative mechanisms.

We also identified brain-expressed, parrot-specific paralogs with known functions in neural development or vocal-learning brain circuits. Intriguingly, parrot-specific changes in conserved regulatory sequences were overwhelmingly associated with genes that are linked to cognitive abilities and have undergone similar selection in the human lineage, suggesting convergent evolution. These findings bring novel insights into the genetics and evolution of longevity and cognition, as well as provide novel targets for exploring the mechanistic basis of these traits.

Link: https://doi.org/10.1016/j.cub.2018.10.050

Today's research results, published a few months ago, are one of a number of examples from recent years of a possible way to suppress or destroy persistent herpesviruses such as cytomegalovirus (CMV). These viruses cannot be effectively cleared from the body by the immune system; they remain latent to reemerge time and again. CMV itself is of particular interest because it is strongly implicated in the age-related dysfunction of the immune system. Research suggests that in old age an unsustainable fraction of immune cells become devoted to CMV, and since the decline of the thymus and hematopoietic stem cells ensure that the supply of replacement immune cells is reduced to a trickle, too few capable immune cells remain to adequately address other threats.

A range of studies provide evidence for people with greater exposure to CMV have a worse prognosis in later life, but it is far from clear as to whether (a) this is a burden that accumulates over time, and length of exposure is important, as studies of childhood adversity suggest, or (b) the burden arrives near entirely in later life, despite life-long infection with CMV, and requires some initial decline in immune function to start the process in earnest. The interesting question is whether it is worth trying to clear CMV from the body, given that it is largely harmless to young people, or whether the real target is the damage done to the immune system.

That damage, in the form of too many specialized immune cells and too low a rate of generation of new immune cells, will remain in effect even if CMV can be banished from the body of an older individual. The deficits of the aged immune system will have to be addressed via other approaches, such as targeted removal of CMV-specialized cells and regeneration of thymus and hematopoietic stem cells to restore a more youthful supply of new immune cells. Achieving those goals may well make CMV irrelevant. That said, it is worth considering getting rid of CMV might be more or less effective as a way to improve health in later life depending on when and how rapidly the consequent immune damage emerges.

Scientists Find a New Way to Attack Herpesviruses

Human cytomegalovirus is a leading cause of birth defects and transplant failures. As it's evolved over time, this virus from the herpes family has found a way to bypass the body's defense mechanisms that usually guards against viral infections. Until now, scientists couldn't understand how it manages to do so. Normally, when a virus enters your cell, that cell blocks the virus's DNA and prevents it from performing any actions. The virus must overcome this barrier to effectively multiply. To get around this obstacle, cytomegalovirus doesn't simply inject its own DNA into a human cell. Instead, it carries its viral DNA into the cell along with proteins called PP71. After entering the cell, it releases these PP71 proteins, which enables the viral DNA to replicate and the infection to spread.

"The way the virus operates is pretty cool, but it also presents a problem we couldn't solve. The PP71 proteins are needed for the virus to replicate. But they actually die after a few hours, while it takes days to create new virus. So how can the virus successfully multiply even after these proteins are gone?" The researchers found that, while PP71 is still present in the cell, it activates another protein known as IE1. This happens within the first few hours of the virus entering the cell, allowing the IE1 protein to take over after PP71 dies and continue creating new virus. To confirm their findings, the team created a synthetic version of the virus that allowed them to adjust the levels of the IE1 proteins using small molecules.

"We noticed that when the IE1 protein degrades slowly, as it normally does, the virus can replicate very efficiently. But if the protein breaks down faster, the virus can't multiply as well. So, we confirmed that the virus needs the IE1 protein to successfully replicate." The new study could lead to a new therapeutic target to attack cytomegalovirus and other herpesviruses.

Feedback-mediated signal conversion promotes viral fitness

A fundamental signal-processing problem is how biological systems maintain phenotypic states (i.e., canalization) long after degradation of initial catalyst signals. For example, to efficiently replicate, herpesviruses (e.g., human cytomegalovirus, HCMV) rapidly counteract cell-mediated silencing using transactivators packaged in the tegument of the infecting virion particle. However, the activity of these tegument transactivators is inherently transient - they undergo immediate proteolysis but delayed synthesis - and how transient activation sustains lytic viral gene expression despite cell-mediated silencing is unclear.

Using an HCMV mutant, we find that positive feedback in HCMV's immediate-early 1 (IE1) protein is of sufficient strength to sustain HCMV lytic expression. Single-cell time-lapse imaging and mathematical modeling show that IE1 positive feedback converts transient transactivation signals from tegument pp71 proteins into sustained lytic expression, which is obligate for efficient viral replication, whereas attenuating feedback decreases fitness by promoting a reversible silenced state. Together, these results identify a regulatory mechanism enabling herpesviruses to sustain expression despite transient activation signals - akin to early electronic transistors - and expose a potential target for therapeutic intervention.

The polarization of the immune cells known as macrophages and microglia is a topic of growing interest in the study of aging and age-related disease. A perhaps overly simplistic summary is that polarization describes the state and preferred activities of a macrophage or microglial cell, changing in response to signals and environment. The states of greatest interest are M1, inflammatory and aggressive in pursuit of pathogens, versus M2, a helper in tissue maintenance and regeneration. Both polarizations are necessary in the grand scheme of things, but in older individuals and in tissues affected by age-related disease, a an excess of M1 macrophages or microglia is a common theme. The result is a diminished capacity for regeneration and necessary processes of maintenance.

Too great a number of M1 polarized cells ties in to the chronic inflammation of aging, as inflammatory signals provoke macrophages into this polarization. In this context, researchers are investigating a range of possible strategies to override polarization, forcing immune cells back into the M2 state. Another aspect of this issue is added here in an open access paper linking the quality of autophagy to polarization. Autophagy is the name given to a collection of cell maintenance processes responsible for breaking down and recycling damaged structures and proteins. That it would be linked to immune cell polarization is most interesting, as autophagic activity is known to decline with age. Increased autophagy is associated with increased longevity in a variety of interventions examined in laboratory species, such as calorie restriction. It remains to be seen how strong this relationship is in comparison to the relationship with inflammation, but it seems that they influence one another, and are not independent.

Neuroinflammation and autophagy dysfunction are closely related to the development of neurodegeneration such as Parkinson's disease (PD). However, the role of autophagy in microglia polarization and neuroinflammation is poorly understood. TNF-α, which is highly toxic to dopaminergic neurons, is implicated as a major mediator of neuroinflammation in PD. In this study, we found that TNF-α resulted in an impairment of autophagic flux in microglia. Concomitantly, an increase of M1 marker expression and reduction of M2 marker expression were observed in TNF-α challenged microglia. Upregulation of autophagy via serum deprivation or pharmacologic activators (rapamycin and resveratrol) promoted microglia polarization toward M2 phenotype, as evidenced by suppressed M1 and elevated M2 gene expression, while inhibition of autophagy with 3-MA or Atg5 siRNA consistently aggravated the M1 polarization induced by TNF-α.

Moreover, Atg5 knockdown alone was sufficient to trigger microglia activation toward M1 status. More important, TNF-α stimulated microglia conditioned medium caused neurotoxicity when added to neuronal cells. The neurotoxicity was further aggravated with Atg5 knockdown in cells, but alleviated given microglia pretreatment with rapamycin, suggesting that activation of AKT/mTOR signaling may contribute to the changes of autophagy and inflammation. Taking together, our results demonstrate that TNF-α inhibits autophagy in microglia through AKT/mTOR signaling pathway, and autophagy enhancement can promote microglia polarization toward M2 phenotype and inflammation resolution.

Link: https://doi.org/10.3389/fnagi.2018.00378

The nervous system in general is not particularly regenerative, but peripheral nervous system tissue is more capable of repair than central nervous system tissue. Focusing on neurons that link these two parts of the nervous system, researchers here report on mechanisms involved in repair of nervous system cells, and propose that it might be possible to make central nervous system cells act more like peripheral nervous system cells in this regard. Whether or not this can be achieved safely is another question, however; this is very early stage work, too early to answer many questions about safety and plausibility.

Neurons in the central nervous system - the brain and spinal cord - and the peripheral nervous system are very similar except in their ability to regenerate. Researchers realized that studying peripheral neurons could help us understand why some damaged neurons regenerate and others do not. They turned to a unique kind of sensory cell that spans both nervous systems. Known as dorsal root ganglion neurons, these cells have long tendrils, called axons, with two offshoots. One branch of the axon connects to cells in the body's periphery and can regenerate if cut; the other side links up with cells in the spinal cord and cannot regrow after injury.

The researchers grew mouse dorsal root ganglion neurons in the lab and then cut them to find out what biological processes occur as the cells regrow their axons. They also cut the sciatic nerve - which runs up the leg and into the spinal cord through the dorsal root ganglia - in mice. The researchers then identified a suite of genes needed to be turned off for the axons to regenerate. "Other people also have shown that a big swath of genes is turned down during regeneration, but as a field we've just said, 'Eh' and ignored them to focus on the genes that are activated. Here, we showed that establishing a regeneration program means some genes have to be turned on but a lot have to be turned off."

In particular, a set of genes related to sending and receiving chemical and electrical signals - the primary duty of mature neurons - had to be silenced for the injury to heal. "The injured neuron has to stop functioning as a neuron and focus on repairing itself. This means the neuron has to transition back to an immature state so it can re-engage developmental programs and regrow." The idea that cells must become less mature in order to regenerate is not new, but the study provides evidence in support of that idea. The researchers identified the key molecular and genetic players involved in regressing to a less mature state, and showed that the timing of the regression was crucial to successful recovery. They are now working on developing a more detailed understanding of when and for how long specific genes must be shut off, and whether silencing the genes in neurons from the central nervous system will induce them to regrow after injury.

Link: https://medicine.wustl.edu/news/regrowing-damaged-nerves-hinges-on-shutting-down-key-genes/

Cryopreservation via a cryonics provider, such as Alcor or the Cryonics Institute in the US, is presently the only option available to the billions who will age to death prior to the advent of a comprehensive package of rejuvenation therapies. Sadly, it is not yet a well-developed industry, operating at scale. The technology exists to vitrify people immediately following clinical death, preserving the fine structure of brain tissue if the vitrification process is of sufficiently high quality, but very few people choose to take advantage of this opportunity. Every year, tens of millions go to oblivion rather than chose the better option. Given preservation, there is the chance of restoration to life in a more technologically advanced future. The odds of success are unknown, but any chance is better than the certain oblivion of any other end of life choice. The cost of cryopreservation is small, provided that preparations are made decades in advance, as it can be funded via life insurance.

