Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.
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- Open Longevity is Attempting the ICO Route for Fundraising
- Senolytic Therapies to Clear Senescent Cells will Transform the Field of Medicine for Age-Related Conditions
- Reduced Mitochondrial Fusion or Increased Fission Slows Aging in Flies
- A Link Between Mechanisms of Calorie Restriction and Ketogenesis
- More Evidence for Senescent Cell Signaling to be a Cause of Age-Related Fibrosis
- An Online Database of Biomarkers of Human Mortality
- Neuroimaging as a Biomarker of Aging
- Suggesting Partial Decellularization as a Way to Accelerate Lung Tissue Engineering
- Is the Gut Microbiome Relevant to Naked Mole-Rat Longevity?
- ANGPTL2 Accelerates Heart Disease Development
- Announcing the 2018 Undoing Aging Conference
- Quantifying the Benefits of Statins over the Long Term
- Gcn4 Slows Aging in Yeast via Reduced Protein Synthesis
- Oxidized Dopamine and Dysfunctional Lysosomes in Parkinson's Disease
- Microbial Theories of Alzheimer's Disease are Gaining Support
Open Longevity is Attempting the ICO Route for Fundraising
The Open Longevity group is a Russian non-profit volunteer organization that emerged from the Science for Life Extension Foundation community, and is working to organize responsible, open trials of potential therapies to address aspects of aging. They are a little too focused on tinkering with metabolism rather than repair of the damage that causes aging for my tastes, but each to their own. Based on recent news it seems they are going to try the Initial Coin Offering (ICO) path of fundraising for their ongoing efforts. It will be interesting to see how this goes, as just about anyone who has watched the frenzy over ICOs this past year has probably at some point wondered how to tap this flow of funding.
A few months ago I asked whether or not ICOs are a viable approach to pull funding into the field of longevity science. Here I mean in any capacity, whether that is running patient-paid clinical trials, conducting fundamental research, commercializing a senolytic drug candidate, and so forth. You should probably look back at that prior post for a brief overview of what an ICO is, how it relates to blockchain technologies such as Bitcoin and Ethereum, and why ICOs presently look like magical money fountains from some angles. Groups with very little credibility are raising tens of millions via this mechanism, bypassing traditional venture funding mechanisms. If they can do it, why not credible efforts in the field of rejuvenation research?
Following that post, a small group of us set up a mailing list to talk about the prospect (if you are knowledgeable regarding blockchain matters and have an interest in longevity science, let me know if you'd like an invite). We fairly quickly came to the conclusion that, magical money fountain or not, the only viable ICOs are those that promise some sort of network effect that, at least in theory, could increase coin value enormously given enough participation in that network. While it is entirely possible to run a Kickstarter-like project through an ICO, using a blockchain to track obligations, and allowing those obligations to be transferred, any sort of token that is at the end of the day exchanged for a product or service has a upper limit to its value. It is rather like a futures contract in nature. This is not interesting to the people pushing funds through the ICO ecosystem. They are looking for unlimited upside, in the same mindset as startup investors: this is true whether or not the ICOs in question are pump and dump schemes, failures waiting to happen in some other way, or actually legitimate ventures taking advantage of the opportunity to obtain funding without having to give up equity.
At this point we found ourselves a little stuck; if the goal is pull in some of the funds flowing through the ICO marketplace, then there must be a suitably attractive coin mechanism, one with network effects and upside. Yet there doesn't seem a good way to attach a suitably attractive coin mechanism to any of the potential near term ventures that our community might undertake. They all look, at best, like Kickstarter projects, or like equity fundraising, and at worst like traditional non-profit fundraising with no return on investment. Without that mechanism, the ICO marketplace will ignore any use of blockchain technologies, and so there is little point in trying to use them. It just complicates the usual process of fundraising, and that is not even to talk about the regulatory issues, which are evolving rapidly now that the SEC has taken an interest.
Has Open Longevity found a viable way forward by tying tokens to a voting mechanism in addition to Kickstarter-like forms of redemption? That is an open question, but we'll see how it goes. I'd suggest reading their white paper. Certainly, I wish them the best of luck in exploring this avenue: any group that pioneers a useful means of bringing more funding into our community has performed a useful service.
Open Longevity Project: a Scientific Approach to Conquer Aging
Open Longevity is organizing research of anti-aging therapies in humans by providing online advisory services. Their ultimate goal is to find and introduce effective methods of radical life extension into clinical practice. Therefore, the tokens are called YEAR. Mikhail Batin, the CEO of Open Longevity, states he is sure that effective ways to delay the onset of aging will be found - it is only a matter of time. He and his colleagues just want to accelerate the research.
The project consists of two parts: clinical trials and online service. Part of the funds raised through ICO will be spent on the first three studies: Longevity Diet-1 (a variant of a fasting mimicking diet); Alzheimer's disease therapy (vitamin B12) and atherosclerosis therapy (sartans + statins). One can even find documents for the first trial in progress, though just in Russian yet. As the trial is planned to be submitted to the NIH's Clinical Trials registry, the documents will be translated into English at some point. All the subsequent studies will later be also funded: life extension projects are expected to be submitted for voting on a general basis, voting will be conducted among all the YEAR token holders.
All clinical trials will be carried out in strict accordance with existing norms. Thus CROs (contract research organizations), laboratories, and clinical institutions that traditionally carry out similar research, will be involved. But the OL team is already talking about making all paperwork more automated. Another part of the funds will be spent on creating an online platform. By uploading biomedical data, users will be able to monitor their health and aging status in dynamics; receive recommendations from specialists and expert system based on AI; and also become volunteers in trials. The service will be accessible to everyone. But payment with YEAR tokens is promised to be more favorable than paying with fiat currencies due to 50% discount.
Open Longevity ICO
Open Longevity is a project that initiates, organizes, and guarantees openness of clinical trials of antiaging therapies. Two important components of our project are an online expert system, which interprets users' biomedical information in terms of aging biology, and new infrastructure for antiaging clinical trials. They are closely connected: the data obtained through trials is taken into account in the operations of the expert system, and the funds raised from users are spent on antiaging research.
At the first stage, the aim of which is the development of the platform and launching of the first trials, we will raise funds through our ICO. Our task is to build a self-sufficient system that will provide paid services to individuals but at the same time solve important problems for humanity on a noncommercial basis. We do not plan to protect our therapies with patents - our research results will be publicly available. We endeavor to direct patients' energy toward the fight against aging, and in our experience, our policy of openness attracts projects, funding, scientists, and volunteers to us.
One of the common concerns in the industry is that, once on the market, antiaging medicine will become available only to the elite. The openness of our project is a possible solution to this potential problem. Moreover, publishing final and intermediate results, as well as research protocols and all related materials, will give us the highest level of expertise. All clinical trials will be carried out in strict accordance with existing norms. We will prepare questionnaires, informed-consent forms, permissions of ethical committees, and brochures describing the design of our experiments. We will involve a CRO (contract research organization), laboratories, and clinical institutions that traditionally carry out similar research. We will include patients in a global movement to seek and test potential antiaging therapies that, once proven effective, will immediately become part of their own lives.
Senolytic Therapies to Clear Senescent Cells will Transform the Field of Medicine for Age-Related Conditions
A new paper published yesterday is perhaps the fourth in a recent series of similar commentaries and reviews from a variety of research groups involved in the study of senescent cells. Each declares in its own way that senolytic therapies, approaches capable of selectively destroying senescent cells in old tissues, are a development of great importance in aging research. Senolytics have the near-future potential to produce sweeping change and improvement in the treatment of age-related conditions. The degree to which removal of senescent cells is better than the vast majority of present day medicine is hard to overstate. Accumulation of senescent cells is one of the root causes of aging, and removing these cells is a form of rejuvenation, capable of partially turning back the progression of most of the common age-related medical conditions.
Senescent cells well illustrate the SENS view of aging as an accumulation of unrepaired damage, generated as a side-effect of the normal operation of metabolism. Senescent cells are generated in large numbers in our tissues, day in and day out, but near all are destroyed, either by their own programmed cell death mechanisms or by the immune system. A tiny, tiny fraction of these cells evade this fate, however, and linger. Senescent cells generate a range of signals - the senescence-associated secretory phenotype, SASP - that corrode nearby tissue structures, change surrounding cell behavior, and generate an inflammatory response in the immune system. This is all beneficial in the short term and in small numbers, and senescent cells play a temporary role in steering embryonic development, or in regeneration of wounds, or in suppression of potentially cancerous cells. The problem arises in the long term, as growing numbers of lingering senescent cells continually run their program of inflammation and corrosion.
In recent years, studies have definitively linked senescent cells to age-related fibrosis, a major cause of organ dysfunction, to the progression of inflammatory conditions such as osteoarthritis and atherosclerosis, to the failing function of lungs, and to a range of other measures of age-related decline. Removing senescent cells from old mice has been shown to partially reverse the progression of many of these conditions. Since the mechanisms of cellular senescence are very similar in mice and humans, the hope is that the benefits of senolytics in old people will be significant. Since human studies have commenced in a variety of venues, we will find out in the next few years just how transformative this new approach to the treatment of aging might be.
