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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- An Update on Leukocyte Transfer Cancer Therapy Development
- This Giving Tuesday, Help to Bring an End to Age-Related Disease, Pain, and Death
- No Great Surprises in a Recent Study of Skin Aging
- An Example of a Pitfall in the Correlation of Excess Fat with Age-Related Disease
- Useful Tests for Self-Experimentation in Rejuvenation Therapies, those Not Requiring the Assistance of a Physician
- Skin Aging Correlates with Conductive Disorders in the Heart
- To What Degree can Vascular Stiffness be Reversed by Overriding Signaling Changes?
- Linking RAGE, DNA Damage, Cellular Senescence, and Reversible Fibrosis
- Expanding the "Don't Eat Me" Signal Blockade Approach to Killing Cancer Cells
- Researchers Demonstrate a Larger Heart Muscle Patch, but Generating Blood Vessels Remains a Challenge
- Aging and the Unfolded Protein Response in the Endoplasmic Reticulum
- There Will Be No Shortage of Geroprotector Drug Candidates
- Aubrey de Grey Summarizes Rejuvenation Research at the MIT Technology Review
- Pol III Inhibition Modestly Extends Life in Flies and Worms
- Sirtuin Research Continues Ever Onward in Search of Relevance
An Update on Leukocyte Transfer Cancer Therapy Development
LIFT, or GIFT, is an approach to cancer therapy that involves transplantation of suitably aggressive leukocyte or granulocyte immune cells. While cancers have numerous ways to suppress the native immune response, they can be vulnerable to foreign immune cells from a donor. Not all donors, but perhaps a few in a hundred on average will have immune cells capable of rapidly destroying a patient's cancer. In principle this approach should be able to target many different types of cancer, which is exactly what we need to see from the research community: more of broadly applicable approaches, and less of very specific cancer therapies. There are only so many researchers and far too many subtypes of cancer. If we are to see meaningful progress in the decades ahead, it must be through classes of treatment that can effectively tackle many different types of cancer, or even all cancers.
GIFT in its original incarnation performed very well in mice, but movement towards human trials has been painfully slow for all of the standard reasons: the regulatory system doesn't like it when a scientist can't explain the exact mechanisms by which a proposed therapy works; the immune system's interaction with cancer is enormously complex, making it expensive and time-consuming to establish any of the relevant mechanisms; it can take years for researchers to learn the ropes when it comes to starting companies and raising venturing funding; it usually takes years to make all of the connections needed; and so forth. GIFT was presented in one of the early SENS conferences, a decade ago, and that was some years in to the investigation. Nothing moves fast in medical research.
I last mentioned this line of research a good few years ago, and last year noted that it has been so long in the making that other research groups are independently recreating similar findings. Over the past couple of years in which I haven't been paying close attention, however, it seems the company LIfT Biosciences has been established, found its feet, and is moving ahead with development. By the sound of it they've made a number of technical advances needed in order to turn this research into a viable product. Congratulations are due to those involved for treading the long path to pass the first hurdles to commercial development; I look forward to seeing how this turns out in the years ahead.
Scientists for the first-time show cancer-killing activity of human neutrophils produced in the laboratory
Early-stage research has shown that cancer cells from a well-known human cancer cell line (HeLa cells) can be killed by human neutrophils (a type of innate immune cell) that have been produced in a laboratory rather than in the body. The research opens up the possibility of being able to give patients access to the kind of exceptional cancer killing abilities that the immune cells of some healthy people naturally have. The work means that LIfT BioSciences, the company behind the work, can now proceed with their mission to create the world's first cell bank of cancer killing immune cells that forms the basis for their potentially curative Leukocyte Infusion Therapy (LIfT).
The work was achieved in partnership with King's College London. Professor Farzin Farzaneh, who is leading the research at King's, commented, "I was initially sceptical about this when LIfT Biosciences approached us. It is something that I don't believe has been done before, and producing these specific cells with cancer killing ability is a notion we had not thought of before. We are excited by these early results and see the potential in LIfT BioSciences' approach for further work". LIfT BioSciences are partnered with King's College London by life sciences cluster organisation, MedCity, after being selected for their 'Collaborate to Innovate' programme.
The breakthrough in the production of cancer-killing immune cells in the laboratory means that LIfT BioSciences's special cells can now potentially be produced in very high volumes without the need for repeated blood donations. LIfT's Prof Zheng Cui discovered over a decade ago that certain individuals naturally have white blood cells with exceptional cancer-killing abilities, which can potentially be transfused into cancer patients. However, until now this was not logistically considered a realistic therapy for the global fight against cancer. Previously, to provide a sufficiently therapeutic volume of these cells would have required the screening of hundreds, or even thousands of donors in order to treat one patient. This new, patent pending invention potentially provides a viable, scalable, and safe method of producing a sufficient number of effective cancer-killing cells for treating cancer patients.
The breakthrough also firmly positions LIfT as a product therapy rather than a medical procedure which means accelerated access to market and patients. Further research to enhance the cancer-killing activity of these neutrophils will confirm the Advanced Therapeutic Medicinal Product (ATMP) status which was awarded to LIfT by the European Medicines Agency earlier this year.
This Giving Tuesday, Help to Bring an End to Age-Related Disease, Pain, and Death
It is Giving Tuesday once more, a time to look ahead and consider how we can improve the future of humanity through philanthropy: to join forces and fund the projects that will build a better tomorrow. A time to not just think about it, but to take action - to make a difference. Many of us believe that the most effective approach given the present human condition is to work towards bringing an end to aging, as the cell and tissue damage that causes aging is by far the greatest source of suffering and death in the world today. That damage can in principle be repaired, and there are now a number of non-profit organizations in our community working in various way to help advance the state of the art in rejuvenation research, from the SENS Research Foundation and Methuselah Foundation that fund research programs in laboratories and companies to the Life Extension Advocacy Foundation that works to raise awareness and enable crowdfunding of novel scientific projects.
Pick your cause and do something to help them move ahead today: do your part to make the world a better place. This year Fight Aging! supports the SENS Research Foundation, aiming to expand the research programs that have led to so much success and progress in past years. Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! have put together a 36,000 challenge fund, and we will match the next year of gifts for anyone who signs up as a SENS Patron by making monthly donations to the SENS Research Foundation. It's easy, just visit the donation page and get started! The SENS Research Foundation also accepts donations of stock and cryptocurrencies such as bitcoins and ether. All single donations made today, on Giving Tuesday, will be matched from a 20,000 challenge fund put up by the Foster Foundation. What better time than now? Help us to empty these challenge funds, and put that money to work in accelerating progress towards working rejuvenation therapies.
Additionally, we have new posters for you to share: spread them far and wide, to help make people outside our community stop and think a moment about their future and the possibility of treating aging as a medical condition. These new fundraising posters were generously provided by Ariel, Vladek, and team, who have also been translating a number of Fight Aging! posts into Russian these past few months on a volunteer basis. The modern longevity science community is spread across many more languages than it used to be, but it remains that case that all too much of our discussion and content is in the English language only. The more translation the better.
No Great Surprises in a Recent Study of Skin Aging
A recent study of skin aging brings no great surprises. The authors are focused on epigenetic changes that alter the rate of production of various proteins, and thus also alter the behavior and function of cells and tissues. People with younger-looking skin at a given chronological age also tend to have younger-looking patterns of gene expression, the process of generating proteins from their DNA blueprints. Aging is a global phenomenon, and progression of all of its aspects tend to correlate to some degree in any given individual. Among the more easily identified differences in the epigenetics of skin aging are those related to well-known processes of aging, such as cellular senescence.