The popular science article noted here presents an array of comments from people for and against cryonics as an endeavor, and captures most of the important divisions. There is the disagreement over whether sufficiently well performed vitrification can preserve the structures that encode the mind, which seems to me to be the case, given the evidence from experiments in nematodes. There is the debate over whether present practices actually constitute sufficiently well performed vitrification. Then there are those who think it is better to go to oblivion than to be restored in a new era, which I can't say I agree with at all. Finally there are those who will never be convinced by any amount of indirect evidence, such as the nematodes or reversible vitrification of whole organs for use in the transplant industry, and will be skeptics until the day that someone is restored to life.

As is the usual case in the popular press, the article title and commentary willfully substitutes "frozen" for "vitrified". These are two very different things. Only the earliest of the preserved individuals were frozen, and we can be rightfully skeptical that there is anything left to restore there. Freezing produces ice crystals that shred cell structures, such as the synapses where it is thought that memory is encoded. Vitrification, on the other hand, involves the use of cryoprotectants that minimize ice crystal formation, turning tissue into a glass-like state. Reversing this process will require advanced nanotechnologies, of a sort that can be envisaged today but will only arise many decades in the future at our current pace of development. For so long as the structure is preserved, then reversal remains a possibility, only waiting on the technical capability to do so.

Will Cryopreserved People Ever Be Revived?

Dr. Joao Pedro de Magalhaes, Biologist at the University of Liverpool and coordinator of the UK Cryonics and Cryopreservation Research Network

I'd say that with today's technology, cryonics severely damages the body's cells. Even under optimal conditions (i.e., the procedure starts right after death), there are several problems in cryonics. In particular, cryoprotectant agents have toxic effects on human tissues with prolonged exposure. Vitrifying large organs like the brain can also result in fractures due to different cooling rates in different parts. Under non-optimal conditions (i.e., if a significant time elapses between death and being cryopreserved) much more damage can occur because cells start to die, and brain cells in particular start to die within minutes after cardiac arrest, due to lack of nutrients and oxygen (called ischemia). Therefore, it will take huge scientific advances in areas like tissue engineering and regenerative medicine to make cryopreserved individuals alive and healthy again. As such, I would say that the chances of cryopreserved individuals ever be revived is low but not impossible. And then the argument is that the worse possible outcome of being cryopreserved is to remain dead, so cryonics gives you a chance of future revival that will not happen if you are buried or cremated.

Mark Kline, Co-Founder and CTO, X-Therma Inc., a company improving cold storage of stem cells, tissues, and whole organs

The hardest thing to solve is: how do you freeze things without damaging them? You mix in all these cryoprotectants - like antifreeze for your car, but geared towards biology - in an effort to prevent ice formation within the cells and tissues. But you need to drastically lower the temperature - down to about -196 degrees C, liquid nitrogen temperature. Preventing ice formation at that temperature, throughout a very large tissue, is very, very difficult. So there's the chemistry problem (preventing ice), the biology problem (tissue damage, connection damage), the physics problem (how do you evenly cool something as large as an organ? And how do you warm it up evenly afterwards, without damaging it?). I think there are much more imminent applications for cryopreservation, like organ preservation. Preserving organs has a high-value impact for the medical system, and also is much more feasible than preserving a whole body. You can save many, many lives with organ preservation.

Nick Bostrom, Professor at the University of Oxford and Director at the Future of Humanity Institute and the Governance of AI program

Technically it seems like it should probably work. The freezing (rather: vitrification or plastination) and storing we can do now. The bringing back part may however require the assistance of machine superintelligence in order to repair the extensive cellular damage that occurs during the suspension process.

Dennis Kowalski, President, Cryonics Institute

The scientifically correct answer is that we do not know, since no one knows the future and what will be possible. However, that is why some people have signed up to preserve their bodies at liquid nitrogen temperatures in hopes that future technology and medicine will be able to answer that very question. New technologies moving forward might mean advanced, AI-guided stem cell therapies that regenerate tissues that have been damaged by aging, freezing, or death itself. Technologically we are advancing at an exponential pace, and this means that things considered impossible even a few decades ago will become reality.

Cathal O'Connell, Researcher in 3D bioprinting and biofabrication at BioFab3D, St Vincent's Hospital, Melbourne

All signs point to no. The freezing-down process is critical. Doing this in a way that preserves cell function - especially regarding connectivity in the human brain - is way beyond our current capabilities. Unfortunately, everyone who has ever been frozen so far is essentially turned to mush. These people will never be revived. Cryonics in its current form is more of a religion than a science. Rather than a divine entity, its followers place their faith in technological progress. The ability of some organisms to survive freezing is a sign from nature that what cryonics promises might one day be possible. But getting there will require a massive investment - billions of dollars, thousands of scientists, decades of research. Without a clear economic incentive, that investment is not forthcoming. As my old professor says, a vision without funding is hallucination.

Ralph Merkle, Director of Alcor Life Extension Foundation, the world's leading cryonics organization

The short version is: many of the patients at Alcor will likely be revived sometime this century. Had you asked a random person in 1940 if flight to the moon was possible, you'd likely have been told "no." If asked why, a typical answer was "because there's no air to push against in space." This scientific-sounding but totally false objection was infamous among knowledgeable scientists, and was the basis for the New York Times' 1920 editorial denouncing Robert Goddard. Yet those knowledgeable about space flight had been forecasting flight to the moon for decades before the event. Similarly, those knowledgeable about nanomedicine have also been forecasting the revival of cryopreserved patients for decades, and those forecasts are likewise based on a sound assessment of physical law. Until the structures in the brain that encode our memories and personality have been so obliterated that they cannot in principle be inferred and restored to a functional state, you are not dead. This information theoretic criterion of death is obviously much more difficult to meet than current legal or medical definitions, hence the belief that cryopreserved patients are not actually dead.

Michael Hendricks, Canada Research Chair in Neurobiology and Behaviour and Assistant Professor of Biology at McGill University and wrote "The False Science of Cryogenics" for the MIT Technology Review

If you mean people who have already had their brains, heads, or bodies cryogenically stored after death (or are doing so with current technology): no, they will never be revived. They are dead, and will remain dead forever. Will it ever be possible to store a dead person (or a dead person's brain) in such a way that they can be revived? Almost certainly not. Look at the world. The only good thing we still reliably do for future generations is get out of their way. Let's not take that away from them too... they will have their hands full with all the horrific problems we've left them because of our selfishness and greed. We shouldn't making them responsible for keeping our bodies cold, too.

These days a fair amount of scientific work is aimed at quantifying the benefits of various different approaches to exercise. The research here is an example of the type, and compares endurance training (aerobic activity) versus resistance training (to build strength). The authors looked at measures of telomerase activity and telomere length in white blood cells obtained from a few hundred volunteers who carried out different programs of training. Some groups showed greater gains than others.

This should not be taken as robust evidence for effects on aging, as firstly this is more an assessment of immune system activity than of the state of the body as a whole, and secondly telomere length is a truly terrible measure of aging. It correlates very poorly with aging in all but the largest groups. All this really tells us is that aerobic activity fires up the immune system more readily than resistance training. It is known that both aerobic and resistance exercise affect aging, and in different ways, but this study isn't the way to usefully quantify those influences.

Our DNA is organised into chromosomes in all the cells in our bodies. At the end of each chromosome is a repetitive DNA sequence, called a telomere, that caps the chromosome and protects its ends from deteriorating. As we grow older, the telomeres shorten and this is an important molecular mechanism for cell aging, which eventually leads to cell death when the telomere are no longer able to protect the chromosomal DNA. The process of telomere shortening is regulated by several proteins. Among them is the enzyme telomerase that is able to counteract the shortening process and can even add length to the telomeres.

Researchers enrolled 266 young, healthy but previously inactive volunteers and randomised them to six months of endurance training (continuous running), high intensity interval training (warm-up, followed by four bouts of high intensity running alternating with slower running, and then a final cool down of slower running), resistance training (circuit training on eight machines, including back extension, crunch, pulldown, seated rowing, seated leg curl and extension, seated chest press and lying leg press), or to an unchanged lifestyle (the control group).

The participants who were randomised to the three forms of exercise undertook three 45-minutes sessions a week, and a total of 124 completed the study. The researchers analysed telomere length and telomerase activity in white blood cells in blood taken from the volunteers at the start of the study, and two to seven days after the final bout of exercise six months later. Telomerase activity was increased two- to three-fold and telomere length was increased significantly in the endurance and high intensity training groups compared to the resistance and control groups.

Previous research has shown that longer telomeres and increased telomerase activity are associated with healthy aging. However, this is the first prospective, randomised controlled study of the effects of different forms of exercise on these two measurements of cellular aging. A possible mechanism that might explain why endurance and high intensity training could increase telomere length and telomerase activity is that these types of exercise affect levels of nitric oxide in the blood vessels, contributing to the changes in the cells.

Link: https://www.escardio.org/The-ESC/Press-Office/Press-releases/endurance-but-not-resistance-training-has-anti-aging-effects

This open access commentary notes the evidence to suggest that therapies based on raised levels of pyrophosphate in blood vessel walls to reduce age-related calcification. The mineralization of blood vessel walls through deposition of calcium, calcification, is one of the mechanisms that contributes to vascular stiffness with age. It impairs the ability of blood vessels to contract and relax as they should. This is a serious issue, as it breaks the feedback mechanisms that control blood pressure, leading to hypertension, vascular disease, and heart failure as heart muscle grows and weakens.

From my point of view, the work here is an excellent example of the wrong way to go about addressing the issues of aging. Researchers note that a process runs awry with aging, so they analyze the dysfunctional and normal operation of the process to find the proteins that regulate it. Then treatment involves finding ways to safely adjust levels of those proteins, overriding their state in older individuals to try to force the process to deliver better outcomes. As the last half century has demonstrated, it is possible to produce marginal, incremental gains at great expense and a high rate of failure via this strategy. The most impressive results involve methods of overriding our biology to reduce blood cholesterol, blood pressure, and inflammation.

But incremental results are all that can be achieved this way. It is a strategy that completely ignores the cause of the issue. Aging results from forms of cell and tissue damage, and then spirals out through a long and complex and poorly understood chain of consequences. Senescent cells - and the chronic, systemic inflammation that they produce - appear to bias cells in blood vessel walls towards deposition of calcium, for example. But senescent cells cause a wide range of other issues. Trying to override cell behavior in the narrow case of calcification while failing to remove senescent cells leaves those errant cells free to contribute to all of the other issues of aging. You can't force a damaged machine to function as though it were undamaged. There is no future in that approach to aging. The research community must look to causes and repair of damage rather than continuing this expensive, marginal, ultimately futile business of trying to override cell behavior, one tiny fraction of aging at a time.