Researchers review the clinical potential of senolytic drugs on aging
Researchers are moving closer to realizing the clinical potential of drugs that have previously been shown to support healthy aging in animals. In a review article aging experts say that, if proven to be effective and safe in humans, these drugs could be "transformative" by preventing or delaying chronic conditions as a group instead of one at a time. The drugs being tested are called senolytic agents, because they target senescent cells. These are cells that have stopped dividing and secrete toxic chemicals that damage adjacent cells. Accumulation of senescent cells, which increases with age, is associated with chronic conditions, including diabetes, cardiovascular disease, most cancers, dementia, arthritis, osteoporosis, and frailty.
In a recent study researchers confirmed that the first senolytic drugs to be discovered effectively clear senescent cells while leaving normal cells unaffected. The study also describes a new screening platform for finding additional senolytic drugs that will more optimally target senescent cells. The platform, together with additional human cell assays, identified and confirmed a new category of senolytic drugs, which are called HSP90 inhibitors. The platform will help researchers quickly identify additional drugs that target aging processes, which he says will be useful as they move closer to clinical intervention. "We've moved rapidly in the last few years, and it's increasingly looking like senolytic drugs, including the recently discovered HSP90 inhibitors, are having an impact on a huge range of diseases. We will need to continue to test whether there are more optimal drugs or drug combinations to broaden the range of senescent cell types targeted."
As senolytic drugs and drug combinations are discovered, researchers then will need to test them in clinical trials. The review article, "The Clinical Potential of Senolytic Drugs," acknowledges the unique challenges of these trials in the field of aging, including the difficulty of testing long-term end points, such as life span and health span - the healthy, productive years of life. Outcomes such as effects on median or maximum lifespan cannot be tested feasibly in humans. That's why researchers are using new clinical trial paradigms, which include testing the effects of senolytic drugs on co-morbidity, accelerated aging like conditions, diseases with localized accumulation of senescent cells, potentially fatal diseases associated with senescent cell accumulation, age-related loss of physiological resilience, and frailty. The authors also call out a need for additional geriatricians with research training to lead future clinical trials.
The Clinical Potential of Senolytic Drugs
Chronological aging is the leading predictor of the major chronic diseases that account for the bulk of morbidity, mortality, and health costs worldwide. Furthermore, age-related chronic diseases, geriatric syndromes, and disabilities tend to cluster within individuals, leading to multimorbidity. These observations support the concept that fundamental aging processes not only cause aging phenotypes, but also predispose to chronic diseases and the geriatric syndromes. Thus, it has been predicted that therapeutically targeting these processes can delay, prevent, or alleviate age-related chronic diseases and disabilities as a group, instead of one at a time-the "geroscience hypothesis."
The biological processes that underlie aging phenotypes and are active at the nidus of most chronic diseases include chronic, low-grade, "sterile" (absence of known pathogens) inflammation; macromolecular and organelle dysfunction (e.g., changes in DNA, such as telomere erosion, unrepaired damage, mutations, polyploidy, proteins - e.g., aggregation, misfolding, autophagy - carbohydrates, lipids, or mitochondria); stem and progenitor cell dysfunction; and accumulation of senescent cells. These four processes are linked; that is, in general, interventions that target one process also attenuate the others. For example, DNA damage causes increased senescent cell burden and mitochondrial and stem or progenitor cell dysfunction. Conversely, reducing senescent cell burden can lead to less inflammation, less macromolecular dysregulation, and enhanced function of stem and progenitor cells.
To remove senescent cells pharmacologically from wild type animals, "senolytic" agents, including small molecules, peptides, and antibodies, are being developed. Since the article describing the first senolytic agents was published in 2015, progress in identifying additional senolytic agents and their effects has been rapid. In that first article, a hypothesis-driven senolytic agent discovery paradigm was implemented. Senescent cells are resistant to apoptosis, despite the SASP factors they release, which should trigger apoptosis. Indeed, pro-apoptotic pathways are up-regulated in senescent cells, yet these cells resist apoptosis. The hypothesis was therefore tested that senescent cells depend on pro-survival pathways to defend against their own pro-apoptotic signaling.
Using bioinformatic approaches based on the ribonucleic acid (RNA) and protein expression profiles of senescent cells, five senescent-cell anti-apoptotic pathways (SCAPs) were identified. That SCAPs are required for senescent cell viability was verified in RNA interference studies, in which levels of key proteins in these pathways were reduced. Through this approach, survival proteins were identified as the Achilles' heel of senescent cells. Knocking down expression of these proteins causes death of senescent but not nonsenescent cells. The SCAPs discovered so far have been used to identify putative senolytic targets.
The first senolytic agents discovered using this hypothesis-driven approach were dasatinib and quercetin. Ten months later, the third senolytic drug, navitoclax, a BCL-2 pro-survival pathway inhibitor, was reported. Since then, a growing number of senolytics have been reported. Yet more senolytics are in development, and additional potential SCAPs are being identified. The SCAPs required for senescent cell resistance to apoptosis vary according to cell type. The Achilles' heels, for example, of senescent human primary adipose progenitors differ from those of a senescent human endothelial cell strain, indicating that agents targeting a single SCAP may not eliminate all types of senescent cells. The senolytics that have been tested across a wide range of senescent cell types have all exhibited a degree of cell type specificity. For example, navitoclax is senolytic in a cell culture-acclimated human umbilical vein endothelial cell strain but is not effective against senescent primary human fat cell progenitors.
Senolytics do not have to be continuously present to exert their effect. Brief disruption of pro-survival pathways is adequate to kill senescent cells. Thus, senolytics can be effective when administered intermittently. For example, dasatinib and quercetin have an elimination half-life of a few hours, yet a single short course alleviates effects of radiation-induced senescent cell creation in vivo for at least 7 months. The frequency of senolytic treatment will depend on rates of senescent cell re-accumulation, which probably varies according to conditions that induce cellular senescence. Advantages of intermittent administration include less opportunity to develop side effects, the feasibility of administering senolytic drugs during periods of relatively good health, and less risk of off-target effects caused by continuous exposure to drugs. Another advantage of senolytics is that cell division-dependent drug resistance is unlikely to occur, because senescent cells do not divide and therefore cannot acquire advantageous mutations, unlike the situation in treating cancers or infectious agents.
The introduction of effective senolytics or other agents that target fundamental aging processes into clinical practice could be transformative. These drugs may be critical to increasing healthspan and delaying, preventing, or alleviating the multiple chronic diseases that account for the bulk of morbidity, mortality, and health costs in developed and developing societies. They could also delay or treat the geriatric syndromes, including sarcopenia, frailty, immobility, and cognitive impairment, as well as age-related loss of physiological resilience, in a way not imaginable until recently. These agents could transform geriatric medicine from being a discipline focused mainly on tertiary or quaternary prevention into one with important primary preventive options centered on a solid science foundation equivalent to, or even better than, that of other medical specialties.
Senolytics might prevent or delay chronic diseases as a group, instead of one at a time in presymptomatic or at-risk individuals. Furthermore, if what can be achieved in preclinical aging animal models can be achieved in humans, it may be feasible to alleviate dysfunction even in frail individuals with multiple comorbidities, a group that until recently was felt to be beyond the point of treatment other than palliative and supportive measures. Although considerable care must be taken, particularly until clinical trials are completed and the potential adverse effects of senolytic drugs are understood fully, it is conceivable that the rapidly emerging repertoire of senolytic agents might transform medicine as we know it.
Reduced Mitochondrial Fusion or Increased Fission Slows Aging in Flies
Researchers have demonstrated that shifting the balance between mitochondrial fusion and fission towards fission increases the life span of flies. The authors provide evidence to suggest that this is because greater fission enhances the operation of the quality control mechanisms of autophagy that clear away damaged mitochondria. This fits in with the wealth of studies that demonstrate modest increases in life span in a variety of species through enhanced autophagy, both of mitochondria and other damaged proteins and structures - better cellular repair and maintenance, in other words. Aging is a process of damage accumulation, and the more aggressively that cells clean up primary damage, the less of a chance that damage has to cause an accumulation of secondary and later effects.
Mitochondria are the evolved descendants of symbiotic bacteria, their presence an ancient and early development in the evolutionary tree of life. Every cell has a herd of hundreds of these structures, stripped of most of their original DNA, and integrated into the cell's quality control systems. Mitochondria divide like bacteria to make up their numbers, and when damaged are, in theory, destroyed by the processes of autophagy: tagged, wrapped, and dismantled by specialized machinery in the cell. Also like bacteria, mitochondria constantly split apart, fuse together, and promiscuously pass around copies of their molecular machinery.
Mitochondria are power plants, the last stage in the conversion of food into energy store molecules that a cell uses to power its operations. They are also generators of potentially damaging oxidative molecules, molecules that are also vital signals that trigger cell housekeeping and maintenance activities. Further, mitochondria play vital roles in a range of other portions of the cell life cycle, from replication to programmed cell death. All of this activity makes it hard to model or visualize in detail the progression of age-related damage in mitochondria, despite the overwhelming evidence for their importance in aging.