The contributions to aging can be separated into primary (or intrinsic) and secondary (or extrinsic) sources, though the dividing line is far from clear-cut. Primary aging happens regardless of choice, side-effects of the normal operation of cellular metabolism that result in the accumulation of waste and molecular damage. Secondary aging is avoidable: the consequences of line items such as excess fat tissue, smoking, and in the case of skin excessive exposure to sunlight, or photoaging. Both primary and secondary aging operate through overlapping mechanisms. That is well illustrated here, in that the researchers find more markers of cellular senescence in skin that is more frequently exposed to sunlight. One can hypothesize about radiation damage to cell structures in this context, but the point is that secondary aging can and does work through the usual mechanisms more commonly associated with primary aging, such as those listed in the SENS rejuvenation research programs. The root causes inside the body are the same, but how those causes are triggered, and to what degree, can depend on circumstances.
The sort of research noted here does seems a little tautological at times, in that younger-looking people are younger-looking because they are physiologically younger. Younger gene expression is just another facet of being younger - it isn't a root cause, and isn't even a particularly satisfying explanation in many cases. All of the items measured in the study are downstream consequences of the actual internal root causes of aging, such as senescent cell accumulation or cross-linking in the extracellular matrix, and those root causes grow at a somewhat different pace in every individual. Some of that is happenstance, but the majority of it is due to lifestyle choices, at least until quite late in life when genetic resistance to high levels of damage becomes influential. Get fat, age more rapidly. Be sedentary, age more rapidly. Take up smoking, and age more rapidly. In the context of skin, sit around in the sun too much and age more rapidly.
Aging increases mortality rate, and exactly when death arrives is a roll of the dice. Some people die early, some people live for a few decades longer. These are small differences considered in the grand scheme of things, however. We should not care all that much about natural variations in human longevity that arise due to lifestyle and chance in the present environment. These differences are small in comparison to what might be achieved in the decades ahead through the implementation of rejuvenation therapies that repair and reverse the root causes of aging - so it is there that our attention should be focused.
Expression of Certain Genes May Be Key to More Youthful Looking Skin
Some individuals' skin appears more youthful than their chronologic age. New research indicates that increased expression of certain genes may be the key to intrinsically younger looking - and younger behaving - skin. "It's not just the genes you are born with, but which ones turn on and off over time. We found a wide range of processes in the skin affected by aging, and we discovered specific gene expression patterns in women who appear younger than their chronologic age."
To produce a comprehensive model of aging skin, researchers collected and integrated data at the molecular, cellular, and tissue levels from the sun-exposed skin (face and forearm) and sun-protected skin (buttocks) of 158 white women ages 20 to 74 years. As part of the study, the team looked for gene expression patterns common in women who appeared years younger than their chronologic age. The physical appearance of facial skin was captured through digital images and analysis. Skin samples were processed for analysis and saliva samples were collected for genotyping. The analyses revealed progressive changes from the 20s to the 70s in pathways related to oxidative stress, energy metabolism, cellular senescence, and skin barrier. These changes were accelerated in the 60s and 70s. Comparing sun-exposed and sun-protected skin samples revealed that certain genetic changes are likely due to photoaging.
The gene expression patterns from the women in the study who were younger appearing were similar to those in women who were actually younger in age. These women had increased activity in genes associated with basic biologic processes, including DNA repair, cell replication, response to oxidative stress, and protein metabolism. Women with exceptionally youthful-appearing facial skin in older age groups also had higher expression of genes associated with mitochondrial structure and metabolism, overall epidermal structure, and barrier function in their facial epidermal samples, as well as dermal matrix production.
Age-induced and photoinduced changes in gene expression profiles in facial skin of Caucasian females across 6 decades of age
Gene expression and ontology analysis of photoexposed and photoprotected skin samples in Caucasian women across 6 decades revealed progressive, age-related changes from their 20s to their 70s. All these aging processes accelerated in the 60s and 70s, co-occurring with menopause. Histologic elastosis was apparent in photoexposed sites (face and dorsal forearm) beginning in the 40-year-old cohort, suggesting that earlier molecular processes are important precursors to what later becomes histologically and clinically apparent changes in skin appearance. The results demonstrate that younger-looking skin in older cohort groups shows gene expression patterns that mimic chronologically younger skin on a molecular level. This finding offers the potential for future inquiry into biologic factors that slow evolution of aging processes.
Genes related to DNA repair and replication, cell growth and survival, chromatin remodeling, response to oxidative stress, autophagy, and protein metabolism are expressed differently in youthful skin than in older-appearing skin. In addition, epidermal structure and barrier, as well as dermal matrix, are also better maintained in youthful-appearing skin, with increased expression of genes such as CDH1, DSC3, and LAMA5 likely contributing. CDH1 and DSC3 are components of cell-cell junctions in the epidermis, and LAMA5 is essential for attachment of keratinocytes to the basement membrane. Expression of these three genes was significantly increased in youthful-appearing skin, intermediate in average-appearing skin, and decreased in older-appearing skin.
In addition, dermal genes associated primarily with extracellular matrix structure were differentially expressed depending on appearance of the facial skin. Genes associated with cellular metabolism also decreased more markedly with age in the epidermis of older- than younger- or average-appearing facial skin. This pattern mirrored individual genes representing examples of different processes related to mitochondrial structure and metabolism. A decrease in cellular energy metabolism has previously been linked to visible signs of skin aging such as wrinkling.
Cell senescence, indicated by CDKN2A expression, increased markedly in the photoexposed arm and facial skin, particularly in the epidermis. CDKN2A codes for multiple proteins including p16INK4a, which is associated with suppression of cell replication and induction of cellular senescence - key causes of aging. Even small fractions of senescent cells can contribute to visible aging and underlying processes, including inflammation in photoexposed skin sites. Increased CDKN2A expression corresponded with sun exposure and aged appearance of facial skin.
In summary, genetics play a fundamental role in setting the pathways of aging, but how aging occurs is associated with changes in expression of these genes over time. Genes associated with youthful-appearing skin represent fundamental cellular repair and metabolic processes, as well as functional properties such as skin barrier. Furthermore, the observed differences in onset and time progression of changes in gene expression across key aging pathways might present interesting biomarkers and targets to provide further insights into skin aging.
An Example of a Pitfall in the Correlation of Excess Fat with Age-Related Disease
Terrible, slow moving age-related diseases that kill you also tend to make you lose weight along the way. Even the lengthy period of gradually increasing disability prior to full-blown disease can achieve that result. This point is very important to bear in mind when looking at association studies that map measures of weight versus disease risk, or life expectancy, or other health metrics. Are the studies using late snapshots of weight, or lifetime maximum weight, or some other measure and time, and does that choice of data succeed in avoiding entanglement with the loss of weight that serious age-related disease tends to produce? If it doesn't, then the result may be suspect.
The study I'll point out today examines a very large set of data, that of more than a million individuals. In the course of processing this data, the study authors well illustrate the point made above. For measures of weight taken decades prior to the development of age-related disease, excess weight correlates with raised risk of disease. But if measuring weight within a few years of the diagnosis of age-related disease, that correlation is reversed - in later life, the group of normal weight people includes some of the least healthy, who have lost weight since their earlier highs due to the early stages of disease and dysfunction. They developed age-related disease because they were overweight, but then their status becomes less visible to simple statistics as the weight is lost.
