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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- Giving Tuesday Approaches: Help us to Fund SENS Rejuvenation Research
- A Review of the Recent History of Parabiosis Research
- Human PAI-1 Loss of Function Mutants Found to Live Seven Years Longer than Peers
- Mild Mitochondrial Stress Found to Prevent Some of the Age-Related Declines in Cellular Maintenance in Nematodes
- Defenestration and the Roots of Age-Related Insulin Resistance
- Why is Sepsis a Condition of the Elderly?
- A Study of Early Life Adversity versus Later Immune Aging Points to Cytomegalovirus as the Problem
- Inhibiting Interleukin 11 can Suppress Fibrosis
- A Klotho Gene Therapy Produces Long-Lasting Cognitive Enhancement in Mice
- Libella Gene Therapeutics Plans Human Telomerase Gene Therapy Trial
- The Limits to Human Longevity, or Lack Thereof
- A Profile of James Clement's Supercentenarian Research
- The Results of Most Potential Biomarkers of Aging Vary Considerably
- Stem Cell Therapy Partially, Unreliably Repairs Spinal Cord Injuries in Rats
- Towards Better Artificial Alternatives to Cartilage Tissue
Giving Tuesday Approaches: Help us to Fund SENS Rejuvenation Research
Giving Tuesday is two weeks away, on November 28th. As manufactured celebrations go, I think we could do far worse than a holiday that encourages philanthropy. While most people are basically well-meaning, and I think would agree in principle that support for medical research is to the common good, we all lead busy lives and need prompting.
So here is a prompt, to remind you that we are all still aging, that aging causes an enormous toll of suffering and death, and that, absent progress, you too will be one of the victims. To offer material support to the research groups that are working to treat the causes of aging is not just the most compassionate thing you can do for the millions suffering today, it is also in your self-interest for tomorrow. If you are organized enough to save for retirement, because it will make your life easier decades from now, then you should also be organized enough to help establish the new medical technologies that will reduce or eliminate the age-related disease that also lies ahead, waiting.
The most effective way to help make progress through charitable contributions is to give to the SENS Research Foundation or their allies such as the Methuselah Foundation. This year we have put out a call for SENS Patrons, people willing to pledge a monthly contribution to the SENS Research Foundation. Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! have put up a 36,000 challenge fund to encourage new supporters, and we will match the next full year of your donations if you sign up before the end of 2017.
There is a growing movement that calls itself Effective Altruism, a reaction to the haphazard nature of most philanthropy, both at the small scale and the large scale. The core of the argument is focused on the individual choice, and suggests that instead of giving to charity on impulse - obtaining a short-term flush, the feeling of having done something, but with the high likelihood of actually having achieved nothing - we are better served by taking the small amount of time needed to choose high impact causes and organizations. To have greater certainty that our contributions do the most amount of good, in other words.
Obviously this is not a binary choice, rather a spectrum of effort, but the central point is that it doesn't in fact take a great deal of effort to prevent a donation from being largely wasted. It also doesn't take a great deal of effort to move a fair way upwards on the curve of utility, the measure of just how much good is achieved for a given amount. What causes the greatest degree of suffering and death in the world today? Aging. Hundreds of millions must live with age-related disease and declines for which there are no effective therapies, and more than 100,000 lives are lost each day, most of those struggling, painful endings. Enormous sums are spent on trying and failing to cope with the consequences of aging. The burden falls most heavily on the poor, as in all such matters. Thus if you identify competent organizations working on treatment of the causes of aging, a donation given should be far more effective when it comes to improving the human condition than is the case for near any other cause.
When it comes to competent organizations working on the treatment of aging, the SENS Research Foundation shines. It is a part of a network, including the Methuselah Foundation, that has made enormous strides over the past fifteen years towards launching a rejuvenation research and development industry. You might take a look at the summary of progress in the Fight Aging! FAQ for a sense of just how much has been accomplished with the charitable donations of past years. There is so much left to achieve, however! The SENS Research Foundation is powered by our donations, and that has proven to be a very effective vehicle for progress. This is why I ask you all to help keep this wheel turning, and why I devote significant amounts of my own resources to this organization and its allies.
An end to the disease and frailty and pain and death of aging can be engineered, and indeed the first rejuvenation therapies are edging their way towards the clinic. But comprehensive, significant success in our lifetimes is only possible given widespread support and far more funding. We lead the way towards making that happen.
A Review of the Recent History of Parabiosis Research
Today, a history of parabiosis studies, albeit one rather biased towards the idea that signals present in young blood might be used to produce benefits in the old. It is possibly a little early to be taking firm sides on that question given the contradictory research results to date. Parabiosis is the name given to linking the circulatory systems of two individuals in order to compare the effects on both sides. Of late it has been used in aging research, joining a young mouse and an old mouse in search of answers regarding the degree to which aging is influenced by a changing balance of signals in the bloodstream. This influence should be a secondary or later consequence in the chain of cause and effect that drives aging: signal and other molecules are secreted by cells, and changes in the mix of these molecules are a reaction to the current state of the cells and their tissues. In the case of age-related change, it is a reaction to underlying molecular damage in cells and their surroundings.
Changing the levels of various signaling molecules carried in the fluids suffusing tissues can have potent effects. Think of most present stem cell therapies, for example: comparatively small numbers of transplanted cells can produce a period of enhanced regeneration and reduced inflammation simply by changing the balance of signals for a short time before they die. This is an essentially compensatory strategy, one that doesn't address root causes, but tries to ameliorate some of their consequences for at least a little while. Far more members of the research community work on this sort of approach than are striking at the root, more is the pity.
Parabiosis is a starting point on the road to identifying which of the signaling changes in blood and tissues are most important, or at the very least, most easily mapped and manipulated. Goals include most of the same outcomes found in stem cell therapies: dampening chronic inflammation; increasing stem cell activity and tissue regeneration; boosting organ function. One might think of parabiosis, stem cell therapy, and a few other related lines of research as parallel roads heading at some pace to the same future destination, which is the ability to directly deliver or block signal molecules to produce the same or greater benefits presently observed in simple stem cell transplants. To adjust the operation of metabolism to disable as much as possible of the harmful further reaction to initial age-related damage. This will probably be a diverse and widespread form of medicine two decades from now, but it is nonetheless second fiddle to the primary goal of repairing the root cause damage of aging. Fix the root cause, and much of the rest of the problem fixes itself.
The Fountain of Youth: A tale of parabiosis, stem cells, and rejuvenation
The claim that blood can rejuvenate our organs has been revitalized by one research group at the Stanford University School of Medicine in 2005 and 2010. These studies stemmed out from observations which show that tissue regenerative capacity declines with age. In tissues such as muscle, blood, liver, and brain this decline has been attributed to a diminished responsiveness of tissue-specific stem and progenitor cells. However, aged muscle successfully regenerates when grafted into muscle in a young host, but young muscle displays impaired regeneration when grafted into an aged host.
Either local or systemic factors could be responsible for these reciprocal effects. In order to test whether systemic factors can support the regeneration of tissues in young animals and/or inhibit regeneration in old animals, the the paper by Conboy and colleagues of 2005 reported an experimental setup in which - in contrast to transplantation - regenerating tissues in aged animals are exposed only to circulating factors of young animals, and vice versa. Thus, they established parabiotic pairings between young and old mice (heterochronic parabioses), with parabiotic pairings between two young mice or two old mice (isochronic parabioses) serving as controls. In parabiosis, two mice are surgically joined, such that they develop a shared blood circulation with rapid and continuous exchange of cells and soluble factors at physiological levels through their common circulatory system.