Vascular calcification is associated with physiological aging and is characterized by the deposition of calcium-phosphate crystals in the aortic media and/or intima, usually as hydroxyapatite, the main component of bone. Vascular calcification reduces aortic and arterial compliance and elastance, hampering cardiovascular system function. It is linked to poor clinical outcomes and contributes to cardiovascular morbidity and mortality. Because tissue mineralization may occur at normal concentrations of calcium and phosphate, regulatory mechanisms exist to limit this process to bone and cartilage. Several endogenous inhibitors of vascular calcification have been identified, including the matrix Gla protein, fetuin A, osteopontin, and pyrophosphate.

Pyrophosphate is a potent inhibitor of calcium-phosphate crystal formation and growth. Vascular tissue mineralization occurs when the synthesis of vascular calcification inhibitors is impaired or when the formation of calcium-phosphate crystals is enhanced, for example, by hyperphosphatemia, the main risk factor for vascular calcification. Despite findings showing that hyperphosphatemia triggers vascular calcification, the effects of hyperphosphatemia on extracellular pyrophosphate metabolism remain unclear. A recent study investigated pyrophosphate metabolism in the context of phosphate-induced vascular calcification. It was found that calcification is a passive process that can be actively prevented by pyrophosphate.

The main conclusion of this new study was that high phosphate concentrations resulted in the increased synthesis of pyrophosphate over time. Moreover, the hydrolysis of pyrophosphate was found to decrease during early stages, but increase during later stages, of hyperphosphatemia. Although overall pyrophosphate production is higher during hyperphosphatemia, it was not sufficient to block calcium-phosphate deposition. A growing body of evidence suggests that pyrophosphate is the predominant endogenous inhibitor of vascular calcification. The results of this study, along with previous findings, suggest that induction of pyrophosphate synthesis may be an easy and effective therapeutic strategy to inhibit vascular calcification associated with aging and other pathological conditions.

Link: https://doi.org/10.18632/aging.101703

There are more than enough conferences focused on aging and the treatment of aging these days to collectively be called a conference circuit, I think. A researcher in the field of aging could find two or more scientific events every month to attend, and the business side of conference hosting is catching up. I had to give up noting every event of interest a number of years ago for the sake of space, and I know of at least one individual who provides a service to the community by maintaining what is becoming quite a lengthy calendar of conferences.

That there are more conferences rather than fewer conferences is a sign of health for the field. When people hold conferences, they do so because there is a sizable scientific or professional organization with the funds to spare, or because a for-profit conference host sees an opportunity to make a profit by providing a conference series as a service to the community. As a rough metric of growth, it is helpful. A field with twenty conferences in a year is better funded and moving more rapidly than one with two.

Today I'll point out a small selection of reports that cover conferences held earlier this year. While looking through these, consider that next year will start off much the same way. There is a good selection of longevity-related conferences and meetings early next year: Longevity Therapeutics, a number of other investor-focused events running alongside the big JP Morgan healthcare conference in San Francisco, the Longevity Leaders event in London, and of course Undoing Aging 2019 in Berlin at the end of the first quarter.

A Summary of the 5th Annual Aging and Drug Discovery Forum 2018

"Why do we age?"; "Can we intervene in the aging process?"; and if so, what approaches should aging science take to transform research into viable therapeutic interventions to improve public health? Understanding the mechanisms of aging will be of vital importance to answering these questions. However, several obstacles stand in the way of generating efficacious and safe interventions that extend the period of healthy life. At the 5th Annual Aging and Drug Discovery Forum which was held during the Basel Life Congress, Basel, Switzerland, September 12-13, 2018, leading aging experts from academia and industry came together to discuss top issues in aging research. Here, we provide a brief overview of the presented results and discussion points.

A Report from the 2018 International Society on Aging and Disease Conference

The International Society on Aging and Disease (ISOAD) recently held its third international conference in Nice, France, bringing together researchers - and longevity activists - from around the world. Prof. Gilson founded the Ircan Institute for Research on Cancer and Aging in Nice in 2012. "It was perhaps the first institute that specifically aimed to couple the themes of aging and cancer in the same laboratory, even if the links between them had been known to some extent. That was its originality. We've laid the foundations - to have the expertise, the right people, the right models - and I think we're going to have important answers for the role of telomeres in aging and, more generally, cellular senescence, which is the favorite current target of a lot of pharmaceutical or fundamental research that we are revisiting via our original models."

Thoughts on the 2018 Eurosymposium on Healthy Ageing

When I first learned about the possibility of achieving human rejuvenation through biotechnological means, little did I know that this would lead me to meet many of the central figures in the field during a conference some seven years later - let alone that I would be speaking at the very same event. Yet, I've had the privilege to attend the Fourth Eurosymposium on Healthy Ageing (EHA) held in Brussels on November 8-10, an experience that gave me a feel of just how real the prospect of human rejuvenation is. The first day of the conference was basically a journey into the world of cellular senescence: methods of targeting senescent cells, the SASP, drug delivery systems, and so forth; however, other topics, such as the extracellular matrix, transcriptomics, and stem cells, were also discussed. A great deal more researchers and other people otherwise involved in the community were present on the first morning than there were at the pre-conference meeting; the peak was probably during the second day, which saw a wider variety of topics, including genomics, DNA repair, bioinformatics, and the first panel of the conference.

These days, an ever larger fraction of the research community is waking to the idea that the effective treatment of age-related disease requires approaches that target the mechanisms of aging. This is a good thing, as it begins to narrow the scope of advocacy within the research community to the task of steering scientists towards better rather than worse ways of going about targeting the mechanisms of aging. It remains the case that most of the better supported lines of work related to aging are, in effect, very challenging ways to produce only small benefits at the end of the day - most researchers are working on methods of slightly slowing aging rather than methods of outright rejuvenation.

Attempts to develop calorie restriction mimetics or other therapies capable of upregulating stress responses and cellular maintenance processes are a good example of the type, and they are much on display in this open access paper (currently available in PDF format only), alongside other targets that, while not being root causes of aging, are thought of as being significant enough in the progression of disease to merit effort. While goals such as suppression of chronic inflammation and overriding the dysfunction of vascular cells are seductive, in the sense that many near-term approaches are viable, this sort of work still leaves the underlying causes of aging untouched, and is thus limited in the benefits it can provide.

Geroscience is a multidisciplinary field that examines the relationship between biological aging and age-related diseases. The Trans-NIH Geroscience Interest Group Summit discussed 7 processes that contribute to biological aging: macromolecular damage, epigenetic changes, inflammation, adaptation to stress, and impairments in proteostasis, stem cell regeneration, and metabolism. Intriguingly, these 7 processes are highly intertwined with one another. Thus, targeting the common biological processes of aging may be an effective approach to developing therapies to prevent or delay age-related diseases.

Biological aging is the leading risk factor for the major debilitating chronic diseases of old age that cause morbidity and mortality, including Alzheimer's disease (AD) and other dementias. Drugs that treat fundamental biological mechanisms of aging have been proposed to be useful for most prevalent chronic diseases of aging. In fact, many repurposed drugs are used to treat other age-related diseases. Despite over 75 years of accumulated research on biological aging, the current drug development pipeline is dominated by therapeutics targeting amyloid-β and tau, and there has been proportionately less translation of biological gerontology into our efforts to develop drugs for AD.

Nevertheless, aging biology provides numerous novel targets for new drug development for AD. Because of the multifaceted nature of biological aging, it is unlikely that drugs addressing a single target will be very successful in effectively treating AD. Nevertheless, single drug clinical trials may be needed to demonstrate incremental benefits, even if modest, before combination trials can be pursued. As interventions that target one aberrant system tend to also attenuate others, ultimately, combination therapies that target multiple age-related dysfunctions may produce synergistic activities.

Combination therapies are already the standard of care for other diseases of aging, including heart disease, cancers, and hypertension, and will likely be necessary in treating AD and other dementias. And because the same biological aging mechanisms underpin the common diseases of aging, repurposing drugs already on the market is a rational strategy for testing new therapies for AD and related dementias, including the sporadic forms of frontotemporal dementia and vascular dementia. Novel therapeutics for new and relevant targets will clearly also be needed.

In addition to combination therapies, addressing the multifaceted nature of the relationship between biological aging and AD with drugs possessing pleiotropic effects (simultaneously producing more than one effect) will be advantageous. Many effective drugs act on multiple targets while single-targeted approaches seldom progress to the final stages of clinical trials. For example, statins are widely used to lower cholesterol levels in patients with dyslipidemia, but statins also have pleiotropic effects that are independent of their effects on cholesterol, including improved endothelial function, inhibition of vascular inflammation, stabilization of atherosclerotic plaques, and immunomodulation. To effectively treat AD, pleiotropic drugs may need to hit the right nodes of relevant biological networks affected by aging such that they positively influence those networks and interconnected pathways.

Finally, a parsimonious approach to drug discovery and development with regard to translating knowledge from biological aging to AD is needed. For example, due to the plethora of misfolded proteins that accumulate with aging in the brain, biologics that attempt to address a single misfolded protein may be far less efficacious than drugs that enhance autophagy and clearance of all misfolded proteins. Similarly, age-related inflammation, vascular disease, epigenetic dysregulation, mitochondrial/metabolic dysfunction, and synaptic failure may be upstream causes of neuronal dysfunction and death leading to the classic pathologic hallmarks that have been historically among the first drug targets in AD. A better understanding and translation of the systemic, cellular, and molecular processes of biological aging that precede and increase vulnerability to AD will help identify new strategies and therapeutic targets for drug discovery and development.

Link: https://doi.org/10.1212/WNL.0000000000006745

Xenotransplantation from genetically engineered pigs to humans is one of the potential approaches that is hoped to provide an arbitrarily large supply of replacement organs. Whether or not this becomes a sizable industry depends on how long it takes for competing researchers to complete the alternative route of generating patient-matched new organs from cell samples. While the production of small functional organoids from patient samples is a going concern, the construction of entire organs continues to be held back by the inability to reliably generate the intricate blood vessel networks that are needed to supply large tissue sections. Not that xenotransplantation is without challenges, as this article illustrates. The problems are largely discovered by running into them, as researchers continue the process of testing transplants between pigs and baboons.