What little DNA mitochondria have left over is prone to damage, either because it has poor repair machinery in comparison to the cell nucleus, because it is right next door to the energy store creation mechanisms that produce damaging oxidative molecules as a byproduct, or because mitochondria replicate their DNA a lot more often than occurs for nuclear DNA. More dramatic forms of damage can block access to necessary proteins, turning off the most efficient energy store creation method, producing a mitochondrion that is both malfunctioning and more resistant to quality control efforts. Its descendants will very quickly take over the entire cell population, and the whole cell falls into a state of senescence or other dysfunction, exporting damaging molecules into the surrounding tissue. This is one of the root causes of aging. Researchers can see these cells after the fact, but observing and mapping the details of the process by which damaged mitochondria take over a cell in this way is yet to be achieved.
Fortunately, understanding exactly how this happens is not necessary in order to prevent it from happening. It doesn't matter how mitochondrial DNA is damaged or how damaged mitochondria overtake a cell if a supply missing proteins can be provided. Having a backup supply of the proteins encoded in mitochondria DNA bypasses all of the thorny questions and big unknowns, which is why it is the chosen strategy for the SENS rejuvenation research programs. The specific implementation involves allotopic expression, a gene therapy to place a mitochondrial gene into the cell nucleus, suitably adjusted such that the resulting protein is shipped back to mitochondria to be used. This has been demonstrated for three of the thirteen genes in recent years, one of which is the center of a commercial effort to repair inherited mitochondrial disease.
In this context, adjustments to mitochondrial dynamics of the sort demonstrated here look a lot like the quest for ways to mimic the response to exercise, the response to calorie restriction, or other favorable altered metabolic states. It is a shift of proportions and relative effectiveness of mechanisms, not a fix to the underlying problem. The potential upside of this sort of approach is typically not large - look at the survival curves in the paper here. This is noteworthy for producing those curves after a short treatment in middle age, rather than a life-long intervention, but it is still the case that it is a small effect in the grand scheme of things. Short-lived species such as flies have much greater plasticity of life span than long-lived species such as our own. In the few cases where effects can be compared fairly directly, adjustments of metabolic state that extend life significantly in worms, flies, and mice only add a few years at most to human life span.
Biologists slow aging, extend lifespan of fruit flies
In a study on middle-aged fruit flies, researchers substantially improved the animals' health while significantly slowing their aging. They believe the technique could eventually lead to a way to delay the onset of age-related diseases in humans. The approach focuses on mitochondria, the tiny power generators within cells that control the cells' growth and determine when they live and die. Mitochondria often become damaged with age, and as people grow older, those damaged mitochondria tend to accumulate in the brain, muscles and other organs. When cells can't eliminate the damaged mitochondria, those mitochondria can become toxic and contribute to a wide range of age-related diseases. Researchers found that as fruit flies reach middle age - about one month into their two-month lifespan - their mitochondria change from their original small, round shape. "We think the fact that the mitochondria become larger and elongated impairs the cell's ability to clear the damaged mitochondria. And our research suggests dysfunctional mitochondria accumulate with age, rather than being discarded."
The scientists removed the damaged mitochondria by breaking up enlarged mitochondria into smaller pieces - and that when they did, the flies became more active and more energetic and had more endurance. Following the treatment, female flies lived 20 percent longer than their typical lifespan, while males lived 12 percent longer, on average. The research highlights the importance of a protein called Drp1 in aging. At least in flies and mice, levels of Drp1 decline with age. To break apart the flies' mitochondria, researchers increased their levels of Drp1. This enabled the flies to discard the smaller, damaged mitochondria, leaving only healthy mitochondria. Drp1 levels were increased for one week starting when the flies were 30 days old.
Researchers further showed that the autophagy-related gene Atg1 also plays an essential role in turning back the clock on cellular aging. They did this by "turning off" the gene, rendering the flies' cells unable to eliminate the damaged mitochondria via autophagy. This proved that Atg1 is required to reap the procedure's anti-aging effects: While Drp1 breaks up enlarged mitochondria, the Atg1 gene is needed to dispose of the damaged ones. "We actually delayed age-related health decline. And seven days of intervention was sufficient to prolong their lives and enhance their health." One specific health problem the treatment addressed was the onset of leaky intestines, which previous research found commonly occurs about a week before fruit flies die. Subsequent research in other laboratories has determined that an increase in intestines' permeability is a hallmark of aging in worms, mice and monkeys. In this study, the condition was delayed after flies were given more Drp1.
In another part of the experiment, also involving middle-aged fruit flies, the scientists turned off a protein called Mfn that enables mitochondria to fuse together into larger pieces. Doing so also extended the flies' lives and improved their health. "You can either break up the mitochondria with Drp1 or prevent them from fusing by inactivating Mfn. Both have the same effect: making the mitochondria smaller and extending lifespan."
Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster
Mitochondrial dysfunction is a key hallmark of aging and has been linked to numerous age-onset pathologies. Therefore, identifying interventions that could improve mitochondrial homeostasis when targeted to aged animals would be highly desirable toward the goal of prolonging healthspan. A growing body of data support the idea that autophagy has an important anti-aging role. However, the relevant autophagic cargo in the context of aging remains elusive. Mitochondrial autophagy (mitophagy) is a type of cargo-specific autophagy, which mediates the removal of dysfunctional mitochondria. Recent studies in mammals, including humans, have reported an age-related decline in mitophagy. Moreover, impairment of mitophagy recapitulates the age-related accumulation of mitochondria in Caenorhabditis elegans. These findings suggest that the mitophagy pathway may represent a therapeutic target to counteract aging. However, a major unanswered question remains: why does mitophagy decline in aged animals?
Mitochondrial dynamics (fission and fusion) and mitophagy are closely related. Mitofusin (Mfn) proteins mediate fusion of the mitochondrial outer membrane, while mitochondrial fission, conversely, requires Dynamin-related protein 1 (Drp1). Several studies indicate that an important event preceding mitophagy is the Parkin-mediated turnover of Mfn leading to a shift in the balance of mitochondrial dynamics toward decreased fusion/increased fission. In yeast, the mitochondrial fission protein, Dnm1, homologous to Drp1, is required for certain forms of mitophagy. Together, these findings support the model that mitochondrial fission can promote the segregation of damaged mitochondria and facilitate their clearance by mitophagy. Critically, however, the interplay between mitochondrial dynamics and mitophagy during aging remains poorly understood, and the question of whether an increase in mitochondrial fission alone is sufficient to prolong lifespan and/or improve mitochondrial function in an aged animal has not been addressed.
Here, we show that inducing Drp1-mediated mitochondrial fission, in midlife, increases lifespan and improves multiple markers of health in aged Drosophila. Remarkably, we show that a transient induction of Drp1, for 7 days, in midlife is sufficient to prolong lifespan. Studying aging flight muscle, we find that a midlife shift toward a more elongated, less circular mitochondrial morphology is linked to the accumulation of dysfunctional mitochondria. Short-term, midlife Drp1 induction restores mitochondrial morphology to a youthful state, improves mitochondrial respiratory function and reduces mitochondrial reactive oxygen species (ROS) levels. Importantly, midlife Drp1 induction facilitates mitophagy and improves proteostasis in aged flies. Finally, we show that disruption of Atg1, a core autophagy gene, inhibits the anti-aging, prolongevity effects of midlife Drp1 induction. Our findings indicate that transient, midlife interventions that promote mitochondrial fission could delay the onset of frailty and mortality in aging mammals.
A Link Between Mechanisms of Calorie Restriction and Ketogenesis
Calorie restriction slows aging in most species and lineages tested to date, though the size of the effect on life span diminishes as species life span increases. Calorie restriction produces very similar short-term health benefits in humans and mice, but mice live as much as 40% longer as a result. We certainly do not. The necessary human studies have yet to run, but the consensus in the research community is that five years of additional life expectancy for calorie restricted humans is about as much as could be expected. The beneficial response to calorie restriction isn't just one mechanism under the hood, though increased autophagy appears to be an outsized contribution. Calorie restriction changes just about everything there is to be measured in cellular metabolism, shifting the behavior of many networks of linked genes and protein interactions. Given these networks, there are a range of other means of provoking some of the same effects. This is true for most aspects of cellular biochemistry: there is never only one way to produce change.
Among the alternative means to touch on some of the changes involved in calorie restriction are intermittent fasting without calorie deficit, protein restriction, such as low methionine diets, and carbohydrate restriction - the much-hyped ketogenic diet, which is the topic for today. All structured popular diets are much-hyped, of course, surrounded by a moat of nonsense and borderline fraudulent commerce. It has to be said that if people spent one hundredth of the effort they put into considerations of diet into useful medical research, we'd be a lot closer to solving the problem of degenerative aging and age-related disease. So much light and noise for so little gain. No alteration you can make to your eating habits will reliably let you live to see a century of life, and even those people with the best, most optimal diets are still decrepit and much harmed by age in later life. The degree of difference that can be made just isn't large enough to justify the investment.