Parabiosis was invented in 1864 by the physiologist Paul Bert in order to see whether a shared circulatory system was created. Clive McCay, a biochemist and gerontologist at Cornell University in Ithaca, New York, was the first to apply parabiosis to the study of ageing, but this technique fell out of favour after the 1970s, likely because many rats died from a mysterious condition termed parabiotic disease, which occurs approximately one to two weeks after partners are joined, and may be a form of tissue rejection. Only at the beginning of the 21st century, Irving Weissman and Thomas A. Rando at the Stanford University brought parabiosis back to life, to study the movement and fate of blood stem cells.
The Stanford group investigated muscle regeneration and liver cell proliferation in the parabiosis setting. Notably, parabiosis with young mice significantly enhanced the regeneration of muscle in old partners. The regeneration of aged muscle was almost exclusively due to the activation of resident, aged progenitor cells, and not to the engraftment of circulating progenitor cells from young partners. In the case of liver studies, and as in muscle, parabiosis to a young partner significantly increased hepatocyte proliferation in aged mice. As also in muscle, the enhancement of hepatocyte proliferation in aged mice was due to resident cells and not the engraftment of circulating cells from young partners.
From that start, the paper walks through more recent years of work, including the ongoing debate over whether GDF11 is or is not important in the effects of parabiosis, and the beginning of human trials of blood transfusion from young donors. It omits last year's findings that suggest dilution of harmful factors in old blood is the more important mechanism in parabiosis studies, possibly because it was written prior to that point. Papers can take a long time to make it through peer review to publication. Results from human transfusion studies are so far entirely unspectacular, which at the outset seemed to me a likely outcome given disappointing results in mice. Transfusion is quite different from parabiosis, but we should at least think that this might be telling us something about which mechanisms are more plausible.
Human PAI-1 Loss of Function Mutants Found to Live Seven Years Longer than Peers
Researchers have found a noteworthy effect on longevity in a small study population that includes the only known individuals with a loss of function mutation in plasminogen activator inhibitor-1 (PAI-1). Individuals with the mutation live seven years longer on average than near relatives without it. Repeating the study with larger groups of people obviously isn't a practical option in the case of rare mutations - we're stuck with the family trees that the research community is fortunate enough to identify - but one nonetheless has to wish for more individuals, in order to obtain a more reliable confirmation, when an effect of this size is reported. It means taking a step back to revisit questions we've asked ourselves about the odds of finding significant longevity-enhancing mutations in our species, based upon the absence of results for the past twenty years of searching.
This is also a finding that can and probably should be taken as support for current work on elimination of senescent cells as a potential rejuvenation therapy. PAI-1 isn't a gene pulled from thin air in this context. It is well studied for its influence on aging, and appears to be one of the driving regulators of the harmful effects of cellular senescence. Lingering senescent cells accumulate with age, and secrete a mix of damaging signal molecules that produce chronic inflammation, damage tissue structure, and alter the behavior of nearby cells for the worse. This is known as the senescence-associated secretory phenotype (SASP), and PAI-1 is involved in both the SASP and in some of the processes by which cells become senescent. Studies show that inhibition or loss of PAI-1 reduces some of the harms now known to be associated with senescent cell presence, and in doing so slows measures of aging.
There is all sorts of past research into PAI-1 and senescent cells that we might choose to draw lines between. To pick one example, PAI-1 inhibition can slow atherosclerosis, just as can removal of senescent foam cells in atherosclerotic plaque. There are no doubt overlapping mechanisms here, though it seems clear that reducing PAI-1 levels has a variety of other effects as well. Those effects can't be all that terrible given the existence of a lineage of thriving human mutants lacking PAI-1, something that is always a good demonstration to have in hand. There are a few other beneficial mutations with a small human population to examine, such as those related to reduced blood lipids; we may see many of these lines of research result in therapies in the years ahead. And yet! While there will no doubt be an avalanche of funding into bringing PAI-1 inhibitors to the clinic, ask yourself this: if tinkering with a fraction of the harmful secretions of senescent cells is this beneficial, how much better will it be to remove these damaging cells entirely via senolytic therapies? All of those involved in this field should spend more time than they do on work with a higher expectation value, I believe.
Genetic mutation in extended Amish family in Indiana protects against aging and increases longevity
The first genetic mutation that appears to protect against multiple aspects of biological aging in humans has been discovered in an extended family of Old Order Amish. An experimental "longevity" drug that recreates the effect of the mutation is now being tested in human trials to see if it provides protection against some aging-related illnesses. Indiana Amish kindred (immediate family and relatives) with the mutation live more than 10 percent longer and have 10 percent longer telomeres (a protective cap at the end of our chromosomes that is a biological marker of aging) compared to Amish kindred members who don't have the mutation.
Amish with this mutation also have significantly less diabetes and lower fasting insulin levels. A composite measure that reflects vascular age also is lower - indicative of retained flexibility in blood vessels in the carriers of the mutation - than those who don't have the mutation. These Amish individuals have very low levels of PAI-1 (plasminogen activator inhibitor,) a protein that comprises part of a "molecular fingerprint" related to aging or senescence of cells. It was previously known that PAI-1 was related to aging in animals but unclear how it affected aging in humans.
"For the first time we are seeing a molecular marker of aging (telomere length), a metabolic marker of aging (fasting insulin levels) and a cardiovascular marker of aging (blood pressure and blood vessel stiffness) all tracking in the same direction in that these individuals were generally protected from age-related changes. That played out in them having a longer lifespan. Not only do they live longer, they live healthier. It's a desirable form of longevity. It's their 'health span.'"
The researchers have partnered with another group in the development and testing of an oral drug, TM5614, that inhibits the action of PAI-1. The drug has already been tested in a phase 1 trial in Japan and is now in phase 2 trials there. The team will apply for FDA approval to start an early phase trial in the U.S., possibly to begin within the next six months. The proposed trial will investigate the effects of the new drug on insulin sensitivity on individuals with type 2 diabetes and obesity because of the mutation's effect on insulin levels in the Amish.
A null mutation in SERPINE1 protects against biological aging in humans
Aging remains one of the most challenging biological processes to unravel, with coordinated and interrelated molecular and cellular changes. Humans exhibit clear differential trajectories of age-related decline on a cellular level with telomere attrition across various somatic tissues and on a physiological level across multiple organ systems. In addition to telomere length, researchers have proposed several molecular drivers of aging, including genomic instability, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Despite knowledge of these potential molecular causes of aging, no targeted interventions currently exist to delay the aging process and to promote healthy longevity.
In the United States, cardiometabolic disease influences life span as a leading cause of death and disability in adult men and women. Cardiometabolic disease is associated with a shorter leukocyte telomere length (LTL). Telomere shortening, which results from replication of somatic cells in vitro and in vivo, may cause replicative senescence. Senescent cells and tissues exhibit a distinctive pattern of protein expression, including increased plasminogen activator inhibitor-1 (PAI-1) as a part of the senescence-associated secretory phenotype (SASP).