There is little doubt that carrying excess visceral fat tissue is very harmful to health. It is in the same ballpark as smoking, when measured in terms of lost years of life expectancy, increased lifetime medical expenditure, and risk of disease. The evidence for this is overwhelming, ranging from many human epidemiological studies of hundreds of thousands of individuals tracked over decades to demonstrations of extended life in mice achieved through surgical removal of visceral fat tissue. Still, while being one of the more straightforward associations to measure, it isn't so straightforward as to prevent a number of research groups falling into the trap of failing to account for disease-related weight loss in their data. This is why studies such as the one below exist.
Body mass index and risk of dementia: Analysis of individual-level data from 1.3 million individuals
The costs of dementia are enormous and increasing globally. Current clinical guidelines for dementia prevention view obesity as one of the modifiable risk factors, but the evidence is based on a relatively limited number of observational studies and the findings are mixed. The most recent meta-analysis, including 4 studies and 16,282 participants, suggested a 1.4-fold increased risk of dementia in the obese. The largest study in the field, published after the inclusion date for the meta-analysis, found no increase in dementia incidence among the obese. On the contrary, higher body mass index (BMI) was linked to lower dementia risk. The reasons for this discordance in findings are unclear.
One possibility is that the observed association between BMI and dementia is attributable to two processes: one is a direct association between higher BMI and increased dementia risk, and the other is an association confounded by weight loss during the preclinical dementia phase, which leads a harmful exposure to appear protective via reverse causation. This hypothesis is supported by the fact that clinical diagnosis of dementia is often preceded by a long (20-30 years) preclinical phase during which cardiometabolic changes, including weight loss, are common. Thus, lower BMI close to dementia onset might be a consequence of preclinical disease rather than a cause of dementia.
The purpose of the present analyses was to investigate the BMI-dementia association using raw unpublished data. We included 39 prospective cohort studies which comprised a total of 1,349,857 participants with no history of dementia; were population based with BMI assessed from all participants before the ascertainment of dementia; recorded hospital-treated dementia or dementia deaths; and had accrued a minimum of 3 years of follow-up. We found that higher BMI was associated with increased dementia risk when weight was measured more than 20 years before dementia diagnosis, but this association was reversed when BMI was assessed less than 10 years before dementia diagnosis. The findings of this study are consistent with the hypothesis that the BMI-dementia association is attributable to two processes: a direct (causal) effect and reverse causation as a result of weight loss during the preclinical dementia phase.
As the present meta-analysis is based on a series of studies in which investigators ascertained dementia in different ways, we had the possibility to undertake a validation exercise. Thus, we repeated the main analyses excluding dementia status drawn from death certificates. The same pattern of results was evident as in the main analyses: higher BMI was associated with greater risk of dementia when BMI was measured many years before dementia onset, whereas an inverse relationship was apparent when BMI was measured closer to dementia ascertainment.
In analyses exploring survival bias, we found that higher baseline BMI was associated with an increased risk of all-cause mortality before the age of 65 years but lower mortality risk after the age of 85 years (the median age of dementia diagnosis). These findings suggest that, compared with their normal weight counterparts, obese individuals were less likely to live long enough to develop dementia and more likely to die from conditions that are known to be related to increased dementia risk, such as diabetes and cardiovascular diseases. Given these findings, differences in survival may have contributed, if anything, to an underestimation of the strength of the association between BMI and dementia.
Useful Tests for Self-Experimentation in Rejuvenation Therapies, those Not Requiring the Assistance of a Physician
This is another in a series of posts in which I think out loud about how to organize and conduct a useful short self-experimentation or single person informal trial of an alleged rejuvenation therapy. The focus is on senolytic drug candidates, because those are the only potential rejuvenation therapies worthy of the name that are currently accessible to ordinary individuals such as you and I. The general points made here are applicable to any other novel therapy that might arise in the years ahead, however - and arise they will - as well as to assessment of personal fitness, should that topic interest you. You might look at the last post in the series for a general outline of how such a study would be planned at the high level.
The usual cautions apply in these matters. There is risk in using senolytic drug candidates: they are chemotherapeutics, and one should well understand their profile of side-effects and hazards - which means, at a minimum, reading through a fair few scientific papers and reports. Further, just about everything to do with taking matters into your own hands with any sort of pharmaceutical is illegal in the US, even those that are not controlled substances, albeit rarely prosecuted when it is a matter of individual use. "Rarely" is not "never," however, and the prevailing cultural zeitgeist is that you are a terrible human being for even trying this, regardless of circumstance. This is a sad state of affairs, especially for those who are dying, priced out of the US market but not the global market for specific pharmaceuticals, and nonetheless forbidden to make the attempt to help themselves.
Here, however, I will say little about senolytics, and instead offer a first take on a practical list of tests that might be used to assess whether or not anything happened as a result of self-experimentation in rejuvenation treatments. This is the essence of the thing: there is no point in trying a treatment and merely hoping for the best. That adds no value, and helps no-one. A world in which hundreds or thousands of people are trying an approach and publishing their own measurements is a different story, however. Should it come to pass, that will go along way towards helping to push more formal trials into progress, by identifying promising directions that might otherwise take some time to be discovered by the slow and formal trial process.
A Short List of Simple Tests
For a first venture, it helps to keep things simple and flexible. The objective is a set of tests that anyone can run without the need to involve a physician, as that always adds significant time and expense. Since we are really only interested in the identification of large and reliable effects as the result of an intervention, we can plausibly expect a collection of cheaper and easier measures known to correlate with age to be useful in this matter. Once that hill has been climbed, then decide whether or not to go further. Don't bite off more than is easy to chew for a first outing. I picked the following:
- A standard blood test, with inflammatory markers.
- Resting heart rate and blood pressure.
- Heart rate variability.
- Pulse wave velocity.
- Biological age assessment via DNA methylation patterns.
The cardiovascular health measures in that list are those that are impacted by changes in the elasticity or functional capacity of blood vessels, such as would be expected to occur to some degree following any rejuvenation therapy that addresses senescent cells, chronic inflammation, or other factors that stiffen blood vessels, such as calcification or cross-linking. Positive change of the average values in most of these metrics are achievable with significant time and effort spent in physical training, so movement in the numbers in a short period of time as the result of a treatment should be an interesting data point.
There are online services such as WellnessFX where one can order up a blood test and then head off the next day to have it carried out by one of the widely available clinical service companies. Of the set of test packages offered by WellnessFX, the Advanced Heart Health is probably the most useful for present purposes. But shop around; this isn't the only provider.
Resting Heart Rate and Blood Pressure
A simple but reliable tool such as the Omron 10 is all you need to measure heart rate and blood pressure. It is worth noting here a couple of general principles for cardiovascular measures. Firstly, the further away from the center of the body that the measurement is taken, the less reliable it is - the more influenced by any number of circumstances, such as position, mood, stress, time of day, and so forth. Fingertip devices are convenient, but nowhere near as useful as something like the Omron 10 that uses pressure on the upper arm. Secondly, all of the above-mentioned line items also influence every cardiovascular measure, so when you are creating a baseline or measuring changes against that baseline, carry out each measure in the same position, at the same time of day, and make multiple measurements over a week and take the average.
Heart Rate Variability
There are surprisingly few consumer tools for measuring heart rate variability. Some of the regulated medical devices are quite easy to manage, but good luck in navigating the system to obtain one. The easiest way is to buy second hand medical devices via one of the major marketplaces open to resellers, but that requires a fair-sized investment in time and effort - which comes back to the rule about keeping things simple at the outset. After some reading around the subject, I settled on the combination of the Polar H10 device coupled with the SelfLoops HRV Android application. I also gave EliteHRV a try, but despite all the recommendations, I could not convince it to produce sensible numbers for the heart rate variability data, while SelfLoops HRV had no issues.