I point out this sort of research because it is interesting, not because it is the road to large increases in healthy human longevity. Researchers are progressively uncovering the details of shared mechanisms touched upon by a wide variety of dietary interventions, exercise, and other environmental factors known to influence health. Under the hood just a few core clusters of cellular behaviors are responsible for steering the bulk of natural variations in the pace of aging within a given species. These natural variations in aging and in health are tools that can be used to learn more about the intricacies of mammalian biochemistry. That is the primary output of these research efforts: knowledge, not practical therapies. You, I, and anyone else can set forth today to obtain all of the potential benefits under examination here: just choose to exercise regularly and eat less, and while doing it give some thought to the myriad fascinating biochemical changes taking place throughout the body and brain. I think we all understand the scope of what is possible via these methods, and just how limited they are in comparison to the potential of the nascent industry of rejuvenation therapies, treatments such as senolytics that are based on damage repair rather than tinkering with the recreation of calorie restricted metabolic states.
Ketogenic diet improves healthspan and memory in aging mice
Eating a ketogenic diet - which is high fat, low protein, and low carbohydrates - ramps up the production of the ketone body beta-hydroxybutyrate acid (BHB). While small studies in humans with cognitive impairment have suggested that BHB could improve memory, this is the first study in aging mammals which details the positive effects of BHB on memory and lifespan. "We're looking for drug targets. The ultimate goal is to find a way for humans to benefit from BHBs without having to go on a restrictive diet."
Reserchers carefully designed three diets that were matched in every way except fat and carbohydrate content: a normal high-carbohydrate diet, a zero-carbohydrate ketogenic diet, and a high-fat, low-carbohydrate diet that was not ketogenic. Mice were fed the ketogenic diet intermittently to prevent them from becoming obese, starting at one year old - middle age for mice. The ketogenic diet-fed mice had a lower risk of dying as they aged from one to two years old, although their maximum lifespan was unchanged. Another group of mice underwent memory testing at both middle age (one year old) and old age (two years old). Mice that had been eating a ketogenic diet performed at least as well on memory tests at old age as they did at middle age, while mice eating the normal diet showed an expected age-associated decline. Mice who ate the ketogenic diet also explored more, and their improved memory was confirmed with another test a few months later.
"We were careful to have all of the mice eating a normal diet during the actual memory testing which suggests the effects of the ketogenic diet were lasting. Something changed in the brains of these mice to make them more resilient to the effects of age. Determining what this is, is the next step in the work. Looking at gene expression, the ketogenic diet suppressed the longevity-related TOR pathway and insulin signaling and up-regulated the fasting-related transcription factor PPAR-alpha, a master regulator that helps the body more efficiently metabolize fat. Exercise also creates ketone bodies - that may be one of the mechanisms why it shows such protective effects on brain function and on healthspan and lifespan."
Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice
BHB is a normal human metabolite that is synthesized in the liver from fat, and then circulates throughout the body as a glucose-sparing energy source. It is intrinsically produced during states such as intermittent fasting and dietary restriction (DR) that result in extended longevity, cognitive protection, cancer reduction, and immune rejuvenation. Recent work has elucidated an array of signaling functions of BHB that suggest that BHB might itself regulate inflammation and gene expression, with implications for health and longevity.
A ketogenic diet is one means to deliver high levels of BHB for a prolonged time outside of a fasting or exercise context. Ketogenic diets generally contain little or no carbohydrate and stimulate endogenous ketogenesis. We sought to test whether a ketogenic diet carefully matched to comparison diets could enhance the longevity and healthspan of normal mice, and to elucidate potential molecular mechanisms of such effects.
We show that long-term exposure to a ketogenic diet, fed every other week starting in middle age, reduces midlife mortality and preserves memory in aging C57BL/6 male mice. Similar feeding of a high-fat, low-carbohydrate non-ketogenic diet appeared to have an intermediate effect on mortality, but survival of this group could not be definitely distinguished from either the control or ketogenic diet groups. These results might be interpreted in the broader context of the health effects of DR and of segmental DR mimetics such as metformin and rapamycin, and suggest that one or more aspects of a ketogenic diet may similarly act as a segmental DR mimetic.
More Evidence for Senescent Cell Signaling to be a Cause of Age-Related Fibrosis
Regeneration and tissue maintenance are highly complex, regulated processes. Unfortunately, these processes run awry as the low-level molecular damage of aging increases over the years. Cells change their behavior, change the signals they produce, and one of the detrimental outcomes of these changes is fibrosis. This is the creation of scar-like collagen structures in place of the expected arrangement of cells and extracellular matrix. Since the fine details of that arrangement matter greatly to the correct function of organs, fibrosis is very harmful. It features prominently in the most common age-related diseases of the lungs, kidneys, liver, and heart, but can be found in other tissues as well.
With the explosion of interest in senescent cells as a cause of aging over the past few years, and a matching increase in funding for studies, research groups have been able to prove that the presence of lingering senescent cells is a significant cause of fibrosis. Senescent cells have an important transient role to play in wound healing and regeneration in general: in a perfect world some cells become senescent, their signals and their interaction with the immune system directs rapid and accurate reconstruction of tissue, and all of these temporary senescent cells then promptly self-destruct or are consumed by the immune cells called macrophages. Unfortunately this system starts to head downhill into disarray given a growing population of senescent cells that stick around for the long term. Their signals produce chronic inflammation, confuse the regulation of regeneration, and make matters worse in numerous other ways as well.
The open access paper noted here doesn't mention senescent cells at all, but it does focus on one of the proteins that both causes cells to become senescent and is also secreted by cells that have become senescent. The protein is called TGF-β1 and is one small part of the senescence-associated secretory phenotype, SASP, a range of molecules important to the short-term tasks carried out by senescent cells, but that cause disruption, damage, and ultimately organ failure when the number of lingering senescent cells grows large over the years. The authors of this paper show that TGF-β1 inhibition reduces fibrosis, a result that dovetails well with studies from the past few years that have demonstrated targeted removal of senescent cells to reduce fibrosis. All things consider, I think it should be taken as more evidence for the potential benefits of senolytic therapies that clear senescent cells from old tissues.
As a further matter of interest, note the comments on tissue stiffness in the paper. Where it occurs in blood vessels, this age-related change is a very important component of vascular aging and heart disease. Solid evidence for senescent cell removal to affect elasticity of tissues has so far only arrived for the lungs, and in mice, but the relevant mechanisms here are much the same in most tissue types. It is reasonable to be cautiously optimistic. If clearance of senescent cells does produce a significant reduction of vascular stiffening in humans, then that outcome is a very big deal. In that scenario, we should expect cardiovascular mortality to fall dramatically as senolytic therapies are deployed to the clinic.
Fibroblast-specific inhibition of TGF-β1 signaling attenuates lung and tumor fibrosis
Tissue fibrosis is a major cause of human morbidity and mortality worldwide. TGF-β1 signaling is a well-known driver of collagen expression and tissue accumulation important to wound repair. Exaggerated TGF-β1 signaling is also strongly implicated in numerous fibrotic diseases, including those involving liver, heart, and lung. For example, approximately 80% of the upregulated genes in lungs of patients with idiopathic pulmonary fibrosis are reported to be direct or indirect TGF-β1 target genes. Pathological collagen accumulation, and its promoting effects on tissue stiffness, are also strongly implicated in cancer progression. TGF-β1 signaling is both an initiator and a driver of tissue stiffness because accumulation of collagen and other matrix proteins promotes integrin-dependent latent TGF-β1 activation and further extracellular matrix deposition. Enhanced stiffness is thought to promote tumor cell β1 integrin activation, leading to more invasive tumor phenotypes and metastasis, consistent with the strong correlation of TGF-β1 signaling with poor cancer prognosis. For these and other reasons there has been much interest in TGF-β1 signaling as a therapeutic target.
Although attractive as a target, the critical roles of TGF-β1 in suppressing inflammation and epithelial proliferation give pause to the idea of global inhibition of TGF-β1 signaling. Indeed, systemic inhibition of TGF-β1 can lead to the development of squamous skin tumors and autoreactive immunity. In addition, chronic administration of several small-molecule inhibitors of TGF-β1 receptor (TβR) kinases has led to enhanced skin and colonic inflammation and abnormalities in cardiac valves. To minimize adverse consequences, an approach of blocking TGF-β1 activation in specific cell types using the unique pathway of αvβ6-dependent latent TGF-β1 activation has developed and is currently in clinical trial. But this integrin is primarily expressed in epithelia of lung, kidney, and skin. In an attempt to develop a more circumscribed inhibitor of TGF-β1 signaling centered on suppression of collagen accumulation, we undertook a high-throughput, image-based phenotypic screen of small molecules that could block TGF-β1-induced epithelial-mesenchymal transition (EMT) in vitro but not directly inhibit TβRI kinase itself.
We identified trihydroxyphenolic compounds as potent blockers of TGF-β1 responses. Remarkably, the functional effects of trihydroxyphenolics required the presence of active lysyl oxidase-like 2 (LOXL2), thereby limiting effects to fibroblasts or cancer cells, the major LOXL2 producers. This selectivity likely avoids the toxicities of long term general TGF-β1 inhibition in chronic disease processes such as fibrosis and cancer progression. Indeed, we have observed no adverse events in mice on the trihydroxyphenolic-rich diet for at least 6 months, including the absence of skin inflammation and discernible lesions in cardiac valves.