PAI-1, which is encoded by the SERPINE1 gene, is the primary inhibitor of endogenous plasminogen activators and is synthesized in the liver and fat tissue. In addition to its role in regulating fibrinolysis, PAI-1 also contributes directly to cellular senescence in vitro. Genetic absence or pharmacologic inhibition of PAI-1 in murine models of accelerated aging provides protection from aging-like pathology, prevents telomere shortening, and prolongs life span. Cross-sectional human studies have demonstrated an association of plasma levels of PAI-1 with insulin resistance. Large genome-wide association studies (GWAS) provide an additional supportive evidence for a casual effect of PAI-1 on insulin resistance and coronary heart disease.
The role of the SASP, in general, and specifically PAI-1 in longevity in humans is uncertain. We have previously reported the identification of a rare frameshift mutation in the SERPINE1 gene in the Old Order Amish (OOA), living in relative geographic and genetic isolation; this mutation results in a lifelong reduction in PAI-1 levels. Therefore, we tested the association of carrier status for the null SERPINE1 mutation with LTL as the prespecified primary end point in the only known cohort with a SERPINE1 null mutation. The central findings of our study are that heterozygosity for the null SERPINE1 gene encoding PAI-1, which is associated with a lifelong reduction in PAI-1, is associated with longer LTL, a healthier metabolic profile with lower prevalence of diabetes, and a longer life span. The Amish kindred provide an unprecedented opportunity to study the biological effects of a private loss-of-function mutation with a large effect on circulating PAI-1 on longevity in humans.
The current study builds upon the available cellular and animal evidence supporting the role of PAI-1, the product of SERPINE1, as an important contributor to aging. PAI-1 expression is increased in senescent cells and tissues and is a fundamental component of the SASP. There is a compelling evidence that senescent cells accumulate in the tissues and contribute to the aging process. In addition to contributing to the molecular fingerprint of senescence, PAI-1 is necessary and sufficient for the induction of replicative senescence in vitro and is a critical downstream target of the tumor suppressor p53. The contribution of PAI-1 to cellular senescence is broadly relevant in the organism as a whole.
Mild Mitochondrial Stress Found to Prevent Some of the Age-Related Declines in Cellular Maintenance in Nematodes
Hormesis is a near ubiquitous phenomenon in living organisms and their component parts: a little damage, a short or mild exposure to damaging circumstances, can result in a net benefit to health and longevity. Cells respond to damage or stress by increasing their self-repair efforts for some period of time, maintaining their function more effectively than would otherwise have been the case. At the high level, the outcomes of hormesis have been measured for a wide variety of stresses and systems, from individual cells to entire organisms. At the low level of specific biochemical processes and interaction of components inside the cell, there is a lot more mapping and cataloging to be accomplished, however.
The research noted below is an example of the this sort of exploration. It is an interesting study for demonstrating that some forms of stress response can turn back a fraction of the age-related decline in cellular maintenance processes, at least temporarily. It is well known that cellular maintenance falters in later life. This is in some cases a form of unhelpful reaction or side-effect caused by rising levels of damage and dysfunction, and in others it is a direct consequence of damage to the systems responsible for maintenance and repair. As an example of the second type, the lysosomes responsible for recycling broken molecules and structures in the cell can become clogged with rare, resilient waste compounds that they cannot process. The whole process of repair runs down when that happens.
The research here appears to touch on the first type of decline, demonstrating that controlling signals can be overridden to turn on the repair machinery once more. In the nematode worms the researchers work with, the species Caenorhabditis elegans, the result is a fair-sized increase in life span. Based on the results of numerous other interventions that increase the activities of cellular maintenance processes, this sort of outcome is expected. It is worth noting that very large increases of this nature in nematode life span - or indeed in any short-lived species - do not map to noteworthy increases in human life span. Our life spans are far less plastic in response to circumstances, despite benefiting from similar types of intervention. Calorie restriction is one of the better known ways to spur greater cellular maintenance activity, and while it certainly improves human health, it doesn't make us live significantly longer, as is the case in short-lived species.
Mitochondrial stress enhances resilience, protects aging cells and delays risk for disease
In a genetic study of the transparent roundworm C. elegans, a research team found that signals from mildly stressed mitochondria (the cellular source of energy) prevent the failure of protein-folding quality-control (proteostasis) machinery in the cytoplasm that comes with age. This, in turn, suppresses the accumulation of damaged proteins that can occur in degenerative diseases, such as Alzheimer's, Huntington's and Parkinson's diseases and amyotrophic lateral sclerosis (ALS).
"People have always known that prolonged mitochondrial stress can be deleterious. But we discovered that when you stress mitochondria just a little, the mitochondrial stress signal is actually interpreted by the cell and animal as a survival strategy. It makes the animals completely stress-resistant and doubles their lifespan. It's like magic. Our findings offer us a strategy for looking at aging in humans and how we might prevent or stabilize against molecular decline as we age. Our goal is not trying to find ways to make people live longer but rather to increase health at the cellular and molecular levels, so that a person's span of good health matches their lifespan."
The study builds on earlier work in which the researchers reported that the molecular decline leading to aging begins at reproductive maturity due to inhibitory signals from the germ line cells to other tissues to prevent induction of protective cell stress responses. In C. elegans, this is between eight and 12 hours of adulthood, yet the animal will typically live another three weeks. The researchers screened the roundworm's approximately 22,000 genes and identified a set of genes, called the mitochondrial electron transport chain (ETC), as a central regulator of age-related decline. Mild downregulation of ETC activity, small doses of xenobiotics and exposure to pathogens resulted in healthier animals, the researchers found.
Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse during Aging
Old age is the primary risk factor for many human diseases, but the overarching principles and molecular mechanisms that drive aging remain poorly understood. Aging has long been thought of as a stochastic process that is characterized by the gradual accumulation of cell damage. However, recent evidence suggests that aging arises, at least in part, from programmed events early in life that promote reproduction. In the nematode Caenorhabditis elegans, the ability to prevent metastable proteins from misfolding and aggregating fails early in adulthood, resulting in the appearance and persistence of protein aggregates in multiple tissues before animals have ceased reproduction.
Proteostasis is routinely maintained through the activity of constitutive and inducible stress response pathways. Among these, the transcription factor HSF-1 promotes the expression of molecular chaperones and enhances protein-folding capacity in the cytosol and nucleus through the heat shock response (HSR). During C. elegans adulthood, the HSR undergoes rapid repression as animals commence reproduction, thereby leaving cells vulnerable to environmental stress and proteostasis collapse well before overt signs of aging are distinguishable. This suggests that precise regulatory switches actively repress the HSR early in life as part of programs that promote reproduction at the cost of proteostasis.
To this end, we performed an unbiased genetic screen to identify genes whose knockdown maintains resistance to thermal stress and prevents repression of the HSR in reproductively active adults. We identified the mitochondrial electron transport chain (ETC) as a robust determinant of the timing and severity of the decline in the HSR and show that mild mitochondrial stress increases HSF-1 binding at target promoters, maintains the HSR, and preserves proteostasis in reproductively active animals. These beneficial effects were achieved without the severe physiological defects typically associated with impaired mitochondrial function, suggesting that modulation of mitochondrial activity is a physiologically relevant determinant of the timing of repression of the HSR and cytosolic proteostasis collapse with age.