Even though humans can give their hearts to compatible persons with little more than a side of immunosuppressants, cross-species transplantation is not so straightforward. More than 60 percent of attempts to replace a baboon's heart with that of a pig ended in the recipients dying within two days. Two important developments pumped hope into the field over the past few years. First, researchers began using the gene-editing tool CRISPR-Cas9 to remove parts of the pig genome that might harm humans or provoke an immune response. Then in 2016 researchers took this further by showing baboons could survive with a genetically engineered pig heart implanted into their abdomens for nearly 1,000 days - if the baboon was on a certain cocktail of immunosuppressants.

For the new work researchers wanted to see if the same genetically engineered pig hearts and immunosuppressant regime could support the life of a baboon. But the first five animals in the new study did not live long. Three died of heart failure almost immediately. It turns out porcine hearts are more vulnerable compared to human hearts. During the period between removal from a pig and implantation into a baboon the heart will sustain damage similar to that caused by a heart attack. Human hearts can often recover from this damage, but the pig hearts could not.

So researchers tried something new with another group of baboons and repeatedly immersed the pig hearts in an experimental nutrient solution for a couple of hours. The researchers think this formulation, originally designed to help transport human hearts long distances, might have helped keep the pig hearts from deteriorating too much. These baboons hung on for about a month before dying - this time because the pig hearts began swelling inside the monkeys' chests, eventually squeezing against the rib cages and failing. "A pig grows to maturity within four months or so, but a baboon takes about 10 years to grow. So the pig heart was growing in the primate as if it was still in a pig. We were just astonished. Nobody had experienced this before - the heart grew like a tumor."

In the third group of baboons researchers added an immunosuppressant drug called temsirolimus, which could also stop the pig hearts' unwanted growth. With the exception of one baboon that died of mechanical heart failure 51 days after surgery, the transplant recipients in this group survived in good health until the researchers euthanized them at 90 or 180 days, an action required under the study protocol approved by officials. The study is invigorating xenotransplantation researchers who, after decades of sometimes dismal attempts, say human trials are finally in sight.

Link: https://www.scientificamerican.com/article/baboons-survive-for-half-a-year-after-heart-transplants-from-pigs/

Mitochondria are the evolved descendants of ancient symbiotic bacteria. They act as the power plants of the cell, responsible for providing chemical energy store molecules (adenosine triphosphate, ATP) that power cellular operations. Each cell contains a herd of mitochondria, replicating like bacteria and culled by quality control mechanisms when they become damaged and dysfunctional. As a legacy of their ancient bacterial origins, mitochondria contain copies of a small circular genome, the mitochondrial DNA. This genome encodes the few important genes necessary for mitochondrial structure and function that have not migrated to the cell nucleus over the course of evolution.

As is the case for all cellular mechanisms and structures, this intricate set of nested systems falls apart with aging. Mitochondria become ragged and dysfunctional throughout the body, their ability to generate ATP declines, and energy-hungry tissues like the brain and muscles suffer for it. Further, mitochondrial DNA becomes damaged by oxidative molecules, and in a small fraction of cases that damage produces mitochondria that are both malfunctioning and resistant to quality control. These broken mitochondria take over cells, making the cells themselves dysfunctional, leading to the mass export of harmful oxididative molecules into tissues and the bloodstream.

In this context, the number of copies of mitochondrial DNA found in cells, the copy number, has been shown to correlate to several measures of aging. To start with, the copy number declines with age. Further, the copy number is associated with telomere length, and more importantly with frailty and mortality risk. More interestingly, researchers have demonstrated that artificially forcing an increase in mitochondrial DNA copy number slows vascular aging in mice. Copy number isn't quite a count of mitochondria, or quite an assessment of mitochondrial function, it should be noted - mitochondria tend to promiscuously pass around their component parts, and any given mitochondrion might well have multiple copies of its genome. But it is at least loosely related.

It remains to be determined as to whether this all boils down to delivery of ATP, and the consequences of too little ATP for cells to function to their full capacity, or whether a broader and more indirect set of mechanisms are involved. Biology is enormously complex, and simplicity in any aspect of it is usually only an illusion. The reality always turns out to be more layered, confusing, and contradictory than we'd like it to be. The research noted here presents another correlation between health and mitochondrial copy number to add to those noted above, but firm answers to the questions raised still lie ahead.

Association of mitochondrial DNA copy number with self-rated health status

The role of the mitochondria has been receiving increasing attention in various health-related research supported by substantial evidence of a causative link between mitochondrial dysfunction and aging and health outcomes. Additionally, it is suggested that the link between inflammation and health conditions may be modulated by mitochondrial dysfunction. Since mitochondrial function is regulated by both the nuclear and mitochondrial genomes, it has been proposed that variation in mitochondrial DNA (mtDNA), an understudied human genome compared to the nuclear genome, may also play an important role in these health conditions.

Additionally, mtDNA mutations are accumulated over a lifetime with several risk factors associated with adverse outcomes, such as smoking exposure, leading to a faster accumulation rate. mtDNA copy number has been suggested to be a link between risk factors and health outcomes. For example, the association between smoking and lung cancer may be explained by changes in mtDNA copy numbers, due to increased oxidative stress and increased somatic mtDNA mutations caused by smoking, which leads to mitochondrial dysfunction.

In this study of 956 participants, we found that patients with higher mtDNA copy number in peripheral blood had better self-rated health independent of age. We also found that older patients had lower mtDNA copy numbers. Lastly, we found that men had lower mtDNA copy numbers than women. These findings are unique and differ from previous studies. These findings should continue to add to our understanding of the relationship of mtDNA copy number to self-rated health as well as the ongoing work on mtDNA and age and gender.

There has been limited previous work in determining the relationship between self-rated health and mtDNA copy number. In one previous study, 1067 combined peripheral blood samples were examined for such an association. The authors found a positive association between better self-rated health and higher mtDNA copy numbers. Our study provides further evidence of the relationship between lower self-rated health and lower mtDNA copy number.

In addition to this main finding, we found that older age was associated with lower mtDNA copy number. The relationship between age and mtDNA copy number depended upon the patient's sex. Previous studies, looking at different tissue types, also showed an age-related decline in mtDNA copy number, but the role of sex and mtDNA copy number differs in our study from previous studies. We found that men had a lower copy number than women. Biologically, the changes in the number of the mitochondria DNA with age may reflect an increase in both inflammation and oxidative stress. The oxidative stress from free radicals may be responsible for the aging process which is tied to the mitochondria.

The innate immune cells called macrophages are known to be important coordinators of regeneration, in addition to their role in protecting tissues from invading pathogens. In recent years, researchers have investigated the altered behavior of macrophages with aging, and linked this to a range of age-related conditions. In older individuals, macrophages are more likely to be inflammatory and aggressive rather than acting to assist tissue regeneration, and the consequence is a much reduced capacity for tissue maintenance.

If the methods by which macrophages act to induce greater regenerative activity on the part of other cell populations can be deciphered, boiled down to a set of signal molecules, then this may open the door to the development of comparatively straightforward therapies that incrementally enhance healing and tissue maintenance in older people. This doesn't address the underlying problems, the damage of aging that causes macrophages to behave badly, but the size of the effect may nonetheless be worth the cost of development.

For a child, recovering from a broken bone is typically a short-lived, albeit painful, convalescence. But for older adults, it can be a protracted and potentially life-threatening process. Researchers have previously shown that introducing bone marrow stem cells to a bone injury can expedite healing, but the exact process was unclear. Now, the same team believes it has pinpointed the "youth factor" introduced alongside bone marrow stem cells - it's the macrophage, a type of white blood cell, and the proteins it secretes that can have a rejuvenating effect on tissue.

After tissue injury, the body dispatches macrophages to areas of trauma, where they undergo functional changes to coordinate tissue repair. During fracture healing, macrophages are found at the fracture site. But when they're depleted, fractures will not heal effectively. Macrophage populations and characteristics can change with aging.

"We show that young macrophage cells produce factors that lead to bone formation, and when introduced in older mice, improves fracture healing. While macrophages are known to play a role in repair and regeneration, prior studies do not identify secreted factors responsible for the effect. Here we show that young macrophage cells play a role in the rejuvenation process, and injection of one of the factors produced by the young cells into a fracture in old mice rejuvenates the pace of repair. This suggests a new therapeutic approach to fracture rejuvenation."

Link: https://corporate.dukehealth.org/news-listing/scientists-identify-%E2%80%98youth-factor%E2%80%99-blood-cells-speeds-fracture-repair

Jeanne Calment is well known as the longest-lived person, with her age at death validated at 122 years. The data for supercentenarians, the exceptionally rare individuals who live to be 110 years of age or older, is very ragged. This is usually the case at the far outside end of a distribution, where the total number of data points is very low. It is usual to find outliers, but some people feel that Jeanne Calment is too much of an outlier given the other validated ages of death for supercentenarians. Only one other person lived to be 119, and no-one else is known to have made it past 117. The yearly mortality rates for supercentenarians appear to be 50% or greater, though it is hard to be exact given the very sparse data. The odds of finding people just a few years older diminish precipitously given that level of risk.

So what is more likely: that Jeanne Calment was the furthest outlier, or that the validation process was flawed, and she was in fact significantly younger? We would be very skeptical of anyone claiming to be 125. Should we be more skeptical of the existing claim of 122 years of age? This sort of discussion is an interesting one, as illustrated by the article here, but whether or not Jeanne Calment did die aged 122 will soon enough become of little importance to the world at large. With the advent of low cost rejuvenation therapies in the form of senolytic drugs, the environment of aging will change rapidly in the decade ahead. The use of these treatments will spread widely through the population. Other rejuvenation therapies will soon follow, amplifying the effects. Remaining life span in later life will be increasingly determined by technology and ever less by genetic resilience and chance.

If you open an article dedicated to supercentenarians, it is very likely that at its very beginning, you will see the name of Jeanne Calment, the oldest known person in the world, who is believed to have lived for up to 122 years. Jeanne is not merely a unique phenomenon from the point of view of statistics; over the years, she became a symbol of extraordinary human capacities. A couple of weeks ago a report shed new light on the case of Jeanne Calment. The main hypothesis of this independent investigation is that the person who we know as Jeanne Calment is actually her daughter, Yvonne, who took the place of her mother after her death in 1934 in order to help her family avoid heavy financial losses related to inheritance. The initiator of this independent investigation, Valery Novoselov, is convinced that Calment's case has to be revalidated.

Valery, you are currently involved in revalidating longevity records. What was your motivation to engage in these investigations in the first place?