Mechanistic studies revealed that trihydroxyphenolics induce auto-oxidation of a LOXL2/3-specific lysine (K731) in a time-dependent reaction that irreversibly inhibits LOXL2 and converts the trihydrophenolic to a previously undescribed metabolite that directly inhibits TβRI kinase. Combined inhibition of LOXL2 and TβRI activities by trihydrophenolics resulted in potent blockade of pathological collagen accumulation in vivo without the toxicities associated with global inhibitors. These findings elucidate a therapeutic approach to attenuate fibrosis and the disease-promoting effects of tissue stiffness by specifically targeting TβRI kinase in LOXL2-expressing cells.
An Online Database of Biomarkers of Human Mortality
Researchers have recently published an online database of biomarkers of human mortality, covering all such measures published and replicated to date. Many of these are not much more than background noise for ongoing efforts to establish a biomarker of biological age that is accurate and reliable enough to be used to assess candidate rejuvenation therapies. For example, excess fat tissue correlates very well with mortality over even fairly small study populations, but this isn't useful if the goal is to measure degree of rejuvenation following treatment. Other biomarkers might be more helpful, and taken as a whole, a database of measures of this nature allows for an easier synthesis of what is presently known about aging and mortality. Here the link points to an open access paper rather than the database itself, but you should take a look at both.
Ultimately, I think that the forms of damage outlined in the SENS vision for rejuvenation therapies will become important biomarkers. For example, senescent cell presence. As therapies for clearance of senescent cells are still in the process of clinical development, it isn't yet possible to use senescent cell counts as a biomarker of aging. Nonetheless, starting with cellular senescence, the next decade or so will see a circular process of verifying various candidate rejuvenation therapies and candidate biomarkers of biological age against one another, step by step. At the end of the day, each type of damage repaired by an effective rejuvenation therapy must be accepted as a valid biomarker of aging in and of itself. That the treatment works is proof of relevance.
Mortality biomarkers are of great clinical and research interest. General clinical applications include identifying high-risk patient groups, prognosticating for individual patients, and helping healthcare providers decide among treatment options. Examples of very well-studied mortality biomarkers include blood pressure, cholesterol, and waist circumference, which have well-established relationships with mortality in various populations documented in dozens of studies, some with thousands or millions of participants. These traditional biomarkers have been joined in more recent years by many biomarkers utilizing modern assays, for example genome-wide methylation levels, cell-free DNA concentration, and leukocyte telomere length.
Biomarkers of human mortality are also centrally important to research on human aging, due largely to the long potential duration of prospective studies on human lifespan. This can be a tremendous obstacle both in terms of resources (i.e. money to support such lengthy trials) and delayed progress (i.e. each research result could take decades to obtain). Mortality biomarkers have solved similar problems in the past by providing surrogate endpoints for crucial clinical outcomes, facilitating studies that might otherwise have been prohibitively expensive or time consuming. Blood pressure and cholesterol are two of many markers that have played this role in the past, by facilitating cardiovascular research aimed at reducing morbidity and mortality. Such biomarkers have also gained clinical importance as surrogate markers in clinical practice, where treatments are often initiated with the explicit goal of changing a patient's biomarker value. While this approach has important potential drawbacks, it is certainly more practical for a patient to track how a new intervention affects her blood pressure or serum cholesterol, rather than how it affects her lifespan, which is unknown until death.
Abundant research on mortality biomarkers has resulted in numerous associations documented across hundreds of publications, generating an unwieldy collection of data that can be difficult for researchers or clinicians to interpret or use effectively. There have been no recent attempts to collate this data nor, to our knowledge, to provide tools for locating, organizing, or comparing data from relevant studies. In the present article, we describe an effort to facilitate a more comprehensive and effective approach to evaluating the literature in this area. We present MortalityPredictors.org, a manually curated, publicly accessible database housing published, statistically-significant relationships in humans between biomarkers and all-cause mortality in population-based or generally healthy samples. To our knowledge, this is the first publicly available resource to collect such information, and we hope it will encourage: 1) the allocation of resources to mortality biomarkers with the greatest potential for accurately predicting human all-cause mortality, 2) efforts to construct multi-biomarker models to further improve such accuracy, and 3) research on human aging and therapies that aim to slow aging or otherwise reduce mortality.
Neuroimaging as a Biomarker of Aging
In this open access paper, evidence is presented for neuroimaging to be the basis for a biomarker of aging that is as good as the best of present candidate DNA methylation biomarkers. This is most interesting, though I suspect that there might be a higher chance that it will prove unhelpful as a way to assess the quality and effectiveness of potential rejuvenation therapies. That process of assessment is the reason why there is at present a considerable interest in the development of biomarkers that reflect chronological or biological age. Today the only practical approach to assessing candidate rejuvenation therapies is to provide the treatment and then wait and see: this is prohibitively expensive in humans, and too expensive for most research groups even in mice. That expense - and the time required to run life span studies - is holding the field back. If potential approaches to rejuvenation could be assessed quickly, that new capability would considerably speed up the pace of progress.
Why do I think that there is a great risk that neuroimaging might fail to be helpful in assessing rejuvenation therapies? Because most of the present proposed candidate treatments will change cellular biochemistry, remove problem cells, or repair forms of cellular damage, but will not repair the secondary outcomes of aging in the brain, such as white matter hyperintensities and other outcomes of the structural failure of blood vessels. These therapies would be expected to alter DNA methylation patterns, however, which are most likely more a reaction to cellular dysfunction and low-level molecular damage than a reaction to larger-scale structural changes. Still, this is an opinion offered in absence of evidence; we shall see how things turn out.
The search for robust, reliable and valid biomarkers of the ageing process is a key goal for gerontological science. Such tools should enable the quantification of individual differences in underlying biological ageing. This could have great utility for mapping personalised ageing trajectories, for predicting risk of future age-related deterioration and disease and for evaluating potential treatments aimed at improving healthspan or even slowing ageing itself. Given the multi-faceted nature of biological ageing, numerous potential candidate biomarkers have been proposed. These can be anthropometric, physiological or blood-based; indexing immune function, epigenetic signatures, gene expression profiles, physical capacity or body composition. To improve on individual predictors of biological age, panels combining multiple markers have also been proposed. While many of these approaches are highly promising, the results have yet to be translated into clinical practice.
The criteria most commonly used for assessing the appropriateness of ageing biomarkers is how strongly they correlate with chronological age in healthy people. In addition, thanks to the increasing use of machine learning, the accuracy with which chronological age can be predicted using multivariate biological data is also a useful indicator of potential biomarker value. Aligned with this, an independent line of research has emerged from the field of neuroscience. Using neuroimaging data, principally magnetic resonance imaging (MRI) brain scans, chronological age can be predicted accurately in a machine-learning framework. This neuroimaging-derived brain-age model is based on data from over 2000 healthy adults and shows excellent test-retest reliability. This presents the intriguing possibility that in-vivo measurements of brain volume could be used as an alternative ageing biomarker.
It is well-known that ageing affects the brain, both in terms of outward behavioural changes and cognitive decline, alongside alterations to the brain's biophysical structure and cellular and molecular functioning. Using measures of brain volume derived from T1-weighted structural MRI, assumed to reflect grey and white matter atrophy, high levels of age prediction accuracy have been consistently achieved. For example, our work found a mean/median absolute error of age prediction of 4.2/3.4 years, with a correlation between age and brain-predicted age of r = 0.96. This is comparable to or better than leading biological age prediction models, for example using DNA methylation status (r = 0.96, median absolute error = 3.6 years) or a panel of blood chemistry markers (r = 0.91, mean absolute error = 5.6 years).
Given the published data on neuroimaging-derived brain-age, it is worth considering its qualification against a set of consensus ageing biomarker criteria. Paraphrasing from the American Federation for Aging Research recommendations, an ageing biomarker must: 1) Predict the rate of ageing (i.e., estimate where a person is in their total life span); 2) Measure a basic process that underlies ageing, not the effects of disease; 3) Be able to be tested repeatedly without causing harm; 4) Work in humans and laboratory animals. Based on the above evidence regarding prediction of survival, neuroimaging-derived brain-age meets criteria #1. Given the accuracy of age prediction and the fact that brain atrophy occurs in the context of non-pathological ageing, this satisfies criteria #2. As a non-invasive imaging technique, T1-weighted MRI meets criteria #3. Finally, the accuracy of this technique in non-human primates has been recently reported, suggesting that it appropriately meets criteria #4.
While perhaps the major caveat regarding the use of neuroimaging in this context is the cost and potential logistics, projects like the UK Biobank imaging study show that collecting neuroimaging data on an extremely large scale are becoming increasingly feasible. It is timely for a marriage of neuroscience and biogerontology, and approaches that combine the most complementary information on the ageing human body will have the greatest utility in developing effective ageing biomarkers.
Suggesting Partial Decellularization as a Way to Accelerate Lung Tissue Engineering
Progress towards the construction of entire organs is gated by the lack of a reliable way to produce sufficient vascular networks. Natural tissue comes equipped with hundreds of tiny capillaries passing through every cubic millimeter, and lacking this network means that engineered tissue can only be a few millimeters in thickness. One way to work around this problem in the near term is to use a donor organ, stripping it of all its cells in the process known as decellularization, leaving the extracellular matrix and its chemical cues to guide replacement cells. Even this isn't enough in cases where a suitable recipe for rebuilding the necessary structures with patient-matched cells has yet to be established. So here, researchers suggest an approach of partial decellularization: only remove the cells and structures that can presently be replaced, and go forward on that basis. Intriguingly, this might even be made to work in a living patient, replacing some types of tissue section by section in damaged or diseased lungs.