Pulse Wave Velocity
For pulse wave velocity, the situation for consumer tools is even more sparse. I was reduced to a fingertip device, the iHeart, picked as being less unreliable and easier to use than the line of scales that measure pulse wave velocity. The recommendations suggest that decently reliable data from non-invasive devices is only going to be obtained by measures at the aorta and other core locations, or with more complicated regulated medical devices that use cuffs and sensors at several places on the body. Still, less reliable data can be smoothed out to some degree by taking the average of measures over time, and being consistent about position, finger used for a fingertip device, time of day, and so forth when the measurement is taken. It is fairly easy to demonstrate the degree to which these items can vary the output - just use the fingertip device on different fingers in succession and observe the result. All of this is a trade-off.
DNA methylation tests can be ordered from either Osiris Green or Epimorphy / Zymo Research. I picked Zymo's product because at the time I first wrote this, the Osiris Green founders were still bailing out their laboratory after Hurricane Irma; they are back in business now, however. The normal level of variability from day to day for individuals in these tests is a question mark at this point in time, but the price is acceptable for that level of uncertainty, given how well this class of test has performed in academic research to date. As for the cardiovascular measures, it is wise to try to make everything as similar as possible when taking the test before and after a treatment: time of day, recency of eating or exercise, recent diet, and so forth.
The schedule for a single person self-experimentation trial might look something as follows:
- Day 1-7: Once or twice a day, take measures for blood pressure, pulse wave velocity, and heart rate variability.
- Day 7: Bloodwork and DNA methylation test.
- Day 8 and on: Carry out the treatment.
- Day 30-36: Repeat the blood pressure, pulse wave velocity, and heart rate variability measures.
- Day 36: Repeat the bloodwork and DNA methylation test.
One person's data is an anecdote. We won't really understand the profiles of potential rejuvenation therapies, or indeed any new interventions, until a great many people have tried them and reported on the results of trying them. At the moment, that proceeds through small trials organized by a variety of companies. History suggests that few people will in fact self-experiment in a useful way that that adds to the bigger picture, but nonetheless, formal trials don't have to be the only effort taking place.
Costs of Measurement
For the choices mentioned above, the rough costs are as follows:
- 2 MyDNAge tests: 600
- 2 Advanced Heart Health tests from WellnessFX: 760
- Omron 10 device: 70
- iHeart device and Android application: 210
- Polar H10 and SelfLoops HRV Android application: 110
Which amounts to 1750, along with a fair amount of time spent reading around the subject and becoming familiar with the devices and their quirks. The hardware is of course reusable for any other health assessment you might want to carry out. There is a lot of reading material out there produced by members of the quantified self movement, for example, that focuses on assessing the results of more mundane matters of exercise, weight, and fitness. I encourage you to explore it.
Skin Aging Correlates with Conductive Disorders in the Heart
Researchers here provide evidence to show that measures of skin aging sensitive to the progression of fibrosis appear to correlate with the risk of suffering conductive disorders of cardiac tissue. The heart is an electrochemical machine, and electrical properties of heart tissue such as the atrioventricular node are vital to the way in which the organ functions. Fibrosis in heart tissue disrupts these electrical properties, just as it disrupts any function of tissue that depends on its fine structure.
Fibrosis is the creation of scar-like deposits in place of normal tissue structure, the result of an age-related disruption of normal regenerative and tissue maintenance processes. It is thought that chronic inflammation and the presence of senescent cells are among the more important causes of fibrosis, though the authors of this paper prefer to focus on cross-linking of AGEs, and these are global issues in the aging body. So while any observed correlation between aspects of aging must be eyed carefully, simply because aging is a collection of interacting processes that all happen at the same time, it is at least plausible that increased prevalence of fibrosis throughout the body is a mechanism to produce the observed results here.
Skin acts as a mirror to the internal state of the body. There are many scoring systems used in the assessment of skin aging. SCINEXA (SCore for INtrinsic and EXtrinsic skin Aging) is an easy-to-use clinical scoring system recently developed to differentiate between chronological (intrinsic) skin aging and photo (extrinsic) skin aging. However, no studies have evaluated the relationship between skin-aging parameters and the incidence of degenerative advanced-degree atrioventricular conduction disorders, or AV block. With increasing age, these disorders are inevitable. About 30% of people older than 65 years have AV conduction or intraventricular conduction defects. Pulse rate interval increases with increasing age caused by delayed conduction in the atrioventricular node (AVN) and the proximal portion of the His bundle.
Can we use skin parameters to predict the presence of heart block? Carotid atherosclerosis is related to perceived age (associated with higher degrees of facial pigmentation), and may be a better predictor of mortality than chronological age. In our study, uneven pigmentation was higher in those with advanced-degree heart block; the grades of fine skin wrinkles were significantly higher in heart block group.
Our skin becomes stiff, thin, and flabby, with the development of more wrinkles with advanced age, and all are related to fibrosis of the skin, as elastic fibers are injured and collagen fibers are broken with the passage of time. New collagen fibers are produced to replace broken elastic fibers and broken collagen fibers. Tissue fibrosis due to progressive deposition of excessive collagen fibers has been observed in most organs with aging, especially the heart. This results in hardening and atrophy of that organ, secondary to loss of parenchyma cells and the increase of collagen substance in tissues. Essential arterial hypertension, sinus node dysfunction, and degenerative AV block are examples of cardiac complications that are caused by tissue fibrosis. In our study, the grades of the lax appearance of the face and reduced fat tissue, prevalence of seborrheic keratosis, and the total score of intrinsic skin aging were significantly higher in the group of heart block.
The association between intrinsic skin aging and degenerative advanced-degree AV block could be explained by the pathogenesis background that may be incriminated in the development of both disorders. Extensive evidence, derived from both clinical and experimental studies, suggests that the aging heart undergoes fibrotic remodeling. Advanced glycation end products (AGEs), which are developed by the glycation and oxidation of different structural proteins, and play an important role in age-dependent changes, were described in skin aging and in organs such as the kidney, blood vessels, and the eye lenses. AGEs are important factors for assessing cardiac aging and fibrosis. Further, diminished expression of connective tissue growth factor (CTGF) is responsible for the progressive loss of dermal collagen. There are positive correlations between the levels of CTGF and cardiovascular fibrotic diseases in the elderly population.
To What Degree can Vascular Stiffness be Reversed by Overriding Signaling Changes?
Vascular stiffness causes hypertension and detrimental remodeling of the heart because it breaks all of the pressure-related feedback mechanisms in our cardiovascular system. Vascular stiffness is caused by mechanisms such as cross-linking in the extracellular matrix, and the inflammatory and other signals of senescent cells that promote calcification in blood vessel walls. The muscle responsible for blood vessel constriction is also involved in stiffening, however, and here we can ask to what degree this contribution is a reaction to the damage of aging, a change in the regulation of muscle tissue activity, rather than the direct result of molecular damage. Reactions can be overridden, even though that can never be as good a strategy as addressing the underlying causes. Sadly, most members of the research community seem very averse to addressing root causes in aging and disease - they are much more willing to tinker with the disease state or its proximate causes, as in the example here.