My main focus of interest is people. I don't like to deal with animals, because I believe that due to evolutionary mechanisms, the processes of aging in different species are not homologous. So, I am only interested in analyzing human data with some practical application of the results. Back in 2016, I was curious how many centenarians there were in the Moscow region. The Department of Labor and Social Security and the Federal Agency of Statistics provided me with two absolutely different sets of data. The one from the agency gave me 4135 people aged 100 and older, and the Department of Labor gave me 735 people. 6-fold difference. The main idea here is this: too much variance of data is likely an indicator of errors. In centenarians, the possibility of error is the highest.

What was the starting point in the investigation of Jeanne Calment's case? What was the first thing that caused the initial skepticism?

In the last few years, there were many interesting articles on the survival curve of centenarians and supercentenarians. Despite their differing views on the survival plateaus of marginal age groups, the case of Jeanne Calment didn't fit into any of the refined math models behind their studies. If we imagine the curves of survival in these studies, Jeanne is a dot away from the main trend that they describe. One more reason for suspicion is how far from other longevity records her age is. All other supercentenarians are several years apart from them. Most longevity records are very close to one another. Whenever a new record is set, the person dies several days or several weeks later, very rarely several months later. However, we are never speaking about years apart, definitely not several years.

So, you started to check the data from this validation group?

I had many ideas at once. I am a geriatrician, and in my work, I rely on visual assessment a lot. My eyes were telling me that Jeanne didn't have the hallmarks of frailty that would correspond to her official age, such as the fact that unlike other supercentenarians, she was able to sit straight in her chair without others' help. I didn't see enough signs of dermal atrophy nor atrophy of subcutaneous tissue. As a first step, I decided to run a survey to see how people assessed Jeanne's age by comparing her photos and videos to the photos and videos of other supercentenarians. The participants (233 random people) were massively reducing her age by around 20-25 years compared to her official age on the date when this picture was taken. The more that we checked, the more that small inconsistencies, errors, and even signs of intentional fraud were revealed. After looking at all the data that we has managed to collect, including the known intentional destruction of the family archive, we developed a hypothesis that is now being checked. In 1934, there was a death in the Calment family. The official story is that in 1934, Jeanne had lost her only daughter, Yvonne. We think that in reality it was Jeanne who had died, aged almost 59, and her daughter took her name and personality.

It is nice to learn that the community is open to the idea of revalidation.

Indeed. However, I am asking myself why the revalidation was not initiated earlier, as the more you dig, the more questions arise. The main lesson of this is still to be learned, however. You see, the current buzz around longevity records can be easily distracting us from the goals that are truly important. I'd really want this story to be reduced to a revalidation by a qualified group of researchers and to an update of all corresponding books. In my view, it just does not deserve the hype. There was a mistake, we will correct it, and that is it. We will be seeing new longevity records again and again; it will never stop, because there is no proven limit of human healthspan and lifespan.

Link: https://www.leafscience.org/valery-novoselov-investigating-jeanne-calments-longevity-record/

Today I'll point out an open access paper in which the authors divide centenarians into two groups based on the degree of age-related dysfunction. They find that centenarians with comparatively lower levels of dysfunction also have longer telomere length and more telomerase activity in white blood cells taken from a blood sample. Further, aspects of their immune response that are not directly related to telomeres and telomerase also appear more capable.

In one sense this telomere length data is the expected result: telomere length is a measure of biological aging. When considered generally it is a measure of the burden of age-related molecular damage and consequent dysfunction, but when measured in white blood cells it is also to some degree a measure of the decline of the immune system. Less functional centenarians are clearly more physiologically aged than more functional centenarians, and therefore should exhibit shorter average telomere length.

On the other hand, telomere length in white blood cells is such a terrible measure of aging that finding no difference between the two groups would also be unsurprising. Over the years, a fair number of comparison studies have failed to find the expected differences in telomere length between study populations of differing health status. Telomere length as it is presently measured only reliably shows correlations with aging over very large study populations, averaging out the large short-term fluctuations resulting from health and environmental changes, and is certainly not much use as a marker for individual decision making in health matters.

Thus I would say that the more important data here is that directly relating to the immune response, rather than the telomere length results. The immune system is critical not just in defense against pathogens, but also in destroying errant and potentially harmful cells, as well as playing an important role in regeneration and tissue maintenance. When the immune system falters with age, declining into chronic inflammation and incapacity, a great many other functions decline with it.

Telomere length and telomerase activity in T cells are biomarkers of high-performing centenarians

It is generally recognized that the function of the immune system declines with increased age and one of the major immune changes is impaired T-cell responses upon antigen presentation/stimulation. Some "high-performing" centenarians (100+ years old) are remarkably successful in escaping, or largely postponing, major age-related diseases. However, the majority of centenarians ("low-performing") have experienced these pathologies and are forced to reside in long-term nursing facilities.

Previous studies have pooled all centenarians examining heterogeneous populations of resting/unstimulated peripheral blood mononuclear cells (PBMCs). T cells represent around 60% of PBMC and are in a quiescent state when unstimulated. However, upon stimulation, T cells rapidly divide and exhibit dramatic changes in gene expression. We have compared stimulated T-cell responses and identified a set of transcripts expressed in vitro that are dramatically different in high- vs. low-performing centenarians.

We have also identified several other measurements that are different between high- and low-performing centenarians: (a) The amount of proliferation following in vitro stimulation is dramatically greater in high-performing centenarians compared to 67- to 83-year-old controls and low-performing centenarians; (b) telomere length is greater in the high-performing centenarians; and (c) telomerase activity following stimulation is greater in the high-performing centenarians. In addition, we have validated a number of genes whose expression is directly related to telomere length and these are potential fundamental biomarkers of aging that may influence the risk and progression of multiple aging conditions.

Real progress in the defeat of cancer will emerge from mechanisms that are common to near all cancers. Given a signature, or a required mechanism, that appears universally in cancer, then it should be possible to craft a single form of treatment that can be applied to any cancer type. That the enormous and massively funded cancer research community has struggled to make progress towards the control of cancer in the present environment of revolutionary progress in the tools of biotechnology largely results from spending too much time and too many resources on technologies that are only narrowly applicable to certain types of cancer. There are hundreds of subtypes of cancer, and only so many research groups with the resources to spend the years needed to build a new therapy. A change of focus is required. Fortunately, a number of candidate mechanisms for means to control most or all forms of cancer do in fact exist, such as the fact that all cancer cells must abuse telomerase or alternative lengthening of telomeres in order to replicate without limit. There are initial signs of others, with the research here being an example of the type.

A quick and easy test to detect cancer from blood or biopsy tissue could eventually result in a new approach to patient diagnosis. Researches have discovered a unique DNA nanostructure that appears to be common to all cancers. Cancer is an extremely complicated and variable disease and different types of cancer have different signatures. It has been difficult to find a simple signature that was distinct from healthy cells and common to all cancers. "This unique nano-scaled DNA signature appeared in every type of breast cancer we examined, and in other forms of cancer including prostate, colorectal, and lymphoma. The levels and patterns of tiny molecules called methyl groups that decorate DNA are altered dramatically by cancer - these methyl groups are key for cells to control which genes are turned on and off. In healthy cells, these methyl groups are spread out across the genome, but the genomes of cancer cells are essentially barren except for intense clusters of methyl groups at very specific locations."

The team discovered that intense clusters of methyl groups placed in a solution caused cancer DNA fragments to fold into unique three-dimensional nanostructures that could easily be separated by sticking to solid surfaces such as gold. Cancer cells released their DNA into blood plasma when they died. "So we were very excited about an easy way of catching these circulating free cancer DNA signatures in blood. Discovering that cancerous DNA molecules formed entirely different 3D nanostructures from normal circulating DNA was a breakthrough that has enabled an entirely new approach to detect cancer non-invasively in any tissue type including blood. This led to the creation of inexpensive and portable detection devices." The new technology has proved to be up to 90 percent accurate in tests involving 200 human cancer samples and normal DNA.

Link: https://www.uq.edu.au/news/article/2018/12/nano-signature-discovery-could-revolutionise-cancer-diagnosis

An early stage clinical study has shown that mesenchymal stem cell transplants reduce measures of age-related frailty. The benefits occur most likely because chronic inflammation is a significant contribution to the state of frailty, and mesenchymal stem cell therapies are known to fairly reliably reduce inflammation for a period of at least some months. That may be long enough for tissues in an older patient to recover somewhat before they are again under siege. It is thought that this temporary abatement of inflammation is accomplished through signals delivered by the transplanted stem cells, changing the behavior of native cells, as very few of the stem cells survive for long.

This is all quite well documented in clinical practice, and mesenchymal stem cell transplants are widely available these days. Unfortunately, the principal challenge with this line of work is that "mesenchymal stem cell" is a very loose definition, and thus the cells used by one research team or clinic may well have little in common with others that go by the very same name. The outcome is unexplained variability in results; this part of the field is in desperate need of a great deal more standardization than has so far taken place.

Chronic diseases and degenerative conditions are strongly linked with the geriatric syndrome of frailty and account for a disproportionate percentage of the health care budget. Frailty increases the risk of falls, hospitalization, institutionalization, disability, and death. By definition, frailty syndrome is characterized by declines in lean body mass, strength, endurance, balance, gait speed, activity and energy levels, and organ physiologic reserve. Collectively, these changes lead to the loss of homeostasis and capability to withstand stressors and resulting vulnerabilities.

There is a strong link between frailty, inflammation, and the impaired ability to repair tissue injury due to decreases in endogenous stem cell production. Although exercise and nutritional supplementation provide benefit to frail patients, there are currently no specific therapies for frailty. Bone marrow-derived allogeneic mesenchymal stem cells (MSCs) provide therapeutic benefits in heart failure patients irrespective of age. MSCs contribute to cellular repair and tissue regeneration through their multilineage differentiation capacity, immunomodulatory, and anti-inflammatory effects, homing and migratory capacity to injury sites, and stimulatory effect on endogenous tissue progenitors. The advantages of using MSCs as a therapeutic strategy include standardization of isolation and culture expansion techniques and safety in allogeneic transplantation.

Based on this evidence, we performed a randomized, double-blinded, dose-finding study in elderly, frail individuals and showed that intravenously delivered allogeneic MSCs are safe and produce significant improvements in physical performance measures and inflammatory biomarkers. We thus propose that frailty can be treated and the link between frailty and chronic inflammation offers a potential therapeutic target, addressable by cell therapy.