Defenestration and the Roots of Age-Related Insulin Resistance
Defenestration is apparently a word with two meanings. The second, a scientific term, is the removal or loss of fenestrations. Let it never be said that this is not a place of learning. What, one might ask, are fenestrations? This is another word adopted by the scientific community and given an additional meaning: it refers to a collection of small openings or pores in our biology. The particular small openings or pores that concern us today are those found in the blood vessels of the liver, one of the organs involved in the development and progression of type 2 diabetes.
While we might tend to think of type 2 diabetes as a disease caused by excess fat tissue, and for more than 90% of patients in our modern era of cheap calories this is entirely true, it is also the case that the damage of aging ultimately leads to a similar dysfunction in insulin metabolism. The path to the same end is quite different, however. While even the comparatively late stages of visceral-fat-induced diabetes can be reversed through a sustained low-calorie diet and loss of that fat, there is nothing much that can yet be done to effectively deal with purely age-related diabetes. This is just one of the many age-related conditions we'd like to reverse through rejuvenation therapies based on the SENS research programs.
The short open access commentary below summarizes some of the mechanisms involved in loss of insulin sensitivity in the old, distinct from those losses caused by fat tissue. This is where the fenestrations of blood vessels in the liver enter the picture. The authors present evidence to suggest the loss of fenestrations - defenestration - increasingly blocks the passage of insulin to where it is needed, producing what is in effect insulin resistance and all of its secondary consequences. To me the interesting questions attend the cause of this change: is it a form of dysfunction in tissue maintenance of the sort that arises due to growing inflammation in aging tissues? Is it some other secondary effect, a change in signaling that disrupts whatever cellular coordination is needed to form fenestrations? Further research is needed.
It's the holes that matter
Before circulating insulin can interact with membrane bound insulin receptors and trigger downstream signalling it must first cross the endothelium of the blood vessels in the target tissue. This transfer across the endothelium from the blood is recognised as a rate limiting step in insulin action in muscle and fat in humans, but the role of the liver endothelium in insulin uptake has not been examined previously. Recent research explores the contribution of insulin transfer from the blood, across the liver sinusoidal endothelium and to the insulin receptors on the hepatocytes as a mechanism for the development of hyperinsulineamia and insulin resistance, as identified as a major risk factor for the development of age-related disease in humans.
The sinusoids, or blood vessels of the liver are lined by specialized endothelial cells that are very thin and perforated with transcellular holes or pores that traverse the entire cell. These pores, known as fenestrations, have no diaphragm and are patent passages through the cell. The fenestrations provide efficient ultrafiltration of small material from the blood into the liver. Coupled with very little extracellular matrix and a highly adapted hepatocyte membrane, uptake of substrates, such as nutrients, toxins, and insulin into the liver for metabolism, detoxification, and signalling is rapid and regularly overlooked. However, in older age, the morphology of the liver sinusoids and the endothelium changes significantly. The cells become thicker, and the diameter and number of fenestrations is reduced by up to 50% (known as defenestration), there is extracellular matrix deposition and evidence of loss of hepatocyte microvilli. Collectively, these changes have been called pseudocapillarization. It has previously been shown that these changes reduce hepatocyte uptake of lipoproteins and some drugs.
In the current work, the hepatic and systemic disposition of insulin was explored in young and old animals and insulin resistance was confirmed to be present in the older animals. Critically, using multiple indicator techniques insulin transfer across the liver endothelium was shown to be significantly impaired. The 20% reduction in insulin's volume of distribution in the liver was consistent with limited transfer across the sinusoidal endothelium and retention of insulin in the sinusoid. In concordance with these changes, there were very high circulating insulin levels indicative of both increased secretion and impaired clearance. Despite normal glucose tolerance tests in the older animals, insulin resistance was present. Of key importance, insulin and glucose uptake into muscle and fat was shown to be unchanged with age, suggesting age related insulin resistance was most likely being driven by impaired hepatic uptake and clearance.
This work suggests that defenestration and pseudocapillarization of the liver sinusoidal endothelium seen in aging prevents the access of insulin to the insulin receptor on the hepatocyte membrane through impaired transfer across the endothelium. This results in hyperinsulinemia, impaired hepatic insulin signalling and insulin resistance. Further the work demonstrates that the liver endothelium does not provide a barrier for the uptake of insulin under normal conditions. In summary, patent fenestrations are required for hepatic insulin uptake, clearance, and signalling and loss of fenestrations is a probable causative mechanism for insulin resistance and diabetes seen with aging. This work provides evidence that maintaining the integrity of the liver sinusoidal endothelium into old age may prevent age-related insulin resistance and excitingly, introduces a novel therapeutic target.
Why is Sepsis a Condition of the Elderly?
Sepsis and consequent septic shock occur more frequently in the old and cause greater harm and mortality in older individuals. The condition occurs when an infection spurs the immune system into a state of runaway inflammation and then shutdown, sufficient to disrupt or permanently damage metabolism and organ function. The open access paper here dives into the details of age-related immune system dysfunction, with an eye to explaining why exactly these failures cause sepsis to be both worse and more prevalent in the elderly. As for so many of the specific frailties of old age, the best solution is to repair the immune system - to address the specific, most important root causes of its decline, such as failing blood stem cells, atrophy of the thymus, and accumulation of malfunctioning or overspecialized immune cells.
The treatment of critically ill aged patients is challenging. Older people frequently exhibit atypical symptomatology, due to comorbidities and dysfunctions throughout all body systems that are related to the aging process. Sepsis is a disease of the elderly. The incidence of sepsis increases exponentially with age, and sepsis-associated long-term sequelae particularly affect older patients. Sepsis survivors are at substantial risk for poor quality of life, functional disability, and cognitive impairment. As advances in medicine and quality of life extend the life expectancy worldwide, a growing number of aged patients need critical care. A recent study demonstrated a significant rise in survivorship after sepsis in the United States, caused by a rising incidence of sepsis rather than improvements in its case fatality rate, generating a substantial population burden of aged patients with disabilities.
The reason for the higher susceptibility to infection and increased mortality in older adults remains in debate. The basal inflammatory state found in healthy seniors suggests that aged people possess a limited capacity to control inflammation. Similarly, the critically ill are frequently affected by overwhelming inflammatory syndromes, where the host response is the major cause of damage. The chronic low-grade inflammation in the elderly and the explosive inflammation in the critically ill share several commonalities. We propose that, together, these processes may have synergistic effects, leading to a worse outcome.
Notably, these synergistic effects have interesting peculiarities. A study performed by our group found that older people are as immunocompetent as young individuals regarding the cytokines, chemokines, and growth factors produced in response to devastating infections. After our analysis of several inflammatory mediators in the plasma of critically ill individuals, we were unable to find any reason that could serve to better explain why the aged show an increased susceptibility and mortality to septic shock. This phenomenon can be partially explained by the fact that aged people probably display a prolonged inflammatory systemic response under acute stress conditions, when compared with the systemic response of the young, even though both groups share the same ability to trigger and sustain the same intensity of inflammatory signaling in the acute phase.
The intestinal mucosal barrier is a fundamental line of defense against undesirable microorganisms, toxins, and antigens, preventing their entrance into the bloodstream. Aged people are in a persistent systemic inflammatory state that may be partially attributed to increased bacterial translocation, secondary to intestinal barrier dysfunction. As people age, the intestinal barrier weakens, partially due to decreased levels of tight junctions connecting epithelial cells, and the enteric immune system becomes ineffective. These observations suggest that the increased mortality of aged patients in critical care conditions is probably due to a prolonged systemic inflammatory response, at least partially caused by increased bacterial translocation and defective bacterial clearance.
