Fight Aging! Newsletter, December 10th 2018

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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  • Immune System Aging and its Contribution to Cardiovascular Disease
  • The Current State of Therapeutic Development Involving Induced Pluripotent Stem Cells
  • Longevity Science is Pretty Much Impenetrable for Journalists
  • High Functioning Centenarians Have Longer Telomeres, More Telomerase Activity, and Better Measures of Immune Function
  • Mitochondrial DNA Copy Number Correlates with Self-Rated Health in Older Adults
  • The Inflammasome in Aging
  • Reducing Levels of Protein Manufacture Slows Measures of Aging in Nematodes
  • All Sorts of Existing Data on Aging is Now Being Connected to Senescent Cells
  • Manipulating Energy Generation in Kidney Cells Can Enhance Regeneration
  • Cellular Senescence Contributes to Impaired Heart Regeneration
  • The Debate over the Existence of Heart Stem Cells Continues
  • Mesenchymal Stem Cell Therapy Reduces Frailty in the Elderly
  • An Epigenetic Signature that Matches the Majority of Cancers
  • Questioning the Validity of Jeanne Calment's Age
  • A Macrophage-Derived Factor from Young Mice Speeds Bone Regeneration in Older Mice

Immune System Aging and its Contribution to Cardiovascular Disease

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

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

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

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

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

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

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

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

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

The Current State of Therapeutic Development Involving Induced Pluripotent Stem Cells

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

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

Increasing Number of iPS Cell Therapies Tested in Clinical Trials

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

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

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

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

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

Longevity Science is Pretty Much Impenetrable for Journalists

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

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

The Death of Death

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

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

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

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

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

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

High Functioning Centenarians Have Longer Telomeres, More Telomerase Activity, and Better Measures of Immune Function

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

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

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

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

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

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

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

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

Mitochondrial DNA Copy Number Correlates with Self-Rated Health in Older Adults

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

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

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

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

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

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

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

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

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

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

The Inflammasome in Aging

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

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

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

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

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

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

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

Reducing Levels of Protein Manufacture Slows Measures of Aging in Nematodes

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

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

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

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

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

All Sorts of Existing Data on Aging is Now Being Connected to Senescent Cells

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

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

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

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

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

Manipulating Energy Generation in Kidney Cells Can Enhance Regeneration

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

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

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

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

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

Cellular Senescence Contributes to Impaired Heart Regeneration

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

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

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

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

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

The Debate over the Existence of Heart Stem Cells Continues

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

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

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

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

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

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

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

Mesenchymal Stem Cell Therapy Reduces Frailty in the Elderly

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

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

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

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

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

An Epigenetic Signature that Matches the Majority of Cancers

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

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

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

Questioning the Validity of Jeanne Calment's Age

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

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

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

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

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

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

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

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

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

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

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

A Macrophage-Derived Factor from Young Mice Speeds Bone Regeneration in Older Mice

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

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

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

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

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


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