Link: https://doi.org/10.3389/fnut.2018.00108

Today I'll point out a recent media article that comments on RAADfest 2018, held in San Diego earlier this year. I attended this year, and wrote up my own thoughts on the event shortly thereafter. The advent of the first working, low cost, narrow focus rejuvenation therapies in the form of senolytic drugs capable of selectively destroying senescent cells is causing a sizable, but slow, shift of alignment and focus in both the scientific community and the historically fraud-ridden "anti-aging" marketplace. RAADfest is where these two communities meet, which makes it an interesting study if you have some insight into the history of scientific (useful) and non-scientific (useless) efforts to do something about aging. The great market of junk and nonsense that exists under the banner of "anti-aging" now has a viable product to sell. Will the good chase out the bad? That is what happened to medicine in general, once science took hold, compressing the fraud and the magical thinking to the edges of the field where they reside today. We can hope that it will happen here too. To the extent that participants presently marketing junk truly desire the goal of control over aging, then they will stop selling junk and start selling senolytics.

The article below is an anthropological commentary rather than consideration of the science, which is symptomatic of an issue I have noted before. Non-technical folk arriving from outside our community really cannot tell the difference between the three broad categories of (a) irrelevant non-scientific junk, (b) scientific approaches that might plausibly slightly slow down the aging process, and (c) scientific approaches that might plausibly produce rejuvenation, and are thus the road to radical life extension and control over aging. These are important distinctions, and few if any journalists working in the mainstream of media are equipped to tell the difference. The various ways of slowing aging and reversing aging are pitched in similar ways by entrepreneurs and scientists, and the non-scientific garbage is cloaked in the guise of science by marketing groups who cherry-pick and outright lie about evidence. So we get anthropological commentaries from the media, which is the journalistic way of noting that there is something going on, but that the authors have no idea what it might be or how to assess it.

The Death of Death

Most of us grew up surrounded by normative clichés about our mortality: Life is short; death is the only constant; live each day like it's your last. What does it look like to live life as if there were no end - no such thing as burning out? More than 1,000 people, many of them adherents of the Scottsdale, Arizona-based immortalist group, People Unlimited, came to RAADfest to find out. The celebratory confab is organized by the Coalition for Radical Life Extension, a gaggle of fringe scientists, biotech start-ups, and immortality enthusiasts united in agreement that "the deathist paradigm" has to go, and that within most of our lifetimes, biological aging can be a thing of the past. In one way or another, each board member's career feeds off the advancement of age reversal science and the popularization of the immortalist ideology - be it via membership dues, supplement sales, or translating intrigue and research findings into investment funds.

For the most serious devotees, immortality-seeking is a full-time commitment to keeping abreast of the latest innovations - they speak of these "modalities" with the same reverence a Christian would of a blessing. A $250 billion industry of anti-aging products and services is there for the collection - and many of their offerings are for sale at RAADfest. An Australian named Ray Palmer was easing into his second hour hooked up to an IV coursing NAD+-replenishing fluid through his veins. The coenzyme's depletion is linked to aging and aging-related disease - a study re-upping the stuff in mice was found to make them livelier, more youthful, and more muscular. People at RAADfest were lined up to try it out. At the Stem Cell Institute booth, you could sign up for stem cell therapies delivered in Panama that, according to their purveyor, cured Mel Gibson's father of liver and kidney failure. A poster boy for the clinic, Hutton Gibson was wheelchair-bound when he came in and walking a month later, the audience was told.

If this all fails, there's the ultimate speculative investment: cryonic preservation. At the Alcor cryonics facility in Scottsdale, there are more than 160 preserved bodies. Another 1,200 are signed up to be put on ice and brought to the facility upon legal death, with most paying in advance via specialized life insurance policies. Bodies have been accumulating here since the 1970s, but none have been resurrected yet - the technology to do so doesn't exist, and no one knows if it ever will.

In recent years, the science moving through the research pipeline - much of it in mice - has shown potential in reversing cell senescence and aging-related damage, which, if effective in humans could, in theory, offer endless opportunities to turn back the clock. And perhaps, with the help of artificial intelligence, research into now-fringe therapies will be expedited to reach the gold standard of human clinical trials ever faster. Perhaps that data will be analyzed at warp speed, spurring FDA-approved drugs and driving prices down as they percolate into the mainstream, and, at long last, into the insurance policies of everyday folks. This is all a big maybe with no real time frame, but for people at RAADFest, it's less of a maybe now than they could have ever imagined.

Bill Faloon is a RAADfest fixture. The owner of Life Extension Foundation - the premier supplement retailer at RAADfest - is also a founder of the Florida-based Church of Perpetual Life. During one of many RAADfest talks, he pulled up a slide citing new research outlining the dangers of "zombie-like" senescent cells that spew harmful proteins, and the potential of senolytic drugs to curb the harm done - progress, but again, in mice. In an "Age Reversal Guide," Faloon outlined a recommended course of senolytics and ways to obtain them via one of his websites. The audience was grateful - but despite senolytics' promise, according to mainstream scientific protocol, such enthusiasm is wildly premature without results from placebo-controlled human trials.

Between the ages of 70 and 90, medical expenses for the elderly increase more than twofold. An American who reaches her 90s will command more than $25,000 per year on average in care costs, much of that going to nursing homes. While there's little debate that the enormous burden of aging is a hallmark of our time, it's mainly regarded as an inevitability by most people and by uber-cautious federal agencies that fund research and green-light drugs. People Unlimited may represent the outer reaches of optimism around age reversal, but it's "1,000 times closer to perfection" than the contrary: a perverse acceptance of a tragic status quo, said Aubrey de Grey. The pot-stirring English gerontologist credits himself with shifting the conversation around aging in the 90s, from slowing aging to actually reversing it. "When people say, 'Death gives meaning to life.' I mean. What. The. Fuck. What is that supposed to mean - you want your mother to get Alzheimer's?" De Grey is baffled by "the desperation to come up with fucked up crazy reasons to pretend that aging is some kind of blessing in disguise."

Does the adult heart contain a sizable population of dormant stem cells that can be roused to acts of regeneration in order to rebuild lost or damaged muscle? If this is the case, then regenerative treatments will be easier to construct, in the form of signaling to direct native stem cells. If not, then the road to such treatments is much less straightforward, requiring the delivery of cells capable of regeneration, as well as the instructions for those cells, or perhaps the conversion of scar tissue cells into heart muscle.

The research community is presently engaged in a debate of evidence and hypothesis over whether or not the claimed heart stem cell populations actually exist in adult individuals. This latest entry to this debate is a gloomy one, in which the researchers provide evidence for there to be no stem cells in the heart capable of regenerating heart muscle in response to damage.

Debates of this nature are actually fairly common in the field. Specific cell populations can be hard to isolate, and different groups may or may not be looking at the same cells as they argue with one another. One might look at the controversy over very small embryonic-like stem cells some years ago, for example. I hesitate to offer an opinion on the topic, save to note that firm answers will be established in the end - it is just a question of how long that takes.

During a myocardial infarction, commonly known as a heart attack, the blood supply to part of the heart muscle is cut off. As a consequence, part of the heart muscle dies. Most tissues of animals and humans contain stem cells that come to the rescue upon tissue damage: they rapidly produce large numbers of 'daughter cells' in order to replace lost tissue cells. For two decades researchers and clinicians have searched for cardiac stem cells, stem cells that should reside in the heart muscle and that could repair the heart muscle after a myocardial infarction. Multiple research groups have claimed the definitive identification of cardiac stem cells, yet none of these claims have held up.

To solve this debate, researchers focused on the broadest and most direct definition of stem cell function in the mouse heart: the ability of a cell to replace lost tissue by cell division. In the heart, this means that any cell that can produce new heart muscle cells after a heart attack would be termed a cardiac stem cell. The authors generated a 'cell-by-cell' map of all dividing cardiac cells before and after a myocardial infarction using advanced molecular and genetic technologies.

The study establishes that many types of cells divide upon damage of the heart, but that none of these are capable of generating new heart muscle. In fact, many of the 'false leads' of past studies can now be explained: cells that were previously named cardiac stem cells now turn out to produce blood vessels or immune cells, but never heart muscle. Thus, the sobering conclusion is drawn that heart stem cells do not exist. In other words, heart muscle that is lost due to a heart attack cannot be replaced. This finding - while disappointing - settles a long-standing controversy.

The authors make a second important observation. Connective tissue cells (also known as fibroblasts) that are intermingled with heart muscle cells respond vigorously to a myocardial infarction by undergoing multiple cell divisions. In doing so, they produce scar tissue that replaces the lost cardiac muscle. While this scar tissue contains no muscle and thus does not contribute to the pump function of the heart, the fibrotic scar 'holds together' the infarcted area. Indeed, when the formation of the scar tissue is blocked, the mice succumb to acute cardiac rupture. Thus, while scar formation is generally seen as a negative outcome of myocardial infarction, the authors stress the importance of the formation of scar tissue for maintaining the integrity of the heart.

Link: https://www.eurekalert.org/pub_releases/2018-12/hi-asc113018.php

This paper is a preprint, meaning it hasn't gone through peer review yet, so apply the appropriate multiple to its chances of containing significant errors. The authors outline evidence for the age-related accumulation of senescent cells to impair heart regeneration. I'd have to say that this is an expected outcome of cellular senescence, given what is presently known of senescent cells, and in particular the ways in which their potent mix of inflammatory signaling disrupts normal tissue function. Of course the scientific community still has to provide satisfactory proof for that to be the case for the heart specifically, and join the dots between the underlying mechanisms.

Since a number of senolytic therapies exist, treatments capable of selectively removing 25-50% of senescent cells from various tissues, it is the case that the best way to proceed in linking aspects of aging to cellular senescence is to destroy senescent cells and see what happens as a result. That is considerably faster and more efficient than purely investigative methods. The challenge here is that senolytic therapies clear senescent cells from most tissues, all tissues are affected in their own particular ways, and there are only so many researchers with the funding to carry out assessments. So while we'd all like to know how senolytics affect lymph nodes, or the stomach lining, or pick your favorite tissue type here, it will probably be a while before the research community works its way down the list to reach these line items.

Ageing is the greatest risk factor for many life-threatening disorders. Although long-term exposure to known cardiovascular risk factors strongly drives the development of cardiovascular pathologies, intrinsic cardiac aging is considered to highly influence the pathogenesis of heart disease. However, the fields of the biology of aging and cardiovascular disease have been studied separately, and only recently their intersection has begun to receive the appropriate attention.

Aging leads to increased cellular senescence in a number of tissues and work suggests senescent cell burden can be dramatically increased in various tissues and organs with chronological ageing or in models of progeria. Cellular senescence is associated with increased expression of the senescence biomarker, p16Ink4a (also known as Cdkn2a), impaired proliferation, and resistance to apoptosis. Senescent cells disrupt tissue structure and function because of the components they secrete, which act on adjacent as well as distant cells, causing fibrosis, inflammation, and a possible carcinogenic response. Indeed, senescent cells possess a senescence-associated secretory phenotype (SASP), consisting of pro-inflammatory cytokines, chemokines, and extracellular-matrix-degrading proteins, which have deleterious paracrine and systemic effects. Remarkably, even a relatively low abundance of senescent cells (10-15% in aged primates) is sufficient to cause tissue dysfunction.