The progressive increase in blood pressure (BP) with age is characterized by a greater increase in isolated systolic hypertension, a larger elevation in systolic blood pressure (SBP) than diastolic blood pressure (DBP), leading to an accelerating rise in pulse pressure (PP). Although it is widely accepted that the increase in SBP with advancing age is mostly consistent with the large artery stiffening, there is still no consensus on what are the primary causes of these disorders. Our recent studies show that increased intrinsic stiffness of vascular smooth muscle cells (VSMCs) in aorta is an important contributor to the pathogenesis of aortic stiffening in both aging and hypertension, and that this could be a novel target for future anti-aortic stiffness drug development. However, less is known about molecular regulation involved in the VSMC stiffening in large arteries.
Rho-associated protein kinase (ROCK) is a serine/threonine protein kinase that has been identified as one of the effector of the small GTP-binding protein Rho. Although accumulating evidence has demonstrated that the ROCK pathway plays a crucial role in the pathogenesis of hypertension, ROCK has not previously been shown to be involved in cellular stiffening of VSMC. Inhibition of ROCK significantly reduced blood pressure in human and animal models of hypertension, despite the precise molecular mechanism underling the anti-hypertensive effect not being fully understood.
Thus, we hypothesize that ROCK participates in the regulation of aortic stiffness via altering VSMC stiffness in hypertension. In this study, we integrated atomic force microscopy (AFM) and molecular approaches to determine whether increased stiffness of aortic VSMCs in hypertensive rats is ROCK-dependent, and whether the anti-hypertensive effect of ROCK inhibitors contributes to the reduction of aortic stiffness via changing VSMC mechanical properties.
Despite a widely held belief that aortic stiffening is associated with changes in extracellular matrix proteins and endothelial dysfunction, our recent studies demonstrated that intrinsic stiffening of aortic VSMCs, independent of VSMC proliferation and migration, is an important contributor to aortic wall stiffening both in hypertensive and aged animals. The present study demonstrates for the first time that ROCK is a novel mediator of aortic VSMC stiffening in hypertension, which has never been described previously. Furthermore, our study also indicated that attenuation of aortic VSMC stiffening by pharmacological inhibition can serve as a promising therapeutic target to correct aortic stiffening not only in hypertension, but also in other age-related vascular diseases.
Linking RAGE, DNA Damage, Cellular Senescence, and Reversible Fibrosis
Researchers here find that loss of RAGE in mice produces accelerated fibrosis that is reversible if RAGE is restored. It is a little early in this line of research to be enthused by it; I think that all that is being shown here is that fibrosis is principle reversible, though this is interesting enough to merit comment in and of itself. It is frequently the case that a form of accelerated disease progression has little relevance to the biochemistry of the real thing. Acceleration usually takes the form of one aspect of the disease progress being exaggerated out of proportion, and that aspect may well not play a significant role in comparison to the other aspects of its biochemistry.
This research is also of interest because RAGE, the receptor for advanced glycation end-products (AGEs), is implicated in age-related inflammation. AGEs come in a variety of types, and readers here are probably more familiar with the persistent glucosepane AGEs that form cross-links in tissue, damaging structural properties and function. There are a whole range of other types of AGEs that are more transient, more dependent on diet, and which cause issues via their interaction with RAGE. The better known activities of RAGE are unrelated to the focus in this paper, however.
Like many proteins, RAGE has more than one job, and those jobs have little relation to one another. Of relevance here, RAGE is vital to DNA repair, and so loss of RAGE produces greater levels of cell dysfunction and cellular senescence, and that in turn leads to fibrosis. The link between cellular senescence and fibrosis is becoming fairly well established at this point: the signaling produced by these cells causes disarray in regenerative processes, and that in turn results in the scarring of fibrosis instead of functional tissue structure. Does restoration of RAGE as shown in this paper perhaps allow senescent cells sufficient self-control to destroy themselves? If so, this work, showing reversal of fibrosis, would be promising support for senolytic therapies, those capable of clearing senescent cells, to be a treatment for fibrosis. Still, as I said, it is way too early to be excited; too many questions remain to be answered.
The endogenous protein RAGE, which has usually been negatively associated with chronic inflammation and diabetic complications, plays a major role in the repair of DNA damage - and also appears to heal tissue damaged as a result of accelerated cell senescence. Researchers discovered the potential therapeutic benefit of the protein in mice that are unable to produce RAGE. As a result of the limited DNA repair, they develop pronounced pulmonary fibrosis, i.e. scarring in the lungs. After treatment with the protein, the scarring healed. "This is astonishing in that fibrosis has so far been considered irreversible. With RAGE, we could for the first time have found a possible starting point to cure this frequent tissue damage. Many questions - e. g. how this healing works in detail - are still unanswered."
RAGE (Receptor of Advanced Glycation Endproducts) is well known in medical research. The protein plays a decisive role not only in diabetes but also in chronic and excessive inflammatory reactions such as atherosclerosis and sepsis, but also in Alzheimer's disease and cancer development. The protein is mainly active on the surfaces of tissue cells and cells of the immune system. On the other hand, inside the cells, to be more precise in the cell nucleus, RAGE shows a completely different side of itself: Here it is responsible for the error-free repair of severe DNA damage, known as double-strand breaks. In these cases of damage, the two interconnected and twisted strands of DNA are completely cut off. Without immediate repair, the cell would quickly perish.
Mice that are unable to form RAGE due to a genetic defect will develop pulmonary fibrosis. The lungs are particularly susceptible to tissue damage, as they are in constant contact with the outside world through the air they breathe and are particularly exposed to environmental influences. In the animal model, the researchers succeeded in elucidating the hitherto unknown molecular mechanism of DNA repair under RAGE involvement and in identifying further important protagonists. If they introduced RAGE into the mice's lungs with the help of modified viruses, it was not only DNA repair that normalized: To the scientists' surprise, the scarred tissue regenerated and regained some of its functionality.
Expanding the "Don't Eat Me" Signal Blockade Approach to Killing Cancer Cells
Cancers evolve to abuse mechanisms that suppress or control the immune system, as any cancer that fails to do so tends to be destroyed early-on by immune cells. One of these mechanisms is the presentation of "don't eat me" signals on the cell surface that prevent macrophage cells of the innate immune system from engulfing and destroying a cancer cell. CD47 was identified some years ago as one of these signals, and bypassing it or suppressing it has the potential to be a broad basis for the treatment of many types of cancer. As a bonus, it also appears to be a potentially viable strategy for treating age-related fibrosis, as the cells that make up fibrotic scar tissue inside aged organs similarly protect themselves with CD47.
Nothing is simple or single-purposed in biochemistry, however. Where there is one signal, there are usually also other overlapping signals that achieve similar or related results. Researchers have now found another, more subtle "don't eat me" signal employed by cancer cells, and as is the case for CD47, this too should have the potential to be useful in a range of future therapies. In fact, the two used together promise to be much better than either on its own, capable of success in more types of cancer.
"The development of cancer cells triggers the generation of SOS molecules recognized by the body's scavenger cells, called macrophages. However, aggressive cancers express a 'don't eat me' signal in the form of CD47 on their surfaces. Now we've identified a second 'don't eat me' signal and its complementary receptor on macrophages. We've also shown that we can overcome this signal with specific antibodies and restore the ability of macrophages to kill the cancer cells. Simultaneously blocking both these pathways in mice resulted in the infiltration of the tumor with many types of immune cells and significantly promoted tumor clearance, resulting in smaller tumors overall. We are excited about the possibility of a double- or perhaps even triple-pronged therapy in humans in which we combine multiple blockades to cancer growth."