A Study of Early Life Adversity versus Later Immune Aging Points to Cytomegalovirus as the Problem
A fair number of research groups study psychological stress and aging, and investigations of early life adversity versus later risk of age-related disease fall into this category. The paper here finds that persistent cytomegalovirus infection is likely the mediating mechanism linking early life stress and later increased risk of age-related disease, acting through accelerated immune system dysfunction. This implies that the early stress may or may not be all that important, as - for whatever reason - the groups selected as examples of stress in early life are also more likely to be infected. That might be the short-term detrimental effects of stress on immune function, or it could be a matter of being in close contact with more distinct groups of people during childhood, as is the case for the adopted individuals in the study here.
Cytomegalovirus is a persistent herpesvirus that the immune system cannot effectively clear from the body. Near everyone becomes infected at some point in life, and extensive evidence links this infection with immune system dysfunction. Increasing numbers of immune cells become dedicated to uselessly fighting cytomegalovirus, and ever fewer are left for everything else the immune system must accomplish. Other than this long-term corrosion, cytomegalovirus doesn't cause obvious symptoms in the vast majority of people - few notice the initial infection. Removing cytomegalovirus isn't that helpful, as the damage is already done in the old, and the young will be reinfected. A more useful approach might be to selectively target and destroy cytomegalovirus-specific immune cells to free up space for their replacement.
Adverse and stressful events in childhood, such as parental loss, low childhood socioeconomic status, or institutionalization, have been associated with elevated levels of inflammation and an increased risk for multiple age-related diseases, such as cardiovascular disease. Many efforts have been made to understand the mechanisms underlying long-term effects of ELA. One of the mechanisms proposed is accelerated aging of the immune system, also known as immunosenescence. Immunosenescence refers to the process of progressive deterioration of immune functions that go hand in hand with normal aging. If ELA affects the rate of immunosenescence, this may explain an increased risk and earlier onset of age-related disorders.
It remains an open question as to what drives ELA-associated immunosenescence. Besides ELA, several other environmental factors have been found to modulate the rate of immunosenescence, such as persistent viral infections. Herpes simplex virus (HSV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) are among the most prevalent viral infections that establish latency after primary infection and reactivate when the immune system is compromised. Latent infections with CMV in particular are believed to play an important role in immunosenescence and are associated with age-related alterations of T cell immunity.
In this study, we investigated T cell-specific immunosenescence (T cell differentiation and CD57 expression) in participants with and without a history of ELA. Participants in the ELA group had experienced separation from their parents in early childhood and were subsequently adopted, which is a standard model of ELA. This study cohort is a healthy subset of the EpiPath cohort, excluding all participants with acute or chronic diseases. With a mediation analysis we examined whether CMV titers may account for immunosenescence observed in ELA.
In this study, we have shown that ELA is associated with higher levels of T cell senescence in healthy participants. Not only did we find a higher number of senescent cells (CD57+), these cells also expressed higher levels of CD57, a cell surface marker for senescence, and were more cytotoxic in ELA compared to controls. Control participants with high CMV titers showed a higher number of senescent cells, compared to controls with low titers. Importantly, we found that the effect of ELA on immunosenescence was associated with CMV infection specifically, rather than being the consequence of continued reactivation of latent viruses in general.
Our findings have important implications for this literature on senescence in ELA. Most evidence for accelerated immunosenescence in ELA comes from telomere length, but none of these studies have accounted for CMV infections. Our results suggest that the association between ELA and shorter telomeres - or immunosenescence in general - may have been largely mediated by CMV infection. First of all, because there is a clear link between CMV infection and immunosenescence. CMV infection is related to expanding populations of specific memory T cells, and a shrinking population of naïve T cells, similar to what is observed in aging. CMV seropositivity has been shown to reduce life expectancy by almost 4 years in an elderly population, especially due to an increase in cardiovascular deaths.
Second, there is reason to believe that children in adverse circumstances are at higher risk for CMV infection. For instance, the likelihood of CMV infection is higher in children raised in poverty and low socioeconomic status. There is no clear epidemiological data on the prevalence of infection in international adoptees, as were included in this study. However, most adopted children have been institutionalized prior to adoption, which arguably increases the risk for CMV infection, as is the case for day-care center attendance.
Inhibiting Interleukin 11 can Suppress Fibrosis
The ability to reverse fibrosis would turn back some fraction of the progression of age-related failure in heart, kidney, lungs, and other organs. Fibrosis is a form of scarring in tissue that forms in place of functional structures, and appears to caused by a chronic inflammation state of the immune system, as well as by the growing number of senescent cells found in older tissues. Normal regeneration and tissue maintenance is a complicated, coordinated process involving stem cells, transient senescent cells, immune cells, somatic cells in the vicinity, and a whole lot of signaling back and forth. So it is perhaps understandable that lingering senescent cells, altered signaling, and a dysfunctional immune system could cause it to run awry.
Removal of senescent cells reverses fibrosis to some degree in studies where it has been attempted. Senescent cells cause chronic inflammation through the mix of signals they generate, known to include the inflammatory cytokine interleukin 6 (IL-6), among many others. IL-6 and interleukin 11 (IL-11) are known to share many commonalities. The latter is not among the interleukins so far found to be secreted by senescent cells, however. So given this, and that senescent cells are now so strongly tied by evidence to fibrosis, it is somewhat interesting see compelling evidence for IL-11 to be a driver of fibrosis. It suggests that it is simplistic to blame direct signaling from senescent cells for all inflammatory issues: a great deal of secondary signaling and activity is no doubt taking place as well, not to mention other possible independent causes of inflammation in aging.
Researchers have discovered that a critical protein, known as interleukin 11 (IL11) is responsible for fibrosis and causes organ damage. While it is surprising that the importance of IL11 has been overlooked and misunderstood for so long, it has now been very clearly demonstrated by this work. A protein known as transforming growth factor beta 12 (TGFB1) has long been known as the major cause of fibrosis and scarring of body organs, but treatments based on switching off the protein have severe side effects. The scientists discovered that IL11, is even more important than TGFB1 for fibrosis and that IL11 is a much better drug target than TGFB1.
Fibrosis is the formation of excessive connective tissue, causing scarring and failure of bodily organs and the skin. It is a very common cause of cardiovascular and renal disease, where excessive connective tissue destroys the structure and function of the organ with scar tissue. Fibrosis of the heart and kidney eventually leads to heart and kidney failure, thus this breakthrough discovery - that inhibiting IL11 can prevent heart and kidney fibrosis - has the potential to transform the treatment of millions of people around the world.
"The team is at the stage of developing first-in-class therapies to inhibit IL11 and this offers hope to patients with heart and kidney disease. This therapeutic target for fibrotic diseases of the heart, kidney and other organs may be exactly what we need to fill the unmet pressing clinical gap for preventing fibrosis in patients. We are proud to announce that the suite of intellectual property arising from this research has been licensed to a newly launched Singapore-funded biotechnology start-up Enleofen Bio."