Here we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease aged 32-86 years. In aged subjects (older than 74 years) over half of CPCs are senescent, unable to replicate, differentiate, regenerate, or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs senescent. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (using the INK-ATTAC model or wild-type mice treated with dasatinib and quercetin senolytics) in vivo activates resident CPCs and increased the number of small, proliferating cardiomyocytes. Thus therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and rejuvenate the regenerative capacity of the heart.

Link: https://doi.org/10.1101/397216

A little more than a decade has passed since the development of a simple cell reprogramming approach that reliably created pluripotent stem cells from ordinary somatic cells, known as induced pluripotent stem cells. These stem cells are very similar, near identical in fact, to the embryonic stem cells that were previously the only reliable source of cells capable of forming any cell type in the body. Arguably the most important aspect of induced pluripotency is not the promise of the ability to generate patient-matched cells for regenerative therapies and tissue engineering of replacement organs, but rather that it is a low cost, robust procedure. It is easily adopted by any laboratory capable of basic cell biology operations, without the requirement of any complicated new knowledge or techniques. It thus spread very rapidly, and many labs were working on further development within a year or two of the first paper published on the topic.

Nonetheless, the highly regulated (and thus enormously expensive) process of clinical development proceeds at its own slow pace, no matter the ease or difficulty of the underlying technology. Trials of regenerative therapies based on induced pluripotency are taking place, but only in recent years, and only a few of them. Beyond the regulatory burden, this is also a symptom of a broader hold-up in stem cell therapies in general, in that the cells transplanted by the vast majority of first generation therapies do not survive and engraft in large numbers. Benefits are transient, achieved through the signals provided by the transplanted cells, rather than any other work accomplished by those cells. The research community is in the midst of establishing techniques to ensure that stem cells survive and then behave correctly in patient tissues, to not only deliver beneficial signals for the long term, but also provide a supply of daughter somatic cells to help restore lost tissue function. This second phase of stem cell therapies will be far more beneficial than the first, once underway in earnest.

Increasing Number of iPS Cell Therapies Tested in Clinical Trials

In a surgical procedure last month, neurosurgeons implanted 2.4 million cells into the brain of a patient with Parkinson's disease. The cells - derived from peripheral blood cells of an anonymous donor - had been reprogrammed into induced pluripotent stem cells (iPSCs) and then into dopaminergic precursor cells, which researchers hope will boost dopamine levels and ameliorate the patient's symptoms. The procedure is the most recent attempt by clinicians to test whether iPSCs can treat disease. In recent years, scientists have launched several clinical studies to examine their efficacy in heart disease and macular degeneration of the eye. And others are exploring ways to turn the cells into treatments for everything from endometriosis to spinal cord injury.

So far, only a handful of patients have undergone iPSC-based treatments. In 2014, a woman with macular degeneration of the eye received a transplant of iPSC-based retinal cells derived from her own cells. The woman treated showed no apparent improvement in her vision, "but the safety of the iPSC-derived cells was confirmed." Last year, five patients were treated for the same eye condition with iPSC-derived retinal cells, which were taken from different donors. One of them patients developed a "serious," but non-life-threatening, reaction to the transplant, forcing doctors to remove it. More clinical studies are underway. Next year, heart surgeons plan to implant sheets of iPSC-derived cardiomyocytes into the hearts of three patients with heart disease, and other researchers hope to treat six more patients with Parkinson's disease by 2022. These are all in the earliest phases of testing.

By now, researchers have figured out how to coax iPSCs to grow into most known cell types. But to get these cells to take on the roles of mature cells in a new tissue environment is another issue. In the heart, for instance, researchers have found that new stem cells have to be electrically aligned with the other cells. How to integrate the new cells so they will survive in injured or diseased tissue is another question. "Do you need a special matrix, a gel, a patch, an organoid, to ensure the success of these cells long term? These challenges are faced in all the organs."

Another concern researchers have frequently raised are the immunosuppressive drugs that patients require if the iPSCs are derived from cells other than the patient's own. The patient with Parkinson's, for instance, will be on immunosuppressants for a year, possibly making the patient less able to fight off infections and cancer. But despite the risks, many researchers have opted to use allogeneic stem cells - those from a donor - foremost because the approach will save time, cost, and labor when the time comes to scale up such treatments for commercialization. The possibility to create "off the shelf" iPSC therapies has also attracted industry, not just academics. For instance, Cynata Therapeutics recently concluded a Phase I trial using iPSC-derived mesenchymal stem cells to treat graft-versus-host disease (GVHD). Conveniently, immune rejection isn't an issue with mesenchymal stem cells because they don't express the donor-specific antigens that trigger rejection.

Developing off-the-shelf treatments is also vastly more cost effective than maturing iPSC-derived cells for individual patients. Personalized T-cell immunotherapies, two of which have been recently FDA-approved, can nearly $500,000 per patient. This is one reason why several groups are developing banks of iPSCs that can be used to develop regenerative therapies at scale. For instance, the Japanese government decided to put around $250 million towards developing an iPSC stock for biomedical research. The donors from whom these cells are derived were carefully selected with immune compatibility in mind: the bank is designed to encompass a diverse set of commonly present human leukocyte antigen (HLA) types, so that they are broadly representative of the majority of the population.

There are multiple distinct mechanisms by which cells can generate the energy needed for operations. Since everything is connected to everything else inside a cell, these various mechanisms are also tied in to the regulation of cell behavior, such as whether or not cells are actively assisting in tissue regeneration. Thus ways to change the balance of energy generation in cells might be a viable path towards enhanced regeneration for damaged organs. Researchers here provide evidence for this approach to be useful in the kidney, at least in mice.

Researchers have discovered a pathway for enhancing the self-repair efforts of injured kidneys. This involves reprogramming the body's own metabolism in order to save damaged kidneys. Normally, a process called glycolysis converts glucose from food into energy, which is necessary for life to continue. But the new discovery shows that when tissue is injured, the body can switch the process into one of repair to damaged cells. Researchers found how to intensify the switching process, resulting in a cascade of tissue-repair molecules that successfully stopped progression of kidney disease in mice.

Normally, when cells break down fat, sugars, and proteins into glucose, the three substances are converted into intermediate products that move into the mitochondria, the powerhouse of cells, providing fuel for life. Things work very differently in injured tissues: in the kidneys for example, the body triggers a "Plan B," converting the glucose into new molecules that carry out cell repair instead. Researchers found that a protein called PKM2 controls whether fuel (glucose) is used to power the cell or shift into repair mode. Disabling PKM2 resulted in a significant increase in cell-repair and a concomitant decrease in energy-generation.

A key molecule in the process is nitric oxide (NO). It was already known that NO protects kidneys and other tissue. NO is the active ingredient in nitroglycerine used for addressing heart disease so it was assumed that NO worked by dilating blood vessels. But the research team found that NO attached to a critical molecule called Co-enzyme A - known as a metabolite - linked to the glycolysis and energy production. Co-enzyme A binds to and transports NO into many different proteins, including PKM2, "turning them off." This determines whether the kidney cells are using their pathways for energy or repair.

In addition to finding that adding NO to PKM2 activates repair, researchers found that a protein called AKR1A1 subsequently removes the NO from PKM2, re-activating a robust energy-generating process. This reversal, after healing is complete, allows glucose to be converted efficiently into fuel. When the research team disabled AKR1A1, the kidneys remained in repair mode and were highly protected from disease. Therefore, the goal is to develop drugs to inhibit PKM2 or AKR1A1.

Link: https://www.eurekalert.org/pub_releases/2018-11/cwru-rtb112818.php

Throughout the research community, scientists involved in the study of aging, inflammation, and various age-related diseases are retrofitting the present appreciation for senescent cells into their past work. Over the past few years, the scientific community has suddenly awoken to the fact that the accumulation of senescent cells is a significant cause of aging and age-related pathology. This sea change of opinions could, in principle, have happened at pretty much any time in the last 30 years, had resources been better directed within the aging research community. But prior to a decade ago next to nobody in the establishment hierarchy wanted to listen to or acknowledge the potential for treating aging as a medical condition, as a pathology with causes, despite the enormous amount of evidence for that position.

But now a different scientific culture has taken hold in the study of aging, bringing with it a newfound willingness to consider the treatment of aging. There is a new acceptance that aging has causes that can be addressed, and that the inflammatory signaling of senescent cells is one of those causes. Thus papers like the one noted here are starting to emerge, picking up on a prior finding and tying it to the biology of cellular senescence, now more widely appreciated. It may well turn out that a good fraction of approaches shown to modestly reduce chronic inflammation in aged animals will turn out to act by in some way dampening the signaling of senescent cells.

As a basis for therapy, suppressing that signaling while leaving the cells intact is far inferior to the senolytic therapies that selectively destroy those errant cells. Suppression is rarely complete, while destruction removes all issues. Examples such as the one below, compounds already widely used and extensively investigated, are very unlikely to be capable of producing large effect sizes in humans, but it is nonetheless interesting to watch this great rethinking of past data as it progresses.

Tocotrienols (T3) have been shown to represent a very important part of the vitamin E family. Experiments conducted in both mice and humans have shown potential health benefits from T3 supplementation, including a distinctive and effective anti-inflammatory activity. The anti-inflammatory activity of T3 has been also proposed as the main mechanism of action of T3 explaining the amelioration of conditions related to a diet-induced metabolic syndrome in rats. The anti-inflammatory activity of T3 has been also proposed to contribute to their protection against neurodegenerative diseases, including Alzheimer's disease (AD).

In this review, we summarize the broad range of anti-inflammatory effects of T3 on aging and the main age-related diseases with the aim to provide a common mechanistic rationale through which tocotrienols may exert their pro-longevity and pro-health action. In particular, we suggest that part of the anti-inflammatory effects of these natural compounds can be due to their modulation of the senescence-associated secretory phenotype (SASP) produced by senescent cells, where their accumulation in aging has been proposed as a key pathological mechanism in different age-related pathologies. T3 may act by a direct suppression of the SASP, mediated by inhibition of NF-kB and mTOR, or by removing the origin of the SASP through senolysis. As a consequence, many age-related pathologies connected with the SASP may be attenuated or prevented by T3 treatment.