Lung transplantation - the only definitive treatment for patients with end-stage lung disease - remains limited by a severe shortage of donor organs such that only 20% of patients waiting for a donor lung undergo transplantation. Strategies aimed at increasing the number of transplantable lungs would have an immediate and profound impact. Tissue engineering strategies are currently under development to regenerate or replace injured lungs. Because of the extreme complexity of the lung, with its hierarchical three-dimensional architecture, diverse cellular composition, highly specialized extracellular matrix (ECM), and region-specific structure and function, bioengineering a functional lung is still an elusive goal. The lungs bioengineered by full decellularization and recellularization have shown a limited and temporary function, largely due to blood clotting and pulmonary edema, which have led to lung failure within a few hours following transplantation. To date, whole-organ engineering methods using lung grafts with denuded vascular networks have failed to produce functional grafts.
Given the essential need for intact and functional pulmonary vasculature, we developed an airway-specific approach to removing the pulmonary epithelium while preserving the surrounding cells, matrix, basement membrane, and vasculature. Previously established methods for decellularization of the entire organ were designed to remove both the epithelium and endothelium and could only be applied ex vivo. This study developed the first procedure for the removal of epithelium from the lung airway with the full preservation of vascular epithelium, which could be applied in vivo to treat diseases of lung epithelium. Whole lung scaffolds with an intact vascular network may also allow for recellularization using patient-specific cells and bioengineering of chimeric lungs for transplantation. In addition to the clinical potential, lung scaffolds lacking an intact epithelial layer but with functional vascular and interstitial compartments may also serve as a valuable physiological model for investigating (i) lung development, (ii) the etiology and pathogenesis of lung diseases involving pulmonary epithelium, (iii) acute lung injury and repair, and (iv) stem cell therapies.
Lung decellularization has resulted in substantial advances in lung bioengineering and the ability to create scaffolds for tissue engineering applications. We believe that our methodology can address some of the challenges that have slowed the progress in lung bioengineering by (i) preserving the vascular endothelium throughout the lung (from large vessels to capillaries) and (ii) targeting the removal of airway epithelium while maintaining structural and cellular components essential for lung repair. In summary, the creation of de-epithelialized whole lungs with functional vasculature may open new frontiers in lung bioengineering and regenerative medicine. Additionally, de-epithelialization could be applied to other organs with dual flow, such as the liver or kidney.
Is the Gut Microbiome Relevant to Naked Mole-Rat Longevity?
Naked mole-rats live something like nine times longer than similarly-sized rodent species, and appear near immune to cancer. As such they are one of the most studied species among researchers who investigate the comparative biology of aging. Finding the underlying reasons for such large differences may inform human medicine, particularly when it comes to cancer, though in the matter of aging in general there is every chance that this sort of research will be overtaken in relevance in the near term by efforts such as clearance of senescent cells that directly address the root causes of aging. In recent years, it has become clear that gut bacteria have a fair degree of influence over natural variations in longevity in any given mammalian species. It is thus reasonable to ask whether they play a role in naked mole-rat longevity, though it is hard to imagine that this could be a significant contribution in comparison to the cellular differences, which include resilient mitochondrial membrane composition, efficient ribosomes, and overpowered anti-cancer mechanisms.
The composition and functionality of complex and rich community of microbes living on the surfaces and cavities of the mammal's body, i.e. microbiota, is well known to be crucial for the health maintenance of the host. An extremely rich and diverse microbial ecosystem inhabits the gastrointestinal tract collectively named as gut microbiota. Studies on humans have demonstrated that the gut microbiota strongly impacts on the prevention of disorders and pathologies, such as obesity and metabolic syndrome, cardiovascular diseases, inflammatory bowel diseases, as well as several types of cancer. The gut microbiota can indeed influence the education and homeostasis of the immune system and metabolism, as well as brain functionality, with as yet unknown long-term effects on human health and lifespan.
The impact of the gut microbiota on human health is a topic of huge interest for the scientific community, as demonstrated by the ever-increasing amount of studies on the microbiological peculiarities of the human gut ecosystem within the context of different lifestyles, genetic backgrounds, or pathologies. It is a matter of fact that, by preserving the biological homeostasis of the human host, the gut microbiota has a role of primary importance in supporting human longevity. However, only few hypotheses on the mechanisms involved have been advanced. Longevity is a tricky trait to be studied in humans, because it is a rare event, with an incredible amount of confounding genetic, lifestyle, and clinical variables, both past and present. Still, the microbiota of human populations with extraordinary longevity rate is being investigated across geographical zones and interesting hypotheses on the role of the microbiome in health-maintenance during aging are being advanced.
In this scenario, the naked mole-rat might represent an extremely interesting model to study health and longevity, since, like for human beings, in naked mole rat the selection against aging is strongly reduced. This eusocial, subterranean mouse-sized mammal occupies underground mazes of sealed tunnels and lives a very long life in large colonies with only one breeding queen and few breeding males. The naked mole-rat shows few age-related degenerative changes, displays an elevated tolerance to oxidative stress, and its fibroblasts have shown resistance to heavy metals, DNA damaging agents, chemotherapeutics and other poisonous chemicals. Moreover, this mammals show remarkably small susceptibility to both spontaneous cancer and induced tumorigenesis. These features of the naked mole-rat are maintained throughout their long lifespan, making this rodent a putative animal example of impressively prolonged "healthspan".
Moreover, the within-colony low genetic diversity (possibly due to the high inbreeding rate), the climatologically stable underground habitats, and the constant diet (mainly tubers and other underground plant storage organs), make the naked mole-rat a unique model for studying the microbiota-host interaction, focusing on the ability of the gut microbes to contribute to health maintenance during aging. Here, we characterized the gut microbiota of the naked mole-rat by next generation sequencing, aiming at understanding of how the rodent´s gut microbiota profile aligns with human microbiome and that of other mammals.
We found that the naked mole-rat possesses a unique gut microbiome composition, which is the result of the host phylogeny and its peculiar ecology. This microbiome layout has many compositional and functional peculiarities - such as the propensity for an oxidative metabolism, an enhanced capacity to produce short-chain fatty acids and mono- and disaccharides, as well as the peculiar structure within Bacteroidetes, the high load and diversity of Spirochetaceae and the presence of Mogibacteriaceae - some of which are shared with gut microbial ecosystems considered as models of healthy aging, as well as metabolic and immune homeostasis. This might suggest a possible role of the gut microbiota as a universal contributor to mammalian health, which goes beyond the host phylogeny and ecology constrains, supporting health and longevity of the mammalian host.
ANGPTL2 Accelerates Heart Disease Development
Genetically engineered loss of ANGPTL2 has been shown to slow the progression of heart disease in mice. Lower levels of ANGPTL2 result from exercise, and higher levels are associated with greater age, greater amounts of visceral fat, and the presence of senescent cells, among other factors - all of which fits well with the range of known risk factors for heart disease. The more ANGPTL2 in circulation, the worse the outcome. This open access review paper covers what is presently known of ANGPTL2 and its role in metabolism and age-related cardiovascular disease: of interest given the past few years of research is that ANGPTL2 may be generated by senescent cells as a part of their harmful senescence-associated secretory phenotype.
Worldwide, the number of patients with heart disease is increasing as populations of elderly people expand. Of the heart diseases, cardiovascular disease (CVD) and heart failure (HF) are associated with adverse health outcomes that decrease a patient's well-being and productivity. Prevention of these conditions is desirable to promote healthy aging and improve patients' lifestyle. The pathologic basis of CVD is atherosclerosis caused by ectopic accumulation of cholesterol in vessel walls; thus advent of therapies aimed at reducing low-density lipoprotein (LDL)-cholesterol levels has succeeded in decreasing the number of CVD events. However, these events continue to occur, even in patients whose LDL-cholesterol levels have been lowered, indicating that the pathologies underlying CVD are highly complex.
Many of our previous studies have revealed that the expression and secretion of angiopoietin-like 2 (ANGPTL2) significantly increase in cells stressed by pathophysiologic stimuli such as hypoxia, reactive oxidative species, and pressure overload. ANGPTL2 expression also increases in cells undergoing senescence, suggesting that ANGPTL2 is a SASP factor. Moreover, excess ANGPTL2 signaling is pro-inflammatory in pathologic states and contributes to the development of aging-associated diseases such as CVD. Thus, to understand the mechanisms underlying these conditions, we focus our discussion here on the role of ANGPTL2 in CVD.
Obesity and associated metabolic diseases predispose individuals to coronary artery disease (CAD), the major common form of CVD. In terms of the mechanisms linking these conditions, accumulating evidence suggests that inflammatory changes in perivascular fat, which is distributed ubiquitously around arteries throughout the body, may have a direct role in promoting the pathogenesis of vascular diseases accelerated by obesity. Interestingly, in obesity, chronic inflammation occurs in both visceral and perivascular adipose tissues. In obese mice, the expression of ANGPTL2 is increased in perivascular adipose tissues surrounding the femoral artery at levels equivalent to those seen in visceral adipose tissues. In mice, we have undertaken adipose tissue transplantation experiments that show that adipose tissue-secreted ANGPTL2 accelerates vascular inflammation, pathologic vascular tissue remodeling and subsequent CVD development.