A Klotho Gene Therapy Produces Long-Lasting Cognitive Enhancement in Mice
Klotho is a longevity-associated gene in mice and humans, but in recent years researchers have seemed more interested in delving into its effects on cognitive function. Now a team has demonstrated that one of the various forms of klotho protein can be increased via gene therapy in order to produce long-lasting cognitive enhancement following a single treatment. This is somewhat more interesting than earlier work involving genetic manipulation of klotho levels, and similar to another study that used a different protein derived from the klotho gene. It remains to be seen as to whether this sort of approach will hold up for human subjects, though some of the evidence for human cognitive function to associate with klotho levels is intriguing.
αKlotho is a gene regulator of aging, increasing life expectancy when overexpressed and accelerating the development of aging phenotypes when inhibited. Research has shown that elevating Klotho levels have beneficial effects on synaptic and cognitive functions through a mechanism involving the NMDA receptor (NMDAR). Moreover, studies in three independent human cohorts showed that human carriers of the klotho KL-VS allele, which increases secretion of Klotho in vitro, obtained better results in various cognitive tests.
To date, all studies have focused on the transmembrane and the processed forms of Klotho (named m-KL and p-KL). In pioneering work, it was recently demonstrated that alternative splicing of Klotho (s-KL) produces a stable truncated isoform. This work also shows a strong correlation between high expression levels of the two klotho transcripts in brain and healthy status while aging. Significantly, the secreted s-KL isoform is almost exclusively found in brain, while m-KL is mostly expressed in kidney and to a lesser extent in brain. This suggests s-KL may have an important role in the brain.
More detailed study revealed that the s-KL protein could be detected in different murine brain regions involved in learning and memory processes, such as prefrontal cortex, motor cortex, and hippocampus. Conceivably both isoforms may have similar roles, but as they are transcribed differently, they may have distinct functions. Here we study the role of s-KL in cognitive processes. We hypothesise it is a neuroprotective protein involved in the onset and/or progression of cognitive deficits associated with aging. To explore its effects, we modified s-KL levels in the brains of adult wild-type C57Bl/6J mice using AAVrh10 gene therapy vectors.
This study demonstrates for we believe the first time in vivo that 6 months after a single injection of s-KL into the central nervous system, long-lasting and quantifiable enhancement of learning and memory capabilities are found. More importantly, cognitive improvement is also observable in 18-month-old mice treated once, at 12 months of age. These findings demonstrate the therapeutic potential of s-KL as a treatment for cognitive decline associated with aging.
Libella Gene Therapeutics Plans Human Telomerase Gene Therapy Trial
My attention was recently directed to another new group planning patient paid human trials of telomerase gene therapy. This is a company associated with Sierra Sciences and the RAAD Festival crowd, meaning the Life Extension Foundation principals. These folk have of late started to fund a number of interesting efforts, such as the Betterhumans senolytics trials. This is another in that series.
Is telomerase gene therapy a useful treatment for aging? In mice it extends life span, most likely through effects such as greater immune activity and greater stem cell activity, but possibly also via other mechanisms. Telomerase acts to lengthen telomeres at the ends of chromosomes, but it also has a range of other functions, some of which might positively impact mitochondrial function. Average telomere length in tissues falls with age: it is a function of the rate of cell division, as telomeres shorten every time a cell divides, and stem cell activity, as stem cells produce daughter cells with long telomeres. So telomere length is very much an assessment of some of the processes of aging, not a cause of aging. In turn, telomerase gene therapy is not a means of targeting the causes of aging - rather, it is one of the more effective classes of compensatory treatment identified to date, alongside forms of stem cell therapy.
Whether telomerase gene therapy will have the same sort of risk and benefit profile in humans as it does in mice is something of an open question. Mice have very different telomere dynamics in comparison to humans, and the risk of cancer may well be quite different as well. Counterintuitively, in mice that risk actually appears to be reduced by introduction of telomerase, though the mechanisms involved are not well understood. We might hypothesize that increased immune system efficiency in removing potentially cancerous cells counterbalances the telomerase-induced tendency for those cells to become more active. Still, how do you find out other than by trying? Making the attempt is the most cost-effective means of obtaining human data.
Our mission is to reverse aging and cure all age-related diseases, starting with Alzheimer's. Libella Gene Therapeutics has exclusively licensed the technology of Sierra Sciences to conduct a human research project. We believe we have the scientist, the technology, the physicians, and the lab partners, all of which are necessary to get this done. By activating telomerase, we hope to lengthen telomeres in the body's cells. To have an effective delivery system for the telomerase to reach every cell in the body, quadrillions of gene therapy particles must be produced for each test subject. The production of enough gene therapy particles to treat one person takes anywhere from four months to a year to complete. Because of the demands on production, we will have a limited number of tests available. We anticipate having around 50 spots over the next 12 months.
We believe the most expedient way to test revolutionary evidence-based technology, such as gene therapy, is a pay to play model. The FDA passed legislation in 2009 allowing for patients to pay for their care when other viable options are not available. Libella Gene Therapeutics (LGT) strongly believes an informed choice is a right, not a privilege. LGT believes that "pay to play" is ethical. The data has continued to mount that telomerase activation and lengthening of telomeres may be the most exciting and disruptional breakthrough in the history of medicine. LGT is committed to bringing telomerase therapy to the world.
Today the majority of human clinical studies are performed outside of the United States. 65% of clinical studies are performed off shore. Typically it is cheaper, quicker, and involves less regulation. LGT believes it is most ethical to conduct our studies outside of the United States where we can move faster, and at a lower cost, as long as there is no reduction in quality or safety for our study participants.
The Limits to Human Longevity, or Lack Thereof
This open access paper is a good resource if you happen to want a list of references to the mainstream scientific discussion of the past twenty years regarding trends in human life expectancy, and the predicted future of those trends. It is somewhat myopic beyond that in the sense that it gives little credit to the idea that the trend might continue or increase, as a result of future technological progress in medicine. The trend is an artifact of human efforts, and as such the size of the trend is entirely dependent on how well medicine can be made to address the causes of aging.
In the past, no effort at all was directed towards treating the causes of aging, and the small degree of extended healthy life with each passing year was an entirely accidental benefit. We are now at a point in time in which the scientific community is transitioning into making deliberate efforts to treat the causes of aging, with increasing enthusiasm and funding. Therefore expecting the future trend to look like the past trend, or even slow down, or thinking that we are in any way approaching a limit to human life span, appears to me to be a nonsensical position. We can understand why human life span is limited today, and why it was limited in the past: it does not follow that it will be limited in the future, because medical science will address the biological mechanisms involved, the accumulation of cell and tissue damage that causes aging.
How long can we live? How fast can we run or swim? Demographers disagree about the lifespan trend and its potential limit, while sports scientists discuss the frontiers of maximal physical performance. Such questions stimulate large and passionate debates about the potential of Homo sapiens and its biological upper limits. Historical series, defined as the measurable data collected since the nineteenth century for lifespan, sport, or height provide crucial information to understand human physiology and the form and nature of our progression over the last 10 generations.
Recent studies about lifespan trends increased interest about the possible ceilings in longevity for humans. This long-lasting debate increased in strength at the beginning of the 1990s. Using biological and evolutionary arguments, the first leading opinion postulated an upper limit for life expectancy at birth and maximal longevity. These limits may have already been approached: around 85-95 years for life-expectancy and 115-125 years for maximal longevity, as a result of nutritional, medical, societal, and technological progress. A second school of thought considered that life expectancy may continue to progress indefinitely at a pace of 2 to 3 added years per decade. They claim that most of the babies born during the 2000s, "if the present yearly growth in life expectancy continues through the twenty-first century," will celebrate their 100th birthday or, potentially reach physical immortality due to undefined scientific breakthroughs.