Link: https://doi.org/10.1186/s12575-018-0087-4

Today's open access paper is a survey of the known ways in which the aged immune system contributes to disruption of function in the cardiovascular system. As the selected snippets illustrate, this is a relationship dominated by chronic inflammation. Raised and constant inflammation is characteristic of the systematic failure of the immune system in late life: it becomes both overactive and ineffective, and the consequent inflammation causes detrimental reactions in many important cell populations.

In the short term inflammation is useful, a necessary part of the response to infection and injury. When it runs without cease, however, the result is a loss of function in vital tissues - such as the vascular system - that ultimately proves fatal. For example, inflammation contributes to vascular stiffness by degrading the normal activities of smooth muscle cells. This causes hypertension, which in turn causes pressure damage to fragile tissue structures and accelerates the development of atherosclerosis. The combination of hypertension and atherosclerosis later results in the catastrophic rupture of a stroke or heart attack.

Thus repairing the contributing causes of immune aging is an important goal for our broader rejuvenation biotechnology community. If achieved, restoration of more youthful immune function will produce significant benefits, but it is by no means a simple task. It will require at least four distinct research and development programs. Firstly, replace the hematopoietic stem cell population in the bone marrow, responsible for generating immune cells, and dampen the harmful signaling that suppresses stem cell function in the old body. Secondly, restore the thymus to youthful size and function. The thymus is where T cells of the adaptive immune system mature, and its age-related atrophy greatly impacts the quality of the immune system. Thirdly, clear out the damaged and malfunctioning immune cells that accumulate over a lifetime, using some form of targeted cell-killing technology. Lastly restore the structure and function of the lymphatic system, used by immune cells to coordinate the immune response.

Inflammation-Accelerated Senescence and the Cardiovascular System: Mechanisms and Perspectives

The pro-inflammatory drive observed with senescence, already defined as inflammaging, and the phenomenon of immunosenescence, which indicates an age-related decline in several immune functions, are multifactorial events of the older age. Growing evidence indicates that these events realize a self-perpetuating condition that favors the development of acute and chronic age-related diseases, spanning from increased susceptibility to infections, to cardiovascular (CV) and neurological diseases. CV diseases (CVD), in particular, are a leading cause of death even at older ages.

Viral infections are one of the triggers to DNA damage response activation. Herpes viruses exploit this mechanism to benefit their replication, thus providing a significant contribution to the accumulation of senescent cells that, in turn, facilitates the development of chronic age-related diseases. As an example, in a cohort of 511 individuals aged ≥65 years who were followed up for 18 years, cytomegalovirus (CMV) infection showed an association with increased mortality, reduced life expectancy by a magnitude of about 3.7 years, and a near doubling of CV deaths.

Recent evidence indicates intestinal microbial imbalance, i.e., dysbiosis, as another trigger to secondary sustained inflammatory responses related to the development of chronic/autoimmune diseases and cancer. A key feature of gut microbial changes with age is the reduced biodiversity, with increase in pathobionts and decreased health-promoting bacteria, such as bifidobacteria. This unbalance at the advantage of pathogenic microbial communities disrupts a fine mechanism of mucosal barrier integrity, where fermentation of starches and dietary fibers normally contributes to the production of mucus and lipid metabolites, such as short-chain fatty acids (acetate, propionate, butyrate), which modulate apoptosis and inflammation.

Functional and anatomical CV consequences of inflammaging/immunosenescence involve endothelial dysfunction and arterial stiffness, the principal mediators of vascular damage that translates into hypertension and atherosclerosis, leading contributors to CVD. Endothelial dysfunction is an early marker of vascular aging. With aging, oxidative and nitrative stress, as well as disruption of basic metabolic pathways, contribute to endothelial dysfunction. Activation of vascular smooth muscle cells (VSMCs) following inflammatory stimuli determines their phenotypic transition from the contractile to the synthetic phenotype, which allows their migration from the vascular media to the intima and increases their capacity to generate extracellular matrix proteins, with consequent arterial wall thickening.

Inflammation-stimulated VSMCs can also transdifferentiate into an osteoblastic phenotype, enabling mineralization and calcium deposition in the arterial media, while the activation of matrix metalloproteinases determines degradation of elastin and collagen of the vessel wall. All these mechanisms contribute to the phenomenon of arterial stiffness.

Researchers here demonstrate that an antibiotic slows aging in nematode worms, providing evidence for it to work through a reduction in protein synthesis. Beyond a slowing of aging, one of the consequences of calorie restriction is exactly this lower level of protein synthesis, a feature that also appears in a number of other interventions shown to slow aging to some degree in short-lived species. Protein synthesis takes place in structures called ribosomes, and so one branch of the now quite diverse field of aging research that has grown from the investigation of calorie restriction is involved in attempting to understand how changes to ribosomal function can influence aging. The interesting part of the research noted here is thus more the ribosomes and less the antibiotic. Unfortunately, and as a general rule, attempts to replicate aspects of calorie restriction have a much smaller effect in humans than is the case in short-lived species. No significant form of rejuvenation should be expected to emerge from this sort of research.

Protein aggregation causes several progressive age-related brain diseases, including amyotrophic lateral sclerosis, Alzheimer's, Parkinson's, and prion disease. This study shows that minocycline prevents this build-up even in older animals with age-impaired stress-response pathways. The number of proteins in a cell is balanced by the rate of protein manufacture and disposal, called proteostasis. As we age, proteostasis becomes impaired. "It would be great if there were a way to enhance proteostasis and extend lifespan and health, by treating older people at the first sign of neurodegenerative symptoms or disease markers such as protein build-up. In this study, we investigated whether the antibiotic minocycline can reduce protein aggregation and extend lifespan in animals that already have impaired proteostasis."

The team first tested 21 different molecules known to extend lifespan in young and old Caenorhabditis elegans (C. elegans) worms. They found that all of these molecules prolonged the lives of young worms; however, the only drug that worked on the older worms was the minocycline. To find out why, the researchers treated young and old worms with either water or minocycline and then measured two proteins called α-synuclein and amyloid-β, which are known to build up in Parkinson's and Alzheimer's disease, respectively. Regardless of the worms' age, those treated with minocycline had reduced aggregation of both proteins as they grew older without even without the activation of stress responses.

The team next turned their attention to the mechanism behind this discovery. First, they looked at whether minocycline switches on stress-signalling proteins that are impaired in older worms, but they found the drug actually reduces their activity. Next, they studied whether it turns off the cell's protein-disposal processes, but this was not its mode of action either. When they used a chemical probe to see how minocycline affects the major protein-regulating molecules in the cell, it revealed that minocycline directly affects the protein-manufacturing machinery of the cell, known as the ribosome. This was true in worms, as well as mouse and human cells.

Finally, the team used worms with increased or decreased protein-manufacturing activity and studied how this altered the effect of minocycline on protein levels and lifespan. As predicted, in mutant worms where protein manufacturing was already decreased, they found that a lower dose of minocycline was needed to further reduce protein levels and extend lifespan. In worms where protein manufacturing was increased, the opposite was seen. This suggested that minocycline extends lifespan by controlling the rate of protein manufacturing at the ribosome.

Link: https://elifesciences.org/for-the-press/57d6122a/antibiotic-could-protect-against-neurodegenerative-diseases-during-aging

The inflammasome is an important piece of molecular machinery in the processes that initiate the inflammatory response, vital in protecting the body from pathogens and in recovery from injury, at least for so long as it only lasts for a short time. The inflammasome is also associated with a form of programmed cell death related to inflammation, known as pyroptosis, and with the oxidative stress that occurs with aging. Researchers here investigate the inflammasome in the context of inflammation in later life.

Unfortunately inflammation becomes chronic in old age, and the sweeping cellular changes of inflammation, optimized for short term operation, cause damage when constantly activated. This inflammation is a significant aspect of aging, seated somewhere in the middle of the long chains of cause and consequence that determine our aging biochemistry. It is produced by upstream molecular damage to cells and tissues, such as that leading to the accumulation of senescent cells and their inflammatory signals, and causes a wide range of downstream dysfunction and disruption.

Inflammation is a major factor in a myriad of diseases, and inflammaging is part of the normal process in an individual's life cycle. It has been previously shown that the inflammasome is a key contributor to the innate immune response seen in the aging population. We have previously shown that inflammasome signaling proteins are elevated in the brain of aged rats when compared to young. In this study, we extend these findings to show that NLRC4, caspase-1, ASC, and IL-18 are elevated in the cytosolic fraction of cortical lysates in the aged brain when compared to young. This suggests a role for the NLRC4 inflammasome in the innate immune response of the aging brain.

We have previously shown that the inflammasome-mediated cell death mechanism of pyroptosis occurs in cortical neurons. Here we show that pyroptosome formation as determined by oligomerization of the inflammasome adaptor protein ASC is evident in cortical and hippocampal lysates of the brain of aged mice when compared to young. These findings suggest that in the aging brain, there is a natural process of cell death that is in part mediated by the inflammasome, which is consistent with previous findings indicating that indeed in the aging brain there is a cell death process. Taken together, this highlights the potential for inflammasome-mediated naturally occurring cell death associated with inflammaging as a precursor to the development of neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease.

Most degenerative conditions are characterized by low-grade inflammation. Moreover, mitochondrial dysfunction is at the core of many diseases in addition to aging. The brain consumes about 20 to 25% of the body's total energy. Thus it is an organ that undergoes major metabolic demands. Most of this energy is spent in the process of neurotransmission and is spent by mitochondria. As we age, mitochondrial electron transport chain function declines, as the production of free radicals increases.

In this study, we show that ASC is elevated in the mitochondrial fraction of the cortex and hippocampus of aged mice when compared to young, consistent with previous reports indicating a role for mitochondria in inflammasome signaling. To further study the role of oxidative stress and the aging process as it pertains to inflammasome signaling, we obtained fibroblasts from a subject who donated his cells at three different ages (49, 52 and 64 years) and discovered that caspase-1 and ASC protein levels were higher at the oldest time-point analyzed than at the other two younger time-points. Moreover, the cells at 52 were more prone to cell death when subjected to oxidative stress when compared to the cells at 49. Thus, highlighting the vulnerability of cells to oxidative stress due to the aging process.

Importantly, when the inflammasome was inhibited with a caspase-1 inhibitor in these cells following oxidative stress, the amount of free radicals produced was decreased. In conclusion, this is the first report to show that pyroptotic cell death occurs in the aging brain and that the inflammasome can be a viable target to decrease the oxidative stress that occurs as a result of aging.

Link: https://doi.org/10.1186/s12950-018-0198-3