Moreover, atherosclerosis progression, including plaque instability, is associated with chronic vessel wall inflammation and is a risk factor for major CAD events. Therefore, therapies designed to inhibit chronic inflammation in vessel walls should slow atherosclerosis progression. Relevant to this, ANGPTL2 is abundantly expressed in vascular endothelial cells of CAD patients. ANGPTL2 expression in endothelial cells also significantly increases in subjects predisposed to atherosclerotic disease brought on by obesity or metabolic disturbances. As expected, increases in endothelial cell-derived ANGPTL2 expression in mice promote vascular inflammation and subsequent endothelial cell dysfunction and atherosclerosis development. Vascular inflammation, which underlies atherosclerotic disease, emerges from the interplay of different cell types, including endothelial cells, smooth muscle cells, and perivascular adipocytes as resident cells, and macrophages as infiltrating cells. Macrophage-secreted ANGPTL2 also accelerates atherosclerotic disease in mice. Thus, ANGPTL2-induced chronic inflammation predisposes individuals to atherosclerotic disease and to CAD development.
Cellular senescence is defined as cell cycle arrest as a means to counteract DNA damage induced by aging and various stressors. Accumulation of senescent cells in various tissues accelerates aging and disease development. A recent report using a transgenic approach in mice demonstrated that clearance of senescent cells delays several age-associated disorders, suggesting that senescent cells promote these conditions. Interestingly, it has been reported that endothelial cells derived from smokers and exhibiting oxidative stress-induced premature senescence show significantly increased ANGPTL2 expression. Moreover, senescent fibroblasts from patients with Werner syndrome (adult progeria) show abundant ANGPTL2 expression and increased expression of other SASP factors. We have also reported that ANGPTL2 expression significantly increases in the hearts of aged compared with young mice. Thus, ANGPTL2 may function as a senescence-associated secretory phenotype in several senescent cell types. If so, markedly increased circulating ANGPTL2 levels seen in patients with chronic aging-related diseases may reflect the accumulation of senescent cells in their organs.
Announcing the 2018 Undoing Aging Conference
The SENS Research Foundation and the Forever Healthy Foundation will be running a new conference on rejuvenation biotechnology in March 2018 in Berlin. This is good news; over the long term, conference series have a high return on investment when it comes to expanding the scope and influence of a field of scientific endeavor. Networking makes the world turn. Over the past few years, the SENS Research Foundation ran the Rejuvenation Biotechnology conferences in the US, bringing together academia and industry to help smooth the path for the transition of rejuvenation therapies from the laboratory to clinical development. Now that same approach will be applied to the European research and development communities.
Given the rapid growth in development of senolytic therapies to clear senescent cells, this is the time to point out that SENS advocates and organizations have been calling for more work on exactly this type of treatment for the past fifteen years - long before the current explosion of interest. It isn't an accident that senolytics are proving effective and very promising in animal studies: it is expected and rational based on (a) the view of aging as an accumulation of molecular damage, and (b) scientific evidence gathered in recent decades. It is of particular importance to broaden the realization that senolytics are not a single fortunate discovery, but one part of a larger scheme, one of numerous potential rejuvenation therapies that are all based on the same concept of damage repair as the best way to treat aging as a medical condition.
Senescent cells are a form of damage, present only in old tissues in any significant number, and removing them is a form of restoration. But beyond that there are a number of other therapies that will be just as important and just as beneficial once developed: cross-link clearance, preventing the consequences of mitochondrial DNA damage, clearance of amyloids and lipofuscin, and so forth. We have the opportunity to educate those newly arriving in our community because they have learned of senescent cell clearance, and show them that this is just one portion of a larger, logical plan for the reversal of aging, most of which still needs greater support and funding in order to progress.
Undoing Aging 2018 is focused on the cellular and molecular repair of age-related damage as the basis of therapies to bring aging under full medical control. The conference, a joint effort of SENS Research Foundation and Forever Healthy Foundation, provides a platform for the existing scientific community that already works on damage repair and, at the same time, offers interested scientists and students a first-hand understanding of the current state of this exciting new field of biomedical research.
Speakers will include leading researchers from around the world focused on topics including stem cells, senescent cells, immunotherapies, biomarkers and drug discovery. Aubrey de Grey, Chief Science Officer of the SENS Research Foundation, will be the scientific organizer for the conference. Undoing Aging 2018 is not only open to the scientific community but also welcomes all interested members of the broader Life Extension movement. The conference will also feature a student poster session showing the work of innovative undergraduate and graduate students in the field of damage repair.
"With the 2018 Undoing Aging Conference, SENS Research Foundation (SRF) resumes its series of conferences previously based in Cambridge. As we did from 2003 to 2013, we will host a scientific conference that will demonstrate the enormous strides currently being made in genuine rejuvenation biotechnologies. The lesson will be clear - the community is broad and deep, and its members see the potential for genuinely comprehensive approaches to the prevention of age-related disease. We're especially pleased that our partnership with Forever Healthy will bring this conference to the heart of the Berlin life sciences community for the first time."
"Forever Healthy is already a vanguard supporter of SRF research programs and rejuvenation biotechnology start-ups. We are now very excited to work with SRF on Undoing Aging 2018, the first conference for our organization. Forever Healthy has two key goals for this conference: To support the remarkable scientific community already working on repair of age related damage and to create an unique opportunity for the broader scientific world to experience that the possibility of bringing aging under complete, genuine medical control is realistic, achievable, and, indeed, beginning to happen."
Quantifying the Benefits of Statins over the Long Term
Statins work to reduce cardiovascular disease risk by reducing blood lipid levels. In the research here, the authors quantify the benefits that have been obtained through the use of this class of drug over the past few decades. This class of drug is broadly considered to be one of the more important contributions to the reduced rate of cardiovascular mortality over that span of time. The data here suggests that statins should be even more widely used than they are at present: there are incrementally greater gains that might be obtained.
The mechanism of cardiovascular damage influenced by statins is one in which lipids oxidized due to other mechanisms of aging drive the pace at which atherosclerosis progresses. Lowering overall lipid levels in the bloodstream also lowers the level of these problem damaged molecules, and so atherosclerosis is slowed. The logical step beyond this in order to produce much better classes of therapy, treatments capable of reversing this condition, is to remove the damaged lipids and their byproducts rather than just slow their impact. The SENS Research Foundation, for example, ran a program to uncover bacterial enzymes that might be modified to accomplish this task for 7-ketocholesterol. For now, however, the only available approaches involve improved ways to lower blood lipids, such as PCSK9 inhibitors. These should be better than statins, but still not as good as repairing the situation by specifically clearing damaged lipids.
Previous research has shown the benefit of statins for reducing high cholesterol and coronary heart disease risk amongst different patient populations. However, until now there has been no conclusive evidence from trials for current guidelines on statin usage for people with very high levels of low density lipoprotein (LDL) cholesterol (above 190mg/dL) and no established heart disease. After studying mortality over a 20-year period, researchers showed that 40mg daily of pravastatin, a relatively weak type of statin, reduced deaths from heart disease in participants by more than a quarter.
"For the first time, we show that statins reduce the risk of death in this specific group of people who appear largely healthy except for very high LDL levels. This legitimises current guidelines which recommend treating this population with statins." In addition, the findings challenge current approaches on treating younger patients with LDL elevations with a 'watch and wait' approach. Instead, even those with slightly elevated cholesterol are at higher long term risk of heart disease, and that the accumulation of modest LDL reductions over time will translate into large mortality benefits. "Our findings suggest that we should consider prescribing statins more readily for those with elevated cholesterol levels above 155 mg/dl and who also appear otherwise healthy."
This research follows on from a five-year 1995 study in which researchers observed the long-term effects of statins on patients involved in the West of Scotland Coronary Prevention Study (WOSCOPS) trial. The researchers took into account the original five-year study and followed the patients for a further 15 years. The WOSCOPS study provided the first conclusive evidence that treating high LDL in men with pravastatin for five years significantly reduces the risk of heart attack or death from heart disease compared with placebo. Statins were subsequently established as the standard treatment for primary prevention in people with elevated cholesterol levels.
Now, researchers have completed analyses of the 15-year follow up of 5,529 men, including 2,560 with LDL cholesterol above 190 mg/dL of the original 6,595, chosen because they had no evidence of heart disease at the beginning of the present study. Participants were aged 45-64 years. During the five-year initial trial they were given pravastatin or placebo. Once the trial ended the participants returned to their primary care physicians, and an additional 15-year period of follow-up ensued. The 5,529 men were split into two groups: those with 'elevated' LDL (between 155 and 190mg/dL) and those with 'very high' LDL (above 190mg/dL). The standard 'ideal' level of LDL for high risk patients is below 100mg/dL, but this varies depending on individual risk factors.