Macrophages are large white blood cells found in nearly all the body's tissues. As part of what's known as the innate immune system, they engulf and kill foreign invaders like bacteria or viruses. They also destroy dead and dying cells and, in some cases, cancer cells whose internal development cues have gone haywire. The newly discovered binding interaction used by cancer cells to evade macrophages capitalizes on a protein structure on the cancer cells' surface called the major histocompatibility complex class 1, or MHC class 1. Human tumors that have high levels of MHC class 1 on their surfaces are more resistant to anti-CD47 treatment than are those with lower levels of the complex, the researchers found.
MHC class 1 is an important component of adaptive immunity. Most cells of the body express MHC class 1 on their surfaces as a way to indiscriminately display bits of many proteins found within the cell - a kind of random sampling of a cell's innards that provides a window into its health and function. If the protein bits, called peptides, displayed by the MHC are abnormal, a T cell destroys the cell. Although the relationship between MHC class 1 and T cells has been well-established, it's been unclear whether and how the complex interacts with macrophages.
Researchers found that a protein called LILRB1 on the surface of macrophages binds to a portion of MHC class 1 on cancer cells that is widely shared across individuals. This binding inhibits the ability of macrophages to engulf and kill the cancer cells, both when growing in a laboratory dish and in mice with human tumors, the researchers found. Understanding the balance between adaptive and innate immunity is important in cancer immunotherapy. For example, it's not uncommon for human cancer cells to reduce the levels of MHC class 1 on their surfaces to escape destruction by T cells. People with these types of tumors may be poor candidates for cancer immunotherapies meant to stimulate T cell activity against the cancer. But these cells may then be particularly vulnerable to anti-CD47 treatment, the researchers believe. Conversely, cancer cells with robust MHC class 1 on their surfaces may be less susceptible to anti-CD47.
Researchers Demonstrate a Larger Heart Muscle Patch, but Generating Blood Vessels Remains a Challenge
In the engineering of tissue grown from a cell sample, researchers are currently limited to building thin slices or small sections, no more than a few millimeters in thickness, the distance that nutrients can perfuse without a capillary network. There is still no reliable, cost-effective solution for generating tissues that incorporate this intricate blood vessel network, and this is a roadblock to the creation of thicker, larger tissue sections. Thus the most advanced uses of tissue engineering at the present time are those in which thin tissue sections can still get the job done. One potential application is the generation of patient-matched cardiac tissue patches to augment the performance of a heart that has been damaged. These have been demonstrated to integrate with the living heart, replacing dead and scarred tissues that are no longer functional. This area of research is progressing quite well, as illustrated by this latest news.
Biomedical engineers have created a fully functioning artificial human heart muscle large enough to patch over damage typically seen in patients who have suffered a heart attack. The advance takes a major step toward the end goal of repairing dead heart muscle in human patients. "Right now, virtually all existing therapies are aimed at reducing the symptoms from the damage that's already been done to the heart, but no approaches have been able to replace the muscle that's lost, because once it's dead, it does not grow back on its own. This is a way that we could replace lost muscle with tissue made outside the body."
Unlike some human organs, the heart cannot regenerate itself after a heart attack. The dead muscle is often replaced by scar tissue that can no longer transmit electrical signals or contract, both of which are necessary for smooth and forceful heartbeats. The end result is a disease commonly referred to as heart failure. New therapies are needed to prevent heart failure and its lethal complications. Current clinical trials are testing the tactic of injecting stem cells derived from bone marrow, blood, or the heart itself directly into the affected site in an attempt to replenish some of the damaged muscle. While there do seem to be some positive effects from these treatments, their mechanisms are not fully understood. Fewer than one percent of the injected cells survive and remain in the heart, and even fewer become cardiac muscle cells.
Heart patches, on the other hand, could conceivably be implanted over the dead muscle and remain active for a long time, providing more strength for contractions and a smooth path for the heart's electrical signals to travel through. These patches also secrete enzymes and growth factors that could help recovery of damaged tissue that hasn't yet died. For this approach to work, however, a heart patch must be large enough to cover the affected tissue. It must also be just as strong and electrically active as the native heart tissue, or else the discrepancy could cause deadly arrhythmias. This is the first human heart patch to meet both criteria.
Finding the right combination of cells, support structures, growth factors, nutrients and culture conditions to grow large, fully functional patches of human heart tissue has taken the team years of work. Every container and procedure had to be sized up and engineered from scratch. And the key that brought it all together was a little bit of rocking and swaying. "It turns out that rocking the samples to bathe and splash them to improve nutrient delivery is extremely important. We obtained three-to-five times better results with the rocking cultures compared to our static samples." Tests show that the heart muscle in the patch is fully functional, with electrical, mechanical and structural properties that resemble those of a normal, healthy adult heart.
Researchers have already shown that these cardiac patches survive, become vascularized and maintain their function when implanted onto mouse and rat hearts. For a heart patch to ever actually replace the work of dead cardiac muscle in human patients, however, it would need to be much thicker than the tissue grown in this study. And for patches to be grown that thick, they need to be vascularized so that cells on the interior can receive enough oxygen and nutrients. Even then, researchers would have to figure out how to fully integrate the heart patch with the existing muscle. "We are actively working on that, as are others, but for now, we are thrilled to have the 'size matters' part figured out."
Aging and the Unfolded Protein Response in the Endoplasmic Reticulum
The endoplasmic reticulum, like many structures in the cell, becomes dysfunctional in old tissues. Since it is involved in the later stages of the construction of properly formed proteins, this is one of the more problematic failures; degraded performance here has many secondary consequences. In this open access paper, researchers review what is known of how the endoplasmic reticulum fails to properly fold proteins in old tissues, and how it tries to respond to that failure with what is known as the unfolded protein response - a maintenance process that itself declines with age.
These disruptions of normal function are a downstream consequence of the fundamental forms of molecular damage that cause aging, those described in the SENS rejuvenation research outline, but the precise chain of cause and effect that lies between these two has yet to be well mapped. Much of the research community is more interested in trying to override consequences rather than repair root cause damage, in effect trying to to force a damaged machine to act as though it isn't damaged. In this case, that means spurring greater unfolded protein response activity. There are obviously limits to how well this approach can work, as the underlying damage remains to cause all of its other harms, but like many of these strategies it can be shown to produce some degree of benefit.
The cellular homeostasis maintains existence of life through integrative communication among various macromolecules working in unity through numerous biochemical pathways. The endoplasmic reticulum (ER) not only maintains Ca2+ homeostasis but also controls translation, folding, maturation, and trafficking of about one third of cellular proteins. Various environmental insults can disturb proper functioning of ER, leading to accumulation of unfolded/misfolded protein cargo in the ER that gives rise to a condition called ER stress. The cell responds through a highly conserved pathway known as the ER unfolded protein response (UPRER). UPRER first focuses on alleviation of the imposed stress by initiating steps of adaptive mechanisms in the secretory pathway for restoration of homeostasis but conditions of prolonged stress and damage provokes a cell into self-destruction through apoptosis.
Aging is notably a process during which the cell witnesses decline in its ability to respond to stress. Age related frailty perturbs the multifarious schematic of UPRER giving rise to a myriad of pathologies characterized by the presence of disease specific misfolded proteins playing havoc with cellular homeostasis. Further, the master transcriptional regulator of inflammation nuclear factor-κB (NF-κB) has been reported to be upregulated during ER stress. UPRER touches inflammatory signaling cascade directly/indirectly through NF-κB.