Human life-expectancy and maximal lifespan trends provide long historical series. Similar to sport achievements, though somewhat less precisely measured, it followed an unprecedented progression during the twentieth century supported by major nutritional, scientific, technological, societal, and medical innovations. From 1900 to 2000 in the majority of high-income countries, life expectancy at birth increased by ~30 years, mostly due to a reduction of child mortality through nutrition, hygiene, vaccination, and other medical improvements.
Concerning the future, trends oscillate, from pessimistic to optimistic views, but recent data suggest a slow-down in the progress of life-expectancy related to the stabilization of a very low level of infant mortality (0.2-1% of births in the healthiest countries in the world). The present slow progress in high-income countries is mostly due to reduced mortality rates of chronic non-communicable diseases, principally among cardiovascular diseases and cancers. However, those advancements have a much lower impact on life-expectancy as compared to vaccination campaigns.
Predicting a continuous linear growth of life-expectancy in the long term may probably not be relevant if the major progresses have already been accomplished. Beyond the fittest mathematical model for estimating future trends, we need to carefully examine the consistency with structural and functional limits determining maximal lifespan related to life-history strategies and evolutionary and environmental constraints. For example, aging is an irreversible process: it is complex as it concerns all physiological functions, organs, and maintenance systems. But, it also has universal characteristics, showing a continuous exponential decline starting in the third decade for all maximal indicators with an accelerated loss of physical performance until death. No escape from decline is observed, despite the best efforts of the oldest old.
Similarly, maximal lifespan increased slightly during the last two centuries, but since 1997, nobody has lived for more than 120 years. Surpassing mathematical models, projecting 300 years into the future without biological considerations, most recent data showed evidence of a lifespan plateau around 115-120 years, despite a sharp increase in the number of centenarians and supercentenarians. Jeanne Calment with 122.4 years has certainly come close to the potential biological limit of our species in term of longevity, at the benefit of an extremely rare long-lived phenotype supported by a specific lifestyle and chance.
A Profile of James Clement's Supercentenarian Research
Should James Clement's name remain well-known in association any of the present day work on human longevity, one would hope it will be as one of the pioneers to first organize trials of senolytic therapies in humans, via his Betterhumans organization. This is far from the only research interest of this citizen scientist, however, and in past years he has put in a great deal of time and effort to expand what is known of the genetics and biochemistry of supercentenarians, rare individuals who survive past the age of 110. That is the focus of the article here.
For my part I think that the genetics of supercentenarians are not the place to look for meaningful therapies to lengthen life. After all, these individuals are still very frail, enormously impacted by the damage of aging. So far as past genetic assessments have shown, there isn't much of a difference between the survivors and the dead in any given birth year. A tiny fraction of people beat the odds even when the odds are long, and that may well be all there is to it: chance in complex system. Still, rare discoveries such as that announced yesterday keep the hope alive that there is some genetic rarity in supercentenarians that might be more relevant to future medicine. Regardless, I see the path forward as something other than genetic mapping. Instead it is that of senolytics and other forms of therapy that aim to periodically repair the damage that causes aging before it rises to pathological levels, to prevent and turn back aging, not just slow it a little.
The full genetic sequences of some three dozen genomes of North American, Caribbean, and European supercentenarians being made available this week by a nonprofit called Betterhumans to any researcher who wants to dive in. A few additional genomes come from people who died at 107, 108 or 109. If unusual patterns in their three billion pairs of A's, C's, G's and T's - the nucleobases that make up all genomes - can be shown to have prolonged their lives and protected their health, the logic goes, it is conceivable that a drug or gene therapy could be devised to replicate the effects in the rest of us.
The rare cache of supercentenarian genomes, the largest yet to be sequenced and made public, comes as studies of garden-variety longevity have yielded few solid clues to healthy aging. Lifestyle and luck, it seems, still factor heavily into why people live into their 90s and 100s. To the extent that they have a genetic advantage, it appears to come partly from having inherited fewer than usual DNA variations known to raise the risk of heart disease, Alzheimer's disease and other afflictions.
That is not enough, some researchers say, to explain what they call "truly rare survival," or why supercentenarians are more uniformly healthy than centenarians in their final months and years. Rather than having won dozens of hereditary coin tosses with DNA variations that are less bad, scientists suggest, supercentenarians may possess genetic code that actively protects them from aging. But the effort to find that code has been "challenged," as a group of leading longevity researchers put it in a recent academic paper, in part by the difficulties in acquiring supercentenarian DNA.
The DNA sequences being released this week were acquired almost single-handedly by James Clement, 61. A professed citizen-scientist, Mr. Clement collected blood, skin, or saliva from supercentenarians in 14 states and seven countries over a six-year period. The usefulness of such a small group for a genetic study is unclear, which is one reason Mr. Clement's company Androcyte, now defunct, has turned into a crowdsourcing project. So despite the limitations of Mr. Clement's database, several prominent researchers have already expressed interest in it. "This could show the utility of starting a bigger collection."
There was, nominally, the prospect of making money. But with a business plan that, even to some of his investors, sounded more like a research project, Mr. Clement seems to have undertaken the task largely because it provided the chance to act on a longstanding interest in human longevity, including his own. A self-described transhumanist who eats mostly low-glycemic vegetables and nuts and walks seven miles a day, Mr. Clement has accumulated an eclectic résumé that includes starting a brew pub, practicing international tax law, and cofounding a futurist magazine. He harbors what he prefers to call a "healthy love of life," rather than an aversion to death, and he is possessed of an apparently genuine conviction that longer lives would make humans more humane.
"My hat was off to someone who was willing to take the time out of his life to go get these precious specimens," said Dr. George Church, the Harvard geneticist, who has devoted a portion of his laboratory to research into the reversal of aging. The kind of ultrarare mutations that supercentenarians might harbor, Dr. Church believed, were not likely to be detected with standard techniques, which scan only the places in the genome where DNA is already known to vary between individuals.
To look for as-yet-uncataloged variations would require sequencing all of the supercentenarians' six billion genetic letters, a far more expensive procedure. When he and Mr. Clement first discussed the idea in 2010, the cost was about 50,000 per genome. But the price was falling. And with the financial support of a handful of like-minded wealthy individuals who agreed to invest in the exploratory phase of the project, "it just seemed," Mr. Clement said, "like something I could do."
The Results of Most Potential Biomarkers of Aging Vary Considerably
As expected, a study finds that the numerous candidate biomarkers of aging vary widely in their assessments of biological age. This makes complete sense, as (a) aging is caused by a number of distinct processes of damage accumulation, and (b) most of the assessments measure one or more metrics that are more influenced by some forms of damage than by others. To pick an easy example, when measuring aging by skin-related metrics such as wrinkles, appearance, and elasticity, what is seen is primarily the consequences of cross-linking. If measuring fibrosis in organs, then that is primarily cellular senescence and immune system dysfunction. If measuring grip strength, falling numbers here are caused by the contributions to sarcopenia, which so far appears to be caused primarily by failing stem cell activity.
Of all of the potential biomarkers of aging, I would hypothesize that those based on patterns of DNA methylation are the best to date, as they likely measure blended cellular responses to all of the forms of damage that cause aging. That said, it is thought-provoking to see the evidence here suggest that a suitable combination of simple measures such as grip strength and bloodwork is more effective. The conclusion that biomarkers of aging are still a work in progress is no doubt an accurate one.