The researchers found that giving pravastatin to men with 'very high' LDL reduced twenty year mortality rates by 18 per cent. Statins also reduced the overall risk of death by coronary heart disease by 28 per cent, and reduced the risk of death by other cardiovascular disease by 25 per cent among those with very high LDL cholesterol. The 15-year follow up also meant the researchers could compare patients' original predicted risk of heart disease with actual observed risk. According to the risk equations for cardiovascular disease, 67 per cent of patients included in the WOSCOPS trial with LDL above 190mg/dL would have less than a 7.5 per cent risk of heart disease by year ten, and thus would not have been treated with statins based on that risk. However, the present study shows that in fact, this group actually had a 7.5 per cent risk by year five, meaning their ten year risk was 15 per cent. Following statin therapy, this group's ten year risk was reduced compared with those that were given placebo during the trial.
Gcn4 Slows Aging in Yeast via Reduced Protein Synthesis
Many methods of modestly slowing aging in laboratory species are accompanied by reduced rates of protein synthesis and higher levels of activity by cellular maintenance processes such as autophagy. The research noted here is one of a number of examples from recent years in which an intervention lowers the rate of protein synthesis and slows aging as a result. This is much more a tool to assist in mapping the details of metabolism and aging than it is the basis for any sort of practical therapy, however. The practice of calorie restriction lowers protein synthesis rates, and no attempt to mimic that has yet produced a practical treatment that is as reliably, effective, and free from side-effects as simply eating less. The scope of the possible results should also be apparent: no-one can reliably live to 100 just by eating less, and even if they make that far, they are still greatly impacted by the aging process. This is not the road to rejuvenation. Only repair of the forms of cell and tissue damage that cause aging, such as that addressed by the SENS research portfolio, can in principle achieve reversal of aging.
For about one hundred years it has been known that nutrient restriction and moderate stress can significantly prolong life. Researchers have now discovered how the transcription factor Gcn4, a protein that regulates the expression of many genes, extends the life of baker's yeast Saccharomyces cerevisiae. In various stress situations, the cells stimulate Gcn4 production which leads to reduced biosynthesis of new proteins and increased yeast lifespan.
It has long been known that protein synthesis - also known as translation - plays an important role in aging. Inhibition of protein synthesis, caused for example by reduced nutrient intake, can have a positive effect on the life expectancy of diverse organisms such as yeast, flies, worms, or fish. Reducing the ribosomes, the protein factories of the cell, can also considerably extend the lifespan of yeast cells. What these cellular stresses have in common is that they activate the production of Gcn4. However, how this protein promotes longevity has remained unclear.
The team exposed yeast cells to different stress conditions, measured their lifespan, protein synthesis rates and Gcn4 expression. "We observed that the level of the Gcn4 protein was positively correlated with the longevity of yeast cells. However, we wanted to understand why. We have now shown for the first time that it is the transcriptional suppression of genes that are important for cellular protein synthesis by Gcn4 that seems to account for its lifespan extension effect. As the translation machinery is limiting, the energy-intensive production of new proteins is overall dampened." From the yeast cell's point of view, this is an advantage: This enables them to live about 40 percent longer than usual.
The transcription factor Gcn4 is conserved in over 50 different organisms, including mammals, and it likely play a significant role in the aging of these organisms as well. The researchers will now investigate whether the mammalian homolog similarly slows aging and extends lifespan by regulating protein synthesis genes in response to nutrients and stress.
Oxidized Dopamine and Dysfunctional Lysosomes in Parkinson's Disease
This research improves on the established links between a few of the forms of molecular damage and cellular dysfunction that central to the SENS view of aging, at least in the case of Parkinson's disease. These are lysosomal failure, mitochondrial dysfunction, and the accumulation of damaged proteins that form solid deposits, alpha-synuclein in this case. All age-related diseases emerge from the various typs of root cause damage that causes aging, some more directly, some with more intervening layers of secondary failure and damage.
Parkinson's disease (PD) is the second most common neurodegenerative disorder, primarily caused by the death of dopamine-containing neurons in the substantia nigra, a region of the brain involved in motor control. While people naturally lose dopamine neurons as they age, patients with PD lose a much larger number of these neurons and the remaining cells are no longer able to compensate. Understanding how and why these neurons die is an important step in identifying treatments. While previous research indicated that the cellular mechanism behind the cell death involved the mitochondria and lysosomes, how these two pathways converge in dopamine neurons to cause cell death remained unknown up until now.
Using human neurons from Parkinson's patients, researchers identified a toxic cascade of mitochondrial and lysosomal dysfunction initiated by an accumulation of oxidized dopamine and a protein called alpha-synuclein. Specifically, the current study demonstrated that an accumulation of oxidized dopamine depressed the activity of lysosomal glucocerebrosidase (GCase), an enzyme implicated in PD. That depression in turn weakened overall lysosomal function and contributed to degeneration of neurons. The accretion of oxidized dopamine didn't just interfere with lysosomes, however. Researchers discovered that the dopamine also damaged the neurons' mitochondria by increasing mitochondrial oxidative stress. These dysfunctional mitochondria led to increased oxidized dopamine levels, creating a vicious cycle.
"The mitochondrial and lysosomal pathways are two critical pathways in disease development. Combined with the alpha-synuclein accumulation, this study links the major pathological features of PD. One of the key strategies that worked in our experiments is to treat dopamine neurons early in the toxic cascade with specific antioxidants that improve mitochondrial oxidative stress and lower oxidized dopamine. With this approach, we found that we can attenuate or prevent the downstream toxic effects in human dopaminergic neurons." Interestingly, when compared to human cellular models, mouse models of PD did not demonstrate the same toxic cascade. The researchers showed this is due to differences in metabolism of dopamine between species, and underscored the importance of studying human neurons to discover new targets for drug development.
Microbial Theories of Alzheimer's Disease are Gaining Support
The lack of concrete progress in the amyloid clearance approach to Alzheimer's disease, despite significant investment and many clinical trials over the past decade, has led to a great deal of theorizing in the research community. Is it that the dominant anti-amyloid strategy of immunotherapy is intrinsically challenging when applied to the brain at this point in the progress of medical biotechnology, or is it that amyloid is not the best target? In the SENS view of aging, amyloid accumulation is a primary difference between old and young tissue, and it should be removed. But Alzheimer's is a very complicated condition, involving multiple forms of altered protein aggregation, immune system issues, and other changes in cellular activity. There is plenty of room to advance novel interpretations of the order of causation, or the identification of new agents of causation, without denying that the presence of amyloid is a problem. Ultimately, the proof will lie in the effectiveness of therapies; those based on a correct model of the disease and targeted at the true root cause should in principle produce better outcomes for patients.
Researchers have recently proposed a novel role for biofilms - colonies of bacteria that adhere to surfaces and are largely resistant to immune attack or antibiotics - in eczema. It was suggested that because biofilms block skin ducts and trigger innate immune responses, they may cause the stubborn skin condition. Other recent work shows that Lyme spirochetes form biofilms, which led the researchers to wonder if biofilms might also play a role in Alzheimer's disease. When they stained for biofilms in brains from deceased Alzheimer's patients, he found them in the same hippocampal locations as amyloid plaques.
Spirochetes, common members of the oral microbiome, belong to a small set of microbes that cross the blood-brain barrier when they're circulating in the blood, as they are during active Lyme infections or after oral surgery. However, the bacteria are so slow to divide that it can take decades to grow a biofilm. This time line is consistent with Alzheimer's being a disease of old age, researchers reasons, and is corroborated by syphilis cases in which the neuroinvasive effects of spirochetes might appear as long as 50 years after primary infection.
Work on biofilms contributes to the revival of a long-standing hypothesis concerning the development of Alzheimer's. For 30 years, a handful of researchers have been pursuing the idea that pathogenic microbes may serve as triggers for the disease's neuropathology. Most came across the connection serendipitously, and some have made it their life's work, in spite of scathing criticism and related challenges in attracting funding and publishing results.
The Alzheimer's field seems primed for a fresh look at a theory that might account for the disease's pathogenesis. Researchers still cannot say with confidence which features of the disease, such as neuroinflammation, tau tangles, and amyloid plaques, are involved in disease progression and thus would make effective targets for treatment. So far, most drugs that have made it to clinical testing have targeted the amyloid-β peptide, the main component of the amyloid plaques that characterize Alzheimer's brains. The idea is that a build-up of amyloid-β causes the neuropathology and that removing amyloid-β - by decreasing its production, impeding aggregation, or aiding removal of the molecule from the brain - will improve, or at least stall, symptoms of dementia. But so far, researchers have come up empty-handed.
In light of continued failures to develop effective drugs, some researchers think it's high time that more effort and funding go into alternative theories of the disease. "Any hypothesis about Alzheimer's disease must include amyloid plaques, tangles, inflammation - and, I believe, infection." And, slowly but surely, Alzheimer's researchers finally seem to be giving the pathogen hypothesis a good, hard look. There remain more questions than answers at this point in terms of the causative factors in Alzheimer's, however. "The pathology is a mess. The brain has been diseased for a long time by the time we see it. We're looking at the end product and trying to determine how it got that way. Most of the resources in this field are spent on a few biomarkers. All the evidence shows that amyloid is important. But causality and centrality are two different things."