The process of aging causes decline in the proper functioning of cellular metabolic pathways. The changes in cells undergoing aging weaken UPRER, causing it to fail to recuperate ER stress. The various molecular chaperones in the ER undergo oxidative damage in the aging cell that diminishes the efficiency of these molecular chaperones to fold proteins; hence, presenting a mass of misfolded protein cargo. This causes protein toxicity, leading to derangement in proteostasis, which becomes an underlying cause of age related diseases.
Neurodegenerative diseases find their source of origin in the perturbations that alter proper functioning of ER. Age related frailty disarms the adaptive arm of UPRER and presents distressing conditions in the brain to promote accumulation of misfolded protein cargo in the ER that later on become inclusions of specific abnormal proteins. Most of the models of aging driven neurodegenerative disease have been marked with the presence of specific protein inclusions because of ER stress in the brain and central nervous system, which are toxic to the post-mitotic neurons.
Studies of model organisms have reinforced the importance of the activation of UPRER molecular markers in stimulating longevity. Age related dysfunction in UPRER promotes the accumulation of misfolded protein cargo, which eventually becomes toxic intracellular inclusions. As the prominent aging driven neurodegenerative diseases share a common pathology of toxic misfolded protein accumulations, this provides an opportunity for therapeutic interventions in the UPRER pathway that can stave off both aging and neuropathologies.
There Will Be No Shortage of Geroprotector Drug Candidates
Portions of the research community are becoming quite proficient at churning out potential drug candidates for specific conditions based on processes that involve a lot more computation and modeling than actual laboratory work. The compound databases these days are huge, containing vast swathes of molecules that are barely explored in the context of medicine. Those researchers interested in very modestly slowing aging through calorie restriction mimetics such as metformin and rapamycin, designated by some as geroprotectors, will be faced with an embarrassment of riches.
This is a strategy I think to be of little worth in comparison to repair-based approaches such as SENS. Still, there will be far too many candidate compounds for the current research community to exhaust any time soon. I imagine that scientists will continue to raise funding and explore much as they are today until that strategy is decisively out-competed by rejuvenation therapies after the SENS model. Repairing the damage that causes aging seems to me an approach that self-evidently must win out in terms of results attained, when considered in comparison to adjusting the operation of metabolism to merely slow down accumulation that damage, given equal quality of implementation on both sides.
Fortunately, a number of damage repair approaches can involve small molecule drug development: clearance of senescent cells, breaking down cross-links, and removal of other metabolic waste such as the constituents making up lipofuscin, for example. All of these lines of development should benefit considerably from highly effective drug candidate identification platforms, just as soon as a few initial candidates are in hand - and that is the case today for senolytics that target senescent cells for destruction. I'm sure we'll be seeing many more of those in the next few years, and a good thing too, as the senolytics discovered to date appear to be fairly specific to tissues or classes of senescent cell. Variety will likely be important in the early years of senolytic therapies.
By 2030, the US Census Bureau projects that one in five people in the US alone will be over the age of 65, a major risk factor for many of the most prevalent, costly, and devastating diseases of today, including cancer, cardiovascular disease, Alzheimer's disease, and Type II diabetes. To offset the burden of this increase, efforts are underway to develop an anti-aging drug or other geroprotective intervention that could extend healthspan, lower disease rates, and maintain productivity in this age group.
Unfortunately, there are many roadblocks to such an intervention. While many aging mechanisms are now catalogued and hundreds of drugs extend lifespan in animal models, approval and testing of new drugs in humans is slow, expensive, and prone to high failure rates. This is particularly true in longevity research and exacerbated by a lack of reliable aging biomarkers other than disease itself. Even if successful, to be used preventatively, anti-aging drugs face extraordinarily high safety and efficacy standards for approval.
One strategy to hasten the process has been the repurposing of existing, FDA-approved drugs that show off-label anti-cancer and anti-aging potential, and at the top of that list are metformin and rapamycin, two drugs that mimic caloric restriction. Taken together, rapamycin and metformin are promising candidates for life and healthspan extension; however, concerns of adverse side effects have hampered their widescale adoption for this purpose. While short term rapamycin use is considered safe, it has been reported to be associated with adverse events. Metformin, while relatively safe, is poorly tolerated in one fourth to one half of patients due to gastrointestinal side effects.
In this work, we initiate an effort to identify safe, natural alternatives to metformin and rapamycin. Our work is done entirely in silico and entails the use of metformin and rapamycin transcriptional and signaling pathway activation signatures to screen for matches amongst natural compounds. We have shown previously that the transcriptional signature of a given drug response, disease state, or other physiological condition, when mapped to the signal pathway activation signature, can be useful for biomarker development and drug screening. In the present study, we apply these methods to screen for nutraceuticals that mimic metformin and/or rapamycin. We reduce a list of over 800 natural compounds to a shortlist of candidate nutraceuticals that show both similarity to the target drugs and low adverse effects profiles.
Aubrey de Grey Summarizes Rejuvenation Research at the MIT Technology Review
In this piece at the MIT Technology Review, Aubrey de Grey of the SENS Research Foundation summarizes the strategy of rejuvenation research based on periodic repair of the cell and tissue damage that causes aging. This is a philosophy of development that has proven its utility over the past fifteen years, and especially recently with the growing data on senolytic therapies that remove senescent cells. Clearance of senescent cells was specifically called out by de Grey in his position paper in 2002, and he and his allies have advocated for it and supported it with research funding where possible since then. SENS, the Strategies for Engineered Negligible Senescence, is an assembly of all that is known of the root causes of aging, coupled with potential means to reverse or bypass them. If all portions of SENS were supported to the same degree as other lines of research into aging, then rejuvenation could be a near future reality.
There is a little history here regarding the venue. The editor of the MIT Technology Review was, back in the day, quite opposed to SENS and spent some effort attempting to find researchers willing to tear it down in public. This led to the SENS Challenge in which a prize was offered to people for success in proving SENS wrong. That came to the expected result, as SENS back then was, as it is now, based on a very large body of research and data, yet a decade ago the culture of science and the popular culture was inclined to dismiss out of hand anyone who talked rationally about treating aging as a medical condition. SENS was correct back then, and it is correct today; the only difference is that a great deal of work has taken place in the intervening years to persuade the scientific community and the world at large that, yes, building therapies to address aging is plausible, practical, and possible. The culture of aging research and the public perception of this research is now very different.
Since the dawn of medicine, aging has been doctors' foremost challenge. Three unsuccessful approaches to conquering it have failed: treating components of age-related ill health as curable diseases, extrapolating from differences between species in the rate of aging, and emulating the life extension that famine elicits in short-lived species. SENS Research Foundation is spearheading the fourth age of anti-aging research: the repair of age-related damage, that is, rejuvenation biotechnology. The Strategies for Engineered Negligible Senescence (SENS) approach was first proposed in 2002; we seek methods to convert a population experiencing a non-negligible level of senescence into one experiencing a negligible level.
To see how the goal of negligible senescence could be "engineered," it is useful to consider a situation in which human ingenuity and perseverance has already achieved an analogous result. Motor vehicles experience a process of wear-and-tear essentially similar to organismal aging; the paint flakes, windowpanes chip, rust infiltrates the pipework, and so forth. Nonetheless, as vintage car owners will attest, it is entirely possible to keep one functional for an essentially indefinite period. Critically, this is achieved not by preventing the wear but by repairing the damage that does occur at a rate sufficient to ensure that the function of the machine is never irretrievably compromised.