A head-to-head comparison of 11 different measures of aging, including blood and chromosome tests like those being sold commercially, has found that they don't agree with one another on how fast a given person is growing older. This comparison is based on a life-long study of nearly 1,000 people in Dunedin, New Zealand who have been studied extensively from birth to age 38. Researchers working with this study cohort had earlier reported that a panel of 18 biological measures might be used to predict the pace of aging, based on how these markers had changed from age 26 to 38 in a given individual. But when they expanded their analysis to look at whether these measures and others all pointed in the same direction at age 38, the picture was much less clear.
"People age at different rates and geriatric medicine needs a way to measure that, but when measuring all sorts of different aspects of a person's physiology, from genes to blood markers to balance and grip strength, you see a lot of disagreement. Based on these results, I'd say it's premature to market aging tests to the public."
For comparisons, the researchers drew on physical measures of aging collected from the Dunedin study group, including balance, grip, motor coordination, physical limitations, cognitive function and decline, self-reported health and facial aging as judged by others. Measuring the length of telomeres, protective caps of DNA at the end of chromosomes that unravel as we age, turned up no evidence of the ability to predict physical or cognitive changes, except possibly facial aging. "Telomeres are a fundamental mechanism of aging and cancer prevention, that's true. But saying it's useful to measure in a 50-year-old to see whether they're aging is a different matter."
The team also examined hundreds of locations in the genome to see changes in the patterns of DNA methylation, molecular controls that govern whether a gene is active or not. These epigenetic patterns have been studied by other researchers as clocks thought to measure the aging rate. The researchers measured the clocks when people were 26 and again when they were 38 and found the expected 12 years of progress. The good news is that the three different epigenetic clocks they tested seem to keep time pretty well. "But the clocks were less clearly related to changes in people's physiology or problems with physical or cognitive performance. That raises questions about whether they could be used to survey patients or populations to predict health span."
The team also applied algorithms developed by other teams to analyze a large collection of physiological measures, including blood markers and tests of heart and lung function, and found a somewhat stronger signal. When they statistically examined all of their tests against each other to see whether biological aging measures could predict physical changes or mental changes, they found that the physiological measures performed somewhat better than telomeres or epigenetic clocks. But none of the measures performed well enough to argue for including them in an annual physical exam. The search will continue. As scientists investigate therapies to slow aging, "we'd like to know in less than 30 years whether the treatment works." Ideally, such a measure would be related to chronological age and would be inexpensive and non-invasive so it could be given to people before and after testing an anti-aging therapy to see whether it's working.
Stem Cell Therapy Partially, Unreliably Repairs Spinal Cord Injuries in Rats
Engineering regeneration of an injured spinal cord is one of the fields to watch as a marker of capabilities in stem cell medicine. There is a fair amount of funding and effort directed towards this goal, and it requires overcoming a number of issues that are relevant to other types of regenerative medicine. These include overcoming scarring, inducing healing in tissues that normally do not regenerate in adults, ensuring the reliability of the outcome, and so forth. As the study here indicates, reliability remains a challenge. In all stem cell therapies, the factors that affect patient outcomes are still poorly understood.
Engineered tissue containing human stem cells has allowed paraplegic rats to walk independently and regain sensory perception. The implanted rats also show some degree of healing in their spinal cords. Spinal cord injuries often lead to paraplegia. Achieving substantial recovery following a complete spinal cord tear, or transection, is an as-yet unmet challenge. The researchers implanted human stem cells into rats with a complete spinal cord transection. The stem cells, which were derived from the membrane lining of the mouth, were induced to differentiate into support cells that secrete factors for neural growth and survival.
The work involved more than simply inserting stem cells at various intervals along the spinal cord. The research team also built a three-dimensional scaffold that provided an environment in which the stem cells could attach, grow and differentiate into support cells. This engineered tissue was also seeded with human thrombin and fibrinogen, which served to stabilize and support neurons in the rat's spinal cord.
Rats treated with the engineered tissue containing stem cells showed higher motor and sensory recovery compared to control rats. Three weeks after introduction of the stem cells, 42% of the implanted paraplegic rats showed a markedly improved ability to support weight on their hind limbs and walk. 75% of the treated rats also responded to gross stimuli to the hind limbs and tail. In addition, the lesions in the spinal cords of the treated rats subsided to some extent. This indicates that their spinal cords were healing. In contrast, control paraplegic rats that did not receive stem cells showed no improved mobility or sensory responses. While the results are promising, the technique did not work for all implanted rats. An important area for further research will be to determine why stem cell implantation worked in some cases but not others.
Towards Better Artificial Alternatives to Cartilage Tissue
It will be interesting to watch the accelerating development of biological versus non-biological replacements for damaged tissue over the next few decades. Both are improving at a fair pace, and there is a sizable area of overlap between the two sides of the field. If a nonbiological alternative gets the job done, then why not use it in place of engineered tissue? At the moment, new patient-matched engineered tissue would be a better long term alternative, considering the various challenges that result from introducing long-term implants into the body, but in near all cases that is not yet an option. Twenty years from now, however, many forms of replacement will have competing tissue engineered and wholly artificial alternatives available in the market, and the trade-offs will be more subtle.
The liquid strength of cartilage, which is about 80 percent water, withstands some of the toughest forces on our bodies. Synthetic materials couldn't match it until "Kevlartilage" was developed. Many people with joint injuries would benefit from a good replacement for cartilage, such as the 850,000 patients in the U.S. who undergo surgeries removing or replacing cartilage in the knee. While other varieties of synthetic cartilage are already undergoing clinical trials, these materials fall into two camps that choose between cartilage attributes, unable to achieve that unlikely combination of strength and water content.
The other synthetic materials that mimic the physical properties of cartilage don't contain enough water to transport the nutrients that cells need to thrive. Meanwhile, hydrogels - which incorporate water into a network of long, flexible molecules - can be designed with enough water to support the growth of the chondrocytes cells that build up natural cartilage. Yet those hydrogels aren't especially strong. They tear under strains a fraction of what cartilage can handle.
The new Kevlar-based hydrogel recreates the magic of cartilage by combining a network of tough nanofibers from Kevlar with a material commonly used in hydrogel cartilage replacements, called polyvinyl alcohol, or PVA. In natural cartilage, the network of proteins and other biomolecules gets its strength by resisting the flow of water among its chambers. The pressure from the water reconfigures the network, enabling it to deform without breaking. Water is released in the process, and the network recovers by absorbing water later. This mechanism enables high impact joints, such as knees, to stand up to punishing forces. Running repeatedly pounds the cartilage between the bones, forcing water out and making the cartilage more pliable as a result. Then, when the runner rests, the cartilage absorbs water so that it provides strong resistance to compression again.
The synthetic cartilage boasts the same mechanism, releasing water under stress and later recovering by absorbing water like a sponge. The nanofibers build the framework of the material, while the PVA traps water inside the network when the material is exposed to stretching or compression. Even versions of the material that were 92 percent water were comparable in strength to cartilage, with the 70-percent version achieving the resilience of rubber. As the nanofibers and PVA don't harm adjacent cells, researchers anticipate that this synthetic cartilage may be a suitable implant for some situations, such as the deeper parts of the knee.