Aging can be characterized as a three-stage process. In the first stage, metabolic processes essential to life produce toxins. Secondly, a small amount of the damage caused by these toxins cannot be removed by the body's endogenous repair systems, and consequently accumulates over time. In the third stage, the accumulation of damage drives age-related pathology. This model - metabolism causes damage causes pathology - allows us to clarify the requirements for successful intervention in aging. Unlike the dynamic processes of metabolism and pathology, accumulated damage represents a relatively stationary target. That is to say, it may not be clear whether a given type of damage is pathological (on balance), but its absence from healthy twenty-year-olds indicates that it is not required for healthy life. Conversely it is clear that the total ensemble of types of damage in a fifty-year-old is pathological.
Accepting the implications of this model leads us to the SENS approach; by identifying and repairing all of the damage accumulated during aging, we can restore the body to a youthful state. Consequently, its dynamic metabolic processes will revert to their own norms, and the risk of mortality will be no higher than in any other equivalently "youthful" individual - whether they have actually lived for twenty years or 120. Furthermore - so long as our inventory of damage classes is sufficiently comprehensive - we can repeat this effort on a regular basis, and thus remain indefinitely below the threshold of pathology.
SENS is a hugely radical departure from prior themes of biomedical gerontology, involving the bona fide reversal of aging rather than its mere retardation. By virtue of a painstaking process of mutual education between the fields of biogerontology and regenerative medicine, it has now risen to the status of an acknowledged viable option for the eventual medical control of aging and its credibility will continue to rise as the underlying technology of regenerative medicine progresses.
Pol III Inhibition Modestly Extends Life in Flies and Worms
As a general rule, a 10% extension of life in short-lived species is nothing of any great significance. There are an increasing number of methods shown to do this, such as the one noted here. Researchers have more than doubled the life span in flies and worms in a few different ways over the past twenty years, however, and where the effects of any given intervention can be compared with the results in humans, it has been found that short-lived species have a much greater plasticity of life span. The large gains of calorie restriction and growth hormone receptor loss of function observed in lower species don't occur in our own species. This should be broadly true for just about everything that involves manipulating the operation of metabolism to slow down the pace at which damage occurs, as near all of that arises from mechanisms related to calorie restriction and insulin or growth hormone metabolism.
One should probably view this sort of work through the lens of scientific interest in mapping and cataloging the way in which aging works at the detail level - why the pace of aging varies somewhat between individuals, which mechanisms are most important, and so forth. Acquisition of knowledge is everything, and application of knowledge to the production of methods of slowing aging in humans is an afterthought. If that was the primary goal, researchers would instead pursue strategies with a much greater expectation of gains in longevity, the potential rejuvenation therapies based on repair of the damage that causes aging.
The enzyme - RNA polymerase III (Pol III) - is present in most cells across all animal species, including humans. While it is known to be essential for making proteins and for cell growth, its involvement in ageing was unexplored until now. A study has found that the survival of yeast cells, and the lifespans of flies and worms were extended by an average of 10% following a modest reduction in Pol III activity in adulthood. "We've uncovered a fundamental role for Pol III in adult flies and worms: its activity negatively impacts stem cell function, gut health, and the animal's survival. When we inhibit its activity, we can improve all these. As Pol III has the same structure and function across species, we think its role in mammals, and humans, warrants investigation as it may lead to important therapies."
The effects of inhibiting Pol III were found to be comparable to the action of the immune-suppressing drug rapamycin, which has previously been shown to extend the lifespans of mice and many other animals. This discovery will help scientists understand the mechanism of action of drugs, such as rapamycin, that show promise for extending the lifespans of mammals. "Understandably, there's a lot of hype around drugs that extend lifespan and promote healthy ageing but very little is known about how they work, which is fundamental knowledge. We now think that Pol III promotes growth and accelerates ageing in response to a signal inhibited by rapamycin, and that inhibiting Pol III is sufficient to result in flies living longer as if they were given rapamycin. If we can investigate this mechanism further and across a wider range of species, we can develop targeted antiaging therapies."
Yeast, flies and worms were used as model organisms as they are not closely related but all contain Pol III. Inhibiting Pol III in the guts of flies and worms, was sufficient to extend lifespan, and when Pol III was inhibited in flies' intestinal stem cells alone, they also lived longer. The team now plan on continuing their work on Pol III to understand its function in an adult organism, and hence shed light on how a reduction in its activity can extend lifespan.
Sirtuin Research Continues Ever Onward in Search of Relevance
As a result of failed commercial efforts a decade ago, research into sirtuins - particularly SIRT1 - in the context of aging is broader than it might otherwise be, and has a great deal of inertia. A lot of funding poured into this area, and as a result efforts to map all of the biochemistry that touches upon SIRT1 continue today, long after the goal of building a therapy to slow aging based upon manipulating SIRT1 was abandoned. The early evidence for SIRT1 to be important enough in aging to be a basis for therapies was demolished, no useful treatment ever emerged, a bunch of investors nonetheless made a very large profit, and the "anti-aging" marketplace continues to sell useless supplements hyped on the basis of sirtuin-related expectations long since shown to be wrong.
Since the primary goal of the scientific community is to gather knowledge, and the one concrete outcome of the sirtuin hype was a foothold of new knowledge in this tiny slice of metabolism, research into sirtuins continues. Since researchers are better able to raise funding when they can offer at least the prospect of application of their research, even when the real goal is only the accumulation of knowledge, sirtuin researchers tend to explain their work in terms of potential impact on aging. But I think that ship has sailed. One should read SIRT1 research nowadays as a matter of interest, an example of the research community making slow progress in building the grand map of how exactly aging functions in detail. That is, sadly, of little relevance to the construction of effective therapies, which can be achieved by bypassing all of that detail to focus on repairing the known root causes of aging, and worrying about how exactly they generate aging in detail further down the line.
A study by researchers reveals that an anti-aging protein can be targeted to rejuvenate cells in the immune system. The protein in question is called SIRT1. The scientists found that it is involved in how cells in the immune system develop with age. They wanted to find out how this anti-aging protein affects a specific category of immune cells known as cytotoxic T cells. These cells are highly specialized guardians of the immune system and their role is to kill cells infected by a virus, damaged cells, or cancer cells.
"Over the course of a person's life, with repeated exposure to bacteria and viruses, these T cells mature and eventually lose a protein called CD28. And as these cells get older, they become more toxic to their environment." This aging process is accelerated by persistent viral infections, such as HIV and cytomegalovirus. In fact, HIV-infected patients accumulate mature cytotoxic T cells at a much younger age than an uninfected person.
When a young (or naive) T cell is in a resting state, it uses oxygen to "breathe". Once it is activated to defend the body against a bacteria or virus, it shifts into enhanced glycolysis and uses sugar to get an immediate boost in energy. This is useful to jump into action, but it isn't sustainable for long-term performance. As the cells age and lose CD28, they can shift into glycolysis much more quickly if breathing is inhibited. They also lose the anti-aging protein SIRT1. This becomes a problem, as it makes them more toxic to the cells around them.
"We studied human T cells, isolated from blood donors of all ages, to compare mature cytotoxic T cells with naive ones." The researchers found that naive T cells have a high concentration of SIRT1. This stabilizes an entire mechanism that prevents the cells from entering glycolysis to use sugar as an energy source, and limits their toxic effects. As the cells age, they lose SIRT1, which changes their basic metabolism. They can then rapidly shift into glycolysis and start producing more toxic proteins called cytokines, which could lead to inflammatory diseases.